An Electronic Health Record Model for Predicting Risk of Hepatic Fibrosis in Primary Care Patients.

BACKGROUND: One challenge for primary care providers caring for patients with nonalcoholic fatty liver disease is to identify those at the highest risk for clinically significant liver disease. AIM: To derive a risk stratification tool using variables from structured electronic health record (EHR) data for use in populations which are disproportionately affected with obesity and diabetes. METHODS: We used data from 344 participants who underwent Fibroscan examination to measure liver fat and liver stiffness measurement [LSM]. Using two approaches, multivariable logistic regression and random forest classification, we assessed risk factors for any hepatic fibrosis (LSM > 7 kPa) and significant hepatic fibrosis (> 8 kPa). Possible predictors included data from the EHR for age, gender, diabetes, hypertension, FIB-4, body mass index (BMI), LDL, HDL, and triglycerides. RESULTS: Of 344 patients (56.4% women), 34 had any hepatic fibrosis, and 15 significant hepatic fibrosis. Three variables (BMI, FIB-4, diabetes) were identified from both approaches. When we used variable cut-offs defined by Youden's index, the final model predicting any hepatic fibrosis had an AUC of 0.75 (95% CI 0.67-0.84), NPV of 91.5% and PPV of 40.0%. The final model with variable categories based on standard clinical thresholds (i.e., BMI ≥ 30 kg/m2; FIB-4 ≥ 1.45) had lower discriminatory ability (AUC 0.65), but higher PPV (50.0%) and similar NPV (91.3%). We observed similar findings for predicting significant hepatic fibrosis. CONCLUSIONS: Our results demonstrate that standard thresholds for clinical risk factors/biomarkers may need to be modified for greater discriminatory ability among populations with high prevalence of obesity and diabetes.

The Prevalence and Determinants of NAFLD and MAFLD and Their Severity in the VA Primary Care Setting.

BACKGROUND & AIMS: A recent panel of international experts proposed the disease acronym metabolic (dysfunction)-associated fatty liver disease (MAFLD) in lieu of nonalcoholic fatty liver disease (NAFLD). We aimed to estimate the burden of and risk factors for NAFLD and MAFLD, and to examine the concordance between definitions in a Veterans population. METHODS: We conducted a cross-sectional study among randomly selected patients within primary care at the Houston Veterans Affairs (VA) facility. Participants completed a survey, provided blood, and underwent Fibroscan. In the absence of heavy alcohol, hepatitis C virus and hepatitis B virus, a controlled attenuation parameter median ≥290 dB/m was used to define NAFLD, whereas MAFLD was defined as controlled attenuation parameter median ≥290 dB/m and either body mass index ≥25 kg/m2 or diabetes, or 2 or more of the following: hypertension, high triglycerides, low high-density lipoprotein cholesterol, and high low-density lipoprotein cholesterol. RESULTS: The mean age of participants was 50.9 years, 55.4% were women, 42.8% were white, and 43.8% were Black. The prevalence of NAFLD was 40.6% (82/202). All 82 patients with NAFLD had a body mass index ≥25 kg/m2, and therefore met our criteria for MAFLD (ie, 100% concordance). Compared with patients with no metabolic trait, patients with ≥3 traits had a 48-fold (adjusted odds ratio, 47.6; 95% confidence interval, 11.3-200) higher risk of NAFLD/MAFLD. Overall, 19 participants (9.4% of the total, 15.9% of those with NAFLD) had at least moderate fibrosis. CONCLUSIONS: NAFLD was present in 40% of Veterans registered in primary care; 9.4% of veterans had at least moderate hepatic fibrosis, with most having concurrent NAFLD. There was perfect concordance between NAFLD and the alternative MAFLD definition.

Reverse transcription-free digital-quantitative-PCR for microRNA analysis.

MicroRNAs (miRNAs) are non-coding RNA sequences that regulate many biological processes and have become central targets of biomedical research. However, their naturally low abundances in biological samples necessitates the development of sensitive analytical techniques to conduct routine miRNA measurements in research laboratories. Digital PCR has the potential to meet this need because of its single-molecule detection capabilities, but PCR analyses of miRNAs are slowed by the ligation and reverse transcription steps first required to prepare samples. This report describes the development of a method to rapidly quantify miRNA in digital microwell arrays using base-stacking digital-quantitative-PCR (BS-dqPCR). BS-dqPCR expedites miRNA measurements by eliminating the need for ligation and reverse transcription steps, which reduces the time and cost compared to conventional miRNA PCR analyses. Under standard PCR thermocycling conditions, digital signals from miRNA samples were lower than expected, while signals from blanks were high. Therefore, a novel asymmetric thermocycling program was developed that maximized on-target signal from miRNA while minimizing non-specific amplification. The analytical response of BS-dqPCR was then evaluated over a range of miRNA concentrations. The digital PCR dimension increased in signal with increasing miRNA copy numbers. When the digital signal saturated, the quantitative PCR dimension readily discerned miRNA copy number differences. Overall, BS-dqPCR provides rapid, high-sensitivity measurements of miRNA over a wide dynamic range, which demonstrates its utility for routine miRNA analyses.

Microfluidic Digital Quantitative PCR to Measure Internal Cargo of Individual Liposomes.

Lipid nanoparticles serve as drug delivery vehicles for biopharmaceutical products. The lipid membrane shields internal nucleic-acid drug cargo from enzymatic degradation and facilitates cellular uptake of the drug. However, existing methods to assess drug loading within liposomes are limited to averaged bulk measurements, which obscures heterogeneity of the biopharmaceutical formulation. This report describes the development of a single-liposome analysis method to measure copy numbers of DNA within liposomes and assess population heterogeneity. This novel measurement was achieved by integrating two orthogonal polymerase chain reaction (PCR) techniques─digital PCR (dPCR) and quantitative PCR (qPCR)─within a single microfluidic assay. The dPCR dimension quantified liposomes to validate their capture in the single-liposome analysis regime. The qPCR dimension quantified DNA copy numbers packaged within each liposome. The ability of digital quantitative PCR (dqPCR) to analyze large numbers of individual liposomes in parallel revealed significant population heterogeneity, which could not be obtained from standard bulk analysis methods. Our innovative measurement of internal DNA cargo from single liposomes has the potential to inform liposome synthesis procedures and create more uniform liposomal biopharmaceutical formulations to enhance drug safety and efficacy.

Prevalence, Anatomic Distribution, and Correlates of Chlamydia trachomatis and Neisseria gonorrhoeae Infections Among a Cohort of Men Who Have Sex With Men in Hanoi, Vietnam.

BACKGROUND: Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) disproportionately affect men who have sex with men (MSM). Data on the prevalence, anatomical distribution, and correlates of NG and CT infections among MSM in Vietnam are limited. METHODS: Between July 2017 and April 2019, MSM 16 years or older without HIV were enrolled into an observational cohort study. Baseline data, including sociodemographics, sexual behavior, and HIV status, were collected. Testing for NG and CT were performed on urine, rectal, and pharyngeal specimens. Multivariate logistic regression models identified factors associated with NG and CT infections at baseline. RESULTS: In total, 1489 participants underwent NG/CT testing. The median age was 22 years (interquartile range, 20-26 years). There were 424 (28.5%) NG or CT infections: 322 (21.6%) with CT and 173 (11.6%) with NG. Rectal infections were most common for CT (73.9%), whereas pharyngeal infections were most common for NG (70.5%). Independent risk factors for CT or NG infection included ≥2 sex partners in the prior month (adjusted odds ratio [aOR], 2.04; 95% confidence interval [CI], 1.44-2.91), condomless anal sex (aOR, 1.44; 95% CI, 1.12-1.86), and meeting sex partners online (aOR, 1.35; 95% CI, 1.03-1.76). Recent genitourinary or rectal symptoms were not associated with infections. CONCLUSIONS: The overall and extragenital prevalences of NG and CT infections were high within this sample of young MSM without HIV in Hanoi. Testing limited to urethral specimens would have missed nearly three-quarters of CT and NG infections, supporting the need for routine testing at multiple anatomic sites.

Pseudoginsenoside-F11 alleviates oligomeric ß-amyloid-induced endosome-lysosome defects in microglia.

Amyloid accumulation in the brain is the major pathological hallmark of Alzheimer disease (AD). Amyloid beta (Aß) is cleared by the endosomal-autophagy-lysosomal system, which is impaired in AD pathogenesis by an unknown mechanism. Pseudoginsenoside-F11 (PF11), an ocotillol-type ginsenoside, has been demonstrated to decrease the level of Aß in APP/PS1 mouse brain and to protect neurons by inhibiting the activation of microglia in vitro. The present study showed that PF11 was capable of increasing the uptake and degradation of oligomeric Aß in cultured microglia. Oligomeric Aß (oAß) interrupted the autophagy-lysosomal degradative system by regulating the nuclear translocation of transcription factor EB (TFEB), a master factor in lysosomal biogenesis. Conversion of Rab5 to Rab7, which is important for the mechanism of cargo progression from early to late endosomes, was also interrupted by high-concentration oAß. Notably, in the PF11-treated microglial cells, a dramatic increase of the lysosome-associated proteins and enzyme expression were observed, along with the intracellular pH steady state, indicating the improvement of lysosomal function. In addition, PF11 induced TFEB nuclear translocation in microglia treated with high-concentration oAß. Furthermore, PF11 was able to restore Rab conversion, suggesting an effective role of PF11 in the maturation of endosomes. These data provide evidence that PF11 can reverse the dysfunction of the endosomal-lysosomal system induced by high-concentration oAß in microglia, and this might be the main mechanism by which PF11 facilitates oAß clearance. Accordingly, we propose that PF11 should be considered as a potential agent for treating AD.

Intraoperative Celiac Plexus Block With Preperitoneal Infusion Reduces Opioid Usage in Major Hepato-pancreato-biliary Surgery: A Pilot Study.

OBJECTIVE: Given the role of celiac plexus block (CPB) in the management of chronic pain, we sought to investigate the utility of CPB in the control of postoperative pain in major hepato-pancreato-biliary surgeries. SUMMARY BACKGROUND DATA: CPB has been in practice for decades for the management of upper abdominal visceral pain, especially in cancer patients. Typically, in this group of patients with chronic pain, a neurolytic agent is injected to cause irreversible neural damage to achieve pain control. We apply this concept to postoperative pain control by injecting bupivacaine to the celiac plexus instead of a neurolytic agent. We aim to investigate if this novel technique decreases postoperative opioid usage, offers better pain relief and leads to earlier ambulation. METHODS: A retrospective, single institution study comparing consecutive patients who received intraoperative CPB and preperitoneal infusion with patients who received only preperitoneal infusion in open hepato-pancreato-biliary surgery between the years 2016 and 2019 by a single surgeon. Patients with incomplete data on patient-controlled analgesia usage and postoperative ambulation information were excluded. RESULTS: Patients with CPB used 31% less morphine on postoperative day 1 compared to patient without CPB and 42% less morphine on postoperative day 2. Overall average morphine usage was significantly lower in patients with CPB. Duration of patient-controlled analgesia was shorter for patient with CPB compared with patient without CPB. The dynamic visual analogue score was marginally better in patients with CPB. Time to ambulation was similar in both groups. CONCLUSIONS: CPB can be considered as part of a multimodal approach for postoperative pain management in open hepato-pancreato-biliary surgeries.

Respiratory failure among patients with COVID-19 in Jiangsu province, China: a multicentre retrospective cohort study.

This study was a retrospective multicentre cohort study of patients with coronavirus disease 2019 (COVID-19) diagnosed at 24 hospitals in Jiangsu province, China as of 15 March 2020. The primary outcome was the occurrence of acute respiratory failure during hospital stay. Of 625 patients, 56 (9%) had respiratory failure. Some selected demographic, epidemiologic, clinical and laboratory features as well as radiologic features at admission and treatment during hospitalisation were significantly different in patients with and without respiratory failure. The multivariate logistic analysis indicated that age (in years) (odds ratio [OR], 1.07; 95% confidence interval [CI]: 1.03-1.10; P = 0.0002), respiratory rate (breaths/minute) (OR, 1.23; 95% CI: 1.08-1.40; P = 0.0020), lymphocyte count (109/l) (OR, 0.18; 95% CI: 0.05-0.69; P = 0.0157) and pulmonary opacity score (per 5%) (OR, 1.38; 95% CI: 1.19-1.61; P < 0.0001) at admission were associated with the occurrence of respiratory failure. Older age, increased respiratory rate, decreased lymphocyte count and greater pulmonary opacity score at admission were independent risk factors of respiratory failure in patients with COVID-19. Patients having these risk factors need to be intensively managed during hospitalisation.

Safety and Efficacy of Tattoo Removal Using a Dual-Wavelength 1064/532-nm Picosecond Laser in Patients With Fitzpatrick Skin Type III and IV.

BACKGROUND AND OBJECTIVES: To investigate the safety and efficacy of a dual-wavelength 1064/532-nm picosecond-domain laser for tattoo removal in Vietnamese patients. STUDY DESIGN/MATERIALS AND METHODS: This prospective clinical study enrolled 30 subjects with 52 decorative tattoos treated with up to six treatments of laser removal at intervals of 6-8 weeks. Safety and efficacy were assessed at each treatment session and at 4 weeks after the final session. A "good" response was defined as at least 75% clearance of tattoo pigments. RESULTS: A significant reduction of tattoo appearance was achieved in all subjects. 88.5% of tattoos exhibited a "good" response to treatment by the end of the six sessions and more than 36% of tattoos exhibited better than "good" responses. Adverse events were common in the early period after treatment but did not persist in most patients. Only one case of prolonged hypopigmentation was reported. CONCLUSIONS: Treatment using a 1064/532-nm picosecond laser is an effective approach for removal of decorative tattoos, which poses a minimal risk of long-term adverse events in patients with Fitzpatrick skin type III or IV. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Environmental impacts of nitrogen emissions in China and the role of policies in emission reduction.

Atmospheric reactive nitrogen (Nr) has been a cause of serious environmental pollution in China. Historically, China used too little Nr in its agriculture to feed its population. However, with the rapid increase in N fertilizer use for food production and fossil fuel consumption for energy supply over the last four decades, increasing gaseous Nr species (e.g. NH3 and NOx) have been emitted to the atmosphere and then deposited as wet and dry deposition, with adverse impacts on air, water and soil quality as well as plant biodiversity and human health. This paper reviews the issues associated with this in a holistic way. The emissions, deposition, impacts, actions and regulations for the mitigation of atmospheric Nr are discussed systematically. Both NH3 and NOx make major contributions to environmental pollution but especially to the formation of secondary fine particulate matter (PM2.5), which impacts human health and light scattering (haze). In addition, atmospheric deposition of NH3 and NOx causes adverse impacts on terrestrial and aquatic ecosystems due to acidification and eutrophication. Regulations and practices introduced by China that meet the urgent need to reduce Nr emissions are explained and resulting effects on emissions are discussed. Recommendations for improving future N management for achieving 'win-win' outcomes for Chinese agricultural production and food supply, and human and environmental health, are described. This article is part of a discussion meeting issue 'Air quality, past present and future'.

[Clinical practice guideline for Tripterygium Glycosides/Tripterygium wilfordii Tablets in treatment of rheumatoid arthritis].

Tripterygium wilfordii Hook.f.(TwHF) is one of the most effective traditional Chinese herbal medicines against rheumatoid arthritis. As the representative agents of TwHF, Tripterygium Glycoside Tablets(TGT) and Tripterygium wilfordii Tablets(TWT) were included as Class A drugs in the 2019 edition of Medicine Catalogue for National Basic Medical Insurance, Injury Insurance and Maternity Insurance, and TGT was also included in 2018 edition of National Essential Drug List and 2015 edition of Chinese Pharmacopoeia. However, it is difficult to grasp the specific clinical applications of TGT and TWT. Side effects occur from time to time. The curative effect is uneven in patients. And the package inserts of TGT and TWT are not described in details. In order to standardize the clinical application of Tripterygium wilfordii preparations, 38 authoritative units and 48 well-known experts in rheumatoid immunology clinical department, drug supervision and management, pharmacy and evidence-based medicine research fields jointly developed Tripterygium Glycoside Tablets and Tripterygium wilfordii Tablets Medication Guide for reference in clinical application, teaching and scientific research. The guideline followed the "evidence-based, consensus-assisted and experience-based" principles to form "recommendations" for the evidence supported ones, and form "consensus suggestions" for those without evidence support by using nominal group method. In this way, the medication recommendations on function, usage and dosage, drug combinations, precautions, efficacy, safety and other aspects of TGT and TWT can be provided. The application of this Guide will help to avoid or reduce the adverse reactions of T. wilfordii preparations, enhance the efficacy and reduce the cost of medicine, with certain demonstration and promotion values to improve the rational use level of traditional Chinese medicine.

[Editorial explanation for Clinical practice guideline for Tripterygium Glycosides/Tripterygium wilfordii Tablets in treatment of rheumatoid arthritis].

Clinical practice guideline for Tripterygium Glycosides/Tripterygium wilfordii Tablets in the treatment of rheumatoid arthritis(T/CACM 1337-2020) was approved on June, 2020 by the Standardization Office of Chinese Association of Chinese Medicine. Our group developed this guideline for the clinical application of Tripterygium Glycosides/Tripterygium wilfordii Tablets according to the manual for the clinical experts consensus of Chinese patent medicine from January, 2018, when this project was approved by Chinese Association of Chinese Medicine. In this article, the detailed information on our compilation process was provided, in order to facilitate the understanding and the application of the guideline, as well as provide reference for the development of clinical practice guideline for other Chinese patent medicine.

Functionalization of activated methylene C-H bonds with nitroarenes and sulfur for the synthesis of thioamides.

We report a method to obtain arylthioamides by the functionalization of sp3 C-H bonds in phenylacetic acids and benzyl alcohols. Reactions proceeded without the use of any solvents and were compatible with many functionalities and heterocycles. These conditions allow for a rapid synthesis of thioamides from simple, commercial substrates.

MicroRNA-363-3p/p21(Cip1/Waf1) axis is regulated by HIF-2α in mediating stemness of melanoma cells.

Melanoma is a malignant tumor. The acquisition of stemness of melanoma cells aggravates the malignant transformation, which can be regulated by microRNAs (miRNAs, miR). MiR-363-3p is a key tumor-related miRNA, but its role in stemness and melanoma cells is still unknown. Presently, miR-363-3p, induced by hypoxia inducible factor (HIF)-2α, played a positive role in the stemness of melanoma cells. The levels of miR-363-3p and HIF-2α were upregulated in melanoma cell lines. Overexpression of HIF-2α significantly increased the levels of miR-363-3p. However, both HIF-2α knockdown and miR-363-3p inhibition inhibited the levels of the stemness markers (CD133, CD271, Jarid1B, and Nanog). Furthermore, the levels of miR-363-3p and HIF-2α were upregulated in fluorescence activated cell sorting (FACS)-sorted CD271high/+ cells. Whereas miR-363-3p depletion reduced the proportion and the spheroidization of the CD271high/+ cells, decreased the levels of CD133, CD271, Jarid1B and Nanog with restrained proliferative activity of CD271high/+ cells. Additionally, miR-363-3p was confirmed a key downstream of HIF-2α. Intriguingly, cyclin-dependent kinase inhibitor 1A [CDKN1A, p21(Cip1/Waf1)], a key inhibitor of S-phase DNA synthesis and cell cycle progression, was confirmed a target gene of miR-363-3p by luciferase reporter gene assay. The protein levels of CD133, CD271, Jarid1B and Nanog were upregulated with enhanced proliferative activity of CD271high/+ cells by inhibition of p21 in melanoma cells. In conclusion, miR-363-3p is induced by HIF-2α to promote the stemness of melanoma cells via inhibiting p21. The present study provides novel insights that HIF-2α/miR-363-3p/p21 signaling may be a potential target of research and therapy of melanoma.

Barriers to access and uptake of antiretroviral therapy among HIV-positive men who have sex with men in Hanoi, Vietnam: from HIV testing to treatment.

Little is known about the experiences of Vietnamese men who have sex with men in accessing HIV testing and treatment. We aimed to explore barriers to access and uptake of antiretroviral therapy (ART) among HIV-positive men who have sex with men in Hanoi. During 2015, we conducted qualitative interviews with 35 participants recruited using snowball sampling based on previous research and social networks. Key individual impediments to ART uptake included inadequate preparation for a positive diagnosis and the dual stigmatisation of homosexuality and HIV and its consequences, leading to fear of disclosure of HIV status. Health system barriers included lack of clarity and consistency about how to register for and access ART, failure to protect patient confidentiality and a reticence by providers to discuss sexual identity and same-sex issues. Results suggest fundamental problems in the way HIV testing is currently delivered in Hanoi, including a lack of client-centred counselling, peer support and clear referral pathways. Overcoming these barriers will require educating men who have sex with men about the benefits of routine testing, improving access to quality diagnostic services and building a safe, confidential treatment environment for HIV-positive men to access, receive and remain in care.

The influence of visual information on auditory processing in individuals with congenital amusia: An ERP study.

While most normal hearing individuals can readily use prosodic information in spoken language to interpret the moods and feelings of conversational partners, people with congenital amusia report that they often rely more on facial expressions and gestures, a strategy that may compensate for deficits in auditory processing. In this investigation, we used EEG to examine the extent to which individuals with congenital amusia draw upon visual information when making auditory or audio-visual judgments. Event-related potentials (ERP) were elicited by a change in pitch (up or down) between two sequential tones paired with a change in spatial position (up or down) between two visually presented dots. The change in dot position was either congruent or incongruent with the change in pitch. Participants were asked to judge (1) the direction of pitch change while ignoring the visual information (AV implicit task), and (2) whether the auditory and visual changes were congruent (AV explicit task). In the AV implicit task, amusic participants performed significantly worse in the incongruent condition than control participants. ERPs showed an enhanced N2-P3 response to incongruent AV pairings for control participants, but not for amusic participants. However when participants were explicitly directed to detect AV congruency, both groups exhibited enhanced N2-P3 responses to incongruent AV pairings. These findings indicate that amusics are capable of extracting information from both modalities in an AV task, but are biased to rely on visual information when it is available, presumably because they have learned that auditory information is unreliable. We conclude that amusic individuals implicitly draw upon visual information when judging auditory information, even though they have the capacity to explicitly recognize conflicts between these two sensory channels.

Do Anxiety Disorders Play a Role in Adolescent Obesity?

BACKGROUND: There have been few prospective studies on the association between anxiety disorders and adolescent obesity; none examine potential reciprocal effects. PURPOSE: The purpose of this paper is to examine the prospective association between anxiety disorders and obesity among adolescents. METHODS: Using data from a two-wave, prospective study of 3134 adolescents, we examined reciprocal effects between body weight and DSM-IV anxiety disorders. RESULTS: Weight status did not increase future risk of anxiety disorders nor did anxiety disorders at baseline increase risk of future obesity in the overall sample. Stratifying by gender revealed an increased risk of overweight and obesity in males with anxiety disorders, but not for females. Major depression did not mediate these associations. CONCLUSION: Similar to prospective studies of depression, it appears anxiety disorders may increase risk of obesity. However, more research is needed on the role of psychopathology in adolescent obesity, in particular anxiety disorders and possible moderators (such as gender) and mediators.

Regulatory Effects of Ca2+ and H+ on the Rat Chorda Tympani Response to NaCl and KCl.

Modulatory effects of pHi and [Ca(2+)]i on taste receptor cell (TRC) epithelial sodium channel (ENaC) were investigated by monitoring chorda tympani (CT) responses to NaCl and KCl at various lingual voltages, before and after lingual application of ionomycin and with 0-10mM CaCl2 in the stimulus and rinse solutions adjusted to pHo 2.0-9.7. 0.1 and 0.5M KCl responses varied continuously with voltage and were fitted to an apical ion channel kinetic model using the same parameters. ENaC-dependent NaCl CT response was fitted to the same channel model but with parameters characteristic of ENaC. A graded increase in TRC [Ca(2+)]i decreased the ENaC-dependent NaCl CT response, and inhibited and ultimately eliminated its pH sensitivity. CT responses to KCl were pHi- and [Ca(2+)]i-independent. Between ±60 mV applied lingual potential, the data were well described by a linear approximation to the nonlinear channel equation and yielded 2 parameters, the open-circuit response and the negative of the slope of the line in the CT response versus voltage plot, designated the response conductance. The ENaC-dependent NaCl CT response conductance was a linear function of the open-circuit response for all pHi-[Ca(2+)]i combinations examined. Analysis of these data shows that pHi and [Ca(2+)]i regulate TRC ENaC exclusively through modulation of the maximum CT response.