Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.

OBJECTIVE: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. DESIGN: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). RESULTS: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10-9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10-5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10-44). CONCLUSION: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.

BACKGROUND & AIMS: Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. METHODS: Three cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). RESULTS: A combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 ± 0.06 vs. 0.61 ± 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. CONCLUSIONS: A risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions. LAY SUMMARY: Excessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients.

Genome-wide Association Study and Meta-analysis on Alcohol-Associated Liver Cirrhosis Identifies Genetic Risk Factors.

BACKGROUND AND AIMS: Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. APPROACH AND RESULTS: We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10-17 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10-10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10-8 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. CONCLUSIONS: Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.

Socio-demographic and psychiatric profile of patients hospitalized due to self-poisoning with suicidal intention.

OBJECTIVE: To identify the psychiatric profile of patients hospitalized due to self-intoxication associated with suicide-related behavior (SRB). METHODS: In this retrospective single-center study, records of consecutive patients treated for suicidal poisoning in our Clinical Toxicology unit between 1st January 2012 and 31st December 2016, who received at least one psychiatric exploration during their inpatient stay, were analyzed with regard to epidemiological data, ingested substances, psychiatric and somatic comorbidities, suicidal circumstances and follow-up therapy. RESULTS: Out of 1289 hospitalized patients, 1090 patients with complete data were analyzed. Mean age was 40.5 ± 17.2 years, 66.7% were female. 32.0% of patients had previously engaged in SRB, in 76.3% intention was suicidal. 64.7% of patients had a pre-existing psychiatric disorder (PD). Patients with a pre-existing PD more often displayed prior SRB than those without PD (40.7% vs 15.3%; p < 0.001; Fisher's exact test), used long-term/on demand medication (70.2% vs 38.9%; p < 0.001), distanced themselves from the current suicide attempt (65.9% vs 50.8%; p < 0.001) and had no detectable trigger (38.7% vs 18.1%; p < 0.001). Partnership conflict was the most commonly named trigger, and it was documented more often in patients without than in those with PD (41.6% vs 25.6%). After psychiatric reevaluation, most patients were diagnosed with mood disorders (29.7%) and stress disorders (17.0%); 32.8% of patients had a combination of two or more PDs. CONCLUSION: Hospitalization due to self-poisoning is associated with pre-existing PD, prior SRB and access to psychiatric medication. Detection of these risk factors could allow timely introduction of effective preventive measures tailored to particularly vulnerable subgroups and appropriate relief. However, lack of a detectable trigger in many cases may hamper the identification of those at risk.

Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1.

BACKGROUND AND AIMS: Little is known about genetic factors that affect development of alcohol-related cirrhosis. We performed a genome-wide association study (GWAS) of samples from the United Kingdom Biobank (UKB) to identify polymorphisms associated with risk of alcohol-related liver disease. METHODS: We performed a GWAS of 35,839 participants in the UKB with high intake of alcohol against markers of hepatic fibrosis (FIB-4, APRI, and Forns index scores) and hepatocellular injury (levels of aminotransferases). Loci identified in the discovery analysis were tested for their association with alcohol-related cirrhosis in 3 separate European cohorts (phase 1 validation cohort; n=2545). Variants associated with alcohol-related cirrhosis in the validation at a false discovery rate of less than 20% were then directly genotyped in 2 additional European validation cohorts (phase 2 validation, n=2068). RESULTS: In the GWAS of the discovery cohort, we identified 50 independent risk loci with genome-wide significance (P < 5 × 10-8). Nine of these loci were significantly associated with alcohol-related cirrhosis in the phase 1 validation cohort; 6 of these 9 loci were significantly associated with alcohol-related cirrhosis in phase 2 validation cohort, at a false discovery rate below 5%. The loci included variants in the mitochondrial amidoxime reducing component 1 gene (MARC1) and the heterogeneous nuclear ribonucleoprotein U like 1 gene (HNRNPUL1). After we adjusted for age, sex, body mass index, and type-2 diabetes in the phase 2 validation cohort, the minor A allele of MARC1:rs2642438 was associated with reduced risk of alcohol-related cirrhosis (adjusted odds ratio, 0.76; P=.0027); conversely, the minor C allele of HNRNPUL1:rs15052 was associated with an increased risk of alcohol-related cirrhosis (adjusted odds ratio, 1.30; P=.020). CONCLUSIONS: In a GWAS of samples from the UKB, we identified and validated (in 5 European cohorts) single-nucleotide polymorphisms that affect risk of alcohol-related cirrhosis in opposite directions: the minor A allele in MARC1:rs2642438 decreases risk, whereas the minor C allele in HNRNPUL1:rs15052 increases risk.

Obesity, Diabetes, Coffee, Tea, and Cannabis Use Alter Risk for Alcohol-Related Cirrhosis in 2 Large Cohorts of High-Risk Drinkers.

INTRODUCTION: Sustained high alcohol intake is necessary but not sufficient to produce alcohol-related cirrhosis. Identification of risk factors, apart from lifetime alcohol exposure, would assist in discovery of mechanisms and prediction of risk. METHODS: We conducted a multicenter case-control study (GenomALC) comparing 1,293 cases (with alcohol-related cirrhosis, 75.6% male) and 754 controls (with equivalent alcohol exposure but no evidence of liver disease, 73.6% male). Information confirming or excluding cirrhosis, and on alcohol intake and other potential risk factors, was obtained from clinical records and by interview. Case-control differences in risk factors discovered in the GenomALC participants were validated using similar data from 407 cases and 6,573 controls from UK Biobank. RESULTS: The GenomALC case and control groups reported similar lifetime alcohol intake (1,374 vs 1,412 kg). Cases had a higher prevalence of diabetes (20.5% (262/1,288) vs 6.5% (48/734), P = 2.27 × 10-18) and higher premorbid body mass index (26.37 ± 0.16 kg/m2) than controls (24.44 ± 0.18 kg/m2, P = 5.77 × 10-15). Controls were significantly more likely to have been wine drinkers, coffee drinkers, smokers, and cannabis users than cases. Cases reported a higher proportion of parents who died of liver disease than controls (odds ratio 2.25 95% confidence interval 1.55-3.26). Data from UK Biobank confirmed these findings for diabetes, body mass index, proportion of alcohol as wine, and coffee consumption. DISCUSSION: If these relationships are causal, measures such as weight loss, intensive treatment of diabetes or prediabetic states, and coffee consumption should reduce the risk of alcohol-related cirrhosis.

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.

BACKGROUND AND AIMS: Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10-6 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10-4 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10-26 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10-23 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10-4 ). CONCLUSIONS: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.

Return of the Quaaludes? Prolonged agitated delirium after intentional ingestion of the methaqualone analog SL-164 - a case report.

Background: A 22-year-old male with a known history of drug abuse presented to our department with prolonged agitated delirium, myocloni, tachycardia and subfebrile temperature after the deliberate ingestion of opium poppy tea (Papaver somniferum L.) together with the methaqualone analog SL-164 (5-chloro-3-(4-chloro-2-methylphenyl)-2-methyl-4(3H)-quinazolinone) which is sold online as a designer drug. Methods: SL-164 and its hydroxy metabolites were detected in serum and urine via liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS). Results: The pronounced delirium was treated with benzodiazepines and neuroleptics; temporary medical restraint had to be applied. Symptoms completely resolved over the next 72 h and the patient was discharged on day three able to give consent. Conclusions: Although methaqualone was a popular and widespread sedative in the 1950s and 60 s before its discontinuation in the USA in 1985, derivatives of the methaqualone class have not previously played a large role as drugs of abuse in the rapidly growing market of new psychoactive substances. To our knowledge, this is the first case of agitated delirium with detection of SL-164 and hydroxylated metabolites in a patient's serum and urine.

[Diagnostics and treatment of selected clinically relevant, acute drug intoxications]. / Diagnostik und Behandlung ausgesuchter akuter Arzneimittelvergiftungen mit hoher klinischer Relevanz.

Acute drug poisoning due to accidental or self-damaging overdoses is responsible for 5-10% of emergency medical interventions in Germany. The treatment of asymptomatic to life-threatening courses requires extensive expertise. On the basis of a selective literature search, this article gives an overview of selected clinically relevant, acute drug poisonings with regard to epidemiology, symptomatology, diagnostics, and therapy.Intoxications with psychotropic drugs are the most common drug intoxications. Poisoning with tricyclic antidepressants causes anticholinergic, central nervous, and cardiovascular symptoms. Less toxic are selective serotonin reuptake inhibitors (SSRIs); the intoxication may be characterized by serotonin syndrome. Malignant neuroleptic syndrome is a severe complication of neuroleptic poisoning.Poisoning with analgesics is clinically relevant due to its high availability. For paracetamol poisoning, intravenous acetylcysteine is available as an antidote. Hemodialysis may be indicated for severe salicylate intoxication. Poisoning with nonsteroidal anti-inflammatory drugs is usually only associated with mild signs of intoxication.Poisoning with cardiac drugs (ß-blockers and calcium antagonists) can cause life-threatening cardiovascular events. In addition to symptomatic therapy, insulin glucose therapy also plays an important role.The majority of acute drug poisonings can be treated adequately by symptomatic and partly intensive care therapy - if necessary with the application of primary and secondary toxin elimination. Depending on the severity of the intoxication, pharmacology-specific therapy must be initiated.

Correction: Genetic Variants in PNPLA3 and TM6SF2 Predispose to the Development of Hepatocellular Carcinoma in Individuals With Alcohol-Related Cirrhosis.

Author Pierre Deltenre, MD should appear in the author list in position 25, between Felix Braun and Thomas Berg. He should also have a PhD degree added to his name.

Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis.

OBJECTIVES: Variants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) are risk factors for the development of alcohol-related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC. METHODS: Risk variants in PNPLA3, TM6SF2, and MBOAT7 were genotyped in 751 cases with alcohol-related cirrhosis and HCC and in 1165 controls with alcohol-related cirrhosis without HCC. Association with the risk of developing HCC was analyzed using multivariate logistic regression. RESULTS: The development of HCC was independently associated with PNPLA3 rs738409 (ORadjusted 1.84 [95% CI 1.55-2.18], p = 1.85 × 10-12) and TM6SF2 rs58542926 (ORadjusted 1.66 [1.30-2.13], p = 5.13 × 10-05), using an additive model, and controlling the sex, age, body mass index, and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (ORadjusted 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined. CONCLUSIONS: Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk-stratification of patients with alcohol-related cirrhosis, and genotype-guided screening algorithms would optimize patient care.

[Intoxications in Children and Adolescents in Germany]. / Deutschlandweites Vergiftungsspektrum im Kindes- und Jugendalter.

BACKGROUND: In Germany, intoxications cause the bulk of emergencies in children, to be prevented or attenuated by preventive measures. Therefore, knowledge about intoxications is essential for pediatricians. The present work provides general and epidemiologic data about intoxications and most frequent categories and single toxicants. METHODS: Data of intoxications in children and adolescents from 6 German poison centers (2012-2016 and 2002-2016) were retrospectively analyzed. Categorical data are given as mean±standard deviation, most frequent toxicants as a score. RESULTS: Calls, especially from non-professionals, increased since 2002. Two third of intoxications occurred in small and pre-school children, more frequently in boys (50%) than girls (44%), in adolescents girls predominated (>60%).<14 years intoxications occur mainly at home, day care or school (>95%), in adolescents suicide attempts and abuse come to the fore (13%). 90% of the cases are asymptomatic or mild, with increasing symptoms at higher ages (adolescents 13% vs. small children 1%). Intoxications with drugs are predominantly in adolescents, surfactant containing cleaning agents and cosmetics, sanitary cleaner, tobacco, glow lights and solute descaler in children. DISCUSSION AND CONCLUSIONS: Increasing incoming calls from professionals and non-professionals point out the importance of the poison centers. Although intoxications in children and adolescents mainly proceed without or mild symptoms, the relevance of preventive measures especially for children<7 should not be underestimated.

Interferon-γ and Tumor Necrosis Factor-α Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis.

BACKGROUND & AIMS: Viral clearance involves immune cell cytolysis of infected cells. However, studies of hepatitis B virus (HBV) infection in chimpanzees have indicated that cytokines released by T cells also can promote viral clearance via noncytolytic processes. We investigated the noncytolytic mechanisms by which T cells eliminate HBV from infected hepatocytes. METHODS: We performed a cytokine enzyme-linked immunosorbent assay of serum samples from patients with acute and chronic hepatitis B. Liver biopsy specimens were analyzed by in situ hybridization. HepG2-H1.3 cells, HBV-infected HepaRG cells, and primary human hepatocytes were incubated with interferon-γ (IFNγ) or tumor necrosis factor-α (TNF-α), or co-cultured with T cells. We measured markers of HBV replication, including the covalently closed circular DNA (cccDNA). RESULTS: Levels of IFNγ and TNF-α were increased in serum samples from patients with acute vs chronic hepatitis B and controls. In human hepatocytes with stably replicating HBV, as well as in HBV-infected primary human hepatocytes or HepaRG cells, IFNγ and TNF-α each induced deamination of cccDNA and interfered with its stability; their effects were additive. HBV-specific T cells, through secretion of IFNγ and TNF-α, inhibited HBV replication and reduced cccDNA in infected cells without the direct contact required for cytolysis. Blocking IFNγ and TNF-α after T-cell stimulation prevented the loss of cccDNA. Deprivation of cccDNA required activation of nuclear APOBEC3 deaminases by the cytokines. In liver biopsy specimens from patients with acute hepatitis B, but not chronic hepatitis B or controls, hepatocytes expressed APOBEC3A and APOBEC3B. CONCLUSIONS: IFNγ and TNF-α, produced by T cells, reduce levels of HBV cccDNA in hepatocytes by inducing deamination and subsequent cccDNA decay.

Overdose of dolutegravir in combination with tenofovir disaproxil fumarate/emtricitabine in suicide attempt in a 21-year old patient.

A 21 year old MSM patient with newly diagnosed HIV infection was hospitalized in our department after ingestion of an overdose of his antiretroviral therapy (ART) comprising dolutegravir (DTG - Tivicay®) and tenofovir disaproxil fumarate/emtricitabine (Truvada®) in suicidal intention. On admission, the patient did not show any clinical signs of intoxication and laboratory findings were unremarkable. After 6 hours of intensive care monitoring, the patient was referred to a psychiatric clinic. 5 days after the day of intoxication, serum creatinine levels increased to high normal values (1.2 mg/dl). However, levels never exceeded the upper threshold. 8 and 12 weeks later, serum creatinine normalized to levels measured prior to the intoxication. No other adverse events occurred, and the patient does not suffer from permanent impairments.

Comparison of a pocket-size ultrasound device with a premium ultrasound machine: diagnostic value and time required in bedside ultrasound examination.

PURPOSE: Time savings and clinical accuracy of a new miniature ultrasound device was investigated utilizing comparison with conventional high-end ultrasound instruments. Our objective was to determine appropriate usage and limitations of this diagnostic tool in internal medicine. METHODS: We investigated 28 patients from the internal-medicine department. Patients were examined with the Acuson P10 portable device and a Sonoline Antares instrument in a cross-over design. All investigations were carried out at the bedside; the results were entered on a standardized report form. The time for the ultrasound examination (transfer time, setting up and disassembly, switching on and off, and complete investigation time) was recorded separately. RESULTS: Mean time for overall examination per patient with the portable ultrasound device was shorter (25.0 ± 4.5 min) than with the high-end machine (29.4 ± 4.4 min; p < 0.001). When measuring the size of liver, spleen, and kidneys, the values obtained differed significantly between portable device and the high-end instrument. In our study, we identified 113 pathological ultrasound findings with the high-end ultrasound machine, while 82 pathological findings (73%) were concordantly detected with the portable ultrasound device. The main diagnostic strengths of the portable device were in the detection of ascites (sensitivity 80%), diagnosis of fatty liver, and identification of severe parenchymal liver damage. CONCLUSIONS: The clinical utility of portable ultrasound machines is limited. There will be clinical roles for distinct clinical questions such as detection of ascites or pleural effusion when used by experienced examiners. However, sensitivity in detecting multiple pathologies is not comparable to high-end ultrasound machines.

Predictors of the accuracy of pulse-contour cardiac index and suggestion of a calibration-index: a prospective evaluation and validation study.

BACKGROUND: Cardiac Index (CI) is a key-parameter of hemodynamic monitoring. Indicator-dilution is considered as gold standard and can be obtained by pulmonary arterial catheter or transpulmonary thermodilution (TPTD; CItd). Furthermore, CI can be estimated by Pulse-Contour-Analysis (PCA) using arterial wave-form analysis (CIpc). Obviously, adjustment of CIpc to CItd initially improves the accuracy of CIpc. Despite uncertainty after which time accuracy of CIpc might be inappropriate, recalibration by TPTD is suggested after a maximum of 8 h. We hypothesized that accuracy of CIpc might not only depend on time to last TPTD, but also on changes of the arterial wave curve detectable by PCA itself. Therefore, we tried to prospectively characterize predictors of accuracy and precision of CIpc (primary outcome). In addition to "time to last TPTD" we evaluated potential predictors detectable solely by pulse-contour-analysis. Finally, the study aimed to develop a pulse-contour-derived "calibration-index" suggesting recalibration and to validate these results in an independent collective. METHODS: In 28 intensive-care-patients with PiCCO-monitoring (Pulsion Medical-Systems, Germany) 56 datasets were recorded. CIpc-values at baseline and after intervals of 1 h, 2 h, 4 h, 6 h and 8 h were compared to CItd derived from immediately subsequent TPTD. Results from this evaluation-collective were validated in an independent validation-collective (49 patients, 67 datasets). RESULTS: Mean bias values CItd-CIpc after different intervals ranged between -0.248 and 0.112 L/min/m(2). Percentage-error after different intervals to last TPTD ranged between 18.6% (evaluation, 2 h-interval) and 40.3% (validation, 6 h-interval). In the merged data, percentage-error was below 30% after 1 h, 2 h, 4 h and 8 h, and exceeded 30% only after 6 h. "Time to last calibration" was neither associated to accuracy nor to precision of CIpc in any uni- or multivariate analysis. By contrast, the height of CIpc and particularly changes in CIpc compared to last thermodilution-derived CItd(base) univariately and independently predicted the bias CItd-CIpc in both collectives. Relative changes of CIpc compared to CItd(base) exceeding thresholds derived from the evaluation-collective (-11.6% < CIpc-CItd(base)/CItd(base) < 7.4%) were confirmed as significant predictors of a bias |CItd-CIpc| ≥ 20% in the validation-collective. CONCLUSION: Recalibration triggered by changes of CIpc compared to CItd(base) derived from last calibration should be preferred to fixed intervals.

The Tanta University risk model could help identify patients with acute poisoning who would require intensive care unit level of care.

OBJECTIVE: To independently validate the negative predictive value of the Tanta University risk model for intensive care requirements in poison center telephone consultations with other physicians. METHODS: This study included 400 consecutive patients with acute poisoning. Clinical and laboratory parameters were recorded during the initial consultation with the poison center. Patients who were already ventilated or on vasopressors at the time of consultation were excluded. The Tanta University risk model score was calculated from the data according to the following equation: Tanta University risk model score = 1.966*Glasgow Coma Scale + 0.329*oxygen saturation (percent) + 0.212*diastolic blood pressure (mmHg) - 0.27*respiratory rate (breaths/minute) + 0.33*standard bicarbonate (mmol/L). Twenty-four hours later, the patients' courses were followed up by telephone. The Tanta University risk model was then compared to a composite endpoint indicating the requirement for admission to an intensive care unit (vasopressors, need for intubation, or death). RESULTS: Four hundred patients with acute poisoning were included. Thirty-seven patients had a complicated clinical course as defined by the composite endpoint. Receiver operating characteristic analysis revealed the area under the curve to be 0.87 (95 percent confidence interval 0.83-0.90). An unfavorable Tanta University risk model score was defined as less than 73.46, using a cut-off derived from a previous study of an unrelated series of patients with acute poisoning admitted to our service. Thirty-one of 37 patients with complicated courses had an unfavorable Tanta University risk model score compared to six patients with complicated courses among 306 patients with a favorable Tanta University risk model score (P < 0.0002, Fisher's exact test). Sixty-three patients had an unfavorable Tanta University risk model score but an uneventful course. The negative predictive value of the Tanta University risk model was 0.98 (95 percent confidence interval 0.96-0.99), sensitivity was 0.84, and specificity 0.83. CONCLUSIONS: In the present study of poison center telephone consultations, the Tanta University risk model was significantly related to the outcomes in patients with acute poisoning. Patients with a favorable Tanta University risk model score (greater than or equal to 73.46) were unlikely to need intensive care unit level of care.

A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry.

BACKGROUND: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis. METHODS: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239). RESULTS: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis. CONCLUSIONS: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.