Super Bound States in the Continuum on a Photonic Flatband: Concept, Experimental Realization, and Optical Trapping Demonstration.

In this Letter, we theoretically propose and experimentally demonstrate the formation of a super bound state in a continuum (BIC) on a photonic crystal flat band. This unique state simultaneously exhibits an enhanced quality factor and near-zero group velocity across an extended region of the Brillouin zone. It is achieved at the topological transition when a symmetry-protected BIC pinned at k=0 merges with two Friedrich-Wintgen quasi-BICs, which arise from the destructive interference between lossy photonic modes of opposite symmetries. As a proof of concept, we employ the ultraflat super BIC to demonstrate three-dimensional optical trapping of individual particles. Our findings present a novel approach to engineering both the real and imaginary components of photonic states on a subwavelength scale for innovative optoelectronic devices.

Sea anemone-anemonefish symbiosis: Behavior and mucous protein profiling.

Fish species of the genus Amphiprion (Perciformes: Pomacentridae) seek protection from predators among the tentacles of sea anemones as their natural habitat, where they live essentially unharmed from stinging by the host's nematocysts. The skin mucus of these anemonefish has been suggested as a protective mechanism that prevents the discharge of the nematocysts upon contact. Whereas some anemonefish species seem to produce their own protective mucous coating, others may acquire mucus (or biomolecules within) from the sea anemone during an acclimation period. In controlled experiments, we show that Amphiprion ocellaris acclimated successfully to their natural host anemone species Stichodactyla gigantea, and also to Stichodactyla haddoni, and in some cases Heteractis crispa, neither of which are natural host species. No symbiosis was observed for three other anemone species tested, Entacmaea quadricolor, Macrodactyla doreensis, and Heteractis malu. We explored the skin mucous protein profile from naive and experienced A. ocellaris during their acclimation to natural and unnatural host anemones. We confidently report the presence of metabolic and structural proteins in the skin mucus of all samples, likely involved in immunological defense, molecular transport, stress response, and signal transduction. For those anemonefish that established symbiosis, there was a clear increase in ribosomal-type proteins. We additionally provide evidence for the presence of anemone proteins only in the skin mucus of individuals that established symbiosis. Our results support previous speculation of the role of skin mucous-associated proteins in anemonefish-anemone symbiosis. Further exploration of these mucosal proteins could reveal the mechanism of anemonefish acclimation to host anemones.

Production of Ochratoxin A and Citrinin and the Expression of Their Biosynthetic Genes from Penicillium verrucosum in Liquid Culture.

Penicillium verrucosum is a fungal pathogen capable of producing two mycotoxins of concern, ochratoxin A (OTA) and citrinin (CIT). The production profile of these two mycotoxins is not well understood but could help mitigate co-contamination in the food supply. As such, the production of OTA and CIT from P. verrucosum DAOMC 242724 was investigated under different growing conditions in liquid culture. We found that among the different liquid media chosen, liquid YES (yeast extract sucrose) medium induced the highest production of both OTA and CIT, when P. verrucosum DAOMC 242724 was cultured in stationary mode. Shake culture significantly reduced the amounts of OTA and CIT produced. Among all culture conditions tested, far greater amounts of CIT were produced compared to OTA. Consequently, upon transcriptomic data analysis, a statistically significant increase in the expression of CIT biosynthetic genes was easier to detect than the expression of OTA biosynthetic genes. Our study also revealed that the putative biosynthetic gene clusters of OTA and CIT in P. verrusocum DAOMC 242724 are likely distinct from each other. It appears that despite sharing a highly similar structure, the isocoumarin rings of OTA and CIT are each assembled by a specialized polyketide synthase enzyme. Our data identified a putative nonreducing polyketide synthase responsible for assembling the carbo-skeleton of CIT. In contrast, a highly reducing polyketide synthase appears to be involved in the biosynthesis of OTA.

Sleep Disorders and Traffic Accidents: Unveiling the Hidden Risks.

BACKGROUND Numerous countries, Vietnam included, have persistently high annual rates of traffic accidents. Despite concerted government efforts to reduce the annual traffic accident rate, the toll of fatalities and consequential injuries from these accidents rises each year. Various factors contribute to these incidents, notably including alcohol consumption while driving, inadequate awareness of traffic regulations, and substandard traffic infrastructure. However, an under-recognized risk in developing nations such as Vietnam is the prevalence of sleep disorders. Conditions such as obstructive sleep apnea syndrome and obesity hypoventilation syndrome, while prevalent, remain inadequately assessed and treated. These disorders represent significant yet largely unaddressed contributors to the heightened risk of traffic accidents. CASE REPORT We describe the case of a 55-year-old Vietnamese man hospitalized due to long-standing respiratory complications and profound daytime sleepiness. Over the past 2 years, the patient gained 10 kg. Consequently, he frequently experienced drowsiness, leading to 4 traffic accidents. Despite previous hospitalizations, this sleep disorder had gone undiagnosed and untreated. Diagnostic assessments confirmed concurrent obstructive sleep apnea and obesity hypoventilation syndrome through polysomnography and blood gas analyses. Treatment involving non-invasive positive airway pressure therapy notably alleviated symptoms and substantially improved his quality of life within a concise 3-month period. CONCLUSIONS Obstructive sleep apnea and obesity hypoventilation syndrome are contributory factors to excessive daytime somnolence, significantly increasing vulnerability to traffic accidents. Regrettably, this critical intersection remains inadequately addressed. Addressing these concerns comprehensively through dedicated research initiatives should be imperative before considering the universal issuance of driver's licenses to all road users in Vietnam.

Fatal Septic Shock Due to Aeromonas Hydrophila in a Cirrhotic Patient; a Case Report.

Aeromonas hydrophila has been identified as a causative agent of necrotizing fasciitis and myonecrosis, with most reported cases having a connection to aquatic-related trauma. Cases without such trauma history are rare in existing literature. Here, we present the case of a 56-year-old cirrhotic patient who lacked any prior aquatic-related trauma and arrived at the emergency department in a state of septic shock. The suspected route of entry was through necrotizing fasciitis and myonecrosis in his left forearm. Unfortunately, the patient succumbed to multi-organ failure and passed away within 12 hours of admission to the emergency department.

Spatial photoluminescence and lifetime mappings of quasi-2D perovskites coupled with a dielectric metasurface.

Light-matter interaction between quantum emitters and optical cavities plays a vital role in fundamental quantum photonics and the development of optoelectronics. Resonant metasurfaces are proven to be an efficient platform for tailoring the spontaneous emission (SE) of the emitters. In this work, we study the interplay between quasi-2D perovskites and dielectric TiO2 metasurfaces. The metasurface, functioning as an open cavity, enhances electric fields near its plane, thereby influencing the emissions of the perovskite. This is verified through angle-resolved photoluminescence (PL) studies. We also conducted reflectivity measurements and numerical simulations to validate the coupling between the quasi-2D perovskites and photonic modes. Notably, our work introduces a spatial mapping approach to study Purcell enhancement. Using fluorescence lifetime imaging microscopy (FLIM), we directly link the PL and lifetimes of the quasi-2D perovskites in spatial distribution when positioned on the metasurface. This correlation provides unprecedented insights into emitter distribution and emitter-resonator interactions. The methodology opens a new (to the best of our knowledge) approach for studies in quantum optics, optoelectronics, and medical imaging by enabling spatial mapping of both PL intensity and lifetime, differentiating between uncoupled quantum emitters and those coupled with different types of resonators.

Adsorption effects of acetone and acetonitrile on defected penta-PdSe2 nanoribbons: a DFT study.

Using DFT calculations, the structural and electronic properties of the ZZ7 p-PdSe2 nanoribbons (ZZ7) with the four kinds of vacancy defects, including ZZ7-VPd, ZZ7-VSe, ZZ7-VPd+Se, and ZZ7-V2Se are studied, in which their stability, diverse geometries, and altered electronic properties are determined through the formation energies, optimal structural parameters, electronic band structures, and DOSs. Specifically, the formation energies of all studied systems show significant negative values around -3.9 eV, evidencing their good thermal stability. The geometries of four defective structures exhibit different diversification, whereas only the ZZ7-V2Se structure possesses the highly enhanced feature, identified as the most effective substrate for the acetone and acetonitrile adsorption. On the electronic behaviors, the ZZ7 band structure displays the nonmagnetic metallic characteristics that become the ferromagnetic half-metallic band structures for the ZZ7-VPd and ZZ7-VSe and the ferromagnetic semi-metallic band structures for the ZZ7-VPd+Se and ZZ7-V2Se. For adsorption of the acetone and acetonitrile on the ZZ7-V2Se structure, the energetic stability, adsorption sites, adsorption distances, charge transfers, and electronic characteristics of the adsorbed systems are determined by the adsorption energies, optimal adsorption sites, adsorption distances, Mulliken populations, and DOSs. The adsorption energies of the acetone- and acetonitrile-adsorbed ZZ7-V2Se systems display significant values at -1.2 eV and -0.86 eV at the preferable sites of 8 and 11, respectively, indicating their great adsorption ability. The adsorption mechanism of the acetone- and acetonitrile-adsorbed systems belongs to the physisorption owing to absence of chemical bonds, in which the bond lengths of the ZZ7-V2Se substrate show a very small deviation. Under the acetone and acetonitrile adsorptions, the ferromagnetic semi-metallic DOSs of the ZZ7-V2Se become the ferromagnetic half-metallic DOSs for the ZZ7-V2Se-acetone-8 and the ferromagnetic semiconducting DOSs for the ZZ7-V2Se-acetonitrile-11. Our systematic results can provide a complete understanding of the acetone- and acetonitrile adsorptions on the potential ZZ7-V2Se structure, which is very useful for nanosensor application.

Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPNs) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for triple negative myelofibrosis (MF) patients who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in triple negative MF, and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs.

Polythiophene-wrapped Chitosan Nanofibrils with a Bouligand Structure toward Electrochemical Macroscopic Membranes.

Exploring structural biomimicry is a great opportunity to replicate hierarchical frameworks inspired by nature in advanced functional materials for boosting new applications. In this work, we present the biomimetic integration of polythiophene into chitosan nanofibrils in a twisted Bouligand structure to afford free-standing macroscopic composite membranes with electrochemical functionality. By considering the integrity of the Bouligand structure in crab shells, we can produce large, free-standing chitosan nanofibril membranes with iridescent colors and flexible toughness. These unique structured features lead the chitosan membranes to host functional additives to mimic hierarchically layered composites. We used the iridescent chitosan nanofibrils as a photonic platform to investigate the host-guest combination between thiophene and chitosan through oxidative polymerization to fabricate homogeneous polythiophene-wrapped chitosan composites. This biomimetic incorporation fully retains the twisted Bouligand organization of nanofibrils in the polymerized assemblies, thus giving rise to free-standing macroscopic electrochemical membranes. Our further experiments are the modification of the biomimetic polythiophene-wrapped chitosan composites on a glassy carbon electrode to design a three-electrode system for simultaneous electrochemical detection of uric acid, xanthine, hypoxanthine, and caffeine at trace concentrations.

[A case of disseminated tuberculosis presenting as a metastasizing tumor, complicated by toxic megacolon caused by Clostridium difficile: Difficulties in diagnosis]. / Metasztatizáló tumor képét adó disszeminált tuberkulózis Clostridium difficile okozta toxicus megacolonnal szövodött esete: a diagnózis nehézségei.

A mára ritkán eloforduló tuberkulózis (tbc) extrapulmonális manifesztációi elorehaladott rosszindulatú daganatok képét utánozhatják, jelentos diagnosztikus dilemmákat okozva. A tbc igazolása gyakorta bonyolult, komplex vizsgálatokat igényel. Egy fiatal vietnámi nobeteg esetét ismertetjük, aki idült hasi fájdalom, fogyás, fejfájás, bal oldali hemiparesis miatt jelentkezett kórházunkban. Az urgens vizsgálatok hasi folyadékgyülemek, lymphadenopathia és peritonealis carcinosis képe mellett az uterushoz asszociált ökölnyi kismedencei térfoglaló képletet, intracranialisan agyödémát és metastaticusnak tuno gócokat ábrázoltak. Neurológiai, belgyógyászati, majd pulmonológiai klinikai vizsgálatok és kezelések során eloször disszeminált gynaecologiai tumor, majd meningealis-, miliaris tüdo- és kiterjedt hasüregi-kismedencei érintettséggel járó tbc gyanúja fogalmazódott meg. Bár mycobactérium jelenléte nem volt igazolható, antituberculoticus- és komplex antibiotikus terápiát alkalmaztak. Ennek szövodményeként Clostridium difficile okozta enterocolitis alakult ki. Átmeneti állapotrosszabbodás miatti intenzív osztályos kezelést követoen a beteget visszahelyezték kórházunk belgyógyászatára. Itt toxicus megacolon, acut peritonitis alakult ki, emiatt sürgos mutétet végeztünk.A hasüregben granulomatosus peritonitis encapsulans, extrém tágult, megrepedt taeniájú colon, hyperaemiás vékonybéltraktus, tuboovarialis tályogok voltak láthatók. Oncotomiát követoen salpingo-oophorectomiát és subtotalis colectomiát végeztünk, Brooke szerinti ileostomát készítettünk. Az intenzív osztályos, majd infektológiai kezelésnek köszönhetoen a beteg reconvalescentiája sikeres volt, kielégíto állapotban emittálták. A specimenek valós ideju PCR-vizsgálata során Mycobacterium DNS nem volt detektálható, végül a hasüregi váladék és granulomák mikroszkópos vizsgálatával sikerült saválló pálcákat identifikálni.Az eset kapcsán áttekintjük az extrapulmonális tbc diagnosztikus lehetoségeit és terápiás nehézségeit.

Tuberous sclerosis complex associated lymphangioleiomyomatosis caused by de novo mutation of TSC2 gene in Vietnam: A case report.

Lymphangioleiomyomatosis (LAM) represents a rare, insidiously progressive disease of the pulmonary system, marked by cystic degradation of lung tissues leading to respiratory compromise. Pulmonary LAM has been identified as being associated with tuberous sclerosis complex (TSC) in its pulmonary manifestation (TSC-LAM), a multisystem genetic disorder resulting from mutations in either the TSC1 or TSC2 genes. Herein, we describe an early 20s female admitted to the hospital with dyspnea, chest pain, hypopigmented macules, and facial fibroadenomas. She has a medical history of renal angiomyolipomas (ALMs) and pneumothoraces. Diagnosis with LAM was confirmed through high-resolution computed tomography (HRCT) scan and histopathology of lung biopsy. Whole exome sequencing analysis identified a frameshift mutation c.4504del (p.L1502Cfs*74) in the patient's TSC2 gene. This variant was de novo due to its absence in the patient's parents. This is the first report on the clinical and genetic etiology of TSC-LAM in Vietnam.

Crucial Roles of Leaving Group and Open-Shell Cation in Photoreaction of (Coumarin-4-yl)methyl Derivatives.

Photoreactions of (coumarin-4-yl)methyl derivatives have been extensively studied in many fields of chemistry, including organic synthesis and photoinduced drug delivery systems. The identification of the reaction intermediates involved in the photoreactions is crucial not only for elucidating the reaction mechanism but also for the application of the photoreactions. In this study, the photoreactions of 7-diethylamino(coumarin-4-yl)methyl thioester 1a [-SC(O)CH3], thionoester 1b [-OC(S)CH3], and ester 1c [-OC(O)CH3] were investigated to clarify the intermediary species and their chemical behavior. While a radical pair [i.e., 7-diethylamino(coumarin-4-yl)methyl radical and CH3C(O)S•] plays an important role in the photoreactions of 1a and 1b, an ion pair [i.e., 7-diethylamino(coumarin-4-yl)methyl cation, and CH3CO2-] was the key in the photoreaction of 1c. 18O-isotope-labeling of 1c revealed a negligible recombination process within the ion pair. The unprecedented observation was rationalized by the open-shell character of the 7-diethylamino(coumarin-4-yl)methyl cation, whose formation was confirmed through product analysis and transient absorption spectroscopy.

Effects of Maturation on Antibacterial Properties of Vietnamese Mango (Mangifera indica) Leaves.

This study, for the first time, has investigated the relationships between alterations of mangiferin contents in mango leaves at different maturity stages and their antibacterial properties. Leaves were classified into six different maturity stages based on their color: (1) young dark reddish brown, (2) young yellow, (3) young light green, (4) mature green, (5) old dark green, and (6) old yellow leaves. Ethanol extracts were then examined against Gram-positive and Gram-negative bacteria, applying broth dilution and agar well diffusion methods. In addition, we also measured the mangiferin contents in leaves at different stages for the purpose of evaluating how the changes in this phytochemistry value affects their activities against bacteria. The results showed that extracts from leaves at young ages had better antibacterial properties than those from old leaves, as evidenced by the lower minimum inhibitory concentrations and larger inhibitory zones. In addition, we also found that the contents of mangiferin were significantly decreased followed the maturation process. These results suggest that mango leaves at young stages, especially dark reddish brown and young yellow leaves, are preferable for application in bacterial infections and other therapies related to mangiferin's constituents.

Retroperitoneal laparoscopic partial nephrectomy for metanephric adenoma in a pediatric patient - The first case report from vietnam.

Metanephric adenoma presents as a rare benign tumor in children with differentiated diagnoses: Wilms tumor or renal cell carcinoma. When confronted with small renal tumors, whether they fall into one of these three diagnostic categories, tumor resection surgery with laparoscopic partial nephrectomy is considered a viable and effective operative approach. Herein, we report the case of an 11-year-old female patient initially diagnosed with stage T1a renal cell carcinoma with postoperative pathology results confirming metanephric adenoma. Successfully treated with laparoscopic partial nephrectomy, the patient showed no signs of recurrence or metastasis during follow-up.

Epigenetic control of adaptive or homeostatic splicing during interval-training activities.

Interval-training activities induce adaptive cellular changes without altering their fundamental identity, but the precise underlying molecular mechanisms are not fully understood. In this study, we demonstrate that interval-training depolarization (ITD) of pituitary cells triggers distinct adaptive or homeostatic splicing responses of alternative exons. This occurs while preserving the steady-state expression of the Prolactin and other hormone genes. The nature of these splicing responses depends on the exon's DNA methylation status, the methyl-C-binding protein MeCP2 and its associated CA-rich motif-binding hnRNP L. Interestingly, the steady expression of the Prolactin gene is also reliant on MeCP2, whose disruption leads to exacerbated multi-exon aberrant splicing and overexpression of the hormone gene transcripts upon ITD, similar to the observed hyperprolactinemia or activity-dependent aberrant splicing in Rett Syndrome. Therefore, epigenetic control is crucial for both adaptive and homeostatic splicing and particularly the steady expression of the Prolactin hormone gene during ITD. Disruption in this regulation may have significant implications for the development of progressive diseases.

HLA alleles associated with susceptibility and severity of the COVID-19 in Vietnamese.

The diversity of clinical manifestations in COVID-19 has been observed not only among individuals but also among various populations in globally. HLA molecules play a central role in physiology, protective immunity, and deleterious, disease-related autoimmune reactivity or overreaction. This study exploited the association between HLA frequencies and SARS-CoV-2 susceptibility and disease severity among the Vietnamese cohort (159 patients and 52 controls). A significant difference in frequency of both HLA class I and II in mild, moderate, and severe/fatal COVID-19 patients and negative exposure individuals - the controls were observed. Regarding SARS-CoV-2 sensitivity, HLA-A*03:01, 30:01, HLA-DQA1*01:02, DRB1*15:01, and DRB5*02:02 presented higher frequency in the control group compared with infected patients but DRB1 09:01 frequency was higher in infected patients. Regarding COVID-19 severity, HLA-F*01:01, 01:03 and DPA1*01:03 and 02:01, DPB1*04:01, DQA1*01:02, and DQB1*05:02 alleles were detected with higher frequency in severe patients but DOB*01:01, DRB1*05:01 and 09:01 had a significantly higher frequency in the mild group than remaining groups. Surprisingly, HLA-DQA1*01:02 and DRB1*09:01 alleles were identified with both inversely potential roles in protective function and severe risk. The obtained data herein will contribute to explore on the role of host genetic background in the pathology of COVID-19 disease.

Cost-Effectiveness of Lecanemab for Individuals With Early-Stage Alzheimer Disease.

BACKGROUND AND OBJECTIVES: Little is known regarding the cost-effectiveness of lecanemab (Leqembi), a monoclonal antibody approved by the US Food and Drug Administration in January 2023 for the treatment of mild cognitive impairment (MCI) or mild dementia due to Alzheimer disease (AD). This study aims to quantify the cost-effectiveness of lecanemab and how it varies based on the accuracy of AD testing and individuals' APOE ε4 status. METHODS: Seven alternative test-treat-target strategies defined by combinations of testing approaches (PET, CSF, or plasma assay), treatment choices (standard of care [SoC] alone or lecanemab in addition to SoC), and targeting strategies (targeting APOE ε4 noncarriers or heterozygous patients or not) were compared. A hybrid decision tree-Markov cohort model was constructed with 5 states: (1) MCI (Clinical Dementia Rating-Sum of Boxes [CDR-SB] 0-4.5); (2) mild dementia (CDR-SB 4.6-9.5); (3) moderate dementia (CDR-SB 9.6-16); (4) severe dementia (CDR-SB >16); and (5) death. Effectiveness was measured by quality-adjusted life years and costs from third-party and societal perspectives were estimated in 2022 US dollars over a lifetime horizon. RESULTS: Among the 7 test-treat-target strategies, SoC alone was the optimal strategy from a cost-effectiveness perspective. Neither targeted lecanemab treatment nor treatment unrestricted by APOE ε4 genotype was cost-effective vs SoC alone, regardless of the test used to diagnose patients with early-stage AD. However, CSF assay followed by targeted treatment would become cost-effective if lecanemab is priced below $5,100 per year. These results were robust to the accuracy of diagnostic testing and rates of lecanemab discontinuation and adverse events. DISCUSSION: Neither targeted lecanemab treatment nor treatment unrestricted by APOE ε4 genotype is cost-effective vs SoC alone for patients with MCI or mild dementia due to AD. Lecanemab would be cost-effective in some settings if priced below $5,100 per year.

Fried Frailty Phenotype in Elderly Patients with Chronic Coronary Syndrome: Prevalence, Associated Factors, and Impact on Hospitalization.

Purpose: To investigate the prevalence and factors associated with frailty and impact of frailty on hospitalization due to any cause in elderly patients with chronic coronary syndrome (CCS). Patients and Methods: We conducted a study wherein we assessed frailty using Fried frailty phenotype for outpatients aged ≥60 years with CCS. Logistic regression analysis was performed to assess the factors associated with frailty. Frailty was adjusted for demographic and geriatric variables and comorbidities to assess its impact on hospitalization. Results: Overall, 420 patients (median age 70 years [interquartile range, 65-77]; men, 74.5%) who completed the 3-month follow-up period were analyzed. Coronary revascularization for > 1 year was the most common clinical scenario for CCS (59.8%; n = 251). The prevalence of non-frail, pre-frail, and frail patients were 22.4% (n = 94), 49.7% (n = 209), and 27.9% (n = 117), respectively. In the adjusted model, three factors associated with frailty were age ≥ 75 years (odds ratio [OR] 2.29, 95% confidence interval [CI] 1.39-3.75, P = 0.001), limitations in instrumental activity of daily living (OR 3.89, 95% CI 2.33-6.48, P < 0.001), and heart failure (OR 2.30, 95% CI 1.32-4.02, P = 0.003). The overall 3-month hospitalization rate was higher in frail patients than in non-frail patients (23.9% vs 13.5%, P = 0.012). Frailty was associated with hospitalization (OR 1.85, 95% CI 1.04-3.30, P = 0.037) but in a weak strength of association (r = 0.126). Conclusion: The prevalence of frailty was 27.9% in the elderly patients with CCS. Age ≥ 75 years, limitations in functional status, and heart failure were associated with increased odds of frailty. Frailty was a predictor of 3-month all-cause hospitalization in these patients.