A new Caenorhabditis elegans model to study copper toxicity in Wilson disease.

Wilson disease (WD) is caused by mutations in the ATP7B gene that encodes a copper (Cu) transporting ATPase whose trafficking from the Golgi to endo-lysosomal compartments drives sequestration of excess Cu and its further excretion from hepatocytes into the bile. Loss of ATP7B function leads to toxic Cu overload in the liver and subsequently in the brain, causing fatal hepatic and neurological abnormalities. The limitations of existing WD therapies call for the development of new therapeutic approaches, which require an amenable animal model system for screening and validation of drugs and molecular targets. To achieve this objective, we generated a mutant Caenorhabditis elegans strain with a substitution of a conserved histidine (H828Q) in the ATP7B ortholog cua-1 corresponding to the most common ATP7B variant (H1069Q) that causes WD. cua-1 mutant animals exhibited very poor resistance to Cu compared to the wild-type strain. This manifested in a strong delay in larval development, a shorter lifespan, impaired motility, oxidative stress pathway activation, and mitochondrial damage. In addition, morphological analysis revealed several neuronal abnormalities in cua-1 mutant animals exposed to Cu. Further investigation suggested that mutant CUA-1 is retained and degraded in the endoplasmic reticulum, similarly to human ATP7B-H1069Q. As a consequence, the mutant protein does not allow animals to counteract Cu toxicity. Notably, pharmacological correctors of ATP7B-H1069Q reduced Cu toxicity in cua-1 mutants indicating that similar pathogenic molecular pathways might be activated by the H/Q substitution and, therefore, targeted for rescue of ATP7B/CUA-1 function. Taken together, our findings suggest that the newly generated cua-1 mutant strain represents an excellent model for Cu toxicity studies in WD.

Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications.

PPFIBP1 encodes for the liprin-ß1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.

Reticulon 2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.

Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to scarcity of supporting evidence. In our study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite Reticulon-2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with Reticulon-2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN, and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.

Stair-Fall Risk Parameters in a Controlled Gait Laboratory Environment and Real (Domestic) Houses: A Prospective Study in Faller and Non-Faller Groups.

BACKGROUND: Falling on stairs is a major health hazard for older people. Risk factors for stair falls have been identified, but these are mostly examined in controlled biomechanics/gait laboratory environments, on experimental stairs with a given set of step dimensions. It remains unknown whether the conclusions drawn from these controlled environments would apply to the negotiation of other domestic staircases with different dimensions in real houses where people live. OBJECTIVES: The aim of this paper is to investigate whether selected biomechanical stepping behavior determined through stair gait parameters such as foot clearance, foot contact length and cadence are maintained when the staircase dimensions are different in real houses. METHODS: Twenty-five older adults (>65 years) walked on a custom-made seven-step laboratory staircase. Older adults were classified into two groups (fallers and non-fallers) based on recent fall history. Among the 25 participants, 13 people had at least one fall, trip, or slip in the last six months and they were assigned to the fallers group; 12 people did not experience any fall in the last six months, so they were assigned to the non-fallers group. In addition, these participants walked on the stairs in three different real exemplar houses wearing a novel instrumented shoe sensor system that could measure the above stair gait parameters. MATLAB was used to extract fall risk parameters from the collected data. One-way ANOVA was used to compare fall risk parameters on the different staircases. In addition, the laboratory-based fall risk parameters were compared to those derived from the real house stairs. RESULTS: There was a significant difference in selected stair-fall biomechanical risk factors among the house and laboratory staircases. The fall risk group comparisons suggest that high-risk fallers implemented a biomechanically riskier strategy that could increase overall falling risk. CONCLUSIONS: The significant differences due to the main effects of the fallers and non-fallers groups were obtained. For example, when ascending, the fallers group had less foot clearance on the entry (p = 0.016) and middle steps (p = 0.003); in addition, they had more foot clearance variability on the entry steps (p = 0.003). This suggests that the fallers group in this present study did not adopt more conservative stepping strategies during stair ascent compared to low-risk older adults. By showing less foot clearance and more variability in foot clearance, the risk for a trip would be increased.

Rectal and gastrointestinal temperature differ during passive heating and subsequent recovery.

We aimed to compare rectal temperature (Trec) and gastro-intestinal temperature (TGI) during passive heating and subsequent recovery with and without ice slurry ingestion. Twelve males (age: 25 ± 4 years, body mass index: 25.7 ± 2.5 kg m-2) were immersed in hot water on two occasions (Trec elevation: 1.82 ± 0.08°C). In the subsequent 60-min recovery in ambient conditions, participants ingested either 6.8 g kg-1 of ice slurry (-0.6°C, ICE) or control drink (37°C, CON). During passive heating, Trec was lower than TGI (P < 0.001), in the recovery, Trec was higher than TGI (P < 0.001). During passive heating, mean bias and 95%LoA (Limits of Agreement) were -0.10(±0.25)°C and -0.12(±0.36)°C for CON and ICE, respectively. In the recovery, mean bias and 95%LoA were 0.30(±0.60)°C and 0.42(±0.63)°C for CON and ICE, respectively. Trec and TGI differed during both heating and recovery, and less favourable agreement between Trec and TGI was found in the recovery from passive heating with or without ice slurry ingestion.

No Association of IFNL4 Genotype With Opportunistic Infections and Cancers Among Men With Human Immunodeficiency Virus 1 Infection.

BACKGROUND: IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. METHODS: We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984-1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. RESULTS: We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval, .76-1.11]), cytomegalovirus infection (0.94 [.71-1.24]), herpes simplex virus infection (1.37 [.68-2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. CONCLUSIONS: The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.

Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals.

PURPOSE: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype-phenotype correlations in individuals with biallelic SLC18A2 variants. METHODS: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm- and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies. RESULTS: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global developmental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involvement (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities. CONCLUSION: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders.

Wheelchair rugby players maintain sprint performance but alter propulsion biomechanics after simulated match play.

The study aimed to explore the influence of a sports-specific intermittent sprint protocol (ISP) on wheelchair sprint performance and the kinetics and kinematics of sprinting in elite wheelchair rugby (WR) players with and without spinal cord injury (SCI). Fifteen international WR players (age 30.3 ± 5.5 years) performed two 10-s sprints on a dual roller wheelchair ergometer before and immediately after an ISP consisting of four 16-min quarters. Physiological measurements (heart rate, blood lactate concentration, and rating of perceived exertion) were collected. Three-dimensional thorax and bilateral glenohumeral kinematics were quantified. Following the ISP, all physiological parameters significantly increased (p ≤ 0.027), but neither sprinting peak velocity nor distance traveled changed. Players propelled with significantly reduced thorax flexion and peak glenohumeral abduction during both the acceleration (both -5°) and maximal velocity phases (-6° and 8°, respectively) of sprinting post-ISP. Moreover, players exhibited significantly larger mean contact angles (+24°), contact angle asymmetries (+4%), and glenohumeral flexion asymmetries (+10%) during the acceleration phase of sprinting post-ISP. Players displayed greater glenohumeral abduction range of motion (+17°) and asymmetries (+20%) during the maximal velocity phase of sprinting post-ISP. Players with SCI (SCI, n = 7) significantly increased asymmetries in peak power (+6%) and glenohumeral abduction (+15%) during the acceleration phase post-ISP. Our data indicates that despite inducing physiological fatigue resulting from WR match play, players can maintain sprint performance by modifying how they propel their wheelchair. Increased asymmetry post-ISP was notable, which may be specific to impairment type and warrants further investigation.

A Novel Smart Shoe Instrumented with Sensors for Quantifying Foot Placement and Clearance during Stair Negotiation.

Trips and slips are significant causal perturbations leading to falls on stairs, especially in older people. The risk of a trip caused by a toe or heel catch on the step edge increases when clearance is small and variable between steps. The risk of a slip increases if the proportion of the foot area in contact with the step is reduced and variable between steps. To assess fall risk, these measurements are typically taken in a gait lab using motion-capture optoelectronic systems. The aim of this work was to develop a novel smart shoe equipped with sensors to measure foot placement and foot clearance on stairs in real homes. To validate the smart shoe as a tool for estimating stair fall risk, twenty-five older adults' sensor-based measurements were compared against foot placement and clearance measurements taken in an experimental staircase in the lab using correlations and Bland-Altman agreement techniques. The results showed that there was a good agreement and a strong positive linear correlation for foot placement (r = 0.878, p < 0.000) and foot clearance (r = 0.967, p < 0.000) between sensor and motion analysis, offering promise for advancing the current prototype into a measurement tool for fall risk in real-life staircases.

Accuracy and Precision of a Novel Photogate System to Measure Toe Clearance on Stairs.

Background: Toe clearance on stairs is typically measured using optoelectronic systems, though these are often constrained to the laboratory, due to their complex setups. Here we measured stair toe clearance through a novel prototype photogate setup and compared this to optoelectronic measurements. Methods: Twelve participants (age 22 ± 3 years) completed 25 stair ascent trials, each on a seven-step staircase. Toe clearance over the fifth step edge was measured using Vicon and the photogates. Twenty-two photogates were created in rows through laser diodes and phototransistors. The height of the lowest photogate broken at step-edge crossing was used to determine photogate toe clearance. A limits of agreement analysis and Pearson's correlation coefficient compared the accuracy, precision and relationship between systems. Results: We found a mean difference of -1.5 mm (accuracy) between the two measurement systems, with upper and lower limits (precision) of 10.7 mm and -13.8 mm, respectively. A strong positive correlation was also found (r = 70, n = 12, p = 0.009) between the systems. Discussion: The results suggest that photogates could be an option for measuring real-world stair toe clearances, where optoelectronic systems are not routinely used. Improvements to the design and measurement factors may help to improve the precision of the photogates.

The role of IFNL4 in liver inflammation and progression of fibrosis.

The discovery that genetic variation within the interferon lambda locus has a profound effect on the outcome of hepatitis C virus (HCV) treatment and spontaneous clearance of HCV is one of the great triumphs of genomic medicine. Subsequently, the IFNL4 gene was discovered and proposed as the causal gene underlying this association. However, there has been a lively debate within the field concerning the causality, which has been further complicated by a change in naming. This review summarizes the genetic data available for the IFNL3/IFNl4 loci and provides an in-depth discussion of causality. We also discuss a new series of interesting data suggesting that the genetic variation at the IFNL4 loci influences the evolution of the HCV virus and the implication this relationship between our genetic makeup and virus evolution has upon our understanding of the IFNL4 system. Finally, new data support an influence of the IFNL4 gene upon liver inflammation and fibrosis that is independent of etiology, thereby linking the IFNL4 gene to some of the major liver diseases of today.

Declining US Hepatocellular Carcinoma Rates, 2014-2017.

Liver cancer is a prominent cause of cancer death in the United States.1 Rates of hepatocellular carcinoma (HCC), the most common histologic subtype,2 increased for decades,3 until recent years when rates flattened,4 and then potentially declined. Previously, we reported that US HCC rates in 2016 were 4% lower than 20155; however, it was unclear from those data whether that finding reflected a true downward trend. Here, we examine HCC rates through 2017.

Nearly Optimal Quantum Algorithm for Estimating Multiple Expectation Values.

Many quantum algorithms involve the evaluation of expectation values. Optimal strategies for estimating a single expectation value are known, requiring a number of state preparations that scales with the target error ϵ as O(1/ϵ). In this Letter, we address the task of estimating the expectation values of M different observables, each to within additive error ϵ, with the same 1/ϵ dependence. We describe an approach that leverages Gilyén et al.'s quantum gradient estimation algorithm to achieve O(sqrt[M]/ϵ) scaling up to logarithmic factors, regardless of the commutation properties of the M observables. We prove that this scaling is worst-case optimal in the high-precision regime if the state preparation is treated as a black box, even when the operators are mutually commuting. We highlight the flexibility of our approach by presenting several generalizations, including a strategy for accelerating the estimation of a collection of dynamic correlation functions.

A phase 1b study of glasdegib + azacitidine in patients with untreated acute myeloid leukemia and higher-risk myelodysplastic syndromes.

This phase 1b study evaluated glasdegib (100 mg once daily) + azacitidine in adults with newly diagnosed acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) who were ineligible for intensive chemotherapy. Of 72 patients enrolled, 12 were in a lead-in safety cohort (LIC) and 60 were in the AML and MDS (including CMML) expansion cohorts. In the LIC, the safety profile of glasdegib + azacitidine was determined to be consistent with those of glasdegib or azacitidine alone, with no evidence of drug-drug interaction. In the expansion cohort, the most frequently (≥ 10%) reported non-hematologic Grade ≥ 3 treatment-emergent adverse events were decreased appetite, electrocardiogram QT prolongation, and hypertension in the AML cohort and sepsis, diarrhea, hypotension, pneumonia, and hyperglycemia in the MDS cohort. Overall response rates in the AML and MDS cohorts were 30.0% and 33.3%, respectively; 47.4% and 46.7% of patients who were transfusion dependent at baseline achieved independence. Median overall survival (95% confidence interval) was 9.2 (6.2-14.0) months and 15.8 (9.3-21.9) months, respectively, and response was associated with molecular mutation clearance. Glasdegib + azacitidine in patients with newly diagnosed AML or MDS demonstrated an acceptable safety profile and preliminary evidence of clinical benefits.Trial registration: ClinicalTrials.gov NCT02367456.

Structure-based optimization of hydroxylactam as potent, cell-active inhibitors of lactate dehydrogenase.

Structure-based design was utilized to optimize 6,6-diaryl substituted dihydropyrone and hydroxylactam to obtain inhibitors of lactate dehydrogenase (LDH) with low nanomolar biochemical and single-digit micromolar cellular potencies. Surprisingly the replacement of a phenyl with a pyridyl moiety in the chemical structure revealed a new binding mode for the inhibitors with subtle conformational change of the LDHA active site. This led to the identification of a potent, cell-active hydroxylactam inhibitor exhibiting an in vivo pharmacokinetic profile suitable for mouse tumor xenograft study.

Children who idiopathically toe-walk have greater plantarflexor effective mechanical advantage compared to typically developing children.

PURPOSE: The effective mechanical advantage (EMA) of the plantarflexor muscles is important for gait function and is likely different from typical in equinus gait. However, this has never been quantified for children who idiopathically toe-walk (ITW), despite being routinely altered through clinical intervention. METHODS: This study quantified the Achilles tendon and ground reaction force (GRF) moment arms, and the plantarflexor EMA of 5 children who ITW and 14 typically developing (TD) children, whilst walking on an instrumented treadmill. RESULTS: There was no difference in the Achilles tendon moment arm length throughout stance between groups (p > 0.05). Children who ITW had a significantly greater GRF moment arm length in early stance (20-24% p = 0.001), but a significantly shorter GRF moment arm length during propulsion (68-74% of stance; p = 0.013) than TD children. Therefore, children who ITW had a greater plantarflexor EMA than TD children when active plantarflexion moments were being generated (60-70% of stance; p = 0.007). Consequently, it was estimated that children who ITW required 30% less plantarflexor muscle force for propulsion. CONCLUSION: Clinical decision making should fully consider that interventions which aim to restore a typical heel-toe gait pattern risk compromising this advantageous leverage and thus, may increase the strength requirements for gait.

Role of Knee and Ankle Extensors' Muscle-Tendon Properties in Dynamic Balance Recovery from a Simulated Slip.

Participants exposed to a simulated slip with forward loss of balance (FLB) develop large lower limb joint moments which may be a limiting factor for those whose muscle-tendon units' (MTUs) properties are deteriorated. Whether the age-related decline in these properties limits participants' capacity to recover their balance following a slip with FLB remains unclear. We combined isokinetic dynamometry, ultrasound and EMG to understand how knee extensor and ankle plantarflexor muscle strength and power, rate of moment development, electromechanical delay, and tendon stiffness affected the balance of young (25.3 ± 3.9 years) and older adults (62.8 ± 7.1 years) when recovering from a single slip with FLB triggered whilst walking on a split-belt instrumented treadmill. Except for the patellar tendon's stiffness, knee extensor and ankle plantarflexor electromechanical delays, older adults' MTUs properties were deteriorated compared to those of young participants (p < 0.05). We found no significant relationship between age or the MTUs properties of participants and balance recovery. These findings provide additional support that neither maximal nor explosive strength training are likely to be successful in preventing a fall for healthy older adults, and that other type of interventions, such as task-specific training that has already proved efficacious in reducing the risk of falling, should be developed.

Testing a digitally distributed method to recruit a network of community organizations to fight the consequences of the drug epidemic: A study in 13 American states.

To mitigate the opioid epidemic, a concerted effort to educate, prevent, diagnose, treat, and engage residents is required. In this study, a digitally distributed method to form a large network of organizations was tested with 99 counties in regions with high vulnerability to hepatitis C virus (HCV). The method involved a cascade of contacts going from email to phone calls, to videoconferencing and measuring the number of contacts required, amount of time taken, and the proportion of success at recruiting at least one community organization per county. A recruitment period of 5 months and 2118 contact attempts led to the recruitment of organizations from 73 out of our 99 target counties. Organizations belonging to health departments required more attempts and time to recruit but ultimately enrolled at higher rates than did other organizations such as coalitions and agencies. Organizations from counties more (vs. less) vulnerable to HCV outbreaks required more attempts to recruit and, using multiple recruitment methods (e.g., emails, phone calls, and Zoom meetings), improved enrollment success. Overall, this method proved to be successful at remotely engaging a large-scale network of communities with different levels of risk within a large geographic region.

A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus.

BACKGROUND: Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. METHODS: To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. RESULTS: A male-specific region near the adenosine diphosphate-ribosylation factor-like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10-07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10-06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. CONCLUSIONS: These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.

Death certificates compared to SEER-Medicare data for surveillance of liver cancer mortality due to hepatitis B or hepatitis C infection.

Hepatocellular carcinoma (HCC) is often caused by hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. To investigate the completeness of death certificates for recording viral hepatitis in HCC death, we compared the proportion of HCC deaths with hepatitis virus infection reported on death certificates to that reported as claims in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database among individuals ≥66 years of age. For 2001-2015, we tabulated proportions of HCC deaths with HBV or HCV infection in each database overall, and by demographic factors. To correct for under ascertainment of viral hepatitis-associated HCC on death certificates, we multiplied by the reciprocal ratio of death certificates to SEER-Medicare. Among HCC decedents, HBV infection was reported on 3.6% of death certificates and 17.2% of Medicare claims. For HCV, corresponding proportions were 14.9% and 26.9%. The ratio of HBV-attributable HCC deaths in death certificates to SEER-Medicare remained ~0.21 over time. The ratio of HCV-attributable HCC deaths decreased 22.1% per year, from 0.70 in 2001 to 0.37 in 2003, and increased 4.1% per year, from 0.47 in 2004 to 0.66 in 2015. Following correction, the 2015 mortality rate from death certificate data increased from 0.2 to 0.9 per 100,000 for HBV-attributable HCC and from 2.3 to 3.5 per 100,000 for HCV-attributable HCC. In conclusion, among older Americans dying from HCC, death certificates captured 21% of HBV and 55% of HCV infections compared to Medicare claims. Our results suggest that death certificates provide incomplete data for viral hepatitis-associated HCC surveillance.