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BACKGROUND AND AIMS: Alcohol-associated hepatitis (AH) is a clinically severe, acute disease that afflicts only a fraction of patients with alcohol use disorder (AUD). Genomic studies of alcohol-associated cirrhosis (AC) have identified several genes of large effect, but the genetic and environmental factors that lead to AH and AC, and their degree of genetic overlap, remain largely unknown. This study aims to identify genes and genetic variation that contribute to the development of AH. APPROACH AND RESULTS: Exome-sequencing of patients with AH (N=784) and heavy drinking controls (N=951) identified exome-wide significant association for AH at PNPLA3, as previously observed for AC in GWAS, although with a much lower effect-size. SNPs of large effect-size at ICOSLG (Chr 21) and TOX4/RAB2B (Chr 14), were also exome-wide significant. ICOSLG encodes a co-stimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation. TOX4 was previously implicated in diabetes and immune system function. Other genes previously implicated in AC did not strongly contribute to AH, and the only prominently implicated (but not exome wide significant) gene overlapping with AUD was ADH1B. Polygenic signals for AH were observed in both common and rare variant analysis and identified genes with roles associated with inflammation. CONCLUSIONS: This study has identified two new genes of high effect size with a previously unknown contribution to ALD, and highlights both the overlap in etiology between liver diseases, and the unique origins of AH.
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BACKGROUND & AIMS: Severe alcohol-associated hepatitis (SAH) is associated with high 90-day mortality. Glucocorticoid therapy for 28 days improves 30- but not 90-day survival. We assessed the efficacy and safety of a combination of anakinra, an IL-1 antagonist, plus zinc (A+Z) compared to prednisone using the Day-7 Lille score as a stopping rule in patients with SAH. METHODS: In this phase IIb double-blind randomized trial in adults with SAH and MELD scores of 20-35, participants were randomized to receive either daily anakinra 100 mg subcutaneously for 14 days plus daily zinc sulfate 220 mg orally for 90 days, or daily prednisone 40 mg orally for 30 days. Prednisone or prednisone placebo was stopped if Day-7 Lille score was >0.45. All study drugs were stopped for uncontrolled infection or ≥5 point increase in MELD score. The primary endpoint was overall survival at 90 days. RESULTS: Seventy-three participants were randomized to prednisone and 74 to A+Z. The trial was stopped early after a prespecified interim analysis showed prednisone was associated with higher 90-day overall survival (90% vs. 70%; hazard ratio for death = 0.34, 95% CI 0.14-0.83, p = 0.018) and transplant-free survival (88% vs. 64%; hazard ratio for transplant or death = 0.30, 95% CI 0.13-0.69, p = 0.004) than A+Z. Acute kidney injury was more frequent with A+Z (45%) than prednisone (22%) (p = 0.001), but rates of infection were similar (31% in A+Z vs. 27% in prednisone, p = 0.389). CONCLUSIONS: Participants with SAH treated with prednisone using the Day-7 Lille score as a stopping rule had significantly higher overall and transplant-free 90-day survival and lower incidence of acute kidney injury than those treated with A+Z. IMPACT AND IMPLICATIONS: There is no approved treatment for severe alcohol-associated hepatitis (SAH). In this double-blind randomized trial, patients with SAH treated with prednisone using the Lille stopping rule on Day 7 had higher 90-day overall and transplant-free survival and lower rates of acute kidney injury compared to patients treated with a combination of anakinra and zinc. The data support continued use of glucocorticoids for patients with SAH, with treatment discontinuation for those with a Lille score >0.45 on Day 7. TRIAL REGISTRATION: NCT04072822.
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Lesión Renal Aguda , Hepatitis Alcohólica , Adulto , Humanos , Prednisona/efectos adversos , Proteína Antagonista del Receptor de Interleucina 1/efectos adversos , Zinc/uso terapéutico , Hepatitis Alcohólica/tratamiento farmacológico , Método Doble Ciego , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Resultado del TratamientoRESUMEN
INTRODUCTION: This study is to evaluate the safety and pharmacokinetics (PK) of larsucosterol (DUR-928 or 25HC3S) in subjects with alcohol-associated hepatitis (AH), a devastating acute illness without US Food and Drug Administration-approved therapies. METHODS: This phase 2a, multicenter, open-label, dose escalation study evaluated the safety, PK, and efficacy signals of larsucosterol in 19 clinically diagnosed subjects with AH. Based on the model for end-stage liver disease (MELD) score, 7 subjects were considered to have moderate AH and 12 to have severe AH. All subjects received 1 or 2 intravenous infusions (72 hours apart) of larsucosterol at a dose of 30, 90, or 150 mg and were followed up for 28 days. Efficacy signals from a subgroup of subjects with severe AH were compared with those from 2 matched arms of those with severe AH treated with standard of care (SOC), including corticosteroids, from a contemporaneous study. RESULTS: All 19 larsucosterol-treated subjects survived the 28-day study. Fourteen (74%) of all subjects including 8 (67%) of the subjects with severe AH were discharged ≤72 hours after receiving a single infusion. There were no drug-related serious adverse events nor early terminations due to the treatment. PK profiles were not affected by disease severity. Biochemical parameters improved in most subjects. Serum bilirubin levels declined notably from baseline to day 7 and day 28, and MELD scores were reduced at day 28. The efficacy signals compared favorably with those from 2 matched groups treated with SOC. Lille scores at day 7 were <0.45 in 16 of the 18 (89%) subjects with day 7 samples. Lille scores from 8 subjects with severe AH who received 30 or 90 mg larsucosterol (doses used in phase 2b trial) were statistically significantly lower ( P < 0.01) than those from subjects with severe AH treated with SOC from the contemporaneous study. DISCUSSION: Larsucosterol was well tolerated at all 3 doses in subjects with AH without safety concerns. Data from this pilot study showed promising efficacy signals in subjects with AH. Larsucosterol is being evaluated in a phase 2b multicenter, randomized, double-blinded, placebo-controlled (AHFIRM) trial.
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Enfermedad Hepática en Estado Terminal , Hepatitis Alcohólica , Humanos , Proyectos Piloto , Índice de Severidad de la Enfermedad , Hepatitis Alcohólica/tratamiento farmacológico , Hepatitis Alcohólica/diagnósticoRESUMEN
BACKGROUND: Systemic thromboxane A2 generation, assessed by quantifying the concentration of stable thromboxane B2 metabolites (TXB2-M) in the urine adjusted for urinary creatinine, is strongly associated with mortality risk. We sought to define optimal TXB2-M cutpoints for aspirin users and nonusers and determine if adjusting TXB2-M for estimated glomerular filtration rate (eGFR) in addition to urinary creatinine improved mortality risk assessment. METHODS: Urinary TXB2-M were measured by competitive ELISA in 1363 aspirin users and 1681 nonusers participating in the Framingham Heart Study. Cutpoints were determined for TXB2-M and TXB2-M/eGFR using log-rank statistics and used to assess mortality risk by Cox proportional hazard modeling and restricted mean survival time. Multivariable models were compared using the Akaike Information Criterion (AIC). A cohort of 105 aspirin users with heart failure was used for external validation. RESULTS: Optimized cutpoints of TXB2-M were 1291 and 5609â pg/mg creatinine and of TXB2-M/eGFR were 16.6 and 62.1 filtered prostanoid units (defined as pg·min/creatinine·mL·1.73â m2), for aspirin users and nonusers, respectively. TXB2-M/eGFR cutpoints provided more robust all-cause mortality risk discrimination than TXB2-M cutpoints, with a larger unadjusted hazard ratio (2.88 vs 2.16, AIC P < 0.0001) and greater differences in restricted mean survival time between exposure groups (1.46 vs 1.10 years), findings that were confirmed in the external validation cohort of aspirin users. TXB2-M/eGFR cutpoints also provided better cardiovascular/stroke mortality risk discrimination than TXB2-M cutpoints (unadjusted hazard ratio 3.31 vs 2.13, AIC P < 0.0001). CONCLUSION: Adjustment for eGFR strengthens the association of urinary TXB2-M with long-term mortality risk irrespective of aspirin use.
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Aspirina , Tromboxanos , Humanos , Pronóstico , Creatinina/orina , Aspirina/uso terapéutico , Tromboxano B2/metabolismo , Riñón/metabolismoRESUMEN
BACKGROUND AIMS: Prolonged systemic inflammation contributes to poor clinical outcomes in severe alcohol-associated hepatitis (AH) even after the cessation of alcohol use. However, mechanisms leading to this persistent inflammation remain to be understood. APPROACH RESULTS: We show that while chronic alcohol induces nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in the liver, alcohol binge results not only in NLRP3 inflammasome activation but also in increased circulating extracellular apoptosis-associated speck-like protein containing a caspase recruitment domain (ex-ASC) specks and hepatic ASC aggregates both in patients with AH and in mouse models of AH. These ex-ASC specks persist in circulation even after the cessation of alcohol use. Administration of alcohol-induced-ex-ASC specks in vivo in alcohol-naive mice results in sustained inflammation in the liver and circulation and causes liver damage. Consistent with the key role of ex-ASC specks in mediating liver injury and inflammation, alcohol binge failed to induce liver damage or IL-1ß release in ASC-deficient mice. Our data show that alcohol induces ex-ASC specks in liver macrophages and hepatocytes, and these ex-ASC specks can trigger IL-1ß release in alcohol-naive monocytes, a process that can be prevented by the NLRP3 inhibitor, MCC950. In vivo administration of MCC950 reduced hepatic and ex-ASC specks, caspase-1 activation, IL-1ß production, and steatohepatitis in a murine model of AH. CONCLUSIONS: Our study demonstrates the central role of NLRP3 and ASC in alcohol-induced liver inflammation and unravels the critical role of ex-ASC specks in the propagation of systemic and liver inflammation in AH. Our data also identify NLRP3 as a potential therapeutic target in AH.
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Hepatitis Alcohólica , Hepatitis , Animales , Ratones , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Hepatitis/etiología , Inflamación , Hepatitis Alcohólica/etiología , Etanol/efectos adversos , Caspasa 1/metabolismo , Interleucina-1beta/metabolismo , Proteínas Adaptadoras de Señalización CARD/metabolismoRESUMEN
BACKGROUND: The performance of rapid antigen tests (Ag-RDTs) for screening asymptomatic and symptomatic persons for SARS-CoV-2 is not well established. OBJECTIVE: To evaluate the performance of Ag-RDTs for detection of SARS-CoV-2 among symptomatic and asymptomatic participants. DESIGN: This prospective cohort study enrolled participants between October 2021 and January 2022. Participants completed Ag-RDTs and reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 every 48 hours for 15 days. SETTING: Participants were enrolled digitally throughout the mainland United States. They self-collected anterior nasal swabs for Ag-RDTs and RT-PCR testing. Nasal swabs for RT-PCR were shipped to a central laboratory, whereas Ag-RDTs were done at home. PARTICIPANTS: Of 7361 participants in the study, 5353 who were asymptomatic and negative for SARS-CoV-2 on study day 1 were eligible. In total, 154 participants had at least 1 positive RT-PCR result. MEASUREMENTS: The sensitivity of Ag-RDTs was measured on the basis of testing once (same-day), twice (after 48 hours), and thrice (after a total of 96 hours). The analysis was repeated for different days past index PCR positivity (DPIPPs) to approximate real-world scenarios where testing initiation may not always coincide with DPIPP 0. Results were stratified by symptom status. RESULTS: Among 154 participants who tested positive for SARS-CoV-2, 97 were asymptomatic and 57 had symptoms at infection onset. Serial testing with Ag-RDTs twice 48 hours apart resulted in an aggregated sensitivity of 93.4% (95% CI, 90.4% to 95.9%) among symptomatic participants on DPIPPs 0 to 6. When singleton positive results were excluded, the aggregated sensitivity on DPIPPs 0 to 6 for 2-time serial testing among asymptomatic participants was lower at 62.7% (CI, 57.0% to 70.5%), but it improved to 79.0% (CI, 70.1% to 87.4%) with testing 3 times at 48-hour intervals. LIMITATION: Participants tested every 48 hours; therefore, these data cannot support conclusions about serial testing intervals shorter than 48 hours. CONCLUSION: The performance of Ag-RDTs was optimized when asymptomatic participants tested 3 times at 48-hour intervals and when symptomatic participants tested 2 times separated by 48 hours. PRIMARY FUNDING SOURCE: National Institutes of Health RADx Tech program.
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COVID-19 , Humanos , COVID-19/diagnóstico , Estudios Prospectivos , SARS-CoV-2 , Reacción en Cadena de la Polimerasa , Cognición , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: We investigated the effect of daily oral Lactobacillus rhamnosus GG (LGG) in reducing liver injury/severity and drinking in patients with alcohol use disorder and moderately severe alcohol-associated hepatitis. METHODS: Forty-six male and female individuals with alcohol use disorder and moderate alcohol-associated hepatitis (12 ≤ model for end-stage liver disease score < 20, aged 21-67 years) received either LGG (n = 24) or placebo (n = 22). Data were collected/assessed at baseline and at 1, 3, and 6 months. RESULTS: LGG treatment was associated with a significant reduction in liver injury after 1 month. Six months of LGG treatment reduced heavy drinking levels to social or abstinence levels. DISCUSSION: LGG treatment was associated with an improvement in both liver injury and drinking.
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Alcoholismo , Enfermedad Hepática en Estado Terminal , Hepatitis Alcohólica , Lacticaseibacillus rhamnosus , Probióticos , Femenino , Humanos , Masculino , Hepatitis Alcohólica/terapia , Probióticos/uso terapéutico , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND AND AIMS: Patients with severe alcohol-associated hepatitis (AH) have high mortality. Corticosteroids improve survival only for 30 days. We targeted inflammation, cellular injury, and gut leakiness in a randomized clinical trial comparing combination therapy to corticosteroids on 180-day survival. APPROACH AND RESULTS: Subjects with a clinical diagnosis of severe AH (Model for End-Stage Liver Disease [MELD] >20, Maddrey discriminant function [MDF] >32) were randomized to receive methylprednisolone (PRED; 28 days) or a combination of anakinra (14 days) plus pentoxifylline (28 days) plus zinc (COMB; 180 days). The primary endpoint was survival at 180 days. The study was designed in 2013, initiated in October 2014, and completed in March 2018. Five hundred patients were screened to randomize 104 subjects with a clinical diagnosis of AH with a MELD score >20. Fifty-three patients were randomized into the COMB and 50 to the PRED treatment; 1 dropped out of the study before randomization. Mean age was 45.3 ± 10.4 years; 60.6% were males, 92.3% White, and mean MELD 25.7 ± 3.9. Kaplan-Meier survival estimate at 180 days was 67.9% in COMB and 56% in PRED (HR = 0.69; p = 0.3001). Survival curves separated by 90 days (COMB, 69.8%; PRED, 58.0%; HR = 0.69; p = 0.28). Survival at 28 days was similar between the COMB (83.4%) and PRED groups (81.2%; HR = 0.91; p = 0.85). There were no unexpected serious adverse events, and incidence of infection was comparable between groups. MELD 20-25 and MELD >26 strata showed nonsignificant treatment effects in favor of COMB. CONCLUSIONS: A combination of anakinra, pentoxifylline plus zinc provides similar survival benefits compared to corticosteroid therapy in severe AH.
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Enfermedad Hepática en Estado Terminal , Hepatitis Alcohólica , Pentoxifilina , Corticoesteroides/uso terapéutico , Adulto , Enfermedad Hepática en Estado Terminal/tratamiento farmacológico , Femenino , Hepatitis Alcohólica/diagnóstico , Humanos , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Pentoxifilina/uso terapéutico , Receptores de Interleucina-1/uso terapéutico , Índice de Severidad de la Enfermedad , Zinc/uso terapéuticoRESUMEN
Current American Academy of Pediatrics (AAP) Guidelines recommend monitoring thyroid function in infants with Down syndrome (DS) at birth, 6 and 12 months, and annually thereafter. This study aimed to determine whether these guidelines are optimal for early diagnosis and treatment of (subclinical) hypothyroidism. Enrolled infants with DS less than age 7 months, born at ≥ 30 weeks gestation to monitor thyroid function test (TFT). A filter paper (FP) blood sample was analyzed for TSH and total T4 at ages 2 and 4 weeks and monthly thereafter until 12 months. Subjects with abnormal FP sample and confirmatory serum TFT for hypothyroidism promptly started treatment. Subjects with thyroid dysfunction identified had thyroid antibodies measured at diagnosis and 12 months. Descriptive statistics determined average time to diagnosis of abnormal TFT. Sixteen (30%) of 54 subjects were diagnosed with a thyroid disorder, the majority with subclinical hypothyroidism (SH) and 1 with hyperthyroidism. Diagnosis occurred in 6 (11%), 9 (17%), and 12 (22.2%) infants in the first 30, 60, and 90 days of life (DOL), respectively. Eight infants had an abnormal NBS and half were diagnosed with a thyroid disorder by DOL 8 and the remainder prior to 4 months. Among subjects with a normal NBS, four were diagnosed at a mean of 104 days and three at a mean of 101 days prior to the 6-month and 12-month routine screens, respectively. Conclusion: Based on current AAP guidelines, thyroid disorder diagnosis would have been delayed in nearly 20% of the subjects. An additional TFT screen at 1 and 3 months can lead to earlier diagnosis and treatment. What is Known: ⢠Current American Academy of Pediatrics (AAP) Guidelines recommend thyroid function tests (TFT) in infants with Down syndrome (DS) at birth and 6 and 12 months. ⢠Peer- reviewed retrospective studies report an increased incidence of hypothyroidism in infants with DS undetected by the newborn screen (NBS) and prior to 6 months. What is New: ⢠This prospective study monitored TFT in infants with DS at age 2 weeks and monthly throughout the first year of life. ⢠The findings in this study support additional TFT screens at 1 and 3 months in infants with DS.
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Hipotiroidismo Congénito , Síndrome de Down , Hipotiroidismo , Enfermedades de la Tiroides , Recién Nacido , Lactante , Humanos , Niño , Síndrome de Down/complicaciones , Síndrome de Down/diagnóstico , Estudios Prospectivos , Estudios Retrospectivos , Hipotiroidismo/complicaciones , Hipotiroidismo/diagnóstico , Enfermedades de la Tiroides/complicaciones , Enfermedades de la Tiroides/diagnóstico , Pruebas de Función de la Tiroides , Tirotropina , Tiroxina , Hipotiroidismo Congénito/diagnósticoRESUMEN
BACKGROUND: Many interventions for widescale distribution of rapid antigen tests for COVID-19 have utilized online, direct-to-consumer (DTC) ordering systems; however, little is known about the sociodemographic characteristics of home-test users. We aimed to characterize the patterns of online orders for rapid antigen tests and determine geospatial and temporal associations with neighborhood characteristics and community incidence of COVID-19, respectively. METHODS: This observational study analyzed online, DTC orders for rapid antigen test kits from beneficiaries of the Say Yes! Covid Test program from March to November 2021 in five communities: Louisville, Kentucky; Indianapolis, Indiana; Fulton County, Georgia; O'ahu, Hawaii; and Ann Arbor/Ypsilanti, Michigan. Using spatial autoregressive models, we assessed the geospatial associations of test kit distribution with Census block-level education, income, age, population density, and racial distribution and Census tract-level Social Vulnerability Index. Lag association analyses were used to measure the association between online rapid antigen kit orders and community-level COVID-19 incidence. RESULTS: In total, 164,402 DTC test kits were ordered during the intervention. Distribution of tests at all sites were significantly geospatially clustered at the block-group level (Moran's I: p < 0.001); however, education, income, age, population density, race, and social vulnerability index were inconsistently associated with test orders across sites. In Michigan, Georgia, and Kentucky, there were strong associations between same-day COVID-19 incidence and test kit orders (Michigan: r = 0.89, Georgia: r = 0.85, Kentucky: r = 0.75). The incidence of COVID-19 during the current day and the previous 6-days increased current DTC orders by 9.0 (95% CI = 1.7, 16.3), 3.0 (95% CI = 1.3, 4.6), and 6.8 (95% CI = 3.4, 10.2) in Michigan, Georgia, and Kentucky, respectively. There was no same-day or 6-day lagged correlation between test kit orders and COVID-19 incidence in Indiana. CONCLUSIONS: Our findings suggest that online ordering is not associated with geospatial clustering based on sociodemographic characteristics. Observed temporal preferences for DTC ordering can guide public health messaging around DTC testing programs.
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COVID-19 , Humanos , COVID-19/diagnóstico , COVID-19/epidemiología , Factores Sociodemográficos , Escolaridad , Censos , Análisis por ConglomeradosRESUMEN
BACKGROUND: It is important to document the performance of rapid antigen tests (Ag-RDTs) in detecting SARS-CoV-2 variants. OBJECTIVE: To compare the performance of Ag-RDTs in detecting the Delta (B.1.617.2) and Omicron (B.1.1.529) variants of SARS-CoV-2. DESIGN: Secondary analysis of a prospective cohort study that enrolled participants between 18 October 2021 and 24 January 2022. Participants did Ag-RDTs and collected samples for reverse transcriptase polymerase chain reaction (RT-PCR) testing every 48 hours for 15 days. SETTING: The parent study enrolled participants throughout the mainland United States through a digital platform. All participants self-collected anterior nasal swabs for rapid antigen testing and RT-PCR testing. All Ag-RDTs were completed at home, whereas nasal swabs for RT-PCR were shipped to a central laboratory. PARTICIPANTS: Of 7349 participants enrolled in the parent study, 5779 asymptomatic persons who tested negative for SARS-CoV-2 on day 1 of the study were eligible for this substudy. MEASUREMENTS: Sensitivity of Ag-RDTs on the same day as the first positive (index) RT-PCR result and 48 hours after the first positive RT-PCR result. RESULTS: A total of 207 participants were positive on RT-PCR (58 Delta, 149 Omicron). Differences in sensitivity between variants were not statistically significant (same day: Delta, 15.5% [95% CI, 6.2% to 24.8%] vs. Omicron, 22.1% [CI, 15.5% to 28.8%]; at 48 hours: Delta, 44.8% [CI, 32.0% to 57.6%] vs. Omicron, 49.7% [CI, 41.6% to 57.6%]). Among 109 participants who had RT-PCR-positive results for 48 hours, rapid antigen sensitivity did not differ significantly between Delta- and Omicron-infected participants (48-hour sensitivity: Delta, 81.5% [CI, 66.8% to 96.1%] vs. Omicron, 78.0% [CI, 69.1% to 87.0%]). Only 7.2% of the 69 participants with RT-PCR-positive results for shorter than 48 hours tested positive by Ag-RDT within 1 week; those with Delta infections remained consistently negative on Ag-RDTs. LIMITATION: A testing frequency of 48 hours does not allow a finer temporal resolution of the analysis of test performance, and the results of Ag-RDTs are based on self-report. CONCLUSION: The performance of Ag-RDTs in persons infected with the SARS-CoV-2 Omicron variant is not inferior to that in persons with Delta infections. Serial testing improved the sensitivity of Ag-RDTs for both variants. The performance of rapid antigen testing varies on the basis of duration of RT-PCR positivity. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.
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COVID-19 , SARS-CoV-2 , Estados Unidos , Humanos , Estudios Prospectivos , Autoevaluación , Sensibilidad y EspecificidadRESUMEN
Evaluation of brain disease in veterinary patients uses a wide variety of MRI sequences. A shortened protocol that maintains consistency of interpretation would reduce radiologist reporting time, patient anesthetic time, and client cost. The aims of this retrospective, methods comparison, observer agreement study were to evaluate whether abbreviated MRI protocols alter differential diagnoses and recommendations compared to our institution's standard protocol; evaluate interobserver agreement on standard brain MRIs; and assess whether differential diagnoses change after postcontrast images. Normal and pathologic canine and feline brain MRIs were retrieved from hospital archives. Three protocols were created from each: a 5-sequence noncontrast enhanced Fast Brain Protocol 1 (FBP1); a 6-sequence contrast-enhanced Fast Brain Protocol 2 (FBP2); and an 11-sequence standard brain protocol (SBP). Three blinded veterinary radiologists interpreted FBP images for 98 cases (1 reader/case) and SBP images for 20 cases (3 readers/case). A fourth observer compared these interpretations to the original MRI reports (OMR). Overall agreement between FBPs and OMR was good (k = 0.75) and comparable to interobserver agreement for multiple reviews of SBP cases. Postcontrast images substantially altered conclusions in 17/97 cases (17.5%), as well as improved interobserver agreement compared to noncontrast studies. The conclusions reached with shortened brain protocols were comparable to those of a full brain study. The findings supported the use of a 6-sequence brain MRI protocol (sagittal T2-weighted [T2w] TSE; transverse T2w turbo spin echo fluid-attenuated inversion recovery, T2*-weighted gradient recalled echo, T1-weighted spin echo, and diffusion weighted imaging/apparent diffusion coefficient; and postcontrast transverse T1-weighted spin echo) for dogs and cats with suspected intracranial disease.
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Enfermedades de los Gatos , Enfermedades de los Perros , Imagen por Resonancia Magnética , Animales , Gatos , Perros , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Enfermedades de los Gatos/diagnóstico por imagen , Enfermedades de los Gatos/patología , Diagnóstico Diferencial , Enfermedades de los Perros/diagnóstico por imagen , Enfermedades de los Perros/patología , Imagen por Resonancia Magnética/normas , Imagen por Resonancia Magnética/veterinaria , Estudios RetrospectivosRESUMEN
BACKGROUND AND AIMS: Given the lack of effective therapies and high mortality in acute alcohol-associated hepatitis (AH), it is important to develop rationally designed biomarkers for effective disease management. Complement, a critical component of the innate immune system, contributes to uncontrolled inflammatory responses leading to liver injury, but is also involved in hepatic regeneration. Here, we investigated whether a panel of complement proteins and activation products would provide useful biomarkers for severity of AH and aid in predicting 90-day mortality. APPROACH AND RESULTS: Plasma samples collected at time of diagnosis from 254 patients with moderate and severe AH recruited from four medical centers and 31 healthy persons were used to quantify complement proteins by enzyme-linked immunosorbent assay and Luminex arrays. Components of the classical and lectin pathways, including complement factors C2, C4b, and C4d, as well as complement factor I (CFI) and C5, were reduced in AH patients compared to healthy persons. In contrast, components of the alternative pathway, including complement factor Ba (CFBa) and factor D (CFD), were increased. Markers of complement activation were also differentially evident, with C5a increased and the soluble terminal complement complex (sC5b9) decreased in AH. Mannose-binding lectin, C4b, CFI, C5, and sC5b9 were negatively correlated with Model for End-Stage Liver Disease score, whereas CFBa and CFD were positively associated with disease severity. Lower CFI and sC5b9 were associated with increased 90-day mortality in AH. CONCLUSIONS: Taken together, these data indicate that AH is associated with a profound disruption of complement. Inclusion of complement, especially CFI and sC5b9, along with other laboratory indicators, could improve diagnostic and prognostic indications of disease severity and risk of mortality for AH patients.
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Hepatitis Alcohólica/diagnóstico , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Complemento C2/análisis , Complemento C3/análisis , Complemento C4/análisis , Complemento C5/análisis , Factor B del Complemento/análisis , Factor D del Complemento/análisis , Proteínas del Sistema Complemento/análisis , Femenino , Hepatitis Alcohólica/inmunología , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
BACKGROUND: Serial screening is critical for restricting spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by facilitating timely identification of infected individuals to interrupt transmission. Variation in sensitivity of different diagnostic tests at different stages of infection has not been well documented. METHODS: In a longitudinal study of 43 adults newly infected with SARS-CoV-2, all provided daily saliva and nasal swabs for quantitative reverse transcription polymerase chain reaction (RT-qPCR), Quidel SARS Sofia antigen fluorescent immunoassay (FIA), and live virus culture. RESULTS: Both RT-qPCR and Quidel SARS Sofia antigen FIA peaked in sensitivity during the period in which live virus was detected in nasal swabs, but sensitivity of RT-qPCR tests rose more rapidly prior to this period. We also found that serial testing multiple times per week increases the sensitivity of antigen tests. CONCLUSIONS: RT-qPCR tests are more effective than antigen tests at identifying infected individuals prior to or early during the infectious period and thus for minimizing forward transmission (given timely results reporting). All tests showed >98% sensitivity for identifying infected individuals if used at least every 3 days. Daily screening using antigen tests can achieve approximately 90% sensitivity for identifying infected individuals while they are viral culture positive.
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Prueba de COVID-19 , COVID-19/diagnóstico , Pruebas Diagnósticas de Rutina , SARS-CoV-2/aislamiento & purificación , Adulto , Anciano , Animales , Antígenos Virales/análisis , Chlorocebus aethiops , Femenino , Humanos , Estudios Longitudinales , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Saliva , Sensibilidad y Especificidad , Células Vero , Adulto JovenRESUMEN
Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.
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Anemia de Células Falciformes/tratamiento farmacológico , Dolor/tratamiento farmacológico , Poloxámero/uso terapéutico , Vasodilatadores/uso terapéutico , Adolescente , Adulto , Analgésicos Opioides/uso terapéutico , Anemia de Células Falciformes/complicaciones , Niño , Método Doble Ciego , Femenino , Humanos , Masculino , Dolor/etiología , Placebos/efectos adversos , Placebos/uso terapéutico , Poloxámero/efectos adversos , Vasodilatadores/efectos adversos , Adulto JovenRESUMEN
BACKGROUND & AIMS: Acute alcoholic hepatitis (AAH) is a major cause of liver-related morbidity and mortality; there are no good blood biomarkers for diagnosis or determining magnitude of cell death. Keratin 18 (KRT18, also called K18), found in epithelial cells, is released from hepatocytes upon death. We investigated whether level of K18 is a better marker of hepatocyte death than standard biomarkers and might be used to identify patients with AAH at risk for death within 90 days. METHODS: We analyzed data from 173 participants in a large trial performed at 4 medical centers. Participants with AAH were classified as severe (n = 57, model for end-stage liver disease [MELD] scores above 20) or moderate (n = 27, MELD scores from 12 to 19); 38 participants had alcohol use disorder with mild (n = 28) or no liver injury (n = 10); 34 participants had nonalcoholic steatohepatitis; and 17 participants were healthy (controls). We quantified serum levels of K18 using ELISAs and APOPTOSENSE kits. RESULTS: Serum level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the ratio of AST:ALT did not correlate with MELD scores. Patients with alcohol use disorder had higher serum levels of ALT than patients with severe AAH. Levels of K18M65 and K18M30 had statistically significant increases as liver disease worsened, as did the degree of necrosis (ratio of K18 M65:M30). The ratio of K18M65:ALT was increased in serum from patients with AAH compared with controls. Serum levels of K18 identified patients who died within 90 days with greater accuracy than commonly used static biomarkers. CONCLUSIONS: There is a stronger association between serum level of keratin 18 and amount of hepatocyte death and liver disease severity than for other biomarkers (AST, ALT, and the AST:ALT ratio). The ratio of K18M65:M30 might be used as marker of mechanism of hepatocyte death, and the ratio of K18M65:ALT might be used to distinguish patients with AAH from patients with nonalcoholic steatohepatitis. Serum levels of K18 might be used to identify patients with severe AAH at risk for death. ClinicalTrials.gov identifier # NCT01922895 and NCT01809132.
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Enfermedad Hepática en Estado Terminal , Hepatitis Alcohólica , Enfermedad del Hígado Graso no Alcohólico , Biomarcadores , Hepatitis Alcohólica/diagnóstico , Humanos , Queratina-18 , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
Although mortality due to acute alcoholic hepatitis (AH) correlates with Model for End-Stage Liver Disease (MELD) scores, biomarkers are critically needed to manage this disease. Increases in inflammatory markers and macrophage activation are associated with acute AH and could be potential biomarkers of clinical events and/or mortality. We enrolled 89 clinically diagnosed AH patients in four US academic medical centers. Plasma from AH patients had a significant increase in gut microbial translocation indicators (endotoxin, bacterial 16S ribosomal DNA) and host response indicators (soluble cluster of differentiation 14 [sCD14] and lipopolysaccharide binding protein [LBP]) compared to controls. Patient MELD score and Glasgow Alcoholic Hepatitis score (GAHS) correlated with endotoxin levels. AH patients also had a significant increase in high mobility group protein 1 (HMGB1), a sterile danger signal molecule, and osteopontin (OPN), a multifunctional phosphoprotein involved in neutrophil activation, compared to controls. Increased levels of OPN positively correlated with increasing MELD score, GAHS, and LBP levels. Consistent with these results, AH patients had significantly increased circulating levels of macrophage activation (sCD163 and sCD206) markers compared to healthy controls, and sCD163 and sCD206 significantly and positively correlated with OPN, HMGB1, and LBP levels as well as with MELD score and GAHS. These findings indicate a connection between microbial translocation, immune cell activation, and AH severity. Plasma sCD14, OPN, sCD163, and sCD206 levels were significantly higher in nonsurvivors than survivors. In multivariate regression models, we identified sCD14, sCD163, and OPN as independent predictors of 90-day mortality, infection, and organ failure development, respectively. Conclusion: Our study suggests that sCD14, LBP, OPN, sCD163, and sCD206 are biomarkers to indicate severity and predict clinical outcomes in AH.
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Proteínas de Fase Aguda/metabolismo , Antígenos CD/metabolismo , Proteínas Portadoras/metabolismo , Progresión de la Enfermedad , Hepatitis Alcohólica/mortalidad , Hepatitis Alcohólica/fisiopatología , Activación de Macrófagos/inmunología , Glicoproteínas de Membrana/metabolismo , Centros Médicos Académicos , Adulto , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Causas de Muerte , Ensayo de Inmunoadsorción Enzimática , Hepatitis Alcohólica/sangre , Humanos , Estimación de Kaplan-Meier , Pruebas de Función Hepática , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC , Medición de Riesgo , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Estados UnidosRESUMEN
BACKGROUND: Patient reminders for influenza vaccination, delivered via an electronic health record patient portal and interactive voice response calls, offer an innovative approach to engaging patients and improving patient care. OBJECTIVE: The goal of this study was to test the effectiveness of portal and interactive voice response outreach in improving rates of influenza vaccination by targeting patients in early September, shortly after vaccinations became available. METHODS: Using electronic health record portal messages and interactive voice response calls promoting influenza vaccination, outreach was conducted in September 2015. Participants included adult patients within a large multispecialty group practice in central Massachusetts. Our main outcome was electronic health record-documented early influenza vaccination during the 2015-2016 influenza season, measured in November 2015. We randomly assigned all active portal users to 1 of 2 groups: (1) receiving a portal message promoting influenza vaccinations, listing upcoming clinics, and offering online scheduling of vaccination appointments (n=19,506) or (2) receiving usual care (n=19,505). We randomly assigned all portal nonusers to 1 of 2 groups: (1) receiving interactive voice response call (n=15,000) or (2) receiving usual care (n=43,596). The intervention also solicited patient self-reports on influenza vaccinations completed outside the clinic. Self-reported influenza vaccination data were uploaded into the electronic health records to increase the accuracy of existing provider-directed electronic health record clinical decision support (vaccination alerts) but were excluded from main analyses. RESULTS: Among portal users, 28.4% (5549/19,506) of those randomized to receive messages and 27.1% (5294/19,505) of the usual care group had influenza vaccinations documented by November 2015 (P=.004). In multivariate analysis of portal users, message recipients were slightly more likely to have documented vaccinations when compared to the usual care group (OR 1.07, 95% CI 1.02-1.12). Among portal nonusers, 8.4% (1262/15,000) of those randomized to receive calls and 8.2% (3586/43,596) of usual care had documented vaccinations (P=.47), and multivariate analysis showed nonsignificant differences. Over half of portal messages sent were opened (10,112/19,479; 51.9%), and over half of interactive voice response calls placed (7599/14,984; 50.7%) reached their intended target, thus we attained similar levels of exposure to the messaging for both interventions. Among portal message recipients, 25.4% of message openers (2570/10,112) responded to a subsequent question on receipt of influenza vaccination; among interactive voice response recipients, 72.5% of those reached (5513/7599) responded to a similar question. CONCLUSIONS: Portal message outreach to a general primary care population achieved a small but statistically significant improvement in rates of influenza vaccination (OR 1.07, 95% CI 1.02-1.12). Interactive voice response calls did not significantly improve vaccination rates among portal nonusers (OR 1.03, 95% CI 0.96-1.10). Rates of patient engagement with both modalities were favorable. TRIAL REGISTRATION: ClinicalTrials.gov NCT02266277; https://clinicaltrials.gov/ct2/show/NCT02266277.
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Registros Electrónicos de Salud/normas , Gripe Humana/terapia , Atención al Paciente/métodos , Portales del Paciente/normas , Sistemas Recordatorios/instrumentación , Envío de Mensajes de Texto/normas , Vacunación/métodos , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: To determine the frequency and types of paramedian incisional complications after prophylactic laparoscopy-assisted gastropexy (LAG) in dogs and to evaluate potential risk factors for complications. STUDY DESIGN: Multi-institutional retrospective study. ANIMALS: Client-owned dogs (N = 411). METHODS: Records for dogs that underwent single-incision-port laparoscopy-assisted gastropexy (SIPLAG) or multiple-port laparoscopy-assisted gastropexy (MPLAG) at five veterinary referral hospitals were reviewed. Information regarding signalment, surgical procedures, perioperative care, and incisional complications was collected. Follow-up information was obtained by review of medical records and/or communication with owners. Potential risk factors for complications were examined statistically. RESULTS: Paramedian incisional complications were observed in 78 of 411 (19%) dogs. The most common complication was seroma formation, which occurred in 51 (12.4%) dogs. Surgical site infections were observed in 16 (3.9%) dogs, and dehiscence or development of excessive scar tissue at the incision site were each observed in nine (2.2%) dogs. Complications resolved with conservative treatment in 75 of 78 (96.2%) dogs and with surgical treatment in three of 78 (3.8%) dogs. The odds of complications were approximately twice as high in dogs undergoing SIPLAG than in dogs undergoing MPLAG (odds ratio, 2.03; P = .006). CONCLUSION: Minor paramedian incisional complications, particularly seroma formation, were frequently observed after LAG. Most complications were successfully managed conservatively. Single-incision-port laparoscopy-assisted gastropexy was associated with a higher complication rate compared with MPLAG. CLINICAL SIGNIFICANCE: Owners should be informed that there is a relatively high rate of minor paramedian incisional complications after LAG. The risk of complications appears to be higher for SIPLAG than for MPLAG.
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Enfermedades de los Perros/cirugía , Gastropexia/veterinaria , Laparoscopía/veterinaria , Vólvulo Gástrico/veterinaria , Infección de la Herida Quirúrgica/veterinaria , Animales , Perros , Femenino , Gastropexia/métodos , Humanos , Laparoscopía/efectos adversos , Masculino , Oportunidad Relativa , Atención Perioperativa , Estudios Retrospectivos , Factores de Riesgo , Seroma/etiología , Vólvulo Gástrico/cirugía , Herida Quirúrgica , Infección de la Herida Quirúrgica/etiologíaRESUMEN
BACKGROUND: Successful anticoagulation is critical for stroke prevention in adults with atrial fibrillation (AF). Anticoagulation satisfaction is a key indicator of treatment success. While physical, cognitive, and psychosocial limitations are common in elderly AF patients, their associations with anticoagulation satisfaction are unknown. OBJECTIVE: Examine whether anticoagulation satisfaction differs among AF patients with and without physical, cognitive, and psychosocial conditions. METHODS: The study comprised AF patients greater than or equal to 65 years old who were prescribed an oral anticoagulant (warfarin 57%; direct oral anticoagulant [DOAC] 43%). Frailty, cognitive function, social support, depressive symptoms, vision, hearing, and anxiety were assessed using validated measures. Anticoagulation satisfaction was measured using the anticlot treatment scale. RESULTS: Participants (n = 1037, 50% female) were on average 76 years old. The following conditions were prevalent: frailty (14%), cognitive impairment (42%), social isolation (13%), vision impairment (35%), hearing impairment (36%), depression (29%), and anxiety (24%). Average anticlot treatment burden scale was 55 out of 60 (lower burden scales indicating higher perceived burden). Patients with high perceived burden were older, more likely to be female, and receive warfarin. After adjusting for confounders, visual impairment (adjusted odds ratio [95% confidence interval]: 1.7 [1.2-2.4]), depressive symptoms (2.4 [1.6-3.7]), and anxiety (1.8 [1.2-2.7]) were significantly associated with high perceived burden. Different conditions were associated with high perceived burden in warfarin vs DOAC users. CONCLUSION: Physical, cognitive, and psychosocial limitations are prevalent and associated with high perceived anticoagulation burden among elderly AF adults. These conditions merit consideration in anticoagulation prescribing.