The "Halo Appearance" of Shear Wave Elastography in the Setting of Fat Necrosis: A Potentially Useful Sonographic Discriminator.

OBJECTIVE: To describe the morphologic sonographic appearances and frequency of the "halo sign" in the setting of fat necrosis on shear wave elastography (SWE). METHODS: Patients with clinically suspected fat necrosis were prospectively scanned using SWE in addition to standard gray-scale and Doppler images. Cases were qualitatively grouped into one of three sonographic appearances: focal hypoechoic lesion with increased internal tissue stiffness ("focal stiffness"), focal hypoechoic lesion with isoechoic or hyperechoic periphery demonstrating increased tissue stiffness relative to the central hypoechoic lesion ("halo stiffness"), heterogeneously echogenic lesion with diffusely increased stiffness ("heterogeneous stiffness"). RESULTS: Exactly 19 patients met inclusion criteria (female n = 14; male n = 5). Shear wave velocities were recorded and retrospectively evaluated. The mean clinical follow-up was 11.4 months (range 3.0-25.5). Lesions demonstrated higher average tissue stiffness than background tissue (overall mass shear wave velocity 3.26 m/s, background 1.42 m/s, P < .001; lesion Young's modulus 40.85 kPa vs background 7.22 kPa, P < .001). The halo sign was identified in 10/19 (55%) patients. CONCLUSION: The halo sign is a potentially useful sign in the setting of fat necrosis seen in the majority of clinically suspected cases.

Sclerosing well-differentiated liposarcoma: two diagnostically challenging mimicker cases and a literature review.

Liposarcoma is a malignant soft tissue tumor with several subtypes, the most common of which is well-differentiated liposarcoma (WDL) or atypical lipomatous tumor (ALT). WDL/ALTs are further divided into three histological subtypes, including lipoma-like, sclerosing, and inflammatory. While the majority of these tumors are predominantly fatty, the sclerosing variant demonstrates diverse histologic and radiographic characteristics, including variable amounts of fibrosis and fat. Because of this histological variability and relative rarity, the sclerosing WDL/ALT can present diagnostic dilemmas. We present two cases of sclerosing WDL/ALT, both of which demonstrated high degrees of fibrosis and a paucity of fat, mimicking desmoid fibromatosis and other fibrotic soft tissue tumors. Thus, it is important for radiologists to be aware of the subtypes of liposarcoma and their unique characteristics, and to consider sclerosing WDL/ALT in cases of fibrotic soft tissue tumors.

No "July Effect" in the management and outcomes of acute myocardial infarction: An 18-year United States national study.

BACKGROUND: There has been conflicting reports on the effect of new trainees on clinical outcomes at teaching hospitals in the first training month (July in the United States of America). We sought to assess this "July effect" in a contemporary acute myocardial infarction (AMI) population. METHODS: Adult (>18 years) AMI hospitalizations in May and July in urban teaching and urban nonteaching hospitals in the United States were identified from the HCUP-NIS database (2000-2017). In-hospital mortality was compared between May and July admissions. A difference-in-difference analysis comparing a change in outcome from May to July in teaching hospitals to a change in outcome from May to July in nonteaching hospitals was also performed. RESULTS: A total of 1,312,006 AMI hospitalizations from urban teaching (n = 710,593; 54.2%) or nonteaching (n = 601,413; 45.8%) hospitals in the months of May and July were evaluated. May admissions in teaching hospitals, had greater comorbidity, higher rates of acute multiorgan failure (10.6% vs. 10.2%, p < 0.001) and lower rates of cardiac arrest when compared to July admissions. July AMI admissions had lower in-hospital mortality compared to May (5.6% vs. 5.8%; adjusted odds ratio 0.94 [95% confidence interval 0.92-0.97]; p < 0.001) in teaching hospitals. Using the difference-in-difference model, there was no evidence of a July effect for in-hospital mortality (p = 0.19). CONCLUSIONS: There was no July effect for in-hospital mortality in this contemporary AMI population.

Dedifferentiated Chondrosarcoma: Diagnostic Controversies and Emerging Therapeutic Targets.

PURPOSE OF REVIEW: The pathogenesis of dedifferentiated chondrosarcoma is controversial, and no genetic abnormality has consistently been identified in the disease. Focusing on the diagnostic challenges encountered in dedifferentiated chondrosarcoma, the following review aims at summarizing the tumor's active neoplastic pathways while highlighting therapeutic modalities that could potentially be explored to enhance patient survivorship. RECENT FINDINGS: Owing to the challenging examination of small needle biopsy sampling as well as the disease's overlapping morphological and immunohistochemical features with other bone and soft-tissue sarcomas, the diagnosis of dedifferentiated chondrosarcoma can be problematic. While combined doxorubicin- and cisplatin-based regimens remain the first-line systemic chemotherapy in the disease, ~50% of tumors carry EXT1/2 or IDH1/2 mutations, advancing EXT or IDH inhibitors as potential alternative therapies, respectively. Despite systemic chemotherapy, dedifferentiated chondrosarcoma remains an aggressive tumor with dismal prognosis and limited survival. A multidisciplinary collaboration across multiple cancer centers is warranted to yield an accurate diagnosis, understand the disease's underlying pathogenesis, develop adequate treatment, and improve patient survivorship.

Co-designing an intervention to improve the process of deprescribing for older people living with frailty in the United Kingdom.

BACKGROUND: In older people living with frailty, polypharmacy can lead to preventable harm like adverse drug reactions and hospitalization. Deprescribing is a strategy to reduce problematic polypharmacy. All stakeholders should be actively involved in developing a person-centred deprescribing process that involves shared decision-making. OBJECTIVE: To co-design an intervention, supported by a logic model, to increase the engagement of older people living with frailty in the process of deprescribing. DESIGN: Experience-based co-design is an approach to service improvement, which uses service users and providers to identify problems and design solutions. This was used to create a person-centred intervention with the potential to improve the quality and outcomes of the deprescribing process. A 'trigger film' showing older people talking about their healthcare experiences was created and facilitated discussions about current problems in the deprescribing process. Problems were then prioritized and appropriate solutions were developed. The review located the solutions in the context of current processes and procedures. An ideal care pathway and a complex intervention to deliver better care were developed. SETTING AND PARTICIPANTS: Older people living with frailty, their informal carers and professionals living and/or working in West Yorkshire, England, UK. Deprescribing was considered in the context of primary care. RESULTS: The current deprescribing process differed from an ideal pathway. A complex intervention containing seven elements was required to move towards the ideal pathway. Three of these elements were prototyped and four still need development. The complex intervention responded to priorities about (a) clarity for older people about what was happening at all stages in the deprescribing process and (b) the quality of one-to-one consultations. CONCLUSIONS: Priorities for improving the current deprescribing process were successfully identified. Solutions were developed and structured as a complex intervention. Further work is underway to (a) complete the prototyping of the intervention and (b) conduct feasibility testing. PATIENT OR PUBLIC CONTRIBUTION: Older people living with frailty (and their informal carers) have made a central contribution, as collaborators, to ensure that a complex intervention has the greatest possible potential to enhance the experience of deprescribing medicines.

Multitargeted inhibition of key enzymes associated with diabetes and Alzheimer's disease by 1,3,4-oxadiazole derivatives: Synthesis, in vitro screening, and computational studies.

A library of 22 derivatives of 1,3,4-oxadiazole-2-thiol was synthesized, structurally characterized, and assessed for its potential to inhibit α-amylase, α-glucosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and antioxidant activities. Most of the tested compounds demonstrated good to moderate inhibition potential; however, their activity was lower than that of the standard acarbose. Significantly, compound 3f exhibited the highest inhibition potential against α-glucosidase and α-amylase enzymes, with IC50 values of 18.52 ± 0.09 and 20.25 ± 1.05 µM, respectively, in comparison to the standard acarbose (12.29 ± 0.26; 15.98 ± 0.14 µM). Compounds also demonstrated varying degrees of inhibitory potential against AChE (IC50 = 9.25 ± 0.19 to 36.15 ± 0.12 µM) and BChE (IC50 = 10.06 ± 0.43 to 35.13 ± 0.12 µM) enzymes compared to the standard donepezil (IC50 = 2.01 ± 0.12; 3.12 ± 0.06 µM), as well as DPPH (IC50 = 20.98 ± 0.06 to 52.83 ± 0.12 µM) and ABTS radical scavenging activities (IC50 = 22.29 ± 0.18 to 47.98 ± 0.03 µM) in comparison to the standard ascorbic acid (IC50 = 18.12 ± 0.15; 19.19 ± 0.72). The kinetic investigations have demonstrated that the compounds exhibit competitive-type inhibition for α-amylase, noncompetitive-type inhibition for α-glucosidase and AChE, and mixed-type inhibition for BChE. Additionally, a molecular docking study was performed on all synthetic oxadiazoles to explore the interaction details of these compounds with the active sites of the enzymes.

Diabetes workshops for providers improve glucose control in coronary artery bypass grafting patients.

OBJECTIVES: Postoperative hyperglycemia occurs in up to 80% of cardiac surgery patients and is associated with poor outcomes. We sought to determine if case-based diabetes workshops for providers would improve postoperative glycemic control and outcomes in patients undergoing coronary artery bypass grafting  (CABG). METHODS: Healthcare providers taking care of patients in the cardiothoracic step-down unit underwent 30-min weekly case-based diabetes workshops over 6 months. Workshops focused on initiation of insulin treatment, titration of insulin dosing, and transitioning from insulin drips to subcutaneous insulin. Isolated-CABG patients were recorded during 29-month periods before (Jan 2013-June 2015) and after training (Jan 2016-June 2018). Glycemic control and outcomes were compared between groups balanced for preoperative risk factors using inverse probability treatment weights. RESULTS: A total of 938 and 1032 patients were included in pre- and posttraining groups, respectively. Compared to the pretraining period, the posttraining period had a lower median of mean patient day glucose levels (151 vs. 144 mg/dl, p < .001) and percentage of patient days with a glucose level >250 mg/dl (20% vs. 14%, p < .001). The percentage of patient days with mean glucose values in the target range (80-180 mg/dl) increased from 71% to 77% (p < .001). The incidence of hypoglycemic events did not significantly change after training (p = .15). The incidence of sepsis was significantly lower in the posttraining period (1.7% vs. 0.2%, p < .001). CONCLUSIONS: Weekly diabetes workshops for healthcare providers were associated with improved glycemic control and reduced postoperative sepsis among isolated CABG patients.

Association of GSTM1 and GSTT1 gene polymorphisms with COVID-19 susceptibility and its outcome.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a global health issue and develops into a broad range of illnesses from asymptomatic to fatal respiratory diseases. SARS-CoV-2 infection is associated with oxidative stress that triggers cytokine production, inflammation, and other pathophysiological processes. Glutathione-S-transferase (GST) is an important enzyme that catalyzes the conjugation of glutathione (GSH) with electrophiles to protect the cell from oxidative damage and participates in the antioxidant defense mechanism in the lungs. Thus, in this study, we investigated the role of GSTM1 and GSTT1 gene polymorphism with COVID-19 susceptibility, as well as its outcome. The study included 269 RT-PCR confirmed COVID-19 patients with mild (n = 149) and severe (n = 120) conditions. All subjects were genotyped for GSTM1 and GSTT1 by multiplex polymerase chain reaction (mPCR) followed by statistical analysis. The frequency of GSTM1-/- , GSTT1-/- and GSTM1-/- /GSTT1-/- was higher in severe COVID-19 patients as compared to mild patients but we did not observe a significant association. In the Cox hazard model, death was significantly 2.28-fold higher in patients with the GSTT1-/- genotype (p = 0.047). In combination, patients having GSTM1+/+ and GSTT1-/- genotypes showed a poor survival rate (p = 0.02). Our results suggested that COVID-19 patients with the GSTT1-/- genotype showed higher mortality.

Antioxidant enzymes and association of CAT SNP-21 A/T (rs7943316) with male infertility.

Infertility is a multifactorial and polygenic disease. A vast majority of infertility is still unexplained despite modern diagnostic techniques. Oxidative stress is considered a factor for male infertility but etiology in terms of functional gene polymorphism and experimental studies on human subjects is scarcely reported. The aim of the study was to investigate the status of three antioxidant enzymes; catalase, superoxide dismutase (SOD), and glutathione reduced (GSH) in clinically diagnosed infertile males and find the potential association of CAT gene variant in the promoter region -21 A/T (rs7943316). The study consisted of 55 clinically diagnosed infertile males and 50 non-infertile volunteers. The activity of antioxidant enzymes was measured through a spectrophotometer. Polymerase chain reaction-restriction fragment length polymorphism was performed for genotyping of single-nucleotide polymorphism. Catalase enzyme activity was significantly decreased while SOD and GSH were substantially increased (p ≤ 0.01) in infertile men in comparison to non-infertile. CAT gene variant rs7943316 had shown significant association in dominant, recessive model and allelic frequencies. The study concludes that rs7943316 has a substantial role in male infertility. The outcome of the study may help in resolving idiopathic infertility cases and may help in evolving novel diagnostic and therapeutic approaches. Other variants of CAT and antioxidant genes are suggested to ascertain further insight.

Dynamic Profiling of ß-Coronavirus 3CL Mpro Protease Ligand-Binding Sites.

ß-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a backup against the emergence of lethal viral variants. One such target is the main protease (Mpro) that plays an indispensable role in viral replication. The availability of over 270 Mpro X-ray structures in complex with inhibitors provides unique insights into ligand-protein interactions. Herein, we provide a comprehensive comparison of all nonredundant ligand-binding sites available for SARS-CoV2, SARS-CoV, and MERS-CoV Mpro. Extensive adaptive sampling has been used to investigate structural conservation of ligand-binding sites using Markov state models (MSMs) and compare conformational dynamics employing convolutional variational auto-encoder-based deep learning. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across ß-CoV homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor.

Does Magnetic Resonance Imaging After Diagnostic Ultrasound for Soft Tissue Masses Change Clinical Management?

OBJECTIVES: To evaluate whether a follow-up magnetic resonance imaging (MRI) scan performed after initial ultrasound (US) to evaluate soft tissue mass (STM) lesions of the musculoskeletal system provides additional radiologic diagnostic information and alters clinical management. METHODS: A retrospective chart review was performed of patients undergoing initial US evaluations of STMs of the axial or appendicular skeleton between November 2012 and March 2019. Patients who underwent US examinations followed by MRI for the evaluation of STM lesions were identified. For inclusion, the subsequent pathologic correlation was required from either a surgical or image-guided biopsy. Imaging studies with pathologic correlations were then reviewed by 3 musculoskeletal radiologists, who were blinded to the pathologic diagnoses. The diagnostic utility of MRI was then assessed on the basis of a 5-point grading scale, and inter-reader agreements were determined by the Fleiss κ statistic. RESULTS: Ninety-two patients underwent MRI after US for STM evaluations. Final pathologic results were available in 42 cases. Samples were obtained by surgical excision or open biopsy (n = 34) or US-guided core biopsy (n = 8). The most common pathologic diagnoses were nerve sheath tumors (n = 9), lipomas (n = 5), and leiomyomas (n = 5). Imaging review showed that the subsequent MRI did not change the working diagnosis in 73% of cases, and the subsequent MRI was not considered to narrow the differential diagnosis in 68% of cases. There was slight inter-reader agreement for the diagnostic utility of MRI among individual cases (κ = 0.10) between the 3 readers. CONCLUSIONS: The recommendation of MRI to further evaluate STM lesions seen with US frequently fails to change the working diagnosis or provide significant diagnostic utility.

Synthetic and Therapeutic Applications of Ammonia-lyases and Aminomutases.

Ammonia-lyases and aminomutases are mechanistically and structurally diverse enzymes which catalyze the deamination and/or isomerization of amino acids in nature by cleaving or shifting a C-N bond. Of the many protein families in which these enzyme activities are found, only a subset have been employed in the synthesis of optically pure fine chemicals or in medical applications. This review covers the natural diversity of these enzymes, highlighting particular enzyme classes that are used within industrial and medical biotechnology. These highlights detail the discovery and mechanistic investigations of these commercially relevant enzymes, along with comparisons of their various applications as stand-alone catalysts, components of artificial biosynthetic pathways and biocatalytic or chemoenzymatic cascades, and therapeutic tools for the potential treatment of various pathologies.

COVID-19 in recent heart transplant recipients: Clinicopathologic features and early outcomes.

BACKGROUND: The impact of COVID-19 on heart transplant (HTx) recipients remains unclear, particularly in the early post-transplant period. METHODS: We share novel insights from our experience in five HTx patients with COVID-19 (three within 2 months post-transplant) from our institution at the epicenter of the pandemic. RESULTS: All five exhibited moderate (requiring hospitalization, n = 3) or severe (requiring ICU and/or mechanical ventilation, n = 2) illness. Both cases with severe illness were transplanted approximately 6 weeks before presentation and acquired COVID-19 through community spread. All five patients were on immunosuppressive therapy with mycophenolate mofetil (MMF) and tacrolimus, and three that were transplanted within the prior 2 months were additionally on prednisone. The two cases with severe illness had profound lymphopenia with markedly elevated C-reactive protein, procalcitonin, and ferritin. All had bilateral ground-glass opacities on chest imaging. MMF was discontinued in all five, and both severe cases received convalescent plasma. All three recent transplants underwent routine endomyocardial biopsies, revealing mild (n = 1) or no acute cellular rejection (n = 2), and no visible viral particles on electron microscopy. Within 30 days of admission, the two cases with severe illness remain hospitalized but have clinically improved, while the other three have been discharged. CONCLUSIONS: COVID-19 appears to negatively impact outcomes early after heart transplantation.

Fibrous Dysplasia-like Lacrimal Sac Tumor Associated With Dacryocystitis.

A 72-year-old woman who presented with right-sided epiphora and conjunctivitis underwent a probing and irrigation procedure with normal results. She improved with antibiotic-steroid drops. A swelling in the medial canthal region completely resolved. One year later, she returned with symptoms of dacryocystitis. An external dacryocystorhinostomy was performed. Characteristic dacryoliths were removed from the sac lumen, and biopsy of the sac wall showed spicules of lamellar bone within a fibrous stroma. Diagnosed as fibrous dysplasia of the lacrimal sac, this rare entity represents the second such case in the literature.The histopathology of an ossified lacrimal sac resembled fibrous dysplasia of bone and exemplifies the second case of this rare entity in the literature.

One-Pot Synthesis of Chiral N-Arylamines by Combining Biocatalytic Aminations with Buchwald-Hartwig N-Arylation.

The combination of biocatalysis and chemo-catalysis increasingly offers chemists access to more diverse chemical architectures. Here, we describe the combination of a toolbox of chiral-amine-producing biocatalysts with a Buchwald-Hartwig cross-coupling reaction, affording a variety of α-chiral aniline derivatives. The use of a surfactant allowed reactions to be performed sequentially in the same flask, preventing the palladium catalyst from being inhibited by the high concentrations of ammonia, salts, or buffers present in the aqueous media in most cases. The methodology was further extended by combining with a dual-enzyme biocatalytic hydrogen-borrowing cascade in one pot to allow for the conversion of a racemic alcohol to a chiral aniline.

Crystal structure of the integral membrane diacylglycerol kinase.

Diacylglycerol kinase catalyses the ATP-dependent phosphorylation of diacylglycerol to phosphatidic acid for use in shuttling water-soluble components to membrane-derived oligosaccharide and lipopolysaccharide in the cell envelope of Gram-negative bacteria. For half a century, this 121-residue kinase has served as a model for investigating membrane protein enzymology, folding, assembly and stability. Here we present crystal structures for three functional forms of this unique and paradigmatic kinase, one of which is wild type. These reveal a homo-trimeric enzyme with three transmembrane helices and an amino-terminal amphiphilic helix per monomer. Bound lipid substrate and docked ATP identify the putative active site that is of the composite, shared site type. The crystal structures rationalize extensive biochemical and biophysical data on the enzyme. They are, however, at variance with a published solution NMR model in that domain swapping, a key feature of the solution form, is not observed in the crystal structures.

Biocatalytic Routes to Lactone Monomers for Polymer Production.

Monoterpenoids offer potential as biocatalytically derived monomer feedstocks for high-performance renewable polymers. We describe a biocatalytic route to lactone monomers menthide and dihydrocarvide employing Baeyer-Villiger monooxygenases (BVMOs) from Pseudomonas sp. HI-70 (CPDMO) and Rhodococcus sp. Phi1 (CHMOPhi1) as an alternative to organic synthesis. The regioselectivity of dihydrocarvide isomer formation was controlled by site-directed mutagenesis of three key active site residues in CHMOPhi1. A combination of crystal structure determination, molecular dynamics simulations, and mechanistic modeling using density functional theory on a range of models provides insight into the origins of the discrimination of the wild type and a variant CHMOPhi1 for producing different regioisomers of the lactone product. Ring-opening polymerizations of the resultant lactones using mild metal-organic catalysts demonstrate their utility in polymer production. This semisynthetic approach utilizing a biocatalytic step, non-petroleum feedstocks, and mild polymerization catalysts allows access to known and also to previously unreported and potentially novel lactone monomers and polymers.

Pyogenic granuloma: A tumor that mimics infection.

This article describes a patient whose cutaneous pyogenic granuloma was mistaken for infection after injury from a fractured smartphone screen. Clinicians should suspect pyogenic granuloma in patients with these types of injuries so that patients can avoid unnecessary procedures, antibiotics, and discomfort.

Crystal structure of the ß2 adrenergic receptor-Gs protein complex.

G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The ß(2) adrenergic receptor (ß(2)AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomeric ß(2)AR and nucleotide-free Gs heterotrimer. The principal interactions between the ß(2)AR and Gs involve the amino- and carboxy-terminal α-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the ß(2)AR include a 14 Å outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an α-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR.