Publications by authors named "Yeh Chen"

66 Publications

Crystal structure and functional implication of a bacterial cyclic AMP-AMP-GMP synthetase.

Nucleic Acids Res 2021 May;49(8):4725-4737

Institute of New Drug Development, China Medical University, Taichung 406, Taiwan.

Mammalian cyclic GMP-AMP synthase (cGAS) and its homologue dinucleotide cyclase in Vibrio cholerae (VcDncV) produce cyclic dinucleotides (CDNs) that participate in the defense against viral infection. Recently, scores of new cGAS/DncV-like nucleotidyltransferases (CD-NTases) were discovered, which produce various CDNs and cyclic trinucleotides (CTNs) as second messengers. Here, we present the crystal structures of EcCdnD, a CD-NTase from Enterobacter cloacae that produces cyclic AMP-AMP-GMP, in its apo-form and in complex with ATP, ADP and AMPcPP, an ATP analogue. Despite the similar overall architecture, the protein shows significant structural variations from other CD-NTases. Adjacent to the donor substrate, another nucleotide is bound to the acceptor binding site by a non-productive mode. Isothermal titration calorimetry results also suggest the presence of two ATP binding sites. GTP alone does not bind to EcCdnD, which however binds to pppApG, a possible intermediate. The enzyme is active on ATP or a mixture of ATP and GTP, and the best metal cofactor is Mg2+. The conserved residues Asp69 and Asp71 are essential for catalysis, as indicated by the loss of activity in the mutants. Based on structural analysis and comparison with VcDncV and RNA polymerase, a tentative catalytic pathway for the CTN-producing EcCdnD is proposed.
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http://dx.doi.org/10.1093/nar/gkab165DOI Listing
May 2021

Prevalence of pelvic organ prolapse among US racial populations: A systematic review and meta-analysis of population-based screening studies.

Neurourol Urodyn 2021 Apr 9. Epub 2021 Apr 9.

Division of Female Pelvic Medicine and Reconstructive Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Aims: To determine the differences in pooled prevalence rates of symptomatic pelvic organ prolapse (POP) across different US racial/ethnic groups using existing screening-based epidemiologic studies.

Methods: A systematic search of MEDLINE, EMBASE, Cochrane, and Scopus was conducted to retrieve eligible studies. We included studies that identified POP by either physical exam or questionnaire, conducted in non-gynecologic care-seeking settings, and had a representative sample of US community-dwelling women from more than one racial/ethnic group with prevalence rates reported for each population. Meta-analysis was performed with the pooled estimates calculated, and χ tests were performed to examine the associations between race and POP prevalence.

Results: Of the 2604 studies reviewed, 5 were included. One study used physical exam findings while others used questionnaires to identify POP. All but one study demonstrated statistically significant differences in POP prevalence rates based on race/ethnicity. The overall pooled POP prevalence rates were determined for each racial/ethnic group-White women: 10.76% (95% confidence interval [CI], 10.30%-11.22%); Hispanic women: 6.55% (95% CI, 5.83%-7.28%); Black women: 3.80% (95% CI, 3.22%-4.38%); and Asian American women: 3.40% (95% CI, 2.09%-4.71%). There was a significant difference in the pooled prevalence rates among these four racial/ethnic groups (p < 0.01).

Conclusions: Our study found that White women had the highest pooled POP prevalence rate overall, while Hispanic women had the highest pooled prevalence among minority women. Additionally, American Indians and Pacific Islanders were absent from the current prolapse epidemiologic literature.
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http://dx.doi.org/10.1002/nau.24672DOI Listing
April 2021

Screening strategy of TMPRSS2 inhibitors by FRET-based enzymatic activity for TMPRSS2-based cancer and COVID-19 treatment.

Am J Cancer Res 2021 1;11(3):827-836. Epub 2021 Mar 1.

Institute of New Drug Development, China Medical University Taichung, Taiwan.

Transmembrane serine protease (TMPRSS2) plays an oncogenic role in prostate cancer as the fusion gene with ERG, and has also been demonstrated to be essential for the cellular entry of severe acute respiratory syndrome coronaviruses (SARS-CoV). Thus, targeting TMPRSS2 is a promising strategy for therapies against both prostate cancer and coronavirus infection. Although Nafamostat and Camostat have been identified as TMPRSS2 inhibitors, severe side effects such as cerebral hemorrhage, anaphylactoid reaction, and cardiac arrest shock greatly hamper their clinical use. Therefore, more potent and safer drugs against this serine protease should be further developed. In this study, we developed a fluorescence resonance energy transfer (FRET)-based platform for effectively screening of inhibitors against TMPRSS2 protease activity. The disruption of FRET between green and red fluorescent proteins conjugated with the substrate peptide, which corresponds to the cleavage site of SARS-CoV-2 Spike protein, was measured to determine the enzymatic activity of TMPRSS2. Through an initiate pilot screening with around 100 compounds, Flupirtine, a selective neuronal potassium channel opener, was identified as a potential TMPRSS2 inhibitor from an FDA-approved drug library by using this screening platform, and showed inhibitory effect on the TMPRSS-dependent infection of SARS-CoV-2 Spike-pseudotyped lentiviral particles. This study describes a platform proven effective for rapidly screening of TMPRSS2 inhibitors, and suggests that Flupirtine may be worthy of further consideration of repurposing to treat COVID-19 patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994159PMC
March 2021

Technology acceptance and critical mass: Development of a consolidated model to explain the actual use of mobile health care communication tools.

J Biomed Inform 2021 Mar 23;117:103749. Epub 2021 Mar 23.

Department of Medicine (Hospital Medicine), Northwestern University Feinberg School of Medicine, USA.

Objective: Secure mobile communication technologies are being implemented at an increasing rate across health care organizations, though providers' use of these tools can remain limited by a perceived lack of other users to communicate with. Enabling acceptance and driving provider utilization of these tools throughout an organization requires attention to the interplay between perceived peer usage (i.e. perceived critical mass) and local user needs within the social context of the care team (e.g. inpatient nursing access to the mobile app). To explain these influences, we developed and tested a consolidated model that shows how mobile health care communication technology acceptance and utilization are influenced by the moderating effects of social context on perceptions about the technology.

Methods: The theoretical model and questionnaire were derived from selected technology acceptance models and frameworks. Survey respondents (n = 1254) completed items measuring perceived critical mass, perceived usefulness, perceived ease of use, personal innovativeness in information technology, behavioral intent, and actual use of a recently implemented secure mobile communication tool. Actual use was additionally measured by logged usage data. Use group was defined as whether a hospital's nurses had access to the tool (expanded use group) or not (limited use group).

Results: The model accounted for 61% and 72% of the variance in intent to use the communication tool in the limited and expanded use groups, respectively, which in turn accounted for 53% and 33% of actual use. The total effects coefficient of perceived critical mass on behavioral intent was 0.57 in the limited use group (95% CI 0.51-0.63) and 0.70 in the expanded use group (95% CI 0.61-0.80).

Conclusion: Our model fit the data well and explained the majority of variance in acceptance of the tool amongst participants. The overall influence of perceived critical mass on intent to use the tool was similarly large in both groups. However, the strength of multiple model pathways varied unexpectedly by use group, suggesting that combining sociotechnical moderators with traditional technology acceptance models may produce greater insights than traditional technology acceptance models alone. Practically, our results suggest that healthcare institutions can drive acceptance by promoting the recruitment of early adopters though liberal access policies and making these users and the technology highly visible to others.
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http://dx.doi.org/10.1016/j.jbi.2021.103749DOI Listing
March 2021

Evaluating performance of covariate-constrained randomization (CCR) techniques under misspecification of cluster-level variables in cluster-randomized trials.

Contemp Clin Trials Commun 2021 Jun 16;22:100754. Epub 2021 Feb 16.

Department of Preventive Medicine, Division of Biostatistics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Covariate constrained randomization (CCR) is a method of controlling imbalance in important baseline covariates in cluster-randomized trials (CRT). We use simulated CRTs to investigate the performance (control of imbalance) of CCR relative to simple randomization (SR) under conditions of misspecification of the cluster-level variable used in the CCR algorithm. We use data from a Patient-Centered Outcomes Research Institute (PCORI)-funded CRT evaluating the Mothers and Babies (MB) intervention (AD-1507-31,473). CCR methodology was used in the MB study to control imbalance in, among other baseline variables, the percent minority (i.e., non-White) participants at each study site. Simulation schemes explored variation in degree of misspecification in the baseline covariate of interest, and include correct report, observed misspecification, and a range of simulated misspecification for intervals within and beyond that observed in the MB study. We also consider three within-site sample size scenarios: that observed in the MB study, small (mean 10) and large (mean 50). Simulations at every level of baseline covariate misspecification suggest that use of the CCR strategy provides between-arm imbalance that is simultaneously lower and less variable, on average, than that produced from the SR strategy. We find that the gains to using CCR over SR are nearly twice as high with accurate reporting (Δ = -5.33) compared to the observed study-level misspecification (Δ = -3.03). Although CCR still outperforms SR as the level of misspecification increases, the gains to using CCR over SR decrease; thus, every effort should still be made to obtain high-quality baseline data.
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http://dx.doi.org/10.1016/j.conctc.2021.100754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941091PMC
June 2021

Comparing the effectiveness of home visiting paraprofessionals and mental health professionals delivering a postpartum depression preventive intervention: a cluster-randomized non-inferiority clinical trial.

Arch Womens Ment Health 2021 Mar 3. Epub 2021 Mar 3.

Department of Preventive Medicine, Division of Biostatistics, Northwestern Feinberg School of Medicine, Chicago, IL, 60611, USA.

To determine whether pregnant women receiving the Mothers and Babies group-based intervention exhibited greater depressive symptom reductions and fewer new cases of major depression than women receiving usual community-based services, and to examine whether groups run by paraprofessional home visitors and mental health professionals yielded similar depressive symptom reductions and prevention of major depression. Using a cluster-randomized design, 37 home visiting programs were randomized to usual home visiting, Mothers and Babies delivered via home visiting paraprofessionals, or Mothers and Babies delivered via mental health professionals. Baseline assessments were conducted prenatally with follow-up extending to 24 weeks postpartum. Eligibility criteria were ≥ 16 years old, ≤ 33 gestation upon referral, and Spanish/English speaking. Depressive symptoms at 24 weeks postpartum was the primary outcome. Eight hundred seventy-four women were enrolled. Neither intervention arm was superior to usual care in decreasing depressive symptoms across the sample (p = 0.401 home visiting paraprofessional vs. control; p = 0.430 mental health professional vs. control). Post hoc analyses suggest a positive intervention effect for women exhibiting mild depressive symptoms at baseline. We have evidence of non-inferiority, as the model-estimated mean difference in depressive symptoms between intervention arms (0.01 points, 95% CI: -0.79, 0.78) did not surpass our pre-specified margin of non-inferiority of two points. Although we did not find statistically significant differences between intervention and control arms, non-inferiority analyses found paraprofessional home visitors generated similar reductions in depressive symptoms as mental health professionals. Additionally, Mothers and Babies appears to reduce depressive symptoms among women with mild depressive symptoms when delivered by mental health professionals. This trial is registered on ClinicalTrials.gov (initial post: December 1, 2016; identifier: NCT02979444).
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http://dx.doi.org/10.1007/s00737-021-01112-9DOI Listing
March 2021

Laparoscopic Major Vascular Injuries in Gynecologic Surgery for Benign Indications: A Systematic Review.

Obstet Gynecol 2021 Mar;137(3):434-442

Department of Obstetrics and Gynecology and the Division of Biostatistics, Department of Preventive Medicine, Northwestern Feinberg School of Medicine, Chicago, Illinois; and the Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Objective: To identify the incidence, location, etiology, and mortality of major vascular injuries in gynecologic laparoscopy for benign indications.

Data Sources: A systematic review of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and MEDLINE was conducted.

Methods Of Study Selection: One thousand ninety-seven studies were screened for inclusion with 147 full-text articles reviewed. Sixty-six studies published between 1978 and 2016 met inclusion criteria, representing 197,062 surgeries. Articles that were included reported the incidence of major vascular injuries during gynecologic laparoscopy for benign indications. Exclusion criteria included surgery for gynecologic malignancy, duplicated data, case series and reports, manuscripts not in English, and studies published only as abstracts.

Tabulation, Integration, And Results: Injuries to the aorta, inferior vena cava, iliac (common, external, or internal), and inferior epigastric vessels were recorded, as were injuries denoted as major but not otherwise specified. A total of 179 major vascular injuries were reported with an incidence of 0.09% (95% CI 0.08-0.10). The inferior epigastric vessels were the most commonly injured vessel (0.04%, 95% CI 0.03-0.05), comprising 48% (95% CI 40-55) of all injuries. The majority of injuries occurred during abdominal entry (82%, 95% CI 76-89), and the remainder occurred during surgical dissection (18%, 95% CI 11-24). Most injuries were recognized intraoperatively (93%, 95% CI 87-100), and approximately half (55%, 95% CI 46-63) required laparotomy for repair. Only two of the 179 major vascular injuries resulted in death, for an overall mortality rate from vascular injuries of 0.001% (95% CI 0.000-0.004).

Conclusion: The incidence of major vascular injury during gynecologic laparoscopy found in this review is very low, and the vast majority of injuries did not result in death. Laparoscopy remains a safe surgical technique in relation to vascular injuries when performed for benign gynecologic disease.
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http://dx.doi.org/10.1097/AOG.0000000000004280DOI Listing
March 2021

Development of Novel Rhodacyanine-Based Heat Shock Protein 70 Inhibitors.

Curr Med Chem 2021 Feb 3. Epub 2021 Feb 3.

Department of Cosmeceutics and Graduate Institute of Cosmeceutics, China Medical University, Taichung 40402. Taiwan.

Background: A growing body of evidence suggests that Hsp70, which is overexpressed in human breast tumors, plays a role in tumorigenesis and tumor progression in breast cancer as well as in its aggressive phenotypes. Hsp70 constitutes a potential therapeutic target in the treatment of this disease.

Method: We developed a new series of rhodacyanine-based Hsp70 inhibitors, represented by compounds 1 and 6, in which the cationic pyridin-1-ium or thiazol-3-ium ring of existing Hsp70 inhibitors (e.g., JG-40 and JG-98) was replaced by a corresponding benzo-fused N-heterocycle.

Results: Several lines of evidence suggest that these benzo-fused derivatives may exert their antitumor activities, in part, by targeting Hsp70. These putative inhibitors displayed differential antiproliferative efficacy against breast cancer cells (IC50 as low as 0.25 µM) versus nontumorigenic MCF-10A breast epithelial cells (IC50 ≥ 5 µM). This was correlated with the corresponding Hsp70 expression levels. Using a protein refolding assay, we confirmed that these agents effectively inhibited the chaperone activity of Hsp70. Moreover, these inhibitors effectively suppressed the expression of well-known oncogenic client proteins of Hsp70's, including FoxM1, HuR, and Akt, which paralleled their antiproliferative efficacy. Supporting the established role of Hsp70 in regulating protein refolding, these derivatives induced autophagy, as manifested by the conversion of LC3B-I to LC3B-II. Notably, these putative Hsp70 inhibitors did not cause a compensatory elevation in Hsp90 expression, contrasting with the previously reported effects of Hsp90 inhibitors on Hsp70 upregulation.

Conclusion: Together with the finding that compounds 1 and 6 showed improved microsomal stability, these results suggest the translational potential of these putative Hsp70 inhibitors to foster new strategies for cancer therapy. However, whether these benzo-fused rhodacyanines act on kinases or other targets remains unclear, which is currently under investigation.
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http://dx.doi.org/10.2174/0929867328666210203204254DOI Listing
February 2021

Tannic acid suppresses SARS-CoV-2 as a dual inhibitor of the viral main protease and the cellular TMPRSS2 protease.

Am J Cancer Res 2020 1;10(12):4538-4546. Epub 2020 Dec 1.

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University Taichung 40402, Taiwan.

The cell surface protein TMPRSS2 (transmembrane protease serine 2) is an androgen-responsive serine protease important for prostate cancer progression and therefore an attractive therapeutic target. Besides its role in tumor biology, TMPRSS2 is also a key player in cellular entry by the SARS-CoV viruses. The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has resulted in huge losses in socio-economy, culture, and human lives for which safe and effective cures are highly demanded. The main protease (M/3CL) of SARS-CoV-2 is a critical enzyme for viral propagation in host cells and, like TMPRSS2, has been exploited for treatment of the infectious disease. Numerous natural compounds abundant in common fruits have been suggested with anti-coronavirus infection in the previous outbreaks of SARS-CoV. Here we show that screening of these compounds identified tannic acid a potent inhibitor of both SARS-CoV-2 M and TMPRSS2. Molecular analysis demonstrated that tannic acid formed a thermodynamically stable complex with the two proteins at a K of 1.1 mM for M and 1.77 mM for TMPRSS2. Tannic acid inhibited the activities of the two proteases with an IC of 13.4 mM for M and 2.31 mM for TMPRSS2. M protein. Consistently, functional assays using the virus particles pseudotyped (Vpp) of SARS-CoV2-S demonstrated that tannic acid suppressed viral entry into cells. Thus, our results demonstrate that tannic acid has high potential of developing anti-COVID-19 therapeutics as a potent dual inhibitor of two independent enzymes essential for SARS-CoV-2 infection.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783773PMC
December 2020

Crystal structure of the N-terminal domain of TagH reveals a potential drug targeting site.

Biochem Biophys Res Commun 2021 01 22;536:1-6. Epub 2020 Dec 22.

Institute of New Drug Development, China Medical University, Taichung, 406, Taiwan; Drug Development Center, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, 40402, Taiwan. Electronic address:

Bacterial wall teichoic acids (WTAs) are synthesized intracellularly and exported by a two-component transporter, TagGH, comprising the transmembrane and ATPase subunits TagG and TagH. Here the dimeric structure of the N-terminal domain of TagH (TagH-N) was solved by single-wavelength anomalous diffraction using a selenomethionine-containing crystal, which shows an ATP-binding cassette (ABC) architecture with RecA-like and helical subdomains. Besides significant structural differences from other ABC transporters, a prominent patch of positively charged surface is seen in the center of the TagH-N dimer, suggesting a potential binding site for the glycerol phosphate chain of WTA. The ATPase activity of TagH-N was inhibited by clodronate, a bisphosphonate, in a non-competitive manner, consistent with the proposed WTA-binding site for drug targeting.
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http://dx.doi.org/10.1016/j.bbrc.2020.12.028DOI Listing
January 2021

Cigarette smoke-induced LKB1/AMPK pathway deficiency reduces EGFR TKI sensitivity in NSCLC.

Oncogene 2021 Feb 17;40(6):1162-1175. Epub 2020 Dec 17.

Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan.

Smoker patients with non-small cell lung cancer (NSCLC) have poorer prognosis and survival than those without smoking history. However, the mechanisms underlying the low response rate of those patients to EGFR tyrosine kinase inhibitors (TKIs) are not well understood. Here we report that exposure to cigarette smoke extract enhances glycolysis and attenuates AMP-activated protein kinase (AMPK)-dependent inhibition of mTOR; this in turn reduces the sensitivity of NSCLC cells with wild-type EGFR (EGFR) to EGFR TKI by repressing expression of liver kinase B1 (LKB1), a master kinase of the AMPK subfamily, via CpG island methylation. In addition, LKB1 expression is correlated positively with sensitivity to TKI in patients with NSCLC. Moreover, combined treatment of EGFR TKI with AMPK activators synergistically increases EGFR TKI sensitivity. Collectively, the current study suggests that LKB1 may serve as a marker to predict EGFR TKI sensitivity in smokers with NSCLC carrying EGFR and that the combination of EGFR TKI and AMPK activator may be a potentially effective therapeutic strategy against NSCLC with EGFR.
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http://dx.doi.org/10.1038/s41388-020-01597-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878190PMC
February 2021

Efficacy of type 2-targeted biologics in patients with asthma and bronchiectasis.

Ann Allergy Asthma Immunol 2021 03 1;126(3):302-304. Epub 2020 Dec 1.

Division of Allergy and Immunology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2020.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028023PMC
March 2021

Elucidating nanoscale mechanical properties of diabetic human adipose tissue using atomic force microscopy.

Sci Rep 2020 11 24;10(1):20423. Epub 2020 Nov 24.

Department of Surgery, Section of General Surgery, University of Michigan Medical School, 2210 Taubman Center-5343, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-5343, USA.

Obesity-related type 2 diabetes (DM) is a major public health concern. Adipose tissue metabolic dysfunction, including fibrosis, plays a central role in DM pathogenesis. Obesity is associated with changes in adipose tissue extracellular matrix (ECM), but the impact of these changes on adipose tissue mechanics and their role in metabolic disease is poorly defined. This study utilized atomic force microscopy (AFM) to quantify difference in elasticity between human DM and non-diabetic (NDM) visceral adipose tissue. The mean elastic modulus of DM adipose tissue was twice that of NDM adipose tissue (11.50 kPa vs. 4.48 kPa) to a 95% confidence level, with significant variability in elasticity of DM compared to NDM adipose tissue. Histologic and chemical measures of fibrosis revealed increased hydroxyproline content in DM adipose tissue, but no difference in Sirius Red staining between DM and NDM tissues. These findings support the hypothesis that fibrosis, evidenced by increased elastic modulus, is enhanced in DM adipose tissue, and suggest that measures of tissue mechanics may better resolve disease-specific differences in adipose tissue fibrosis compared with histologic measures. These data demonstrate the power of AFM nanoindentation to probe tissue mechanics, and delineate the impact of metabolic disease on the mechanical properties of adipose tissue.
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http://dx.doi.org/10.1038/s41598-020-77498-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686328PMC
November 2020

Hepatic Steatosis: An incidental finding that deserves attention.

Acad Emerg Med 2020 Nov 18. Epub 2020 Nov 18.

Department of Emergency Medicine, UT Southwestern Medical Center, Dallas, TX, USA.

Nonalcoholic fatty liver disease (NAFLD) is a public health crisis and the most common chronic liver disease in the US with a current prevalence of 25% in US adults and rising. NAFLD results from the accumulation of fat within hepatocytes in patients without a history of heavy alcohol use or other causes (e.g., medication, hepatitis C). NAFLD is a spectrum of disease ranging from simple steatosis (NAFL) to steatohepatitis (NASH), fibrosis, and cirrhosis. NAFLD is associated with risk for hepatocellular carcinoma, need for liver transplantation, type 2 diabetes, chronic kidney disease, and cardiovascular disease. Risk for these complications increases with the degree of fibrosis. Identifying advanced fibrosis previously required expensive and invasive liver biopsy, but recently several biomarkers and scoring systems can reliably establish risk for advanced fibrosis. The fibrosis-4 (FIB-4) index is a well-validated tool that uses common clinical information (patient age, ALT, AST, and platelet count) to estimate risk of advanced fibrosis (low, indeterminate, and high) in patients with hepatic steatosis..
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http://dx.doi.org/10.1111/acem.14174DOI Listing
November 2020

Get PrEPPT (pre-exposure prophylaxis and pregnancy termination): an exploration of the values, attitudes and preferences regarding HIV and PrEP among women seeking abortion.

BMJ Sex Reprod Health 2020 Oct 29. Epub 2020 Oct 29.

Obstetrics and Gynecology, Section of Family Planning, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Introduction: Pre-exposure prophylaxis (PrEP) for the prevention of HIV transmission is under utilised by women in the US. Women seeking abortion have a higher HIV prevalence than women who continue prenatal care and could benefit from HIV risk assessment and PrEP counselling. We assessed the knowledge, attitudes, and preferences of women seeking abortion care regarding their HIV risk and knowledge of PrEP, and identified individual and system barriers to PrEP access.

Methods: We performed a cross sectional descriptive study of English speaking women at a freestanding abortion clinic through an anonymous survey. Participants with indications for PrEP care included those who performed sex work, experienced a recent sexually transmitted infection, or had multiple sexual partners and inconsistent condom use. We performed descriptive statistics on response data; Wilcoxon tests were used to compare continuous variables across groups.

Results: 64 (32.3%) participants had indications for PrEP, but only 31 (16.1%) had previous knowledge of PrEP. After the concept was explained, attitudes towards PrEP were generally positive, and 54 participants (27.8%) would consider starting PrEP in the next 6 months. Participants were most interested in receiving PrEP care from their primary care provider rather than from an abortion clinic.

Conclusions: Among women seeking abortion, women vulnerable to HIV infection outnumbered those with PrEP knowledge by 2 to 1. Prior knowledge of PrEP as an HIV prevention method was low, but women found PrEP acceptable. While women reported preferring to receive PrEP from a primary care provider, the abortion clinic visit may also represent an important time for HIV education and risk screening.
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http://dx.doi.org/10.1136/bmjsrh-2020-200623DOI Listing
October 2020

Sleep Duration during Pregnancy using an Activity Tracking Device.

AJP Rep 2020 Jul 23;10(3):e309-e314. Epub 2020 Sep 23.

Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

 The aim of this study was to describe sleep duration across gestation in women who wore an activity-tracking device (ATD) during pregnancy, and to study the association between sleep duration and adverse maternal and neonatal outcomes  Women ≥ 18 years old who owned a smartphone were approached to participate in 2016 to 2017. Participants received instructions to wear and sync an ATD daily. Steps, sedentary hours, and sleep duration were wirelessly transmitted via cellular technology. We measured sleep duration for the main episode of sleep and excluded sleep times < 120 minutes. Mixed models were used to assess the trajectory of mean weekly hours of sleep by gestational age. Secondary analyses evaluated differences in pregnancy outcomes between insufficient (< 7/24 hours) and sufficient sleep (≥ 7/24 hours) groups, based on mean hours of sleep within the first 7 days of ATD use.  The majority of 94 participants self-reported minority racial-ethnic status (33% non-Hispanic black and 51% Hispanic), had government insurance (83%), were nulliparous (61%), and had pre-pregnancy overweight or obesity (56%). The mean (standard deviation) duration of sleep was 7.2 ± 2.4 hours per 24 hours. In mixed models analyses, gestational age was statistically significantly associated with mean hours of sleep ( = -0.02; 95% confidence interval: -0.04 to -0.01;  < 0.001). Women who had < 7 hours of sleep had greater median daily steps compared with those who had ≥ 7 hours of sleep (median: 7,122; interquartile range [IQR]: 5,167-8,338 vs. median: 5,005; IQR: 4,115-7,059;  < 0.01), but there were no significant differences in other outcomes (sedentary time, gestational weight gain, pregnancy associated hypertension, gestational diabetes, gestational age at delivery, cesarean delivery, or mean birthweight),   > 0.05 for all comparisons.  The mean sleep duration was 7.2 ± 2.4 hours among the 94 women in this cohort and decreased with advancing gestational age. Further research is required to evaluate sleep measurements with ATD in pregnant women and how sleep duration and quality is related to maternal and neonatal outcomes.
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http://dx.doi.org/10.1055/s-0040-1715172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571555PMC
July 2020

Can embryo morphokinetic parameters predict euploid pregnancy loss?

Fertil Steril 2021 Feb 12;115(2):382-388. Epub 2020 Oct 12.

Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois. Electronic address:

Objective: To use time-lapse imaging to compare embryo morphokinetic parameters between embryos resulting in euploid pregnancy loss and euploid embryos resulting in live birth.

Design: Retrospective cohort study.

Setting: Single academic fertility center.

Patient(s): All euploid single embryo transfers between October 2015 and January 2018.

Intervention(s): Collection and analysis of baseline characteristics, cycle parameters, and outcomes.

Main Outcome Measure(s): Embryo morphokinetic measurements assessed with time-lapse imaging for time to syngamy (TPNf), time to two cells, time to three cells, time to four cells, time to eight cells, time to morula, and time to blastocyst.

Result(s): The study included 192 euploid single-embryo transfers. Of these, the pregnancy rate was 78% (150 of 193) and the live-birth rate was 63% (121 of 193). There were 43 transfers that did not result in pregnancy, 15 biochemical pregnancy losses, 13 clinical losses, and 121 live births. There was no statistically significant difference in age, body mass index, or number of oocytes retrieved between the groups. Unadjusted and adjusted models revealed no differences in the morphokinetics of embryos resulting in euploid miscarriage compared with those resulting in live birth.

Conclusion(s): Embryos that resulted in a euploid miscarriage did not display evidence of abnormal morphokinetics on time-lapse imaging. Euploid pregnancy loss is likely multifactorial, including both embryo and endometrial factors. Further research is needed to identify factors that can predict and prevent euploid loss.
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http://dx.doi.org/10.1016/j.fertnstert.2020.08.021DOI Listing
February 2021

Author Correction: PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis.

Nat Cell Biol 2020 Nov;22(11):1396

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41556-020-00599-1DOI Listing
November 2020

Ribonuclease 7-driven activation of ROS1 is a potential therapeutic target in hepatocellular carcinoma.

J Hepatol 2021 Apr 5;74(4):907-918. Epub 2020 Oct 5.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan. Electronic address:

Background & Aims: There are currently limited therapeutic options for hepatocellular carcinoma (HCC), particularly when it is diagnosed at advanced stages. Herein, we examined the pathophysiological role of ROS1 and assessed the utility of ROS1-targeted therapy for the treatment of HCC.

Methods: Recombinant ribonucleases (RNases) were purified, and the ligand-receptor relationship between RNase7 and ROS1 was validated in HCC cell lines by Duolink, immunofluorescence, and immunoprecipitation assays. Potential interacting residues between ROS1 and RNase7 were predicted using a protein-protein docking approach. The oncogenic function of RNase7 was analyzed by cell proliferation, migration and invasion assays, and a xenograft mouse model. The efficacy of anti-ROS1 inhibitor treatment was evaluated in patient-derived xenograft (PDX) and orthotopic models. Two independent patient cohorts were analyzed to evaluate the pathological relevance of RNase7/ROS1.

Results: RNase7 associated with ROS1's N3-P2 domain and promoted ROS1-mediated oncogenic transformation. Patients with HCC exhibited elevated plasma RNase7 levels compared with healthy individuals. High ROS1 and RNase7 expression were strongly associated with poor prognosis in patients with HCC. In both HCC PDX and orthotopic mouse models, ROS1 inhibitor treatment markedly suppressed RNase7-induced tumorigenesis, leading to decreased plasma RNase7 levels and tumor shrinkage in mice.

Conclusions: RNase7 serves as a high-affinity ligand for ROS1. Plasma RNase7 could be used as a biomarker to identify patients with HCC who may benefit from anti-ROS1 treatment.

Lay Summary: Receptor tyrosine kinases are known to be involved in tumorigenesis and have been targeted therapeutically for a number of cancers, including hepatocellular carcinoma. ROS1 is the only such receptor with kinase activity whose ligand has not been identified. Herein, we show that RNase7 acts as a ligand to activate ROS1 signaling. This has important pathophysiological and therapeutic implications. Anti-ROS1 inhibitors could be used to treatment patients with hepatocellular carcinoma and high RNase7 levels.
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http://dx.doi.org/10.1016/j.jhep.2020.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979498PMC
April 2021

Involvement of the Estrogen and Progesterone Axis in Cancer Stemness: Elucidating Molecular Mechanisms and Clinical Significance.

Front Oncol 2020 4;10:1657. Epub 2020 Sep 4.

Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.

Estrogen and progesterone regulate the growth and development of human tissues, including the reproductive system and breasts, through estrogen and progesterone receptors, respectively. These receptors are also important indicators for the clinical prognosis of breast cancer and various reproductive cancers. Many studies have reported that cancer stem cells (CSCs) play a key role in tumor initiation, progression, metastasis, and recurrence. Although the role of estrogen and progesterone in human organs and various cancers has been studied, the molecular mechanisms underlying the action of these hormones on CSCs remain unclear. Therefore, further elucidation of the effects of estrogen and progesterone on CSCs should provide a new direction for developing pertinent therapies. In this review, we summarize the current knowledge on the estrogen and progesterone axis involved in cancer stemness and discuss potential therapeutic strategies to inhibit CSCs by targeting relevant pathways.
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http://dx.doi.org/10.3389/fonc.2020.01657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498570PMC
September 2020

PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis.

Nat Cell Biol 2020 10 14;22(10):1264-1275. Epub 2020 Sep 14.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Although pyroptosis is critical for macrophages against pathogen infection, its role and mechanism in cancer cells remains unclear. PD-L1 has been detected in the nucleus, with unknown function. Here we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumour necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing the transcription of the gasdermin C (GSDMC) gene. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on the cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8 and GSDMC are required for macrophage-derived TNFα-induced tumour necrosis in vivo. Moreover, high expression of GSDMC correlates with poor survival. Antibiotic chemotherapy drugs induce pyroptosis in breast cancer. These findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/caspase-8 mediates a non-canonical pyroptosis pathway in cancer cells, causing tumour necrosis.
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http://dx.doi.org/10.1038/s41556-020-0575-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653546PMC
October 2020

Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anti-coronaviral drug.

Am J Cancer Res 2020 1;10(8):2535-2545. Epub 2020 Aug 1.

Institute of New Drug Development, China Medical University Taichung 40402, Taiwan.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or 2019 novel coronavirus (2019-nCoV), took tens of thousands of lives and caused tremendous economic losses. The main protease (M) of SARS-CoV-2 is a potential target for treatment of COVID-19 due to its critical role in maturation of viral proteins and subsequent viral replication. Conceptually and technically, targeting therapy against M is similar to target therapy to treat cancer. Previous studies show that GC376, a broad-spectrum dipeptidyl M inhibitor, efficiently blocks the proliferation of many animal and human coronaviruses including SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), porcine epidemic diarrhea virus (PEDV), and feline infectious peritonitis virus (FIPV). Due to the conservation of structure and catalytic mechanism of coronavirus main protease, repurposition of GC376 against SARS-CoV-2 may be an effective way for the treatment of COVID-19 in humans. To validate this conjecture, the binding affinity and IC value of M with GC376 was determined by isothermal titration calorimetry (ITC) and fluorescence resonance energy transfer (FRET) assay, respectively. The results showed that GC376 binds to SARS-CoV-2 M tightly (K = 1.6 μM) and efficiently inhibit its proteolytic activity (IC = 0.89 μM). We also elucidate the high-resolution structure of dimeric SARS-CoV-2 M in complex with GC376. The cocrystal structure showed that GC376 and the catalytic Cys145 of M covalently linked through forming a hemithioacetal group and releasing a sulfonic acid group. Because GC376 is already known as a broad-spectrum antiviral medication and successfully used in animal, it will be a suitable candidate for anti-COVID-19 treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471349PMC
August 2020

Embryo transfer training in fellowship: national and institutional data.

Fertil Steril 2020 Nov 2;114(5):1006-1013. Epub 2020 Sep 2.

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illiinois.

Objective: To evaluate current national practices in embryo transfer (ET) training in United States reproductive endocrinology and infertility (REI) fellowship programs and live birth rates after ET performed by fellows versus attending physicians.

Design: Cross-sectional survey of U.S. fellowship program directors and fellows in 2019 and retrospective cohort study of IVF cycle outcomes after ET performed by fellows versus attending physicians.

Setting: Not applicable.

Patient(s): Fellowship program directors and fellows completed a survey. Embryo transfers from 2015-2018 were analyzed.

Intervention(s): A survey assessed experiences with ET training. Cycle outcomes were analyzed.

Main Outcome Measure(s): Proportion of fellows performing ET during training, and live birth rate following fellow and faculty ETs.

Result(s): Anonymous surveys were sent to 51 REI fellowship program directors and 142 fellows. Twenty-one percent (15/73) reported that no ETs were performed by fellows. Forty-four percent of third-year fellows had performed fewer than ten ETs during fellowship training. Retrospective review of 940 blastocyst ETs revealed no difference in live birth rates between fellows and attending physicians: 51.6% (131/254) versus 49.4% (339/686), respectively.

Conclusion(s): This study revealed striking differences between fellowship programs regarding the adequacy of ET training; nearly one-half of third-year fellows had performed fewer than ten ETs. With appropriate supervision, there is no difference in live birth rate between ETs performed by fellows and attending physicians. Efforts should be made to address barriers and set minimums for the number of transfers performed during fellowship.
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http://dx.doi.org/10.1016/j.fertnstert.2020.06.004DOI Listing
November 2020

Influence of Age of Onset on Huntington's Disease Phenotype.

Tremor Other Hyperkinet Mov (N Y) 2020 07 9;10:21. Epub 2020 Jul 9.

Northwestern University Feinberg School of Medicine, Department of Neurology, US.

Background: Older patients with Huntington's disease (HD) are often thought to have a slower progressing disease course with less behavioral symptoms than younger patients. However, phenotypic differences based on age of onset have not been well characterized in a large HD population. This study will determine the difference in manifestations and disease progression between patients with young, typical, and late onset adult HD at different stages of disease.

Methods: Data obtained from Enroll-HD. Adults with manifest HD were included. Age groups were defined as young onset (YO: 20-29 years), typical onset (TO: 30-59 years), and late onset (LO: 60+ years). Subjects were categorized by TFC score, from Stage I (least severe) to Stage V (most severe). Motor, cognitive, and behavioral symptoms were analyzed. Descriptive statistics and Bonferroni p-value correction for pairwise comparison were calculated.

Results: 7,311 manifest HD participants were included (612 YO, 5,776 TO, and 923 LO). The average decline in TFC score from baseline to second visit (1.5-2.5 years) was significantly faster for YO (-1.75 points) compared to TO (-1.23 points, p = 0.0105) or LO (-0.97 points, p = 0.0017). Motor deficits were worse for LO participants at early stages of HD, and worse for YO participants at advanced stages. YO and TO participants had greater burden of behavioral symptoms at early stages of disease compared to LO.

Discussion: YO is predictive of a faster functional decline for adults with HD when compared to those with TO and LO. Motor and behavioral manifestations differ based on age of onset.

Highlights: This study compares HD manifestations while controlling for disease severity, detailing robust phenotypic differences by age of onset alone. These findings have implications for the clinical management of HD symptoms and have the possibility to improve prognostic and treatment precision.
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http://dx.doi.org/10.5334/tohm.536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394225PMC
July 2020

Understanding HD Psychosis: An Analysis from the ENROLL-HD Database.

Tremor Other Hyperkinet Mov (N Y) 2020 07 7;10:16. Epub 2020 Jul 7.

Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, US.

Background: Psychosis is considered rare in Huntington's Disease, with an estimated prevalence of 3-11%. However, it has a profound impact on quality of life and disease burden. This study uses the Enroll-HD database to determine the prevalence, onset, and severity of psychosis in Huntington's Disease and to determine demographic and disease characteristics associated with psychosis.

Methods: Data were obtained from Enroll-HD. Adults with manifest Huntington's Disease were included. Descriptive statistics were calculated. Simple logistic regression was used to calculate the odds ratio with 95% confidence interval for association with each characteristic.

Results: 7,966 manifest Huntington's Disease participants were analyzed, and 12.95% had a history of psychosis. Mean age of psychosis onset (48.34 years, SD 13.26) mirrored Huntington's Disease onset. Family history of psychosis in a first degree relative was documented in 23.6% of participants with psychosis. Variables significantly (p < 0.05) associated with presence of psychosis in manifest HD included lower education level, unemployment, single marital status, depression, decreased verbal fluency score, and decreased total functional capacity & functional assessment score.

Discussion: Psychosis in Huntington's Disease is more prevalent than many prior studies have reported. It is associated with several demographic & psychiatric features, decreased cognitive capacity, and worse functional outcomes.

Highlights: Psychosis in HD is more prevalent than prior studies have reported. It is associated with a range of demographic and psychiatric variables, worse cognition, and worse functional outcomes suggesting several features that may be used to predict onset of psychosis and improve understanding and management of psychosis in HD.
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http://dx.doi.org/10.5334/tohm.395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394199PMC
July 2020

MLL3 Induced by Luteolin Causes Apoptosis in Tamoxifen-Resistant Breast Cancer Cells through H3K4 Monomethylation and Suppression of the PI3K/AKT/mTOR Pathway.

Am J Chin Med 2020 ;48(5):1221-1241

Department of Cell and Tissue Engineering, Changhua 500, Taiwan, R.O.C.

Tamoxifen is one of the most common hormone therapy drug for estrogen receptor (ER)-positive breast cancer. Tumor cells with drug resistance often cause recurrence and metastasis in cancer patients. Luteolin is a natural compound found from various types of vegetables and exhibit anticancer activity in different cancers. This study demonstrated that luteolin inhibits the proliferation and induces apoptosis of tamoxifen-resistant ER-positive breast cancer cells. Luteolin also causes cell cycle arrest at the G2/M phase and decreases mitochondrial membrane potential. Besides, luteolin reduces the levels of activated PI3K/AKT/mTOR signaling pathway. The combination treatment of luteolin and PI3K, AKT, or mTOR inhibitors synergistically increases apoptosis in tamoxifen-resistant ER-positive breast cancer cells. Ras gene family (K-Ras, H-Ras, and N-Ras), an activator of PI3K, was transcriptionally repressed by luteolin via induction of tumor suppressor mixed-lineage leukemia 3 (MLL3) expression. MLL3 increases the level of monomethylation of Histone 3 Lysine 4 on the enhancer and promoter region of Ras genes, thus causes repression of Ras expressions. Our finding implies that luteolin was a promising natural agent against tamoxifen resistance of breast cancer.
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http://dx.doi.org/10.1142/S0192415X20500603DOI Listing
October 2020

Is BMI Higher in Younger Patients with COVID-19? Association Between BMI and COVID-19 Hospitalization by Age.

Obesity (Silver Spring) 2020 10 25;28(10):1811-1814. Epub 2020 Aug 25.

Department of Medicine, Division of Infectious Diseases, Northwestern Memorial Hospital, Feinberg School of Medicine, Chicago, Illinois, USA.

Objective: Obesity has been found to be a risk factor for hospitalization with coronavirus disease (COVID-19). This study investigated whether patients hospitalized with COVID-19 differed in BMI at older versus younger ages and whether trends were independent of diabetes and hypertension.

Methods: A cross-sectional analysis of patients hospitalized with moderate to severe COVID-19 at Northwestern Memorial Hospital from March 19, 2020, until April 4, 2020, was performed. Patients hospitalized with COVID-19 above and below the age of 50 were compared as well as those hospitalized without COVID-19.

Results: Patients younger than 50 years of age hospitalized with COVID-19 without diabetes or hypertension had mean BMI greater than those older than 50 years of age, with BMI 43.1 (95% CI: 34.5-51.7) versus 30.1 (95% CI: 27.7-32.5) (P = 0.02). Furthermore, BMI appeared to inversely correlate with increasing age among patients hospitalized with COVID-19. We did not detect the same difference or trend for patients hospitalized without COVID-19.

Conclusions: Younger patients (age < 50 years) with COVID-19 had higher mean BMI than older patients with COVID-19, with and without diabetes and hypertension. This trend did not exist in patients without COVID-19 hospitalized during the same time period.
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http://dx.doi.org/10.1002/oby.22947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361943PMC
October 2020

Effects of Changes to Hospitalist Admitter Staffing on Hospitalist Perception of Workload.

J Gen Intern Med 2020 Jun 24. Epub 2020 Jun 24.

Department of Medicine, Division of Hospital Medicine, Northwestern University Feinberg School of Medicine , Evanston, IL, 60208, USA.

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http://dx.doi.org/10.1007/s11606-020-05961-5DOI Listing
June 2020

Prevalence and characterization of asthma in hospitalized and nonhospitalized patients with COVID-19.

J Allergy Clin Immunol 2020 08 15;146(2):307-314.e4. Epub 2020 Jun 15.

Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill. Electronic address:

Background: The Centers for Disease Control and Prevention advises that patients with moderate to severe asthma belong to a high-risk group that is susceptible to severe coronavirus disease 2019 (COVID-19). However, the association between asthma and COVID-19 has not been well-established.

Objective: The primary objective was to determine the prevalence of asthma among patients with COVID-19 in a major US health system. We assessed the clinical characteristics and comorbidities in asthmatic and nonasthmatic patients with COVID-19. We also determined the risk of hospitalization associated with asthma and/or inhaled corticosteroid use.

Methods: Medical records of patients with COVID-19 were searched by a computer algorithm (March 1 to April 15, 2020), and chart review was used to validate the diagnosis of asthma and medications prescribed for asthma. All patients had PCR-confirmed COVID-19. Demographic and clinical features were characterized. Regression models were used to assess the associations between asthma and corticosteroid use and the risk of COVID-19-related hospitalization.

Results: Of 1526 patients identified with COVID-19, 220 (14%) were classified as having asthma. Asthma was not associated with an increased risk of hospitalization (relative risk, 0.96; 95% CI, 0.77-1.19) after adjusting for age, sex, and comorbidities. The ongoing use of inhaled corticosteroids did not increase the risk of hospitalization in a similar adjusted model (relative risk, 1.39; 95% CI, 0.90-2.15).

Conclusions: Despite a substantial prevalence of asthma in our COVID-19 cohort, asthma was not associated with an increased risk of hospitalization. Similarly, the use of inhaled corticosteroids with or without systemic corticosteroids was not associated with COVID-19-related hospitalization.
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http://dx.doi.org/10.1016/j.jaci.2020.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295471PMC
August 2020

Structural evolution of in situ boron-doped SiGe ultrathin film analyzed by multi-optical methods.

Nanotechnology 2020 Apr 27;31(27):275702. Epub 2020 Mar 27.

Department of Physics, National Cheng Kung University, Tainan 701, Taiwan.

In situ boron (B)-doped SiGe (BSG) layer is extensively used in the source (S)/(D) drain of metal-oxide-semiconductor field-effect transistors. An unexpected structural evolution occurs in BSG during metallization and activation annealing during actual fabrication, which involves a correlated interaction between B and SiGe. Herein, the complicated phenomena of the structural evolution of BSG were analyzed by 325 nm micro-Raman spectroscopy, x-ray photoelectron spectroscopy (XPS), reflective second harmonic generation (RSHG), and synchrotron x-ray diffraction (XRD). Optical inspection was integrated into these processes to establish a multi-optical method. 325 nm micro-Raman spectroscopy was used to determine variations in Si-Si, Si-Ge, and Ge-Ge bonds in BSG. XPS exhibited the binding energy evolution of Ge3d during different annealing processes at varied Ge ratios and B concentrations. RSHG revealed the polar Si-B and Ge-B bonds formed during annealing. Synchrotron XRD provided the structure and strain changes of BSG. Secondary-ion mass spectrometer profiles provided the species distribution, which was used to examine the results of multi-optical method. Furthermore, double-layered BSG (DBSG) with different B concentrations were analyzed using the multi-optical method. Results revealed that Ge aggregated in the homogeneous interface of DBSG, and that B dopants in BSG served as carrier providers that strongly influenced the BSG structure. However, BSG with excessive B concentration was unstable and increased the B content (SiB) through metallization. For BSG with a suitable B concentration, the formation of Si-B and Ge-B bonds suppressed the diffusion of Ge from SiGe, thereby reducing the possibility of Ge loss and further B pipe-up in the heavily doped S/D region.
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http://dx.doi.org/10.1088/1361-6528/ab8422DOI Listing
April 2020