Gate-tunable subband degeneracy in semiconductor nanowires.

Degeneracy and symmetry have a profound relation in quantum systems. Here, we report gate-tunable subband degeneracy in PbTe nanowires with a nearly symmetric cross-sectional shape. The degeneracy is revealed in electron transport by the absence of a quantized plateau. Utilizing a dual gate design, we can apply an electric field to lift the degeneracy, reflected as emergence of the plateau. This degeneracy and its tunable lifting were challenging to observe in previous nanowire experiments, possibly due to disorder. Numerical simulations can qualitatively capture our observation, shedding light on device parameters for future applications.

Lymphoid organ-targeted nanomaterials for immunomodulation of cancer, inflammation, and beyond.

Nanomaterials exhibit significant potential for stimulating immune responses, offering both local and systemic modulation across a variety of diseases. The lymphoid organs, such as the spleen and lymph nodes, are home to various immune cells, including monocytes and dendritic cells, which contribute to both the progression and prevention/treatment of diseases. Consequently, many nanomaterial formulations are being rationally designed to target these organs and engage with specific cell types, thereby inducing therapeutic and protective effects. In this review, we explore crucial cellular interactions and processes involved in immune regulation and highlight innovative nano-based immunomodulatory approaches. We outline essential considerations in nanomaterial design with an emphasis on their impact on biological interactions, targeting capabilities, and treatment efficacy. Through selected examples, we illustrate the strategic targeting of therapeutically active nanomaterials to lymphoid organs and the subsequent immunomodulation for infection resistance, inflammation suppression, self-antigen tolerance, and cancer immunotherapy. Additionally, we address current challenges, discuss emerging topics, and share our outlook on future developments in the field.

Selective-Area-Grown PbTe-Pb Planar Josephson Junctions for Quantum Devices.

Planar Josephson junctions are predicted to host Majorana zero modes. The material platforms in previous studies are two-dimensional electron gases (InAs, InSb, InAsSb, and HgTe) coupled to a superconductor such as Al or Nb. Here, we introduce a new material platform for planar JJs, the PbTe-Pb hybrid. The semiconductor, PbTe, was grown as a thin film via selective area epitaxy. The Josephson junction was defined by a shadow wall during the deposition of superconductor Pb. Scanning transmission electron microscopy reveals a sharp semiconductor-superconductor interface. Gate-tunable supercurrents and multiple Andreev reflections are observed. A perpendicular magnetic field causes interference patterns of the switching current, exhibiting Fraunhofer-like and SQUID-like behaviors. We further demonstrate a prototype device for Majorana detection wherein phase bias and tunneling spectroscopy are applicable.

Inhibition of heme oxygenase 1 alleviates thoracic aortic aneurysm via restoration of extracellular matrix.

BACKGROUND: Thoracic aortic aneurysm (TAA) is a silent but life-threatening cardiovascular disease. Heme oxygenase 1 (HO-1) plays an important role in the cardiovascular diseases but is poorly understood in TAA. This study aims at investigating the role of HO-1 in TAA. METHODS: Single-cell RNA sequencing, Western blot and histological assay were performed to identify specific cellular expression of HO-1 in both human and ß-aminopropionitrile (BAPN)-induced mice TAA. Zinc protoporphyrin (ZnPP), a pharmacological inhibitor of HO-1, was used to investigate whether inhibition of HO-1 could attenuate BAPN-induced TAA in rodent model. Histological assay, Western blot assay, and mRNA sequencing were further performed to explore the underlying mechanisms. RESULTS: Single-cell transcriptomic analyses of 113,800 thoracic aortic cells identified an increase of HO-1(+) macrophage in aneurysmal thoracic aorta from BAPN-induced TAA mice and TAA patients. Histological assay verified HO-1 overexpression in clinical TAA specimens, which was co-localized with CD68(+) macrophage. HO-1(+) macrophage was closely associated with pro-inflammatory response and immune activation. Inhibition of HO-1 through ZnPP significantly alleviated BAPN-induced TAA in mice and restored extracellular matrix (ECM) in vivo. Further experiments showed that ZnPP treatment suppressed the expression of matrix metalloproteinases (MMPs) in aneurysmal thoracic aortic tissues from BAPN-induced TAA mice, including MMP2 and MMP9. Macrophages from myeloid specific HO-1 knockout mice displayed weakened pro-inflammatory activity and ECM degradation capability. CONCLUSION: HO-1(+) macrophage subgroup is a typical hallmark of TAA. Inhibition of HO-1 through ZnPP alleviates BAPN-induced TAA in mice, which might work through restoration of ECM via suppressing MMP2 and MMP9 expression.

Non-invasive visualization of liver fibrosis with [68Ga]Ga-DOTA-FAPI-04 PET from preclinical insights to clinical translation.

PURPOSE: The reversibility of early liver fibrosis highlights the need for improved early detection and monitoring techniques. Fibroblast activation protein (FAP) is a promising theranostics target significantly upregulated during fibrosis. This preclinical and preliminary clinical study investigated a FAP-targeted probe, gallium-68-labeled FAP inhibitor 04 ([68Ga]Ga-DOTA-FAPI-04), for its capability to visualize liver fibrosis. METHODS: The preclinical study employed [68Ga]Ga-DOTA-FAPI-04 micro-positron emission tomography (PET)/computed tomography (CT) on carbon tetrachloride-induced mice model (n = 34) and olive oil-treated control group (n = 26), followed by validation of the probe's biodistribution. Hepatic uptake was correlated with fibrosis and inflammation levels, quantified through histology and serum assays. FAP and α-smooth muscle actin expression were determined by immunohistochemistry, as well as immunofluorescence. The subsequent clinical trial enrolled 26 patients with suspected or confirmed liver fibrosis to undergo [68Ga]Ga-DOTA-FAPI-04 PET/magnetic resonance imaging or PET/CT. Key endpoints included correlating [68Ga]Ga-DOTA-FAPI-04 uptake with histological inflammation grades and fibrosis stages, and evaluating its diagnostic and differential efficacy compared to established serum markers and liver stiffness measurement (LSM). RESULTS: [68Ga]Ga-DOTA-FAPI-04 mean uptake in mice livers was notably higher than in control mice, increasing from week 6 [0.70 ± 0.11 percentage injected dose per cubic centimeter (%ID/cc)], peaking at week 10 (0.97 ± 0.15%ID/cc) and slightly reducing at week 12 (0.89 ± 0.28%ID/cc). The hepatic biodistribution and FAP expression showed a consistent trend. In the patient cohort, hepatic [68Ga]Ga-DOTA-FAPI-04 uptake presented moderate correlations with inflammation grades (r = 0.517 to 0.584, all P < 0.05) and fibrosis stages (r = 0.653 to 0.698, all P < 0.01). The average SUVmax to background ratio in the liver showed superior discriminative ability, especially between stage 0 and stage 1, outperforming LSM (area under curve 0.984 vs. 0.865). CONCLUSION: [68Ga]Ga-DOTA-FAPI-04 PET shows significant potential for non-invasive visualization and dynamic monitoring of liver fibrosis in both preclinical experiment and preliminary clinical trial, especially outperforming other common clinical indicators in the early stage. TRIAL REGISTRATION: NCT04605939. Registered October 25, 2020, https://clinicaltrials.gov/study/NCT04605939.

Liver-specific delivery of spherical DNA frameworks for alleviation of hepatic ischemic reperfusion injury.

DNA nanostructures have long been developed for biomedical purposes, but their controlled delivery in vivo proposes a major challenge for disease theranostics. We previously reported that DNA nanostructures on the scales of tens and hundreds nanometers showed preferential renal excretion or kidney retention, allowing for sensitive evaluation and effective protection of kidney function, in response to events such as unilateral ureter obstruction or acute kidney injury. Encouraged by the positive results, we redirected our focus to the liver, specifically targeting organs noticeably lacking DNA materials, to explore the interaction between DNA nanostructures and the liver. Through PET imaging, we identified SDF and M13 as DNA nanostructures exhibiting significant accumulation in the liver among numerous candidates. Initially, we investigated and assessed their biodistribution, toxicity, and immunogenicity in healthy mice, establishing the structure-function relationship of DNA nanostructures in the normal murine. Subsequently, we employed a mouse model of liver ischemia-reperfusion injury (IRI) to validate the nano-bio interactions of SDF and M13 under more challenging pathological conditions. M13 not only exacerbated hepatic oxidative injury but also elevated local apoptosis levels. In contrast, SDF demonstrated remarkable ability to scavenge oxidative responses in the liver, thereby mitigating hepatocyte injury. These compelling results underscore the potential of SDF as a promising therapeutic agent for liver-related conditions. This aimed to elucidate their roles and mechanisms in liver injury, providing a new perspective for the biomedical applications of DNA nanostructures.

Ballistic PbTe Nanowire Devices.

Disorder is the primary obstacle in the current Majorana nanowire experiments. Reducing disorder or achieving ballistic transport is thus of paramount importance. In clean and ballistic nanowire devices, quantized conductance is expected, with plateau quality serving as a benchmark for disorder assessment. Here, we introduce ballistic PbTe nanowire devices grown by using the selective-area-growth (SAG) technique. Quantized conductance plateaus in units of 2e2/h are observed at zero magnetic field. This observation represents an advancement in diminishing disorder within SAG nanowires as most of the previously studied SAG nanowires (InSb or InAs) have not exhibited zero-field ballistic transport. Notably, the plateau values indicate that the ubiquitous valley degeneracy in PbTe is lifted in nanowire devices. This degeneracy lifting addresses an additional concern in the pursuit of Majorana realization. Moreover, these ballistic PbTe nanowires may enable the search for clean signatures of the spin-orbit helical gap in future devices.

Feasibility Study of a Novel Transapical Chordal Implantation System in a Porcine Model.

Transapical beating-heart mitral repair with chordal implantation system has been considered as an alternative treatment for degenerative mitral regurgitation. This study aimed to assess the feasibility and safety of the E-Chord system (Med-Zenith Medical, Beijing, China) for transapical beating-heart mitral valve repair in a porcine model. Artificial chordae were transapically implanted on the mitral valves of 12 anesthetized pigs under epicardial echocardiographic guidance and secured outside the left ventricular apex. The study endpoints included procedural success, device durability, and tissue response to the device. The procedural success rate was 100% (12/12). All animals were implanted with E-Chord in the anterior and posterior leaflets, respectively, and survived uneventfully until euthanized as planned. During the 180-day follow-up, no animal had significant mitral valve dysfunction. The gross observation showed no evidence of anchor detachment and chordal rupture, and there was no obvious damage or changes to mitral leaflets. Microscopic evaluation revealed that the endothelialization of anchor and chordae was completed 90 days after implantation and there was no evidence of chordal rupture, thrombosis, or infection during the 180-day follow-up. The E-Chord system was found to be feasible and safe for heart-beating mitral chordal implantation in a porcine model. The findings of this study suggest that the E-Chord system may be a potential alternative for the treatment of degenerative mitral regurgitation in humans.

Single-cell transcriptome analysis identifies Versican(+) myofibroblast as a hallmark for thoracic aortic aneurysm marked by activation of PI3K-AKT signaling pathway.

BACKGROUND: Thoracic aortic aneurysm (TAA) is a silent but dangerous cardiovascular disease. Understanding molecular mechanisms of TAA on single-cell level might provide new strategies for preventing and treating TAA. METHODS: Single-cell RNA sequencing was performed on control and aneurysmal thoracic aorta to find out specific cell clusters and cell types. Western blot and histological staining were used to verify the findings of single-cell transcriptome analysis. Characteristics of Versican (VCAN) overexpressed myofibroblast was evaluated through bioinformatic methods and experimental validation. RESULTS: A total of 3 control and 8 TAA specimens were used for single-cell transcriptome analysis including 48,128 thoracic aortic cells. Among these cells, we found out a specific cell cluster containing both hallmarks of smooth muscle cell (SMC) and fibroblast. Thus, we defined these cells as myofibroblast. Further single-cell transcriptome analysis identified VCAN as a cellular marker of myofibroblast. Western blot and histological staining revealed that VCAN(+) myofibroblast was significantly increased in TAA specimens compared with control individuals. Differential analysis, functional, pathway enrichment analysis and cell-cell communication analysis demonstrated that VCAN(+) myofibroblast was closely associated with previous reported TAA associated pathological process including SMC proliferation, SMC migration and extracellular matrix (ECM) disruption. Pathway analysis found out significant activation of PI3K-AKT signaling pathway within VCAN(+) myofibroblast, which was further confirmed by experimental validation. CONCLUSIONS: Single-cell RNA sequencing identified VCAN(+) myofibroblast as a typical cellular hallmark of TAA. These cells might participate in the pathogenesis of TAA through activation of PI3K-AKT signaling pathway to link SMC proliferation, SMC migration and ECM disruption.

68Ga-FAPI PET visualize heart failure: from mechanism to clinic.

PURPOSE: Heart failure (HF) is a chronic progressive clinical syndrome associated with structural and/or functional heart abnormalities. Active fibroblasts and ventricular remodelling play an essential role in HF progression. 68Ga-labelled fibroblast activation protein (FAP) inhibitor (68Ga-FAPI) binds to FAP. This study aimed to examine the feasibility of using 68Ga-FAPI positron emission tomography (PET)/computed tomography (CT) to visualize changes in cardiac fibrosis and function over time in the HF setting. METHODS: After establishing an isoproterenol (ISO)-induced HF rat model (14 consecutive days of intraperitoneal ISO injections), echocardiography and 68Ga-FAPI PET/CT were performed weekly in experimental and control groups. Rat hearts were examined weekly for biodistribution analysis; autoradiography; and haematoxylin and eosin, FAP immunofluorescence and Masson's trichrome staining analysis. Rat blood was sampled weekly for enzyme-linked immunosorbent assay analysis of various plasma indicators. A preliminary clinical study was also performed in seven HF patients who underwent both 13N-amino (NH3) perfusion and 68Ga-FAPI cardiac PET imaging. RESULTS: In the animal experiments, myocardial 68Ga-FAPI uptake, expression of FAP and myocardial contractility peaked on day 7 after the initial ISO injection. Only slight fibrotic changes were observed on histopathological examination. 68Ga-FAPI uptake and ventricular wall motion decreased over time as cardiac fibrosis and degree of myocardial injury gradually increased. In the human HF patient study, 68Ga-FAPI PET imaging identified varying degrees of 68Ga-FAPI uptake in the myocardium that did not precisely match with 13N-NH3 myocardial perfusion. CONCLUSION: As HF progresses, 68Ga-FAPI uptake is high in the early stages and then gradually decreases. Although preliminary, our findings suggest that 68Ga-FAPI PET can be used to demonstrate active myocardial fibrosis. Active myocardial FAP expression is followed by myocardial remodelling and fibrosis. Detection of early active FAP expression may assist treatment decision making in HF patients. CLINICAL TRIAL REGISTRATION: NCT04982458.

Transcatheter tricuspid valve-in-valve implantation for degenerated surgical bioprosthesis.

BACKGROUND: Isolated redo surgery for degenerated tricuspid bioprosthesis is of very high risk. We aimed to evaluate the safety and efficacy of transcatheter valve-in-valve (TVIV) implantation using a novel balloon expandable Renato valve. METHODS: A prospective multicenter study was conducted to enroll patients with degenerated tricuspid bioprostheses. A total of 12 patients underwent TVIV implantation using the Renato valve system via transfemoral, transjugular, or transatrial approaches at three institutions from May 2021 to October 2021. All-cause mortality and hemodynamic performance were evaluated up to 6 months after procedure. RESULTS: The median age was 68.2 years, and 75.0% were female. Six patients had a history of rheumatic left-sided valve surgery and late tricuspid valve replacement. The median preoperative Society of Thoracic Surgeons score was 9.9%. The procedures were successful in all cases. Tricuspid regurgitation and paravalvular leak were none or mild in all patients. The median transvalvular gradient decreased from 7.8 mmHg preoperatively to 4.5 mmHg at 6 months after TVIV, respectively. No death occurred and all patients recovered to New York Heart Association functional class I or II during a 6-month follow-up. CONCLUSIONS: TVIV implantation with the Renato valve was a safe and effective treatment for degenerated bioprostheses in high-risk patients.

Impact of body mass index on perioperative mortality of acute stanford type A aortic dissection: a systematic review and meta-analysis.

BACKGROUND: Obesity may increase perioperative mortality of acute Stanford type A aortic dissection (ATAAD). However, the available evidence was limited. This study aimed to systematically review published literatures about body mass index (BMI) and perioperative mortality of ATAAD. METHODS: Electronic literature search was conducted in PubMed, Medline, Embase and Cochrane Library databases. All observational studies that investigated BMI and perioperative mortality of ATAAD were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a random-effects model. Meta-regression analysis was performed to assess the effects of different clinical variables on BMI and perioperative mortality of ATAAD. Sensitivity analysis was performed to determine the sources of heterogeneity. Egger's linear regression method and funnel plot were used to determine the publication bias. RESULTS: A total of 12 studies with 5,522 patients were eligible and included in this meta-analysis. Pooled analysis showed that perioperative mortality of ATAAD increased by 22% for each 1 kg/m2 increase in BMI (OR = 1.22, 95% CI: 1.10-1.35). Univariable meta-regression analysis indicated that age and female gender significantly modified the association between BMI and perioperative mortality of ATAAD in a positive manner (meta-regression on age: coefficient = 0.04, P = 0.04; meta-regression on female gender: coefficient = 0.02, P = 0.03). Neither significant heterogeneity nor publication bias were found among included studies. CONCLUSIONS: BMI is closely associated with perioperative mortality of ATAAD. Optimal perioperative management needs to be further explored and individualized for obese patient with ATAAD, especially in elderly and female populations. TRIAL REGISTRATION: PROSPERO (CRD42022358619). BMI and perioperative mortality of ATAAD.

Species diversity and related ecology of chiggers on small mammals in a unique geographical area of Yunnan Province, southwest China.

Chiggers are common ectoparasites and the exclusive vector of scrub typhus. Based on previous investigations from a unique geographical area in Yunnan Province of southwest China, the Three Parallel Rivers Area, we retrospectively studied the species diversity and related ecology of chiggers on rodents and other small mammals. A very high species diversity of 120 chigger species was identified. Five dominant chigger species accounted for 59.4% (5238/8965) of total chiggers, and among them Leptotrombidium scutellare is the second major vector of scrub typhus in China. Species diversity of the chigger community fluctuates greatly in different altitudinal and latitudinal gradients. There are significant differences in species composition, species diversity and dominant species of chiggers among hosts with apparent community heterogeneity. Based on the species abundance distribution, the expected total number of chigger species was estimated to be 170, 50 more than the number of actually collected species; this further indicates a very high chigger species diversity in this area. The bipartite ecological network analysis revealed the intricate relationships between chigger and host species-positive and negative correlations existed among some species of dominant and vector chiggers.

Advances in aptamer-based nuclear imaging.

Aptamers are short oligonucleotides that bind to specific target molecules. They have been extensively explored in biomedical applications, including biosensing, medical imaging, and disease treatment. Their adjustable affinity for specific biomarkers stimulates more translational efforts, such as nuclear imaging of tumors in preclinical and clinical settings. In this review, we present recent advances of aptamer-based nuclear imaging and compare aptamer tracers with other biogenic probes in forms of peptides, nanobodies, monoclonal antibodies, and antibody fragments. Fundamental properties of aptamer-based radiotracers are highlighted and potential directions to improve aptamer's imaging performance are discussed. Despite many translational obstacles to overcome, we envision aptamers to be a versatile tool for cancer nuclear imaging in the near future.

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is more prone to distant metastasis and visceral recurrence in comparison to other breast cancer subtypes, and is related to dismal prognosis. Nevertheless, TNBC has an undesirable response to targeted therapies. Therefore, to tackle the huge challenges in the diagnosis and treatment of TNBC, Nectin-4 was selected as a theranostic target because it was recently found to be highly expressed in TNBC. We developed anti-Nectin-4 monoclonal antibody (mAbNectin-4)-based theranostic pair, 99mTc-HYNIC-mAbNectin-4 and mAbNectin-4-ICG. 99mTc-HYNIC-mAbNectin-4 was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAbNectin-4-ICG to mediate photothermal therapy (PTT) for relieving TNBC tumor growth. METHODS: Nectin-4 expression levels of breast cancer cells (MDA-MB-468: TNBC cells; and MCF-7, non-TNBC cells) were proved by western blot, flow cytometry, and immunofluorescence imagning. Cell uptake assays, SPECT imaging, and biodistribution were performed to evaluate Nectin-4 targeting of 99mTc-HYNIC-mAbNectin-4. A photothermal agent (PTA) mAbNectin-4-ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAbNectin-4-ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAbNectin-4-ICG mapping in vivo. In vivo PTT treatment effects on TNBC tumors and corresponding systematic toxicity were evaluated. RESULTS: Nectin-4 is overexpressed in MDA-MB-468 TNBC cells, which could specifically uptake 99mTc-HYNIC-mAbNectin-4 with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAbNectin-4-ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAbNectin-4-ICG with excellent tumor-targeting and retention in vivo. Moreover, mAbNectin-4-ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity. CONCLUSION: mAbNectin-4-based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAbNectin-4-mediated PTT shows a powerful anti-tumor effect. Our findings demonstrate that this Nectin-4 targeting strategy offers a simple theranostic platform for TNBC.

Non-malignant findings of focal 68Ga-FAPI-04 uptake in pancreas.

PURPOSE: 68Ga-Labelled Fibroblast Activation Protein Inhibitor (68Ga-FAPI) has shown promise in tumour positron emission tomography (PET) imaging, including malignant pancreatic lesions. Here, we showed several non-malignant findings of focal 68Ga-FAPI-04 uptake in the pancreas which were occasionally found by PET/MR. The study aimed to investigate the reasons for the focal uptake and remind caution for the diagnosis. METHODS: We retrospectively analysed imaging data of 103 patients who underwent 68Ga-FAPI-04 PET/MR at our institute from May 22 to July 8, 2020. Seven patients had focally elevated uptake of 68Ga-FAPI-04 in the pancreas; four of these underwent simultaneous 18F-FDG PET/CT scans. The clinical data, PET/MR imaging features, pathological, and follow-up results were further collected and analysed. RESULTS: The cases showed that 68Ga-FAPI-04 accumulation can occur in any part of the pancreas, with corresponding negative 18F-FDG uptake. Most lesions were small with no significant changes in CT or MR signals. The SUVmax value of 68Ga-FAPI-04 had a wide range of 3.1-9.1. All the pancreatic lesions were proven to be non-neoplastic by pathology confirmation or follow-up imaging. Lesions with uptake were identified including pancreatic pseudocysts, sites of prior pancreatitis, and foci of IgG 4-related disease. CONCLUSION: Though 68Ga-FAPI-04 demonstrates great potential for oncological diagnosis, focal 68Ga-FAPI-04 uptake could occur in benign pancreatic lesions and should be carefully evaluated. Fortunately, combined with MR, 68Ga-FAPI-04 PET/MR may potentially avoid the misdiagnosis of some pancreatic lesions. CLINICAL TRIAL REGISTRATION: NCT04554719 and NCT04605939. Registered September 13, 2020 and October 25, 2020, respectively.

Efficacy of delayed 18F-FDG hybrid PET/MRI for epileptic focus identification: a prospective cohort study.

OBJECTIVE: We sought to investigate the contribution of delayed 18F-FDG imaging data to epileptogenic zone (EZ) identification using a hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) system. METHODS: Forty-one patients with epilepsy underwent a brain dual time point 18F-FDG PET/MRI examination. All early imaging was acquired at approximately 40 min. Late imaging was classified as short delay (150.1 ± 20.2 min) or long delay (247.8 ± 24.6 min). Visual evaluation and scoring of 18F-FDG uptake at dual time points were performed. An SUVmean asymmetry index (AI) was calculated representing the difference in uptake between the EZ and the contralateral side. The EZ location was defined by a multidisciplinary team based on findings on video electroencephalography, 18F-FDG, and MRI. EZ location was classified as extratemporal lobe epilepsy (extra-TLE) or temporal lobe epilepsy (TLE). MRI findings were classified as positive if there were signal/structural abnormalities, or negative. AI of dual time points was compared between MRI-positive and MRI-negative, between extra-TLE and TLE, and between short delay and long delay of the late imaging time point. RESULTS: The AI at the delayed time points was increased by a mean of 3.7 over the early time point in all patients (P < 0.01). The biggest AIs were found in the MRI-positive group. The ΔAI between two imaging points were 3.71 ± 3.50 and 4.67 ± 7.94 for MRI-positive and MRI-negative; 4.52 ± 6.70 and 2.51 ± 2.42 for extra-TLE and TLE; and 4.24 ± 6.52 and 3.46 ± 2.90 for short delay and long delay groups, respectively. There were more patients with increased AI at the delayed time with MRI-positive (95.8%, 23/24), with extra-TLE (96.8%, 30/31), and with short delay time (93.7%, 30/32). Two observers who had no knowledge of the images chose 85.4% and 82.9% of the delay-time point images as the more obvious asymmetry from all images. The kappa value between the two observers was 0.66 with good agreement. CONCLUSION: Delayed 18F-FDG PET imaging can be used to better identify EZs with relatively greater metabolic asymmetry between the EZ and contralateral regions.

Derivation of a Clinical Risk Score to Predict 14-Day Occurrence of Hypoxia, ICU Admission, and Death Among Patients with Coronavirus Disease 2019.

BACKGROUND: Uncertainty surrounding COVID-19 regarding rapid progression to acute respiratory distress syndrome and unusual clinical characteristics make discharge from a monitored setting challenging. A clinical risk score to predict 14-day occurrence of hypoxia, ICU admission, and death is unavailable. OBJECTIVE: Derive and validate a risk score to predict suitability for discharge from a monitored setting among an early cohort of patients with COVID-19. DESIGN: Model derivation and validation in a retrospective cohort. We built a manual forward stepwise logistic regression model to identify variables associated with suitability for discharge and assigned points to each variable. Event-free patients were included after at least 14 days of follow-up. PARTICIPANTS: All adult patients with a COVID-19 diagnosis between March 1, 2020, and April 12, 2020, in 10 hospitals in Massachusetts, USA. MAIN MEASURES: Fourteen-day composite predicting hypoxia, ICU admission, and death. We calculated a risk score for each patient as a predictor of suitability for discharge evaluated by area under the curve. KEY RESULTS: Of 2059 patients with COVID-19, 1326 met inclusion. The 1014-patient training cohort had a mean age of 58 years, was 56% female, and 65% had at least one comorbidity. A total of 255 (25%) patients were suitable for discharge. Variables associated with suitability for discharge were age, oxygen saturation, and albumin level, yielding a risk score between 0 and 55. At a cut point of 30, the score had a sensitivity of 83% and specificity of 82%. The respective c-statistic for the derivation and validation cohorts were 0.8939 (95% CI, 0.8687 to 0.9192) and 0.8685 (95% CI, 0.8095 to 0.9275). The score performed similarly for inpatients and emergency department patients. CONCLUSIONS: A 3-item risk score for patients with COVID-19 consisting of age, oxygen saturation, and an acute phase reactant (albumin) using point of care data predicts suitability for discharge and may optimize scarce resources.

Heterozygous deletion of Seipin in islet beta cells of male mice has an impact on insulin synthesis and secretion through reduced PPARγ expression.

AIMS/HYPOTHESIS: Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is an autosomal recessive disorder characterised by lipodystrophy and insulin resistance. BSCL2 is caused by loss-of-function mutations in the Seipin gene (also known as Bscl2). Deletion of this gene in mice induces insulin resistance, glucose intolerance and a loss of adipose tissue. This study evaluated the effects of genetic deletion of Seipin on islet beta cell function. METHODS: We examined seipin expression in islet cells and measured glucose profiles, insulin synthesis, glucose-stimulated insulin secretion (GSIS), islet expression of peroxisome proliferator-activated receptor γ (PPARγ), levels of Pdx-1, Nkx6.1, Glut2 (also known as Slc2a2) and proinsulin mRNA, nuclear translocation of pancreatic duodenal homeobox 1 (PDX-1), islet numbers, and beta cell mass and proliferation in male and female Seipin-knockout homozygous (Seipin-/-) and heterozygous (Seipin+/-) mice. RESULTS: Male and female Seipin-/- mice displayed glucose intolerance, insulin resistance, hyperinsulinaemia and a lack of adipose tissue. By contrast, male but not female Seipin+/- mice showed glucose intolerance without adipose tissue loss or insulin resistance. Seipin was highly expressed in islet beta cells in wild-type mice. Expression of islet PPARγ was reduced in male Seipin-/- and Seipin+/- mice but not in female Seipin-/- or Seipin+/- mice. Treatment of male Seipin+/- mice with rosiglitazone corrected the glucose intolerance. Male Seipin+/- mice displayed a decrease in islet insulin concentration and GSIS with low expression of Pdx-1, Nkx6.1, Glut2 and proinsulin, and a decline in PDX-1 nuclear translocation; these changes were rescued by rosiglitazone administration. Male Seipin-/- mice showed obvious, but rosiglitazone-sensitive, increases in islet insulin concentration, islet number and beta cell mass and proliferation, with a notable decline in GSIS. Ovariectomised female Seipin+/- mice displayed glucose intolerance and deficits in insulin synthesis and secretion, with a decline in islet PPARγ level; these deleterious effects were reversed by administration of oestradiol or rosiglitazone. CONCLUSIONS/INTERPRETATION: Heterozygous deletion of Seipin in islet beta cells impacts on insulin synthesis and secretion through reduced PPARγ expression. This leads to glucose intolerance and is relieved by oestradiol, which rescues PPARγ expression.

18F-FDG PET/CT in diagnostic and prognostic evaluation of patients with cardiac masses: a retrospective study.

PURPOSE: Correct diagnosis and prognostic assessment of cardiac masses are crucial before therapy. We evaluated the diagnostic and prognostic value of 18F-FDG PET/CT in patients with cardiac masses. METHODS: 18F-FDG PET/CT images of 64 patients with 65 cardiac masses were retrospectively analysed (34 men, 30 women; average age, 51.2 ± 17.5 years). Comparisons of CT features and 18F-FDG metabolic indices between benign and malignant entities, as well as among primary and secondary malignancies and lymphoma, were performed. The diagnostic values of PET/CT for distinguishing benign versus malignant masses were calculated. PET/CT data were further assessed for the predictive value for overall survival (OS) using the Cox proportional hazards model to assess potential independent predictors. Kaplan-Meier curves were generated to assess the value of PET/CT for prognostication. RESULTS: Statistically significant differences in various morphological features and metabolic indices between benign and malignant masses were found. An SUVmax of 6.75 was the optimal cutoff value to differentiate between benign and malignant masses, and the diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 92.11%, 88.89%, 90.77%, 92.11%, and 88.89%, respectively. Taking CT features and SUVmax ≥ 6.75 as a criterion, the values were 76.32%, 100.00%, 86.15%, 100.00%, and 75.00%, respectively; taking ≥ 3 CT features or SUVmax ≥ 6.75 as a criterion, the values were 94.74%, 88.89%, 92.31%, 92.31%, and 92.31%, respectively, indicating optimal diagnostic performance when paired with the anatomic information provided by the CT component. A univariate analysis of OS determined that surrounding tissue infiltration, epicardial infiltration, necrosis, multiple chambers or vessel involvement, distant metastasis, SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were significant predictors of survival. In the multivariate analysis, only SUVmax ≥ 6.715 was significant (P < 0.01). Median OS was 1460 days for SUVmax < 6.715 and 342 days for SUVmax ≥ 6.715 (P < 0.01). CONCLUSION: 18F-FDG PET/CT is helpful in the diagnosis of cardiac masses before treatment and has value in detecting extracardiac primary or secondary tumours. 18F-FDG PET/CT could also be a promising tool to provide prognostic information for these patients, especially SUVmax displaying independent prognostic value.