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Background & aims Hepatic fibrosis secondary to HCV infection can lead to cirrhosis and hepatic decompensation. Sustained virologic response (SVR) is possible with direct-acting antiviral drug regimens; however, patients with advanced fibrosis have an increased risk for HCC. Heat shock protein 47 (HSP47), a key collagen chaperone, has been implicated in fibrosis development. Here, we evaluated the efficacy and safety of BMS-986263, a lipid nanoparticle delivering siRNA designed to degrade HSP47 mRNA, for the treatment of advanced fibrosis. Approach & results NCT03420768 was a Phase 2, randomized (1:1:2), placebo-controlled trial conducted at a hepatology clinic in the USA. Patients with HCV-SVR (for ≥1 year) and advanced fibrosis received once-weekly intravenous infusions of placebo or BMS-986263 (45 mg or 90 mg) for 12 weeks. The primary endpoint was ≥1 METAVIR stage improvement at Week 12; key secondary endpoints included Ishak score improvement, pharmacokinetics, fibrosis biomarkers, and safety. All 61 patients completed treatment and 2/15 (13%; placebo), 3/18 (17%; 45 mg), and 6/28 (21%; 90 mg) had METAVIR improvements of ≥1 stage at Week 12. Five patients in the 90 mg arm had Ishak improvements by ≥2 stages. BMS-986263 plasma concentrations increased in a generally dose-proportional fashion between BMS-986263 doses, with no notable accumulation with weekly dosing. All adverse events (AEs) were mild or moderate in intensity; most treatment-related AEs were infusion-related reactions in the BMS-986263 arms. At baseline, collagen levels were low, indicating low levels of fibrogenesis in these patients. Conclusions In patients with HCV-SVR, BMS-986263 administration was generally well tolerated through Week 36 and resulted in METAVIR and Ishak score improvements. Further evaluation of BMS-986263 in patients with active fibrogenesis is warranted.

Background Covid-19 in Mexico is on the rise in different parts of the country. We aimed to study the symptoms and comorbidities that associate with this pandemic in 3 different regions of Mexico. Methods We analyzed data from SARS-CoV-2 positive patients evaluated at healthcare centers and hospitals of Mexico (n = 1607) including Northwest Mexico (Sinaloa state), Southeast Mexico (Veracruz state) and West Mexico (Jalisco state) between March 1 and July 30, 2020. Mexico consists of a total population that exceeds 128 million. Demographics, comorbidities and clinical symptoms were collected. Statistical descriptive analysis and correlation analyses of symptoms, comorbidities and mortality were performed. Results A total of 1607 hospitalized patients positive for COVID-19 across all 3 regions of Mexico were included. The average age was 54.6 years and 60.4% were male. A mortality rate of 33.1% was observed. The most common comorbidities were hypertension (43.2%), obesity (30.3%) and diabetes (31.4%). Hypertension was more frequent in West (45%), followed by Northwest (37%) and Southeast Mexico (29%). Obesity was around 30% in Northwest and West whereas an 18% was reported in Southeast. Diabetes was most common in West (34%) followed by Northwest (22%) and Southeast (13%). This might be related to the highest mortality rate in Northwest (31%) and West (37%) when compared to Southeast. Most common symptoms in our overall cohort were fever (80.8%), cough (79.8%), headache (66%), dyspnea (71.1%), myalgia (53.8%), joints pain (50.8%) and odynophagia (34.8%). Diarrhea was the main gastrointestinal (GI) symptom (21.3%), followed by abdominal pain (18%), and nausea/ vomiting (4.5%). Diarrhea and abdominal pain were more common in West (23.1 and 21%), followed by Southeast (17.8, and 9.8%) and Northwest (11.4 and 3.1%). Conclusion Our study showed a high mortality rate likely related to high frequencies of comorbidities (hypertension, obesity and diabetes). Mortality was different across regions. These discrepancies might be related to the differences in the frequencies of comorbidities, and partially attributed to differences in socio-economic conditions and quality of care. Thus, our findings stress the need for improved strategies to get better outcomes in our population.

Interventional procedures have been performed on an outpatient basis in the hospital setting for many years, although there has been a clear trend toward performing these procedures in an outpatient facility, such as an ambulatory surgery center or office-based lab. And while this trend initially began with dialysis interventions and then endovascular interventions, interventional oncology is starting to catch on. Radioembolization has routinely been performed in an outpatient setting, and has recently gained traction in office-based labs due to new reimbursement codes, which became available in 2017. This article will outline the safety and feasibility, including economic considerations and demonstrated growth, of performing radioembolization in an office-based lab.

Clinical relevance: The ability to articulate clinical findings to patients through effective communication is a key skill in all health-care professions.\ud \ud Background: Unannounced standardised patients (SPs) are successful in measuring quality of clinical care provided by qualified optometrists but have not been used in optometry training. Final-year undergraduate optometry students examine members of the public during primary care clinics observed by visiting clinical tutors (VCTs) who provide individualised feedback, highlighting areas for improvement. This pilot study investigates whether unannounced SPs can be used as an additional resource providing enhanced feedback on communication skills in undergraduate optometry education.\ud \ud Methods: Two SPs received intensive training on reporting on students eye examinations and communication skills through completion of pre-designed checklists for each patient encounter. Each SP presented 16 times as an unannounced patient for routine eye examinations. SPs' comments on communication skills of 32 students during 32 examinations was compared to feedback from 10 VCTs. SPs' performance was monitored to ensure consistency. Evaluation of differences in quality and quantity of feedback provided by SPs and VCTs was performed using thematic analysis and chi-squared tests. Student feedback on the use of SPs was obtained on completion of the study.\ud \ud Results: Qualitative thematic analysis revealed six overarching themes emerging from 64 sets of feedback. SPs gave significantly more feedback, both positive comments and comments with recommendations, than VCTs for the (a) total number of comments for each theme (p = 0.0000) and (b) detail and depth of these comments. Students reported that SPs commented on aspects of communication (e.g., establishing rapport and body language) not noted by VCTs.\ud \ud Conclusions: Unannounced SPs can provide enhanced feedback on communication skills to final-year undergraduate optometry students. Students greatly valued VCTs feedback; however, they felt SPs commented on elements of communication not noted by VCTs.

Clinical relevance: Accuracy of tonometers is of vital importance in the detection and treatment of glaucoma.Background: This study investigates: agreement in intraocular pressure measurements between three tonometers and Goldmann applanation tonometry (GAT); inter-optometrist agreement for each tonometer; intra-optometrist agreement for GAT; association between central corneal thickness (CCT) and IOP measurements with each tonometer.Methods: IOP was measured using: CT-1P Non-Contact Tonometer (NCT) (Topcon Corporation, Tokyo, Japan), Pulsair IntelliPuff (Keeler Ltd., Windsor, UK) and Icare rebound tonometer (Icare, Helsinki, Finland) by two optometrists in a random order. Two GAT readings were obtained by each optometrist in a randomised masked manner. Mean differences, and 95% limits of agreement (LoA) for each measurement were calculated. CCT was measured by CT-1P pachymeter.Results: Forty-one participants' IOPs were measured. Mean differences (95% LoA) between NCT, Pulsair, Icare compared to GAT for one optometrist were: 0.8 (-5.4 to 6.9) mmHg, -1.7 (-8.2 to 4.8) mmHg, -1.6 (-9.0 to 5.9) mmHg. Mean differences (95% LoA) in inter-optometrist agreement for GAT, NCT, Pulsair and Icare were: 0.3 (-6.7 to 7.3) mmHg, 0.4 (-2.1 to 2.9) mmHg, -0.9 (-3.6 to 1.9) mmHg and -0.2 (-4.9 to 4.5) mmHg, respectively. Mean differences (95% LoA) for intra-optometrist agreement for GAT were 0.2 (4.3 to -4.7) mmHg and 0.1 (3.6 to -3.9) mmHg for each optometrist, respectively. There was a weak positive association between CCT and both GAT (r2 = 0.11) and NCT (r2 = 0.12).Conclusion: Pulsair and Icare may measure IOP lower than GAT. Mean differences for inter-optometrist agreement for all tonometers were < 1 mmHg; Pulsair showed a statistically significant difference. Intra-optometrist agreement for GAT was good. IOP measurements taken by two community optometrists are comparable using tonometers used in community practice.

Nonalcoholic steatohepatitis (NASH) is a major cause of liver‐related morbidity and mortality worldwide. Liver fibrosis stage, a key component of NASH, has been linked to the risk of mortality and liver‐related clinical outcomes. Currently there are no validated noninvasive diagnostics that can differentiate between fibrosis stages in patients with NASH; many existing tests do not reflect underlying disease pathophysiology. Noninvasive biomarkers are needed to identify patients at high‐risk of NASH with advanced fibrosis. This was a retrospective study of patients with histologically proven NASH with fibrosis stages 0‐4. The SOMAscan proteomics platform was used to quantify 1,305 serum proteins in a discovery cohort (n = 113). In patients with advanced (stages 3‐4) versus early fibrosis (stages 0‐2), 97 proteins with diverse biological functions were differentially expressed. Next, fibrosis‐stage classification models were explored using a machine learning–based approach to prioritize the biomarkers for further evaluation. A four‐protein model differentiated patients with stage 0‐1 versus stage 2‐4 fibrosis (area under the receiver operating characteristic curve [AUROC] = 0.74), while a 12‐protein classifier differentiated advanced versus early fibrosis (AUROC = 0.83). Subsequently, the model’s performance was validated in two independent cohorts (n = 71 and n = 32) with similar results (AUROC = 0.74‐0.78). Our advanced fibrosis model performed similarly to or better than Fibrosis‐4 index, aspartate aminotransferase–to‐platelet ratio index, and nonalcoholic fatty liver disease (NAFLD) fibrosis score–based models for all three cohorts. Conclusion: A SOMAscan proteomics‐based exploratory classifier for advanced fibrosis, consisting of biomarkers that reflect the complexity of NASH pathophysiology, demonstrated similar performance in independent validation cohorts and performed similarly or better than Fibrosis‐4 index, aspartate aminotransferase–to‐platelet ratio index, and NAFLD fibrosis score. Further studies are warranted to evaluate the clinical utility of these biomarker panels in patients with NAFLD.

We aimed to characterize the contribution of hepatitis E virus (HEV) in perpetuating the cytokine-mediated inflammatory setting related to liver damage in the context of obesity. Herein, serum samples from patients with liver disease were retrospectively analyzed and categorized as normal-weight patients (NW), overweight patients (OW), obese patients (ObP), and high alcohol consumer patients (HAC), and biochemical, anthropometrical, and transient elastography measurements were obtained. The positivity for immunoglobulin M (IgM) and immunoglobulin G (IgG) anti-HEV antibodies in samples was determined by enzyme-linked immunosorbent assay. Available samples from ObP were tested by reverse transcription-nested polymerase chain reaction for the presence of HEV-RNA. Cytokine profile in the serum of ObP was identified using a multiplexed immune assay. Globally, the highest frequency of IgG anti-HEV was found in ObP (57.5%), followed by HAC (20%), OW (15%), and NW (7.5%). A strong association between HEV serology and obesity was found (odds ratio = 4.21, confidence interval = 1.91.9.27) with a cutoff of 29.3 kg/m

One of the hallmark characteristics of chronic diabetic wounds is the presence of biofilm-forming bacteria. Bacteria encapsulated in a biofilm may coexist as a polymicrobial community and communicate with each other through a phenomenon termed quorum sensing (QS). Here, we describe the QS circuits of bacterial species commonly found in chronic diabetic wounds. QS relies on diffusion of signaling molecules and the local concentration changes of these molecules that bacteria experience in wounds. These biochemical signaling pathways play a role not only in biofilm formation and virulence but also in wound healing. They are, therefore, key to understanding the distinctive nature of these infections. While several in vivo and in vitro models exist to study QS in wounds, there has been limited progress in understanding the interplay between QS molecules and host factors that contribute to wound healing. Lastly, we examine the potential of targeting QS for both diagnosis and therapeutic intervention purposes.

Highlights • There is a high distribution of BVDV in the evaluated área. • Significant statistical association was found for breed, age, management practices. • Age group > 4 years, Normande breed, PI3 and grazing lease were risk factors., Worldwide distributed Bovine Viral Diarrhea Virus (BVDV) represents a high risk of infection in most bovine farms, in which it is associated with gastrointestinal, respiratory, and reproductive diseases. The purpose of this research was to establish the seroprevalence and the main risk factors associated with the presentation of BVDV in the municipality of Sotaquirá, Colombia. Samples were taken from 1000 cattle of Holstein, Ayrshire, Jersey, Normande Gyr and Holstein x Gyr. Epidemiological surveys were implemented, reproductive and management variables were taken into consideration. Indirect ELISA was performed to detect specific antibodies against BVDV using the commercial kit SERELISA® BVD p80 Ab Mono Blocking. The overall seroprevalence of antibodies against BVDV was 42.5% (425/1000), where the Gyr breed (59.1% apparent prevalence (AP); 60.3% real prevalence (PR)) and the age group > 4 years (53.0% PA; 54.4% PR) presented the highest seroprevalences. A significant statistical association was found for the breed, age, management practices evaluated and the presentation of PI3 (p ≤ 0.05). Age group > 4 years, Normande breed, presentation of PI3 and grazing lease were established as risk factors associated with BVDV in the herds. These infections are mainly associated with dairy cattle and herds with many animals, so it is important to consider vaccination plans as a preventive system and follow up on the most common diseases., Graphical abstract Image, graphical abstract

The m.8993T&gt, G mutation of the mitochondrial MT-ATP6 gene is associated with NARP syndrome (neuropathy, ataxia and retinitis pigmentosa). The equivalent point mutation introduced in yeast Saccharomyces cerevisiae mitochondrial DNA considerably reduced the activity of ATP synthase and of cytochrome-c-oxidase, preventing yeast growth on oxidative substrates. The overexpression of the mitochondrial oxodicarboxylate carrier (Odc1p) was able to rescue the growth on the oxidative substrate by increasing the substrate-level phosphorylation of ADP coupled to the conversion of α-ketoglutarate (AKG) into succinate with an increase in Complex IV activity. Previous studies showed that equivalent point mutations in ATP synthase behave similarly and can be rescued by Odc1p overexpression and/or the uncoupling of OXPHOS from ATP synthesis. In order to better understand the mechanism of the ATP synthase mutation bypass, we developed a core model of mitochondrial metabolism based on AKG as a respiratory substrate. We describe the different possible metabolite outputs and the ATP/O ratio values as a function of ATP synthase inhibition.

Hiperplasia prostática benigna (HPB) se caracteriza por el crecimiento de estroma prostático y las células epiteliales, con lo que se forman nódulos grandes, bastante delimitados en la región periuretral de la próstata, produciendo presión sobre la vejiga urinaria y la uretra que dificulta el flujo de orina. Se realiza un estudio descriptivo retrospectivo evaluando los hallazgos clínicos, de laboratorio y patológicos de 171 pacientes con diagnóstico de hipertrofia prostática benigna, que consultaron a la clínica especializada en urología y cirugía general de adultos y niños atendida por el cirujano urólogo Dr. Edgar Petzey, ubicada en la 9na avenida, zona 1 de la cuidad de Chiquimula. Se demostró que el rango de edad más afectado fue entre 60 a 69 años (35%), la etnia ladina fue la más frecuente con un 85% (N=146), el 78% (N=134) de los pacientes estaba casado y el lugar de mayor consulta es el departamento Chiquimula con un 54% (N=92). Al momento de realizar el examen dígito rectal, el 94% presentó un hallazgo sospechoso, de los cuales se encuentran por debajo de los niveles de antígeno plasmático especifico total de 4 ng/mL, entre los niveles de PSA 0.0 a 2.4 ng/mL se encuentra el 55% (N=95) de los pacientes, seguido entre los niveles 2.5 a 3.9 ng/mL con un 18% (N=30), Del total de pacientes en los cuales no se encontraron hallazgos patológicos fue de un 98% (N=167) dentro del puntaje 0 a 4 del score de Gleason.

Background Minimally invasive gastric cancer surgery requires an extended liver retraction in order to provide optimal operative view, working space for lymph node dissection, and esophageojejunal reconstruction. Ideally, it should avoid reposition of the retractor, additional skin incision or puncture, and liver parenchyma injury. Herein, we introduced an intracorporeal W-shaped liver retraction technique (W-LRT) for minimally invasive gastric cancer surgery without an additional incision or abodminal puncture. Methods Between October 2013 and October 2016, the W-LRT was applied in 80 patients undergoing minimally invasive gastric cancer surgery. The W-LRT was performed using one 75 cm 3-0 monocryl suture with its end fixed to one hemoclip. The perioperative outcome was recorded. Results The W-LRT was applied in 80 gastric cancer patients using either laparoscopic approach (N=69) or robotic approach (N=11). The mean age was 62.7±14 years and the mean body mass index (BMI) was 24.1±3.6 kg/m. The time required for W-LRT was 5.6±5.2 minutes in laparoscopic approach and 6.2±4.7 minutes in robotic approach. This technique was successfully applied in all procedures and no other technique or additional instrument was required. Major complications developed in 7 patients (8.8%), classified as greater than Clavien-Dindo classification II; however, there was neither any intraoperative nor postoperative major complication related to W-LRT. The length of hospital stay was 9.1±4.4 days. Conclusions In laparoscopic or robotic gastric cancer surgery, the W-LRT can provide excellent operative view during lymph node dissection and reconstruction of esophagojejunostomy and eliminate an additional skin incision or abdominal puncture.

Background & Aims Increased serum bile acids (BAs) have been observed in patients with non-alcoholic steatohepatitis (NASH). Pegbelfermin (PGBF), a polyethylene glycol-modified (PEGylated) analogue of human fibroblast growth factor 21 (FGF21), significantly decreased hepatic steatosis and improved fibrosis biomarkers and metabolic parameters in patients with NASH in a phase IIa trial. This exploratory analysis evaluated the effect of PGBF on serum BAs and explored potential underlying mechanisms. Methods Serum BAs and 7α-hydroxy-4-cholesten-3-one (C4) were measured by HPLC-mass spectrometry (MS) using serum collected in studies of patients with NASH (NCT02413372) and in overweight/obese adults (NCT03198182) who received PGBF. Stool samples were collected in NCT03198182 to evaluate faecal BAs by liquid chromatography (LC)-MS and the faecal microbiome by metagenetic and metatranscriptomic analyses. Results Significant reductions from baseline in serum concentrations of the secondary BA, deoxycholic acid (DCA), and conjugates, were observed with PGBF, but not placebo, in patients with NASH; primary BA concentrations did not significantly change in any arm. Similar effects of PGBF on BAs were observed in overweight/obese adults, allowing for an evaluation of the effects of PGBF on the faecal microbiome and BAs. Faecal transcriptomic analysis showed that the relative abundance of the gene encoding choloylglycine hydrolase, a critical enzyme for secondary BA synthesis, was reduced after PGBF, but not placebo, administration. Furthermore, a trend of reduction in faecal secondary BAs was observed. Conclusions PGBF selectively reduced serum concentrations of DCA and conjugates in patients with NASH and in healthy overweight/obese adults. Reduced choloylglycine hydrolase gene expression and decreased faecal secondary BA levels suggest a potential role for PGBF in modulating secondary BA synthesis by gut microbiome. The clinical significance of DCA reduction post-PGBF treatment warrants further investigation. Lay summary Pegbelfermin (PGBF) is a hormone that is currently being studied in clinical trials for the treatment of non-alcoholic fatty liver disease. In this study, we show that PGBF treatment can reduce bile acids that have previously been shown to have toxic effects on the liver. Additional studies to understand how PGBF regulates bile acids may provide additional information about its potential use as a treatment for fatty liver., Graphical abstract, Highlights • Bile acids are elevated in patients with non-alcoholic steatohepatitis. • Pegbelfermin, a PEGylated human FGF21 analogue, is in phase II trials for non-alcoholic steatohepatitis. • Pegbelfermin treatment was associated with secondary, but not primary, bile acid reductions. • Pegbelfermin reduced expression of a gene responsible for secondary bile acid synthesis. • Further study is needed to assess the clinical significance of these observations.

Abnormal regulation of glucagon secretion contributes to impaired glycemic control in patients with T1D. We conducted two 12-week, double-blind, randomized, placebo-controlled trials to evaluate the efficacy of blocking glucagon action with the glucagon receptor antagonist antibody, volagidemab (VOLA), on glycemic control in patients with T1D. In both trials, participants were randomized in a 1:1:1 fashion to weekly subcutaneous injection with placebo (PBO), VOLA 35 mg, or VOLA 70 mg. Participants in Trial 1 (n=75) were unblinded and participants in Trial 2 (n=78) were blinded to the data from the study-provided continuous glucose monitoring (CGM). All participants could monitor glucose values by fingerstick or their own CGM, if these modalities were part of their usual care before the study. In Trial 1, baseline A1C was 7.5% and decreased by 0.39% (PBO), 0.64% (35 mg, p=0.029), and 0.69% (70 mg, p=0.008) at week 12. An A1C target of ≤ 7.0% was achieved in 43% (PBO), 70% (VOLA 35 mg), and 71% (VOLA 70 mg) of participants. Insulin total daily dose (TDD) decreased by 6.3% (PBO), 12.9% (VOLA 35 mg, NS) and 12.2% (VOLA 70 mg, NS) at week 12. In Trial 2, baseline A1C was 7.9% and decreased by 0.03% (PBO), 0.63% (VOLA 35 mg, p=0.001) and 0.66% (VOLA 70 mg, p=0.001). An A1C target of ≤7.0% was achieved in 17% (PBO), 50% (VOLA 35 mg), and 38% (VOLA 70 mg) of participants. Insulin TDD decreased by 3.5% (PBO), 15.1% (VOLA 35 mg, NS), and 10.2% (VOLA 70 mg, NS). A majority of adverse events were Grade 2 or lower in severity. Intermittent Increases in BP and ALT were observed in VOLA vs. placebo participants during the dosing period and returned to BL after treatment discontinuation. These data demonstrate that treatment with VOLA 35 mg or 70 mg once weekly as an adjunct to insulin is safe, well-tolerated, and decreases A1C with a trend toward decreased insulin dosing in people with T1D. Disclosure J. Pettus: Advisory Panel; Self; Novo Nordisk, Sanofi, Consultant; Self; Diasome Pharmaceuticals, Inc., Insulet Corporation, Lilly Diabetes, MannKind Corporation, Tandem Diabetes Care. B. W. Bode: Advisory Panel; Self; Eli Lilly and Company, Consultant; Self; Bigfoot Biomedical, Inc., Companion Medical, Lexicon Pharmaceuticals, Inc., Medtronic, Novo Nordisk Inc., Zealand Pharma A/S, Research Support; Self; Abvance Therapeutics, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Dompe, Eli Lilly and Company, Eyenuk, Inc., Insulet Corporation, Jaeb Center for Health Research, Medtronic, Nova Biomedical, Novo Nordisk, Provention Bio, Inc., REMD Biotherapeutics, Sanofi, Senseonics, Viacyte, Inc., vTv Therapeutics, Xeris Pharmaceuticals, Inc., Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MannKind Corporation, Medtronic, Novo Nordisk, Sanofi, Stock/Shareholder; Self; AgaMatrix, Aseko, Inc., Glytec, LLC. E. D. Bautista: Consultant; Self; REMD Biotherapeutics. H. Yan: Board Member; Self; REMD Biotherapeutics, Other Relationship; Spouse/Partner; REMD Biotherapeutics. D. Thai: Employee; Self; REMD Biotherapeutics. S. K. Garg: Advisory Panel; Self; Eli Lilly and Company, Medtronic, Novo Nordisk Inc., Zealand Pharma A/S, Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Medtronic. S. Klein: Advisory Panel; Self; Altimmune, Merck & Co., Inc., Novo Nordisk Inc., ProSciento, Research Support; Self; Janssen Research & Development, LLC. S. C. Boeder: Consultant; Self; Cecelia Health, Research Support; Self; Dexcom, Inc. M. P. Christiansen: Research Support; Self; Abbott Diabetes, Biolinq, Dexcom, Inc., Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Viacyte, Inc. D. S. Denham: None. T. S. Bailey: Consultant; Self; Abbott Diabetes, LifeScan, Novo Nordisk, Sanofi, Research Support; Self; Abbott, Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Livongo, Medtronic, Medtrum Technologies, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker’s Bureau; Self; BD, Medtronic, Sanofi. H. K. Akturk: Consultant; Self; American Diabetes Association, Research Support; Self; Dexcom, Inc., Eli Lilly and Company, IM Therapeutics, MannKind Corporation, REMD Biotherapeutics, Senseonics, Speaker’s Bureau; Self; American Diabetes Association. L. J. Klaff: Research Support; Self; Abbott Diabetes, Dong-A ST Co. Ltd., Gan & Lee Pharmaceuticals, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics. J. Rosenstock: Board Member; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Consultant; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo No

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have a high prevalence of obesity, insulin resistance (IR), increased blood pressure (BP), and activation of the renin angiotensin system (RAS). Effective evidence-based therapeutics to ameliorate the cardiometabolic complications in PCOS are lacking. The sodium-glucose cotransporter-2 (SGLT2) inhibitor Empagliflozin (EMPA) reduces BP and hyperglycemia in type 2 diabetes mellitus. We hypothesized that hyperandrogenemia upregulates renal SGLT2 expression and that EMPA ameliorates cardiometabolic complications in a hyperandrogenemic PCOS model. Four-week-old female Sprague Dawley rats were treated with dihydrotestosterone (DHT) for 90 days, and EMPA was co-administered for the last three weeks. DHT upregulated renal SGLT2, SGLT4, and GLUT2, but downregulated SGLT3 mRNA expression. EMPA decreased DHT-mediated increases in fat mass, plasma leptin, and BP, but failed to decrease plasma insulin, HbA1c, or albuminuria. EMPA decreased DHT-mediated increase in renal angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AGT1R) mRNA and protein expression. In summary, SGLT2 inhibition proved beneficial in adiposity and BP reduction in a hyperandrogenemic PCOS model, however, additional therapies may be needed to improve IR and renal injury.

Background Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD); no approved therapies for NASH currently exist. Pegbelfermin (PGBF), a human fibroblast growth factor 21 analog, has metabolic effects that may provide benefit for patients with NASH. Design The FALCON 1 and 2 studies are Phase 2b, multicenter, double-blind, placebo-controlled, randomized trials to assess safety and efficacy of PGBF treatment in patients who have histologically-confirmed NASH with stage 3 liver fibrosis (FALCON 1; NCT03486899 ) or compensated cirrhosis (FALCON 2; NCT03486912 ). In both studies, randomized patients receive once weekly subcutaneous injections of PGBF (10, 20, or 40 mg) or placebo during a 48-week treatment period and are then followed for an additional 4 weeks. Endpoints The primary efficacy endpoint for FALCON 1 is the proportion of patients who achieve ≥1 stage improvement in fibrosis (by NASH CRN fibrosis score) without NASH worsening or NASH improvement (≥2 point decrease in NAFLD Activity Score) without fibrosis worsening at Week 24. For FALCON 2, the primary efficacy endpoint is ≥1 stage improvement in fibrosis without NASH worsening at Week 48. Key safety endpoints for both studies include incidence and frequency of adverse events, bone mineral density and immunogenicity. Summary Previous clinical trial data show that PGBF can reduce hepatic fat and improve metabolic factors and biomarkers of hepatic injury and fibrosis. The FALCON studies aim to evaluate PGBF treatment specifically in patients with NASH and advanced fibrosis, who are at greatest risk of poor clinical outcomes over time.

Introduction: BMS-986278 is being investigated as a treatment (tx) for idiopathic pulmonary fibrosis (IPF). In vitro studies demonstrated that OATP mediates human hepatic uptake of BMS-986278. Patients with IPF often receive concomitant medications, including OATPi. Aims and Objectives: To evaluate the effects of rifampin (rif) on the PK and tolerability of BMS-986278 in healthy adult participants (ppts). Methods: This was an open-label drug-interaction study. Fasted ppts received an oral dose of 30 mg BMS-986278 on d1 followed by a 7-d washout; on d8, ppts received an oral dose of 600 mg rif and 30 mg BMS-986278. Plasma PK was measured for BMS-986278 and rif; tolerability was monitored. Results: All 15 enrolled ppts completed the study (73% male, 73% white, mean [SD] age 46.1 [12.7] y and BMI 25.2 [2.7] kg/m2). Following coadministration with rif, BMS-986278 mean area under the curve from 0 to infinity (AUC0-inf) and maximum concentration (Cmax) were elevated by 3.13- and 2.75-fold, respectively, vs BMS-986278 alone. Median time to Cmax (Tmax) increased from 1.1 h (BMS-986278) to 2.0 h (BMS-986278+rif). Rif PK matched published data. BMS-986278+rif and BMS-986278 alone demonstrated a similar safety profile. Of 4 reported adverse events, 3 were mild (back pain, nausea, and presyncope) and 1 was moderate (constipation); none were deemed related to tx. Conclusions: BMS-986278+rif and BMS-986278 alone were generally well tolerated; increases in exposure up to 3x of BMS-986278 were observed with co-administration of rif. Concomitant OATPi medications anticipated to increase BMS-986278 exposure

Background Preservation of splenic vessels can minimize the risks of splenic infarction and gastric varices in laparoscopic spleen preserving distal pancreatectomy. A well-established procedure would provide high splenic vessels and spleen preservation rate. This study evaluated the outcomes and depending factors of laparoscopic splenic vessels and spleen preservation distal pancreatectomy (LsvspDP) via inferior-posterior splenic vein approach. Materials and methods This retrospective study enrolled patients who underwent LsvspDP via inferior-posterior splenic vein approach in National Cheng-Kung University Hospital from February 2009 to June 2019. The clinic-pathologic data were collected and analyzed. The primary outcome of this study was the learning curve based on the cumulative sum analysis. The secondary outcomes were to evaluate the critical factors for the failure of splenic vessels and spleen preservation. Results During the study period, a total of 64 patients received LsvspDP attempt. Splenic vessels were successfully preserved in 49 patients and the overall spleen preservation rate was 76.6%. According to cumulative sum analysis, the learning curve of LsvspDP was the 33rd case and several plateaus were observed during the learning curve phase. Old age (P=0.001), tail location (P=0.038), and large tumor (P=0.01) were independent risk factors of failed splenic vessels preservation, whereas the cut-off point of tumor size for prediction of spleen preservation was 5.4 cm. The complication rates were 7.8%, 7.8%, and 12.5% for Clavien grade I, II, and III, respectively, and 0% for Clavien grade IV or V. The rate of postoperative pancreatic fistula-grade B was 14.8%, among which the tail location was lower than the nontail location (0% vs. 24.3%; P=0.008). The mean value of operative time, blood loss, and hospital stay were 198±67 minutes, 139±242 mL, and 8.5±5.6 days, respectively. Conclusions In LsvspDP, the inferior-posterior splenic vein approach resulted in high splenic vessels and spleen preservation rate. Thirty-three patients were required to overcome the learning curve. Old age, tail location, and large tumor size were independent factors for the failure of splenic vessels preservation, whereas the cut-off value for tumor size was 5.4 cm to predict splenic vessels preservation.

Hsin-Hsien Yu,1–3 Mao-Chih Hsieh,2,3 Szu-Yuan Wu,4,5 Edgar D Sy,6 Yan-Shen Shan1,6 1Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 3Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 5Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 6Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan Background: Duodenal–jejunal bypass (DJB) is an important component of many types of current bariatric surgery including Roux-en-Y gastric bypass, mini-gastric bypass, biliopancreatic diversion, duodenal switch, and DJB plus sleeve gastrectomy. Surgery is often observed to ameliorate nonalcoholic steatohepatitis (NASH), but without a clearly delineated mechanism. In this study, we investigated the effects of DJB in diet-induced obese rats with NASH. Materials and methods: Male Wistar rats were divided into four groups and fed the following diets over 6 months: A) normal chow (NC group, n=6); B) methionine–choline-deficient (MCD)–high-fat (HF) diet (HF group, n=6); C) MCD–HF diet for 3 months followed by DJB and MCD–HF diet for subsequent 3 months (DJB group, n=6); and D) MCD–HF diet for 3 months followed by treatment with pioglitazone (PGZ) with MCD–HF diet for subsequent 3 months (PGZ group, n=6). Body weight, glucose tolerance, the homeostatic model assessment-insulin resistance index, and lipid profiles were compared. Liver and visceral adipose tissue histology, inflammatory marker and hepatic stellate cell (HSC) activity, and hepatocyte autophagy were assessed. Results: Compared with the HF group, the DJB group showed improved body weight, insulin sensitivity, lipid metabolism, and steatosis severity. The DJB group exhibited a significantly lower nonalcoholic fatty liver disease activity score than the HF and PGZ group (P

Objective Obesity and type 2 diabetes mellitus (T2DM) are risk factors for nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis. This study assessed pegbelfermin (BMS-986036), recombinant PEGylated human fibroblast growth factor 21 (FGF21), in patients with obesity and T2DM predisposed to fatty liver. Methods In this randomized, double-blind, placebo-controlled study, patients with T2DM and BMI of 30 to 50 kg/m2 received subcutaneous pegbelfermin (1, 5, or 20 mg daily or 20 mg weekly; n = 96) or placebo (n = 24) for 12 weeks. Primary end points were safety, tolerability, and change in HbA1c. Additional end points included insulin sensitivity, lipids, adiponectin, and disease progression biomarkers. Results There were no significant effects of pegbelfermin versus placebo on HbA1c. Pegbelfermin 20 mg/d significantly improved high-density lipoprotein cholesterol (P = 0.015) and triglycerides (P = 0.037). All pegbelfermin regimens significantly increased adiponectin levels; 20-mg daily and weekly regimens decreased serum PRO-C3. Most adverse events were mild; the most frequent adverse events were injection-site bruising and diarrhea. Conclusions Twelve-week pegbelfermin treatment did not impact HbA1c concentrations, but QW and higher daily doses were associated with improved metabolic parameters and fibrosis biomarkers in patients with obesity and T2DM predisposed to fatty liver. These results support evaluation of pegbelfermin in patients with obesity-related metabolic diseases (e.g., nonalcoholic steatohepatitis).

Fibrosis, resulted from the imbalance of fibrogenesis and fibrolysis, is a key readout of disease progression in nonalcoholic steatohepatitis (NASH) and reflects mortality risk. Non-invasive biomarkers capable of diagnosing fibrosis stages and monitoring fibrosis changes in NASH patients are urgently needed. This study is to evaluate collagen formation and degradation biomarkers, reflective of fibrogenesis or fibrolysis, in patients with biopsy proven NASH. Collagen formation biomarker PRO-C3 and PRO-C6 levels were significantly higher in patients with advanced fibrosis stage 3–4 than those with fibrosis stage 0–2. Elevated PRO-C3 levels were also associated with severe lobular inflammation and ballooning, but not with steatosis. Multivariate logistic regression analysis identified PRO-C3 and PRO-C6 to be independently related to fibrosis stage. PRO-C3 showed similar performance to identify patients with advanced fibrosis in discovery and validation cohorts. Furthermore, in a longitudinal study cohort with paired biopsies, mean PRO-C3 increased with worsening of fibrosis and decreased with fibrosis improvement. The results suggest that PRO-C3 may be a potentially useful biomarker in identifying patients with advanced fibrosis and active fibrogenesis, as well as in assessing changes in fibrosis over time. It is worthy of further evaluation to confirm its diagnostic value and clinical utility.

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by androgen excess and ovarian dysfunction and presents with increased cardiometabolic risk factors such as obesity, insulin resistance, and elevated blood pressure (BP). We previously reported that administration of dihydrotestosterone (DHT) to female rats elicits cardiometabolic derangements similar to those found in women with PCOS. In this study, we tested the hypothesis that the DHT-mediated cardiometabolic derangements observed in PCOS are long lasting despite DHT withdrawal. Four-week-old female Sprague Dawley rats were treated with DHT (7.5 mg/90 days) or placebo for 6 months. DHT was discontinued (ex-DHT), and rats were followed for 6 additional months. After 6 months of DHT withdrawal, food intake, body weight, fat and lean mass, fasting plasma insulin, leptin, and adiponectin were elevated in ex-DHT rats. BP remained significantly elevated, and enalapril, an angiotensin-converting enzyme (ACE) inhibitor, normalized BP in ex-DHT rats. Expression of components of the intrarenal renin-angiotensin system was increased in ex-DHT rats. The cardiometabolic features found in ex-DHT rats were associated with lower plasma androgen levels but increased expression of renal and adipose tissue androgen receptors. In summary, androgen-induced cardiometabolic effects persisted after DHT withdrawal in a PCOS experimental model. Activation of intrarenal renin-angiotensin system plays a major role in the androgen-mediated increase in BP in ex-DHT. Upregulation of the renal and adipose tissue androgen receptor may explain the long-lasting effects of androgens. In clinical scenarios characterized by hyperandrogenemia in women, prompt normalization of androgen levels may be necessary to prevent their long-lasting cardiometabolic effects., Cardiometabolic derangements persist after 6 months of dihydrotestosterone withdrawal in a rat model of androgen-induced polycystic ovary syndrome.

Synthesis of silver nanoparticles (AgNPs) was carried out in aqueous solutions. Silver nitrate was used as precursor, carboxymethyl cellulose (CMC) as stabilising agent, and sodium borohydride as reducing agent. The reaction was semicontinuous by feeding both the precursor and reducing agent into the stabilising agent aqueous solution in an alternated fashion. Weight ratios of 1:1 AgNO3:CMC were used in the reduction reactions. AgNPs were characterised by UV–vis spectroscopy, transmission electronic microscopy (TEM), and X-ray diffraction. The formation of AgNPs was confirmed by the presence of an absorption peak about 400 nm using UV–vis spectrophotometry. Spheroidal nanoparticles with an average diameter between 5 and 90 nm were observed by TEM. High productivity of AgNPs was obtained at lower reaction times and at low temperature compared with others previously reported in the literature.

The aim of the current study (Clinical trial reg. no. NCT02715193, clinicaltrials.gov) was to study the efficacy and safety of REMD-477, a glucagon receptor antagonist, in type 1 diabetes. This was a randomized controlled trial in which 21 patients with type 1 diabetes were enrolled. Glycaemic control and insulin use were evaluated in outpatient and inpatient settings, before and after a single 70-mg dose of REMD-477 (half-life 7-10 days) or placebo. Inpatient insulin use was 26% (95% CI, 47%, 4%) lower 1 day after dosing with REMD-477 than with placebo (P = .02). Continuous glucose monitoring during post-treatment days 6 to 12 showed that average daily glucose was 27 mg/dL lower (P.001), percent time-in-target-range (70-180 mg/dL) was ~25% greater (~3.5 h/d) (P = .001), and percent time-in-hyperglycaemic-range (180 mg/dL) was ~40% lower (~4 h/d) (P = .001) in the REMD-477 group than in the placebo group, without a difference in percent time-in-hypoglycaemic-range (70 mg/dL). No serious adverse events were reported. Glucagon receptor antagonism decreases insulin requirements and improves glycaemic control in patients with type 1 diabetes.

Cholera is a global health problem causing up to 143,000 deaths every year. With the surge of suspected cholera cases exceeding 1.2 million in the largest ongoing worldwide humanitarian crisis since 2016, cholera has come to the fore as a global problem. Taking into consideration that the disease is mainly spread by contaminated water, there is a crucial need to ensure that water sources and food are not contaminated with toxigenic Vibrio cholerae, which is the pathogen that causes cholera disease. Determining if water sources are contaminated with the bacteria, and early diagnosis of suspected cholera cases are the two most important strategies to prevent the spread of this disease. However, plate culturing remains the gold standard for V. cholerae detection, which takes days to obtain results. Although molecular detection techniques are faster and more sensitive in detecting the bacteria, they require infrastructure and trained users that are not available in many situations. The field of biosensors is evolving away from sensing mechanisms to focus on the needs of healthcare providers and consumers. Medical professionals and industry care about using the best device for a specific problem more than how the instrument performs its function. Therefore, this review is organized by specific use cases and lists which analytical tools are currently available for each situation associated with Vibrio cholerae detection/monitoring and cholera disease diagnosis. We believe this format will help accelerate the translation of technology from the bench into products and provide insights about which areas require additional research.

Objective: We aimed to detect and characterize hepatitis E virus (HEV) RNA in sera samples from a pediatric population infected with the hepatitis A virus (HAV) exhibiting acute hepatitis and to correlate the infection status with the clinical outcome. Methods: Seventy-five ELISA-positive samples from children containing anti-HAV and anti-HEV IgM were used to amplify and characterize partial regions within HEV ORF2. A statistical comparison of clinical data between HEV IgM-positive/HEV RNA-positive patients and HEV IgM-positive/HEV RNA-negative patients was performed. Results: Thirteen out of 75 IgM-positive samples provided amplification of discrete regions of the HEV genome. Nested RT-PCR-based detection and subsequent sequencing of 5 samples confirmed the identity of HEV genotype 1 (G1), which had not been previously reported in Mexico. Though not significant, a trend towards exacerbated clinical manifestations was found in HEV RNA-positive patients relative to HEV RNA-negative patients. Conclusions: An elevated rate of G1 RNA was detected. Hepatitis E seems to be a neglected disease in Mexico and epidemic strains of HEV are likely to play a role as causative agents of acute hepatitis in highly exposed children. Although HAV is endemic in Mexico, an HEV-RNA detection rate of 17% in co-infected samples shows the need for screening for HEV as a part of future vaccination strategies.

Burkitt's lymphoma (BL) is usually diagnosed in children and young adults. Adults with Burkitt's lymphoma, particularly those with advanced stage disease, present with poorer prognosis compared to children and very rarely as multiorgan tumors. Involvement of the gastrointestinal (GI) tract presents with GI tract symptoms and can cause intussusception. Herein, we report a 42-year-old, chronic schizophrenic woman, presenting with lower GI bleeding secondary to intussusception, and the radiologic study revealed multiple site organs involvement including terminal ileum, cecum, and bilateral ovaries. She underwent optimal cytoreduction procedure, bilateral salpingo-oophorectomy and radical right hemicolectomy with ileocolostomy, and adjuvant multiagents chemotherapy postoperatively with the regimen of CODOX-M/IVAC for four courses without radiologic evidence of tumor recurrence after a 6-year follow-up.

In clinical practice, delays in obtaining culture results impact patient care and the ability to tailor antibiotic therapy. Despite the advancement of rapid molecular diagnostics, the use of plate cultures inoculated from swab samples continues to be the standard practice in clinical care. Because the inoculation culture process can take between 24 and 48h before a positive identification test can be run, there is an unmet need to develop rapid throughput methods for bacterial identification. Previous work has shown that pyocyanin can be used as a rapid, redox-active biomarker for identifying Pseudomonas aeruginosa in clinical infections. However, further validation is needed to confirm pyocyanin production occurs in all clinical strains of P. aeruginosa. Here, we validate this electrochemical detection strategy using clinical isolates obtained from patients with hospital-acquired infections or with cystic fibrosis. Square-wave voltammetric scans of 94 different clinical P. aeruginosa isolates were taken to measure the concentration of pyocyanin. The results showed that all isolates produced measureable concentrations of pyocyanin with production rates correlated with patient symptoms and comorbidity. Further bioinformatics analysis confirmed that 1649 genetically sequenced strains (99.9%) of P. aeruginosa possess the two genes (PhzM and PhzS) necessary to produce pyocyanin, supporting the specificity of this biomarker. Confirming the production of pyocyanin by all clinically-relevant strains of P. aeruginosa is a significant step towards validating this strategy for rapid, point-of-care diagnostics.

This paper presents the design of a variable impedance actuator, called BAFSA, for the knee joint of a portable human gait rehabilitation exoskeleton. Such an actuator is specifically tailored to this joint, aimed at the application of robotic-assisted gait training therapies to restore the normal function of the impaired knee, taking into account kinematics, kinetics and anthropometric requirements along the gait cycle. Mechanical design and functioning of the actuator are thoroughly shown, with particular emphasis upon the variable stiffness mechanism, which consists of an axial floating spring, bidirectionally actuated in an antagonistic way. This is combined with a complimentary system, named BLAPS, that allows to vary automatically the preload stiffness, and sustain it before external loads with no further energy cost to the actuator motors. Simulations reproducing a normal gait cycle on level terrain are carried out to demonstrate the feasibility of the design, considering both power and energy consumption to validate the actuator performance. Thus, the actuator here developed is suitable to implement different rehabilitation strategies on the impaired knee joint. Finally, complete disclosure is achieved by presenting the technical specifications of the BAFSA, which fulfills all the requirements that were initially established as design criteria.

Background Solid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs) and circulating tumor DNAs (ctDNA). Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches. Methods We isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments. Results Mutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II) and late stage (III and IV) cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177) of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that are consistent with cancer progression or response to EGFR drug treatment. Conclusions This study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0468-1) contains supplementary material, which is available to authorized users.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have an elevated prevalence of cardiometabolic risk factors that worsen after menopause. Liraglutide (Lira), a glucagon-like peptide-1 receptor agonist, has shown beneficial metabolic effects in small clinic trials in reproductive-age women with PCOS. We have shown that chronic hyperandrogenemia in an experimental model of postmenopausal PCOS is associated with an adverse cardiometabolic profile and upregulation of the intrarenal renin-angiotensin system (RAS). We analyzed the effect of Lira in the cardiometabolic profile, intrarenal RAS, and blood pressure (BP) in postmenopausal PCOS. Four-week-old female Sprague Dawley rats were treated with DHT or placebo for 17 months. Lira administration during the last 3 weeks caused a bigger reduction in food intake, body weight, fat mass, and homeostasis model assessment of insulin resistance index in PCOS than in control rats. Moreover, Lira improved dyslipidemia and elevated leptin levels in PCOS. In contrast, Lira decreased intrarenal expression of RAS components only in the control group. Lira transiently increased heart rate and decreased BP in control rats. However, Lira did not modify BP but increased heart rate in PCOS. The angiotensin-converting-enzyme inhibitor enalapril abolished the BP differences between PCOS and control rats. However, Lira coadministration with enalapril further reduced BP only in control rats. In summary, Lira has beneficial effects for several cardiometabolic risk factors in postmenopausal PCOS. However, hyperandrogenemia blunted the BP-lowering effect of Lira in postmenopausal PCOS. Androgen-induced activation of intrarenal RAS may play a major role mediating increases in BP in postmenopausal PCOS.

INTRODUCTION: Treatment options are limited for people infected with hepatitis C virus (HCV) with decompensated liver disease. The C-SALT study assessed elbasvir (EBR) plus grazoprevir (GZR) in individuals with HCV genotype 1 infection and Child-Pugh class B (CP-B) cirrhosis. METHODS: In this 12-week, phase 2, nonrandomized, open-label study (NCT02115321; Protocol MK-5172-059), participants with CP-B cirrhosis received EBR 50 mg plus GZR 50 mg once daily, and a control group of noncirrhotic participants received EBR 50 mg plus GZR 100 mg once daily. The primary endpoint was sustained virologic response 12 weeks after the end of therapy. RESULTS: Sustained virologic response at 12 weeks after the end of therapy was achieved by 27/30 (90.0%) CP-B participants and 10/10 (100.0%) noncirrhotic participants. Two participants relapsed, and one died during follow-up after having undetectable HCV RNA at the end of treatment. Most CP-B participants had stable or improved model for end-stage liver disease and Child-Pugh scores at follow-up week 12 compared with baseline. There was no significant difference in drug exposure between groups, despite the differing GZR dose. Adverse events occurring in >10% of participants were fatigue (CP-B: 30.0%; noncirrhotic: 30.0%), arthralgia (16.7%; 20.0%), nausea (10.0%; 20.0%), and headache (10.0%; 50.0%). No serious treatment-related adverse events or hepatic events of clinical interest occurred. CONCLUSIONS: EBR 50 mg plus GZR 50 mg once daily for 12 weeks was highly effective and well tolerated in a traditionally hard-to-treat population. TRANSLATIONAL IMPACT: Although EBR plus reduced-dose GZR is not available for people with CP-B cirrhosis, these results complement phase 2/3 trial data and real-world experience with EBR/GZR.

This review provides a comprehensive summary of issues associated with treating polyclonal bacterial biofilms in chronic diabetic wounds. We use this as a foundation and discuss the alternatives to conventional antibiotics and the emerging need for suitable drug delivery systems. In recent years, extraordinary advances have been made in the field of nanoparticle synthesis and packaging. However, these systems have not been incorporated into the clinic for treatments other than for cancer or severe genetic diseases. We present a unifying perspective on how the field is evolving and the need for an early amalgamation of engineering principles and a biological understanding of underlying phenomena in order to develop a therapy that is translatable to the clinic in a shorter time.

Preparation of silver nanoparticles was carried out by semicontinuous reduction of Ag+ ions at low temperatures. Silver nitrate was used as the Ag0 precursor, the carboxymethyl cellulose (CMC) as stabilizer and primary reducing agent, and sodium borohydride as reducing agent. Weight ratios of 1 : 1 and 1 : 2 of AgNO3 : CMC were used for carrying out the reactions. Silver nanoparticles were characterized by UV-VIS spectroscopy, transmission electronic microscopy (TEM), and X-ray diffraction (XRD). The formation of silver nanoparticles was confirmed by XRD spectroscopy and by the presence of an absorption peak around 400 nm in the UV-visible spectrum. Unimodal size distributions of spheroidal nanoparticles were observed by TEM. Greater productivities than those reported by other authors were obtained with the advantage of using a lower temperature and minor reaction times. By using a higher CMC/AgNO3 weight ratio or a higher concentration of AgNO3, AgNPs with larger average size were produced. Antibacterial activity of AgNPs against S. aureus and E. coli was determined by the agar disk diffusion method. The higher the AgNPs concentration, the larger the inhibition zone. The minimum inhibitory concentration (MIC) of AgNPs against S. aureus and E. coli was 5 μg/disk.

In clinical practice, point-of-care diagnostic testing has progressed rapidly in the last decade. For the field of wound care, there is a compelling need to develop rapid alternatives for bacterial identification in the clinical setting, where it generally takes over 24 hours to receive a positive identification. Even new molecular and biochemical identification methods require an initial incubation period of several hours to obtain a sufficient number of cells prior to performing the analysis. Here we report the use of an inexpensive, disposable electrochemical sensor to detect pyocyanin, a unique, redox-active quorum sensing molecule released by Pseudomonas aeruginosa, in wound fluid from patients with chronic wounds enrolled in the WE-HEAL Study. By measuring the metabolite excreted by the cells, this electrochemical detection strategy eliminates sample preparation, takes less than a minute to complete, and requires only 7.5 μL of sample to complete the analysis. The electrochemical results were compared against 16S rRNA profiling using 454 pyrosequencing. Blind identification yielded 9 correct matches, 2 false negatives, and 3 false positives giving a sensitivity of 71% and specificity of 57% for detection of Pseudomonas. Ongoing enhancement and development of this approach with a view to develop a rapid point-of-care diagnostic tool is planned.

Highlights • Combination of vitelline fistula and omphalocele during postnatal life is a rare congenital. • Non-meconium stained amniotic fluid does not proved the absence of patent vitelline fistula. • At birth, vitelline fistula associated with omphalocele can be easily diagnosed by the stoma like lesion located lateral to umbilical cord insertion and post-partum passage of meconium stool. • Bowel perforation with rupture of omphalocele sac can be differentiated by the absence of meconium contamination of abdomen, absence inflammatory change of bowel and stoma like lesion on the intact omphalocele sac. • Surgical option for vitelline duct, includes fistulectomy, wedge resection or segmental resection of bowel while omphalocele can be close depending of the size defect, either primary or stage repair., Introduction Combination vitelline fistula (VF) and omphalocele at birth is a rare congenital anomaly as a result disturbance in organogenesis with failure of normal return of intestines into the abdominal cavity and failed obliteration of the vitelline duct. Case presentation A newborn presented with omphalocele sac with visible intestine, stoma like lesion with prolapsing mucosa just lateral to the umbilical cord and passage of meconium stool. Operative surgery was confirmed an intact omphalocele sac and vitelline fistula. Fistulectomy, using wedge resection of the small bowel and primary closure abdominal wall defect. Discussion In our review of literature, VF associated with omphalocele had not been reported. Combination of anomaly maybe misleading, however, can be easily diagnosed the location of VF opening on the omphalocele sac, which is adjacent to the umbilical cord and luminal passage of meconium stool after birth. A fistulogram may be the best initial diagnostic imaging approach for identifying and confirmation of a fistula tract. Conclusion VF associated with omphalocele is rare. Post-natal diagnosis is easily by gross appearance stoma like lesion, which is located just lateral of the umbilical cord, an intact omphalocele sac and post-natal meconium stool passage.