Chest CT is emerging as a valuable diagnostic tool for clinical management of COVID-19 associated lung disease. Artificial intelligence (AI) has the potential to aid in rapid evaluation of CT scans ...for differentiation of COVID-19 findings from other clinical entities. Here we show that a series of deep learning algorithms, trained in a diverse multinational cohort of 1280 patients to localize parietal pleura/lung parenchyma followed by classification of COVID-19 pneumonia, can achieve up to 90.8% accuracy, with 84% sensitivity and 93% specificity, as evaluated in an independent test set (not included in training and validation) of 1337 patients. Normal controls included chest CTs from oncology, emergency, and pneumonia-related indications. The false positive rate in 140 patients with laboratory confirmed other (non COVID-19) pneumonias was 10%. AI-based algorithms can readily identify CT scans with COVID-19 associated pneumonia, as well as distinguish non-COVID related pneumonias with high specificity in diverse patient populations.
Background. Chronic granulomatous disease (CGD) is due to defective nicotinamide adenine dinucleotide phosphate oxidase activity and characterized by recurrent infections with a limited spectrum of ...bacteria and fungi as well as inflammatory complications. To understand the impact of common severe infections in CGD, we examined the records of 268 patients followed at a single center over 4 decades. Methods. All patients had confirmed diagnoses of CGD, and genotype was determined where possible. Medical records were excerpted into a standard format. Microbiologic analyses were restricted to Staphylococcus, Burkholderia, Serratia, Nocardia, and Aspergillus. Results. Aspergillus incidence was estimated at 2.6 cases per 100 patient-years; Burkholderia, 1.06 per 100 patient-years; Nocardia, 0.81 per 100 patient-years; Serratia, 0.98 per 100 patient-years, and severe Staphylococcus infection, 1.44 per 100 patient-years. Lung infection occurred in 87% of patients, whereas liver abscess occurred in 32%. Aspergillus incidence was 55% in the lower superoxide-producing quartiles (quartiles 1 and 2) but only 41% in the higher quartiles (rate ratio, <0.0001). Aspergillus and Serratia were somewhat more common in lower superoxide producing gp91phox deficiency. The median age at death has increased from 15.53 years before 1990 to 28.12 years in the last decade. Fungal infection carried a higher risk of mortality than bacterial infection and was the most common cause of death (55%).Gastrointestinal complications were not associated with either infection or mortality. Conclusions. Fungal infections remain a major determinant of survival in CGD. X-linked patients generally had more severe disease, and this was generally in those with lower residual superoxide production. Survival in CGD has increased over the years, but infections are still major causes of morbidity and mortality.
Study objective Copperhead snake ( Agkistrodon contortrix ) envenomation causes limb injury resulting in pain and disability. It is not known whether antivenom administration improves limb function. ...We determine whether administration of antivenom improves recovery from limb injury in patients envenomated by copperhead snakes. Methods From August 2013 through November 2015, we performed a multicenter, randomized, double-blind, placebo-controlled, clinical trial to evaluate the effect of ovine Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) antivenom therapy on recovery of limb function in patients with copperhead snake envenomation at 14 days postenvenomation. The study setting was 18 emergency departments in regions of the United States where copperhead snakes are endemic. Consecutive patients aged 12 years or older with mild- to moderate-severity envenomation received either FabAV or placebo. The primary outcome was limb function 14 days after envenomation, measured by the Patient-Specific Functional Scale. Additional outcomes included the Patient-Specific Functional Scale at other points; the Disorders of the Arm, Shoulder, and Hand, Lower Extremity Functional Scale, and Patient’s Global Impression of Change instruments; grip strength; walking speed; quality of life (Patient-Reported Outcomes Measurement Information System Physical Fucntion-10); pain; and analgesic use. Results Seventy-four patients received study drug (45 FabAV, 29 placebo). Mean age was 43 years (range 12 to 86 years). Fifty-three percent were men, 62% had lower extremity envenomation, and 88% had mild initial severity. The primary outcome, the least square mean Patient-Specific Functional Scale score at 14 days postenvenomation, was 8.6 for FabAV-treated subjects and 7.4 for placebo recipients (difference 1.2; 95% confidence interval 0.1 to 2.3; P =.04). Additional outcome assessments generally favored FabAV. More FabAV-treated subjects experienced treatment-emergent adverse events (56% versus 28%), but few were serious (1 in each group). Conclusion Treatment with FabAV reduces limb disability measured by the Patient-Specific Functional Scale 14 days after copperhead envenomation.
Aspergillus flavus is an agriculturally significant micro-fungus having potential to contaminate food and feed crops with toxic secondary metabolites such as aflatoxin (AF) and cyclopiazonic acid ...(CPA). Research has shown A. flavus strains can overcome heterokaryon incompatibility and undergo meiotic recombination as teleomorphs. Although evidence of recombination in the AF gene cluster has been reported, the impacts of recombination on genotype and metabolomic phenotype in a single generation are lacking. In previous studies, we paired an aflatoxigenic MAT1-1 A. flavus strain with a non-aflatoxigenic MAT1-2 A. flavus strain that had been tagged with green fluorescent protein and then 10 F1 progenies (a mix of fluorescent and non-fluorescent) were randomly selected from single-ascospore colonies and broadly examined for evidence of recombination. In this study, we determined four of those 10 F1 progenies were recombinants because they were not vegetatively compatible with either parent or their siblings, and they exhibited other distinctive traits that could only result from meiotic recombination. The other six progenies examined shared genomic identity with the non-aflatoxigenic, fluorescent, and MAT1-2 parent, but were metabolically distinct. This study highlights phenotypic and genomic changes that may occur in a single generation from the outcrossing of sexually compatible strains of A. flavus.
Valid, reliable, and clinically relevant outcome measures are necessary in clinical studies of snake envenomation. The aim of this study was to evaluate the psychometric (validity and reliability) ...and clinimetric (minimal clinically important difference MCID) properties of the Patient-Specific Functional Scale (PSFS) in snakebite envenomation.
We performed a secondary analysis of two existing snakebite trials that measured clinical outcomes using the PSFS as well as other quality of life and functional assessments. Data were collected at 3, 7, 10, and 17 days. Reliability was determined using Cronbach's alpha for internal consistency and the intraclass correlation coefficient (ICC) for temporal stability at 10 and 17 days. Validity was assessed using concurrent validity correlating with the other assessments. The MCID was evaluated using the following criteria: (1) the distribution of stable patients according to both standard error of measurement (SEM) and responsiveness techniques, and (2) anchor-based methods to compare between individuals and to detect discriminant ability of a positive change with a receiver operator characteristic (ROC) curve and optimal cutoff point.
A total of 86 patients were evaluated in this study. The average PSFS scores were 5.37 (SD 3.23), 7.95 (SD 2.22), and 9.12 (SD 1.37) at 3, 7, and 10 days, respectively. Negligible floor effect was observed (maximum of 8% at 3 days); however, a ceiling effect was observed at 17 days (25%). The PSFS showed good reliability with an internal consistency of 0.91 (Cronbach's alpha) (95% CI 0.88, 0.95) and a temporal stability of 0.83 (ICC) (95% CI 0.72, 0.89). The PSFS showed a strong positive correlation with quality of life and functional assessments. The MCID was approximately 1.0 for all methods.
With an MCID of approximately 1 point, the PSFS is a valid and reliable tool to assess quality of life and functionality in patients with snake envenomation.
Patients with hepatocellular carcinoma (HCC) have a poor prognosis and limited therapeutic options. Alpha‐fetoprotein (AFP) is often expressed at high levels in HCC and is an established clinical ...biomarker of the disease. Expression of AFP in nonmalignant liver can occur, particularly in a subset of progenitor cells and during chronic inflammation, at levels typically lower than in HCC. This cancer‐specific overexpression indicates that AFP may be a promising target for immunotherapy. We verified expression of AFP in normal and diseased tissue and generated an affinity‐optimized T‐cell receptor (TCR) with specificity to AFP/HLA‐A*02+ tumors. Expression of AFP was investigated using database searches, by qPCR, and by immunohistochemistry (IHC) analysis of a panel of human tissue samples, including normal, diseased, and malignant liver. Using in vitro mutagenesis and screening, we generated a TCR that recognizes the HLA‐A*02‐restricted AFP158‐166 peptide, FMNKFIYEI, with an optimum balance of potency and specificity. These properties were confirmed by an extension of the alanine scan (X‐scan) and testing TCR‐transduced T cells against normal and tumor cells covering a variety of tissues, cell types, and human leukocyte antigen (HLA) alleles. Conclusion: We have used a combination of physicochemical, in silico, and cell biology methods for optimizing a TCR for improved affinity and function, with properties that are expected to allow TCR‐transduced T cells to differentiate between antigen levels on nonmalignant and cancer cells. T cells transduced with this TCR constitute the basis for a trial of HCC adoptive T‐cell immunotherapy.
Metformin is a biguanide that is used as first-line treatment of type 2 diabetes mellitus and is effective as monotherapy and in combination with other glucose-lowering medications. It is generally ...well-tolerated with minimal side effects and is affordable. Although the safety and efficacy of metformin have been well-established, there is discussion regarding whether metformin should continue to be the first choice for therapy as other anti-hyperglycemic medications exhibit additional advantages in certain populations. Despite a long-standing history of metformin use, there are limited cardiovascular outcomes data for metformin. Furthermore, the available studies fail to provide strong evidence due to either small sample size or short duration. Recent data from glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter-2 inhibitor cardiovascular and renal outcomes trials demonstrated additional protection from diabetes complications for some high-risk patients, which has impacted the guidelines for diabetes management. Post-hoc analyses comparing hazard ratios for participants taking metformin at baseline versus not taking metformin are inconclusive for these two groups. There are no data to suggest that metformin should not be initiated soon after the diagnosis of diabetes. Furthermore, the initiation of newer glycemic-lowering medications with cardiovascular benefits should be considered in high-risk patients regardless of glycemic control or target HbA1c. However, cost remains a major factor in determining appropriate treatment.
Underutilization of therapies to reduce ischemic risk in peripheral artery disease (PAD) persists.
The purpose was to conduct an implementation trial of lipid management in vascular disease.
The ...OPTIMIZE PAD-1 (Implementation of Vascular Care Team to Improve Medical Management of PAD Patients) trial randomized patients with peripheral artery disease with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL to management via a vascular care team including a clinical pharmacist and an algorithm of intensive lipid management to achieve goal LDL-C in 1 step vs usual care plus provider education. Medications were obtained using commercial insurance. The primary endpoint was percent change in LDL-C at 12 months.
Of 166 enrolled patients, 74.2% did not have an LDL-C level at goal. Among 114 randomized patients (mean age 66 years, 36.0% women, and 15.8% Black), 50.9% received high-intensity statin, and 7.9% received ezetimibe at baseline. The mean 12-month LDL-C change was −49.1% (95% CI: −58.7% to −39.5%) with vascular care team management and −5.4% (95% CI: −15.3% to 4.6%) with usual care; the between-group least-squares mean difference was −43.7% (95% CI: −57.6% to −29.9%; P < 0.0001). Mean LDL-C was reduced in vascular care team patients from 100.6 mg/dL at baseline to 54.8 and 50.1 mg/dL by week 4 and month 12, respectively. At 12 months, vascular care team patients were >3 times as likely to achieve LDL-C <70 mg/dL and 8 times as likely to achieve LDL-C <55 mg/dL (P < 0.0001) than usual care.
OPTIMIZE PAD-1 showed that an interprofessional, algorithm-based program can achieve rapid LDL-C lowering in vascular patients using available insurance and therapies, and LDL-C targets can be met in most patients if enabled by optimized systems of care.
Display omitted
A substantial obstacle to the success of adoptive T cell-based cancer immunotherapy is the sub-optimal affinity of T-cell receptors (TCRs) for most tumor antigens. Genetically engineered TCRs that ...have enhanced affinity for specific tumor peptide-MHC complexes may overcome this barrier. However, this enhancement risks increasing weak TCR cross-reactivity to other antigens expressed by normal tissues, potentially leading to clinical toxicities. To reduce the risk of such adverse clinical outcomes, we have developed an extensive preclinical testing strategy, involving potency testing using 2D and 3D human cell cultures and primary tumor material, and safety testing using human primary cell and cell-line cross-reactivity screening and molecular analysis to predict peptides recognized by the affinity-enhanced TCR. Here, we describe this strategy using a developmental T-cell therapy, ADP-A2M4, which recognizes the HLA-A2-restricted MAGE-A4 peptide GVYDGREHTV. ADP-A2M4 demonstrated potent anti-tumor activity in the absence of major off-target cross-reactivity against a range of human primary cells and cell lines. Identification and characterization of peptides recognized by the affinity-enhanced TCR also revealed no cross-reactivity. These studies demonstrated that this TCR is highly potent and without major safety concerns, and as a result, this TCR is now being investigated in two clinical trials (NCT03132922, NCT04044768).
The Morungava region (east of Porto Alegre-Rio Grande do Sul, Brazil), in the southern half of the Paraná-Etendeka Large Igneous Province (LIP), hosts Serra Geral Group subvolcanic intrusions (sill ...complex). These intrusions comprise various chemical compositions, including high-Mg rocks. So far, only a few examples of high-Mg rocks have been discovered in the Paraná-Etendeka LIP. Many investigations have been conducted in the Morungava region, yet several questions regarding the distribution, geometry, composition, and structural framework of the subvolcanic bodies in the subsurface remain unanswered. Therefore, we built a three-dimensional geological model of the Serra Geral Group sills and their associated stratigraphic framework in the Morungava region. This was achieved through the combined analysis of geological data (boreholes and geological maps), as well as petrophysical and chemical data, to improve the understanding of these subvolcanic bodies underground. The stratigraphic framework depicts the Precambrian basement topography, the distribution of the Paraná Basin units, and the Rio Grande do Sul Coastal Plain strata, which span the majority of the examined area. To categorize the Serra Geral Group rocks intersected by the boreholes, we established a validation and correlation technique using three separate data sources: laboratory geochemical data, portable X-ray fluorescence measurements, and gamma-ray logs. Using this technique, we classified the Serra Geral Group rocks in the Morungava region into three types (1, 2, 3), which share compositional similarities with Palmas, Vale do Sol, and Torres formations, respectively. Additionally, we identified a fourth type that could be compared to the Lomba Grande Complex, Silica Saturated Olivine Tholeiite-type dikes, and some high-Mg rocks from Namibia.
•We compiled geochemical data from the lava piles and subvolcanic bodies in southern Paraná-Etendeka LIP (Brazil).•We carried out pXRF, magnetic susceptibility and NRM measurements on lava piles and subvolcanic bodies in Morungava region.•We built a 3D stratigraphic framework to represent the basement, the Paraná Basin and the Rio Grande do Sul Coastal Plain.•Four compositional types of the Serra Geral Group rocks were identified.
PDF
