Treatment of hepatitis C virus leads to economic gains related to reduction in cases of hepatocellular carcinoma and decompensated cirrhosis in Japan.

Hepatocellular carcinoma (HCC) is a serious complication of hepatitis C virus (HCV) infection. Sustained virologic response (SVR) for HCV is associated with a reduction in cirrhosis, HCC and mortality and their associated costs. Japanese HCV patients are older with higher prevalence of HCC. Here we used a decision-analytic Markov model to estimate the economic benefit of HCV cure by reducing HCC and DCC burden in Japan. A cohort of 10 000 HCV genotype 1b (GT1b) Japanese patients was modelled with a hybrid decision tree and Markov state-transition model capturing natural history of HCV over a lifetime horizon. Treatment options were approved all-oral direct-acting anti-virals (DAAs) vs no treatment. Treatment efficacy was based on clinical trials and transition rates and costs obtained from Japan-specific data. Cases of HCC, decompensated cirrhosis (DCC) and quality-adjusted life years (QALYs) were projected for patients treated with DAAs vs NT. QALYs were monetized using a willingness-to-pay threshold of ¥4-to-¥6 million. Incremental savings with treatment were calculated by adding the projected cost of complications avoided to the monetized gains in QALYs. The model showed that DAA treatment vs no treatment, reduces 2057 cases of HCC and 1478 cases of decompensated cirrhosis and saves ¥850 446.73 and ¥338 229.90 per patient (ppt). Additionally, treatment can lead to additional 2.64 QALYs gained per patient. The indirect economic gains associated with treatment-related QALY improvements were ¥10 576 000, ¥13 220 000 and ¥15 864 000 ppt (willingness-to-pay thresholds of ¥4 million, ¥5 million and ¥6 million). Total economic savings of treatment with DAAs (vs no treatment) was ¥7 526 372.63, ¥10 170 372.63 and ¥12 814 372.63, at these different willingness-to-pay thresholds. In conclusion treatment of HCV GT1b with all-oral DAAs in Japan can lead to significant direct and indirect savings related to avoidance of HCC and DCC.

Direct medical costs associated with the extrahepatic manifestations of hepatitis C infection in Europe.

Hepatitis C virus (HCV) infection is a systemic disease associated with both hepatic and extrahepatic manifestations. The burden associated with the hepatic manifestation of HCV infection has been well documented in Europe, although that of HCV extrahepatic manifestations remains unknown. In this study, we estimated the annual direct medical costs associated with HCV extrahepatic manifestations in five European countries. A previously validated economic model was used to estimate the annual direct medical cost associated with HCV extrahepatic manifestations. Global excess prevalence of extrahepatic manifestations in HCV patients relative to that in non-HCV patients was obtained from a recent meta-analysis. Per-patient per-year inpatient, outpatient and medication costs to treat each extrahepatic manifestation were from the literature, national databases or expert opinion if unavailable otherwise. All costs were adjusted to 2016 euros (€). The overall direct medical costs associated with HCV extrahepatic manifestations were calculated by multiplying the total per-patient per-year costs of each by the respective excess prevalence rates and then by the size of the HCV-infected population in each country. Treatment impact with direct-acting antivirals (DAAs) was explored using HCV extrahepatic manifestations excess prevalence rates among cured patients compared to untreated HCV patients, as sourced from a meta-analysis. The total annual direct medical cost associated with HCV extrahepatic manifestations was estimated to be 2.17 billion euro (€), with a per-HCV-patient cost ranging from €899 to €1647 annually. DAA treatment was projected to result in cost savings of €316 million per year. We find that the annual economic burden of extrahepatic manifestations is significant and may be partly mitigated by treatment with DAAs.

Impact of eradicating hepatitis C virus on the work productivity of chronic hepatitis C (CH-C) patients: an economic model from five European countries.

CH-C negatively affects work productivity (WP), creating a large economic burden. The aim of this study was to model the impact of sustained virologic response (SVR) on WP in CHC genotype 1 (GT1) patients in five European countries (EU5). Work Productivity and Activity Index-Specific Health Problem questionnaire was administered to patients across the ION clinical trials (n = 629 European patients). The analysis modelled a population of GT1 CHC patients over one year, who had been either not treated or treated with LDV/SOF. Sensitivity analyses assessed the possibility that CHC patients' labour costs were lower than the general population's and presented results by fibrosis stage. Before initiation of treatment, EU patients with CHC GT1 exhibited absenteeism and presenteeism impairments of 3.54% and 9.12%, respectively. About 91.8% of EU patients in the ION trials achieved SVR and improved absenteeism and presenteeism impairments by 16.3% and 19.5%, respectively. Monetizing these data, treatment with LDV/SOF resulted in an annual productivity gain of €435 million and a weighted average per-employed patient (PEP) gain of €900 in the EU5. PEP gains from treatment are projected to be higher in cirrhotic than in noncirrhotic patients. If CHC patients are assumed to earn 20% less than the general population, gains of €348 million (€720 PEP) annually are projected. CHC results in a significant economic burden to European society. Due to improvements in WP, SVR with treatment could provide substantial economic gains, partly offsetting the direct costs related to its widespread use.

Cystic fibrosis: decreased conjugation and excretion of [14C]spermidine.

Free and conjugated [14C]spermidine were measured in plasma samples from normal individuals and cystic fibrosis patients. Within 4 minutes, the 14C-labeled material in the plasma from normal individuals was 70 percent conjugated compared to no detectable conjugation by cystic fibrosis patients. Further, the patients excreted only 11 to 13 percent of the [14C]spermidine in their urine within 72 hours whereas normal excretion was 60 to 76 percent. In both cases, the labeled material was in a conjugated form.

Energy-dependent nucleolar localization of p53 in vitro requires two discrete regions within the p53 carboxyl terminus.

The p53 tumor suppressor is a nucleocytoplasmic shuttling protein that is found predominantly in the nucleus of cells. In addition to mutation, abnormal p53 cellular localization is one of the mechanisms that inactivate p53 function. To further understand features of p53 that contribute to the regulation of its trafficking within the cell, we analysed the subnuclear localization of wild-type and mutant p53 in human cells that were either permeabilized with detergent or treated with the proteasome inhibitor MG132. We, here, show that either endogenously expressed or exogenously added p53 protein localizes to the nucleolus in detergent-permeabilized cells in a concentration- and ATP hydrolysis-dependent manner. Two discrete regions within the carboxyl terminus of p53 are essential for nucleolar localization in permeabilized cells. Similarly, localization of p53 to the nucleolus after proteasome inhibition in unpermeabilized cells requires sequences within the carboxyl terminus of p53. Interestingly, genotoxic stress markedly decreases the association of p53 with the nucleolus, and phosphorylation of p53 at S392, a site that is modified by such stress, partially impairs its nucleolar localization. The possible significance of these findings is discussed.

Correction: Energy-dependent nucleolar localization of p53 in vitro requires two discrete regions within the p53 carboxyl terminus.

Following the publication of this article the authors noted that two images were duplicated in Figure 2B. The corrected figure 2B is below. The authors wish to apologize for any inconvenience caused.

Brain-stem auditory response in Ondine's syndrome.

Brain-stem auditory evoked responses were measured during sleep in four infants with congenital central alveolar hypoventilation syndrome (Ondine's syndrome) and four controls matched for age and sex. Delays in peak latencies p III and interpeak latencies p I-III were consistently seen in these patients but not in the control children. These abnormalities were reproducible and suggested disruption in the normal auditory pathways at the level of the mid to upper brain stem through which fibers pass close to the area of respiratory control. These abnormalities, both electrophysiologic and metabolic, imply a functional disturbance of brain-stem control of ventilation during sleep in infants and children suffering from Ondine's syndrome.

Hypoelectrolytemia and metabolic alkalosis in infants with cystic fibrosis.

The records of all children in the Tucson area diagnosed as having cystic fibrosis (CF) before the age of 12 months were reviewed to ascertain the prevalence of metabolic alkalosis as a major presenting manifestation of CF. Five of eleven infants (46%) in whom CF had been diagnosed between 1 and 12 months of age initially were seen with hypokalemia, hypochloremia, and metabolic alkalosis unassociated with marked dehydration, hyperpyrexia, or major pulmonary and/or gastrointestinal symptoms. Two infants had repeated episodes of metabolic alkalosis; for one of these infants, both episodes of metabolic alkalosis occurred before the diagnosis of CF. It is postulated that chronic loss of sweat electrolytes together with mild gastrointestinal or respiratory illness may predispose the infant with cystic fibrosis to a severe electrolyte and acid-base disturbance. The lack of shock and hyperpyrexia together with the apparent chronicity of electrolyte losses differentiates metabolic alkalosis from the heat prostration syndrome, a more acute complication of cystic fibrosis. Quantitative sweat testing should be part of the evaluation of any infant with unexplained metabolic alkalosis. Serum electrolytes should be assessed regularly in infants with cystic fibrosis during hot weather months.

Arthrogryposis multiplex congenita as part of an inherited symptom complex: two case reports and a review of the literature.

Two first cousins appear to have an autosomal recessive disorder consisting of arthrogryposis multiplex congenita (AMC), pterygium coli, congenital cervical spine fusions, and some features of the Eagle-Barrett syndrome. A review of the literature is summarized including the broad concepts of AMC as well as some syndromes in which AMC is but one manifestation.

A comparison of tracheal breath sounds, airflow, and impedance pneumography in the detection of childhood apnea.

Impedance respiratory monitoring is not capable of detecting obstructive apneas. We compared a microphone breath sound detector, coupled to the chest wall, with a standard impedance device in 10 sleeping infants and children in order to determine the ability of the breath sound detector to detect normal respirations and central and obstructive apneas. Airflow was used as a standard for all measurements. No difference was found between the breath sound detector and impedance device techniques in the detection rate of either normal respirations or central apneic intervals. There was no statistically significant difference between breath sounds and airflow in the ability of either technique to detect obstructive apnea. The use of a breath sound detector avoids unnecessary stimulation of a sleeping child, whose monitoring would otherwise require that two or three airflow sensing devices be taped on the face. Breath sound monitoring may represent an alternative to impedance and airflow techniques for evaluation of apnea in closely observed infants and children.

Pulmonary risk factors compromising postoperative recovery after surgical repair for congenital heart disease.

STUDY OBJECTIVES: To identify pulmonary risk factors associated with prolonged ICU stay in young children (< or = 2 years) undergoing surgical repair for congenital heart disease (CHD). DESIGN: Retrospective case series analysis. SETTING: Tertiary-care facility. PATIENTS: Clinical records of 134 consecutive patients aged < or = 2 years undergoing cardiac surgery for CHD were reviewed, and 37 were excluded according to inclusion criteria. Thus, 97 patients were allocated to two groups based on the duration of ICU stay: < or = 7 days (group 1, n = 57), and > 7 days (group 2, n = 40). RESULTS: Mean ICU duration for groups 1 and 2 was 3.0 +/- 0.4 days and 28.1 +/- 4.4 days, respectively (p < 0.001). In group 1, there were three extubation failures, whereas 41 extubation failures occurred in group 2 (p < 0.0001). A total of 22 patients (4 in group 1 and 18 in group 2) developed noninfectious pulmonary complications, such as airway problems, including extrinsic airway compression and tracheobronchomalacia (n = 6); pulmonary hypertension (n = 5); phrenic nerve palsy (n = 7); and pleural effusion (n = 8). These 22 patients (23%) contributed to the majority of total ventilator days (67%) as well as ICU stay (61%). CONCLUSIONS: Pulmonary complications in general, and central airway problems in particular, are a frequent cause for delayed recovery following cardiac surgery in young children.

Benign hemangioendothelioma--a rare type of posterior mediastinal mass in children.

Two infants with benign hemangioendotheliomas of the posterior mediastinum are reported here. The neoplasms did not produce symptoms and were fortuitously discovered by chest roentgenograms. Computed tomography (CT) was useful in delineating the extent of the lesions preoperatively.