Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 127
Filter
2.
J Pediatr ; 272: 114099, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38754775

ABSTRACT

OBJECTIVE: To increase the percentage of patients who undergo rapid magnetic resonance imaging (rMRI) rather than computed tomography (CT) for evaluation of mild traumatic brain injury (TBI) from 45% in 2020 to 80% by December 2021. STUDY DESIGN: This was a quality improvement initiative targeted to patients presenting to the pediatric emergency department presenting with mild TBI, with baseline data collected from January 2020 to December 2020. From January 2021 to August 2021, we implemented a series of improvement interventions and tracked the percentage of patients undergoing neuroimaging who received rMRI as their initial study. Balancing measures included proportion of all patients with mild TBI who underwent neuroimaging of any kind, proportion of patients requiring sedation, emergency department length of stay, and percentage with clinically important TBI. RESULTS: The utilization of rMRI increased from a baseline of 45% to a mean of 92% in the intervention period. Overall neuroimaging rates did not change significantly after the intervention (19.8 vs 23.2%, P = .24). There was no difference in need for anxiolysis (12 vs 7%, P = .30) though emergency department length of stay was marginally increased (1.4 vs 1.7 hours, P = < 0.01). CONCLUSION: In this quality improvement initiative, transition to rMRI as the primary imaging modality for the evaluation of minor TBI was achieved at a level 1 pediatric trauma center with no significant increase in overall use of neuroimaging.

3.
Clin Toxicol (Phila) ; 62(3): 183-189, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38587109

ABSTRACT

INTRODUCTION: Mental health problems among youth have escalated over the past decade, with increased rates of self-harm, including suicide attempts by ingestion. Social media use has been linked to youth mental health, including "challenges" urging youth to ingest substances for recreational and other purposes. We hypothesized that social media challenges for particular substances would temporally correspond with increased ingestions of these substances. METHODS: We identified peak Google Trends search times for social media ingestion challenges involving diphenhydramine, laundry pods, nutmeg, and cinnamon, and used data from America's Poison Centers National Poison Data System to plot reported ingestions 3 months before and after peak searches in school-aged children. RESULTS: There were 2,169 individuals in the analysis. Diphenhydramine was the most frequently reported ingestion for misuse/abuse and suicidal purposes (n = 266 and 1,609, respectively). For all ingestions together, 45 percent (n = 979) had a moderate health effect, and 6.35 percent (n = 137) had a major health effect. Time of peak searches corresponded with increased ingestions for each substance. DISCUSSION: We found a temporal relationship between peak Google Trends searches for ingestion challenges and ingestions of that substance reported to United States poison centers. Compared to misuse/abuse ingestions, most suicidal ingestions peaked 1-2 months later, suggesting a public health opportunity for intervention. LIMITATIONS: This retrospective observational study does not establish causal effect. All data are a result of self-reporting of the exposures, which may lead to a reporting bias. Google Trends is not the only search engine and likely underestimates the true incidence of social media posts. CONCLUSIONS: Additional research is needed on the relationship between social media and youth mental health, particularly around "challenges" that place youths' health at risk. There may be opportunities for intervention to decrease medical and mental health sequelae of these challenges.


Subject(s)
Poison Control Centers , Social Media , Humans , Poison Control Centers/statistics & numerical data , Child , Adolescent , Male , Female , Suicide, Attempted/statistics & numerical data , United States/epidemiology , Diphenhydramine/poisoning
4.
BMJ Open ; 14(1): e074918, 2024 01 18.
Article in English | MEDLINE | ID: mdl-38238179

ABSTRACT

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) affects approximately one in four individuals and its prevalence continues to rise. The advanced stages of NAFLD with significant liver fibrosis are associated with adverse morbidity and mortality outcomes. Currently, liver biopsy remains the 'gold-standard' approach to stage NAFLD severity. Although generally well tolerated, liver biopsies are associated with significant complications, are resource intensive, costly, and sample only a very small area of the liver as well as requiring day case admission to a secondary care setting. As a result, there is a significant unmet need to develop non-invasive biomarkers that can accurately stage NAFLD and limit the need for liver biopsy. The aim of this study is to validate the use of the urine steroid metabolome as a strategy to stage NAFLD severity and to compare its performance against other non-invasive NAFLD biomarkers. METHODS AND ANALYSIS: The TrUSt-NAFLD study is a multicentre prospective test validation study aiming to recruit 310 patients with biopsy-proven and staged NAFLD across eight centres within the UK. 150 appropriately matched control patients without liver disease will be recruited through the Oxford Biobank. Blood and urine samples, alongside clinical data, will be collected from all participants. Urine samples will be analysed by liquid chromatography-tandem mass spectroscopy to quantify a panel of predefined steroid metabolites. A machine learning-based classifier, for example, Generalized Matrix Relevance Learning Vector Quantization that was trained on retrospective samples, will be applied to the prospective steroid metabolite data to determine its ability to identify those patients with advanced, as opposed to mild-moderate, liver fibrosis as a consequence of NAFLD. ETHICS AND DISSEMINATION: Research ethical approval was granted by West Midlands, Black Country Research Ethics Committee (REC reference: 21/WM/0177). A substantial amendment (TrUSt-NAFLD-SA1) was approved on 26 November 2021. TRIAL REGISTRATION NUMBER: ISRCTN19370855.


Subject(s)
Non-alcoholic Fatty Liver Disease , Humans , Biomarkers , Biopsy/adverse effects , Liver/pathology , Liver Cirrhosis/diagnosis , Metabolome , Multicenter Studies as Topic , Non-alcoholic Fatty Liver Disease/epidemiology , Retrospective Studies , Steroids , Validation Studies as Topic
5.
Aliment Pharmacol Ther ; 59(2): 186-200, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37904314

ABSTRACT

BACKGROUND: Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects. AIMS: To evaluate the long-term safety and efficacy of seladelpar in patients with PBC. METHODS: In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years. RESULTS: There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2. CONCLUSIONS: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. CLINICALTRIALS: gov: NCT03301506; Clinicaltrialsregister.eu: 2017-003910-16.


Subject(s)
Cholestasis , Liver Cirrhosis, Biliary , Humans , Ursodeoxycholic Acid/adverse effects , Liver Cirrhosis, Biliary/drug therapy , Cholestasis/drug therapy , Cholestasis/chemically induced , Biomarkers , Alkaline Phosphatase , Bilirubin
6.
J Clin Transl Sci ; 7(1): e235, 2023.
Article in English | MEDLINE | ID: mdl-38028345

ABSTRACT

Background: The pediatric medical device development (PMDD) process is highly complex, beset by a variety of financial, technical, medical, and regulatory barriers. Startup company innovators and academic investigators often struggle with accessing specialized knowledge relating to regulatory requirements, product development, research, and marketing strategies. Objectives: The West Coast Consortium for Technology & Innovation in Pediatrics (CTIP) conducted an educational needs assessment to understand knowledge gaps and inform our educational strategy. Methods: We surveyed a total of 49 medical device startups and 52 academic investigators. Electronic surveys were developed for each group on Qualtrics and focused on manufacturing, regulatory, research, commercialization, and funding. Descriptive statistics were used. Results: A larger proportion of academic investigator respondents had a clinical background compared to the startup respondents (45% vs. 22%). The biggest barriers for academic investigators were understanding regulatory and safety requirements testing (52%) and finding and obtaining non-dilutive funding was the most difficult (54%). Among startups, understanding clinical research methods and requirements was the biggest barrier (79%). Conclusion: Startup companies and academic investigators have similar, but not identical, educational needs to better understand the PMD development process. Investigators need more support in identifying funding sources, while startup companies identified an increased need for education on research regulatory topics. These findings can help guide curriculum development as well as opportunities for partnerships between academia and startups.

7.
JHEP Rep ; 5(12): 100897, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38023607

ABSTRACT

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is associated with liver and cardiovascular morbidity and mortality. Recently published NAFLD Quality Standards include 11 key performance indicators (KPIs) of good clinical care. This national study, endorsed by British Association for the Study of the Liver (BASL) and British Society of Gastroenterology (BSG), aimed to benchmark NAFLD care in UK hospitals against these KPIs. Methods: This study included all new patients with NAFLD reviewed in the outpatient clinic in the months of March 2019 and March 2022. Participating UK hospitals self-registered for the study through BASL/BSG. KPI outcomes were compared using Fisher's exact or Chi-square tests. Results: Data from 776 patients with NAFLD attending 34 hospitals (England [25], Scotland [four], Wales [three], Northern Ireland [two]) were collected. A total of 85.3% of hospitals reported established local liver disease assessment pathways, yet only 27.9% of patients with suspected NAFLD had non-invasive fibrosis assessment documented at the point of referral to secondary care. In secondary care, 79.1% of patients had fibrosis assessment. Assessment of cardiometabolic risk factors including obesity, type 2 diabetes, hypertension, and smoking were conducted in 73.2%, 33.0%, 19.3%, and 54.9% of all patients, respectively. There was limited documentation of diet (35.7%) and exercise advice (55.1%). Excluding those on statins, only 9.1% of patients with NAFLD at increased cardiovascular risk (T2DM and/or QRISK-3 >10%) had documented discussion of statin treatment. Significant KPI improvements from 2019 to 2022 were evident in use of non-invasive fibrosis assessment before secondary care referral, statin recommendations, and diet and exercise recommendations. Conclusions: This national study identified substantial variation in NAFLD management in the UK with clear areas for improvement, particularly fibrosis risk assessment before secondary care referral and management of associated cardiometabolic risk factors. Impact and implications: This study identified significant variation in the management of NAFLD in the UK. Only 27.9% of patients with suspected NAFLD had non-invasive fibrosis assessment performed to identify those at greater risk of advanced liver disease before specialist referral. Greater emphasis is needed on the management of associated cardiometabolic risk factors in individuals with NAFLD. Hospitals with multidisciplinary NAFLD service provision had higher rates of fibrosis evaluation and assessment and management of cardiometabolic risk than hospitals without multidisciplinary services. Further work is needed to align guideline recommendations and real-world practice in NAFLD care.

10.
Am J Emerg Med ; 70: 61-65, 2023 08.
Article in English | MEDLINE | ID: mdl-37201452

ABSTRACT

OBJECTIVE: To evaluate the association between capillary refill time (CRT) measured by a medical device and sepsis among patients presenting to the Emergency Department (ED). METHODS: This prospective observational study enrolled adult and pediatric patients during ED triage when sepsis was considered a potential diagnosis by the triage nurse. Patients were enrolled at an academic medical center between December 2020 and June 2022. CRT was measured by a research assistant using an investigational medical device. The outcomes included sepsis and septic shock defined using sep-3 criteria, septic shock defined as IV antibiotics and a vasopressor requirement, ICU admission, and hospital mortality. Other measures included patient demographics and vital signs at ED triage. We evaluated univariate associations between CRT and sepsis outcomes. RESULTS: We enrolled 563 patients in the study, 48 met Sep-3 criteria, 5 met Sep-3 shock criteria, and 11 met prior septic shock criteria (IV antibiotics and vasopressors to maintain mean arterial pressure of 65). Sixteen patients were admitted to the ICU. The mean age was 49.1 years, and 51% of the cohort was female. The device measured CRT was significantly associated with the diagnosis of sepsis by sep-3 criteria (OR 1.23, 95% CI 1.06-1-43), septic shock by sep-3 criteria (OR 1.57, 95% CI 1.02-2.40), and septic shock defined as receipt of IV antibiotics and a vasopressor requirement (OR 1.37, 95% CI 1.03-1.82). Patients with CRT >3.5 s measured by the DCR device had an odds ratio of 4.67 (95%CI 1.31-16.1) of septic shock (prior definition), and an odds ratio of 3.97 (95% CI 1.99-7.92) of ICU admission, supporting the potential for the 3.5-s cutoff of the DCR measurement. CONCLUSIONS: CRT measured by a medical device at ED triage was associated with the diagnosis of sepsis. Objective CRT measurement using a medical device may be a relatively simple way to improve sepsis diagnosis during ED triage.


Subject(s)
Sepsis , Shock, Septic , Adult , Humans , Female , Child , Middle Aged , Triage , Retrospective Studies , Emergency Service, Hospital , Vasoconstrictor Agents/therapeutic use , Hospital Mortality , Anti-Bacterial Agents
11.
Am J Emerg Med ; 69: 1-4, 2023 07.
Article in English | MEDLINE | ID: mdl-37027956

ABSTRACT

OBJECTIVES: Pediatric mental health presentations continue to increase across the US. These patients often board for significant periods of time and may require more resources than other acute non-mental health patients. This has important implications for the overall function of the emergency department (ED) as well as care of all ED patients. METHODS: This study evaluated a policy developed to allow for inpatient hospital admission when 30% of the ED was occupied by boarding patients at a tertiary care children's hospital. RESULTS: We found an increase in the number of patients for whom this policy applied, and increased days/month this policy was executed over time. There was an increase in the average ED LOS and left without being seen rate during this time which we hypothesize would have been higher without this policy. CONCLUSIONS: A hospital policy allowing mental health patients to be admitted to the inpatient hospital once stabilized has the potential to improve ED flow and functionality.


Subject(s)
Hospitalization , Patient Admission , Humans , Child , Length of Stay , Retrospective Studies , Emergency Service, Hospital
13.
Pediatr Emerg Care ; 39(8): 569-573, 2023 Aug 01.
Article in English | MEDLINE | ID: mdl-36252055

ABSTRACT

OBJECTIVE: Dehydration is a commonly encountered problem worldwide. Current clinical assessment is limited by subjectivity and limited provider training with children. The objective of this study is to investigate a new noninvasive, point-of-care technology that measures capillary refill combined with patient factors to accurately diagnose dehydration. METHODS: This is a prospective observational study at a tertiary care children's hospital in Buenos Aires, Argentina. Patients were eligible if younger than 10 years who presented to the emergency department with vomiting and/or diarrhea whom the triage nurse deems to be potentially dehydrated. Patients had the digital capillary refill device done on presentation in addition to standard of care vital signs and weight. Patients had serial weights measured on hospital scales throughout their stay. The primary outcome was dehydration, which was calculated as a percent change in weight from admission to discharge. RESULTS: Seventy-six children were enrolled in the study with 56 included in the final analysis. A stepwise forward method selection chose malnutrition, temperature, and systolic blood pressure for the multivariable model. The area under the curve for the final model was fair (0.7431). To further look into the utility of such a device in the home setting where blood pressure is not available often, we reran the model without systolic blood pressure. The area under the curve for the final model was 0.7269. CONCLUSIONS: The digital capillary refill point-of-care device combined with readily available patient-specific factors may improve the ability to detect pediatric dehydration and facilitate earlier treatment or transfer to higher levels of care.


Subject(s)
Dehydration , Point-of-Care Systems , Child , Humans , Infant , Dehydration/diagnosis , Dehydration/therapy , Prospective Studies , Diarrhea , Technology
14.
Clin Toxicol (Phila) ; 61(1): 64-71, 2023 01.
Article in English | MEDLINE | ID: mdl-36469528

ABSTRACT

CONTEXT: Childhood and adolescent misuse and abuse exposures remain a serious public health challenge in the United States. This study aimed to describe recent trends and patterns of intentional substance misuse and abuse exposures among school-aged children and adolescents in the United States. METHODS: This study was a retrospective cohort study of intentional misuse and abuse exposures in children 6 through 18 years reported to the National Poison Data System (NPDS) from January 1, 2000, through December 31, 2020. Demographic trends, reported clinical effects, treatments, management sites, and health outcomes were assessed overall and within four age categories: 6-9, 10-12, 13-15, and 16-18. RESULTS: Between 2000 and 2020, there were 338,727 cases regarding intentional misuse and abuse exposures for children ages 6 through 18 years old. Overall, misuse/abuse ingestions fluctuated over time, with a peak in 2011. The majority of intentional misuse/abuse ingestions occurred in males (58.3%), and more than 80% of all reported exposure cases occurred in youth aged 13 to 18. 32.6% of ingestions resulted in worse than minor clinical outcomes. Older age groups had a greater number of severe medical outcomes compared to younger age groups. Major or life-threatening exposures (including those resulting in death) were more common in males. Overall, deaths were rare (n = 450), 0.1%). Male sex, older age, abuse ingestions, exposure site of a public area or other residence, and multiple ingested substances were other factors associated with increased mortality. Marijuana exposure rates had the highest average monthly increase overall, with the most dramatic rise occurring from 2017 to 2020. Edible marijuana preparations accounted for the highest increase in call rates compared with all other forms of marijuana. DISCUSSION AND CONCLUSION: With over 330,000 poison center cases reported during the 20-year study period, intentional substance misuse and abuse exposures substantially impact the pediatric population. The substances most commonly misused/abused are more widely available substances such as over-the-counter medications, household products and pharmaceuticals commonly prescribed to youth. Differences in age and sex were evident, with males and adolescents more likely to abuse and misuse substances. Our study describes an upward trend in marijuana misuse/abuse exposures among youth, especially those involving edible products. These findings highlight an ongoing concern about the impact of rapidly evolving cannabis legalization on this vulnerable population.


Subject(s)
Cannabis , Marijuana Abuse , Poisons , Humans , Child , Male , United States/epidemiology , Adolescent , Aged , Retrospective Studies , Poison Control Centers , Eating
15.
Materials (Basel) ; 15(19)2022 Sep 27.
Article in English | MEDLINE | ID: mdl-36234032

ABSTRACT

A new cell topology named the dodecagonal (a polygon with twelve sides, short for Dod) cell is proposed to optimize the gate-to-drain capacitance (Cgd) and reduce the specific ON-resistance (Ron,sp) of 4H-SiC planar power MOSFETs. The Dod and the octagonal (Oct) cells are used in the layout design of the 650 V SiC MOSFETs in this work. The experimental results confirm that the Dod-cell MOSFET achieves a 2.2× lower Ron,sp, 2.1× smaller high-frequency figure of merit (HF-FOM), higher turn on/off dv/dt, and 29% less switching loss than the fabricated Oct-cell MOSFET. The results demonstrate that the Dod cell is an attractive candidate for high-frequency power applications.

16.
BMJ Open ; 12(9): e061167, 2022 09 28.
Article in English | MEDLINE | ID: mdl-36171027

ABSTRACT

OBJECTIVES: Previous literature on the effects of marijuana exposure on neonatal outcomes has been limited by the reliance on maternal self-report. The objective of this study was to examine the relationship of prenatal marijuana exposure on neonatal outcomes in infants with marijuana exposure confirmed with meconium drug testing. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Meconium drug screens obtained on infants born in a hospital system in the Pacific Northwest in the USA over a 2.5-year period. 1804 meconium drug screens were initially obtained, with 1540 drug screens included in the analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: Neonates with meconium drug screens positive for delta-9-tetrahydrocannabinol (THC) only were compared with neonates with negative drug screens. The following neonatal outcomes were examined: gestational age, preterm birth (<37 weeks), birth weight, low birth weight (defined as birth weight <2.5 kg), length, head circumference, Apgar scores and admission to the neonatal intensive care unit (NICU). Using multivariable logistical and linear regression, we controlled for confounding variables. RESULTS: 1540 meconium drug screens were included in the analysis, with 483 positive for delta-9-THC only. Neonates exposed to delta-9-THC had significantly lower birth weight, head circumference and length (p<0.001). Neonates with THC exposure had 1.9 times the odds (95% CI 1.3 to 2.7, p=0.001) of being defined as low birth weight. Birth weight was on average 0.16 kg lower (95% CI 0.10 to 0.22, p<0.001) in those exposed to THC. CONCLUSIONS: Prenatal marijuana exposure was significantly associated with decreases in birth weight, length and head circumference, and an increased risk of being defined as low birth weight. These findings add to the previous literature demonstrating possible negative effects of prenatal marijuana use on neonatal outcomes.


Subject(s)
Cannabis , Premature Birth , Birth Weight , Cannabis/adverse effects , Dronabinol/adverse effects , Female , Humans , Infant , Infant, Newborn , Pregnancy , Premature Birth/epidemiology , Retrospective Studies
17.
Pediatr Emerg Care ; 38(6): e1304-e1308, 2022 Jun 01.
Article in English | MEDLINE | ID: mdl-35510725

ABSTRACT

OBJECTIVE: The aim of this study was to assess national trends in recreational and suicidal ingestions of over-the-counter cough preparations that contain Coricidin. METHODS: Using the American Association of Poison Control Center's National Poison Data System, we obtained data from 2004 to 2017 on patients aged 13 to 19 years with an ingestion of "Coricidin." We examined trends over time overall and ingestion intent (recreational vs suicidal) using linear regression. We compared patient characteristics, substances ingested, clinical effects and therapies, and outcomes by suicidal versus misuse or recreational intention. RESULTS: An initial search with the inclusion criteria found 19,213 calls that matched study inclusion criteria. On average, there was a yearly linear increase of 180.0 (95% confidence interval [CI], 136.6-223.3; P < 0.01) ingestions per year. Within suicide ingestions, there was an average yearly increase of 97.9 (95% CI, 66.9-128.9; P < 0.01) ingestions, and within misuse/recreational ingestions, there was an average yearly increase of 82.1 (95% CI, 60.3-103.9; P < 0.01) ingestions. The most common clinical effect was tachycardia, which occurred in 42.4% of ingestions. Altered mental status, mydriasis, and ataxia were all more common in misuse/recreational ingestions. Suicidal ingestions resulted in more hospital admissions and need for medical treatment. Recreational-use coded calls peaked in 2013, whereas calls coded for suicide attempts have continued to rise dramatically, with a 50% increase in the 14-year study period. CONCLUSION: Combination Coricidin products are a major source of morbidity in adolescents. Targeted preventive measures in primary care offices or larger-scale policy/legislative efforts may be helpful to address this.


Subject(s)
Poison Control Centers , Suicidal Ideation , Adolescent , Eating , Humans , Nonprescription Drugs , Retrospective Studies , Suicide, Attempted , United States/epidemiology
18.
J Hepatol ; 77(2): 353-364, 2022 08.
Article in English | MEDLINE | ID: mdl-35367282

ABSTRACT

BACKGROUND & AIMS: We examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid. METHODS: In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy endpoint was ALP change from baseline to Week 8. RESULTS: Mean baseline ALP was 300, 345, and 295 U/L in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean ± standard error ALP reductions from baseline were 26 ± 2.8%, 33 ± 2.6%, and 41 ± 1.8% in the 2 mg (n = 11), 5 mg (n = 49), and 10 mg (n = 52) cohorts (all p ≤0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2 mg and 5 mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events. CONCLUSIONS: Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus. GOV NUMBER: NCT02955602 CLINICALTRIALSREGISTER. EU NUMBER: 2016-002996-91 LAY SUMMARY: Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10 mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores.


Subject(s)
Liver Cirrhosis, Biliary , Acetates , Adult , Alkaline Phosphatase , Disease Progression , Humans , Liver Cirrhosis, Biliary/drug therapy , Pruritus/chemically induced , Pruritus/etiology , Ursodeoxycholic Acid/adverse effects
19.
Sci Rep ; 12(1): 5562, 2022 04 01.
Article in English | MEDLINE | ID: mdl-35365728

ABSTRACT

Lipids play essential roles in the hepatitis C virus (HCV) life cycle and patients with chronic HCV infection display disordered lipid metabolism which resolves following successful anti-viral therapy. It has been proposed that HCV genotype 3 (HCV-G3) infection is an independent risk factor for hepatocellular carcinoma and evidence suggests lipogenic proteins are involved in hepatocarcinogenesis. We aimed to characterise variation in host lipid metabolism between participants chronically infected with HCV genotype 1 (HCV-G1) and HCV-G3 to identify likely genotype-specific differences in lipid metabolism. We combined several lipidomic approaches: analysis was performed between participants infected with HCV-G1 and HCV-G3, both in the fasting and non-fasting states, and after sustained virological response (SVR) to treatment. Sera were obtained from 112 fasting patients (25% with cirrhosis). Serum lipids were measured using standard enzymatic methods. Lathosterol and desmosterol were measured by gas-chromatography mass spectrometry (MS). For further metabolic insight on lipid metabolism, ultra-performance liquid chromatography MS was performed on all samples. A subgroup of 13 participants had whole body fat distribution determined using in vivo magnetic resonance imaging and spectroscopy. A second cohort of (non-fasting) sera were obtained from HCV Research UK for comparative analyses: 150 treatment naïve patients and 100 non-viraemic patients post-SVR. HCV-G3 patients had significantly decreased serum apoB, non-HDL cholesterol concentrations, and more hepatic steatosis than those with HCV-G1. HCV-G3 patients also had significantly decreased serum levels of lathosterol, without significant reductions in desmosterol. Lipidomic analysis showed lipid species associated with reverse cholesterol transport pathway in HCV-G3. We demonstrated that compared to HCV-G1, HCV-G3 infection is characterised by low LDL cholesterol levels, with preferential suppression of cholesterol synthesis via lathosterol, associated with increasing hepatic steatosis. The genotype-specific lipid disturbances may shed light on genotypic variations in liver disease progression and promotion of hepatocellular cancer in HCV-G3.


Subject(s)
Hepacivirus , Hepatitis C , Cholesterol , Genotype , Hepacivirus/genetics , Humans , Lipid Metabolism/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...