Toward a Mobile Platform for Real-world Digital Measurement of Depression: User-Centered Design, Data Quality, and Behavioral and Clinical Modeling.

BACKGROUND: Although effective mental health treatments exist, the ability to match individuals to optimal treatments is poor, and timely assessment of response is difficult. One reason for these challenges is the lack of objective measurement of psychiatric symptoms. Sensors and active tasks recorded by smartphones provide a low-burden, low-cost, and scalable way to capture real-world data from patients that could augment clinical decision-making and move the field of mental health closer to measurement-based care. OBJECTIVE: This study tests the feasibility of a fully remote study on individuals with self-reported depression using an Android-based smartphone app to collect subjective and objective measures associated with depression severity. The goals of this pilot study are to develop an engaging user interface for high task adherence through user-centered design; test the quality of collected data from passive sensors; start building clinically relevant behavioral measures (features) from passive sensors and active inputs; and preliminarily explore connections between these features and depression severity. METHODS: A total of 600 participants were asked to download the study app to join this fully remote, observational 12-week study. The app passively collected 20 sensor data streams (eg, ambient audio level, location, and inertial measurement units), and participants were asked to complete daily survey tasks, weekly voice diaries, and the clinically validated Patient Health Questionnaire (PHQ-9) self-survey. Pairwise correlations between derived behavioral features (eg, weekly minutes spent at home) and PHQ-9 were computed. Using these behavioral features, we also constructed an elastic net penalized multivariate logistic regression model predicting depressed versus nondepressed PHQ-9 scores (ie, dichotomized PHQ-9). RESULTS: A total of 415 individuals logged into the app. Over the course of the 12-week study, these participants completed 83.35% (4151/4980) of the PHQ-9s. Applying data sufficiency rules for minimally necessary daily and weekly data resulted in 3779 participant-weeks of data across 384 participants. Using a subset of 34 behavioral features, we found that 11 features showed a significant (P<.001 Benjamini-Hochberg adjusted) Spearman correlation with weekly PHQ-9, including voice diary-derived word sentiment and ambient audio levels. Restricting the data to those cases in which all 34 behavioral features were present, we had available 1013 participant-weeks from 186 participants. The logistic regression model predicting depression status resulted in a 10-fold cross-validated mean area under the curve of 0.656 (SD 0.079). CONCLUSIONS: This study finds a strong proof of concept for the use of a smartphone-based assessment of depression outcomes. Behavioral features derived from passive sensors and active tasks show promising correlations with a validated clinical measure of depression (PHQ-9). Future work is needed to increase scale that may permit the construction of more complex (eg, nonlinear) predictive models and better handle data missingness.

Transradial Versus Transfemoral Arterial Access in Liver Cancer Embolization: Randomized Trial to Assess Patient Satisfaction.

PURPOSE: To determine whether transradial access (TRA) or transfemoral access (TFA) provides better patient satisfaction during intra-arterial therapy (IAT) for liver cancer. MATERIALS AND METHODS: This randomized, prospective, intra- and interpatient controlled trial compared TRA vs TFA accesses in patients with primary or metastatic liver cancer undergoing IAT. After having one of each type of access (1 TRA and 1 TFA), all patients selected their preferred access regardless of whether a third intervention was indicated. The primary endpoint was patient access preference; secondary endpoints were access-related complications, procedure time, contrast agent volume, and radiation doses to the patient and operator. Patients were evaluated on postprocedure days 1 and 30. RESULTS: Fifty-five patients with liver cancer (31 hepatocellular carcinoma, 24 metastatic disease) were enrolled, and 124 IAT procedures were performed. A total of 36 patients underwent at least 1 intervention each with TRA and TFA. Of those, 29 patients (81%) preferred TRA and 7 (19%) preferred TFA (ratio, 4:1; P < .001). Median radiation exposure to the operator was significantly lower for TRA (5.5 mrem) vs TFA (13 mrem; P = .01). Incidences of complications, procedure time, contrast agent volume, and radiation exposure to patients were similar between groups. CONCLUSIONS: TRA was the preferred access for the majority of patients and was associated with less radiation exposure to the operator. No differences were detected in incidence of adverse events, procedure time, contrast agent volume, or patient radiation exposure.

Linear measurements of the cerebral ventricles are correlated with adult ventricular volume.

Computation of ventricular volume has important clinical applications but is challenging. We compared linear ventricular measurements to ventricular volume to find a simple to perform quantitative measurement of ventricular size. Linear measurements were correlated with ventricular volumes to different degrees and were reproducible between investigators. Linear measurements provide a quick and simple quantification of ventricular size for use in clinical settings.

Microwave spectra of the deuterium isotopologues of cis-hexatriene and a semiexperimental equilibrium structure.

Microwave transitions and ground state rotational constants are reported for five newly synthesized deuterium isotopologues of cis-1,3,5-hexatriene (cHTE). These rotational constants along with those of the parent and the three (13)C species are used with vibration-rotation constants calculated from an MP2/cc-pVTZ model to derive an equilibrium structure. That structure is improved by the mixed estimation method. In this method, internal coordinates from good-quality quantum chemical calculations (with appropriate uncertainties) are fit simultaneously with moments of inertia of the full set of isotopologues. The new structure of cHTE is confirmed to be planar and is stabilized by an interaction between the hydrogen atoms H2 and H5, which form a bond and participate in a six-membered ring. cHTE shows larger structural effects of π-electron delocalization than does butadiene with the effects being magnified in the center of the molecule. Thus, strong structural evidence now exists for an increase in π-electron delocalization as the polyene chain lengthens.

Semiexperimental equilibrium structure of the lower energy conformer of glycidol by the mixed estimation method.

Rotational constants were determined for (18)O-substituted isotopologues of the lower energy conformer of glycidol, which has an intramolecular inner hydrogen bond from the hydroxyl group to the oxirane ring oxygen. Rotational constants were previously determined for the (13)C and the OD species. These rotational constants have been corrected with the rovibrational constants calculated from an ab initio cubic force field. The derived semiexperimental equilibrium rotational constants have been supplemented by carefully chosen structural parameters, including those for hydrogen atoms, from medium level ab initio calculations. The combined data have been used in a weighted least-squares fit to determine an equilibrium structure for the glycidol H-bond inner conformer. This work shows that the mixed estimation method allows us to determine a complete and reliable equilibrium structure for large molecules, even when the rotational constants of a number of isotopologues are unavailable.

Ventricular width and complicated recovery following deep brain stimulation surgery.

BACKGROUND: Candidates for deep brain stimulation (DBS) must be carefully evaluated to balance expected benefits with the possibility of serious complications. Several predictive factors exist but are imperfect. OBJECTIVES: The aim of this study was to determine whether linear measurements of the lateral ventricles predict complications following DBS. METHODS: We retrospectively studied a cohort of DBS patients. The primary outcome was postoperative confusion; secondary outcomes were discharge disposition and all in-hospital complications. For each case, a control matched for age, sex, diagnosis, and DBS target was identified. Linear measurements were made from routine preoperative axial MRIs for both cases and controls. RESULTS: A total of 40 patients met one or more of the end points. Patients with postoperative confusion had a significantly larger minimum width of the lateral ventricles than controls. Patients discharged to a higher level of care and those with any complications also had significantly greater maximum and minimum ventricular widths than controls. CONCLUSIONS: These results suggest that preoperative measurement of the maximum and minimum width of the lateral ventricles may help predict which patients are at risk for complicated recoveries following DBS.

Microwave, infrared, and Raman spectra, r0 structural parameters, conformational stability, and vibrational assignment of allyl thiol.

FT-microwave spectrum of allyl thiol, H(2)CCHCH(2)SH, has been recorded, and 19 transitions have been assigned for the most abundant isotopologue of Gg conformer, and the rotational constants have been determined; A=20,041.439 (4), B=2795.830 (1), C=2701.084 (1). From the determined microwave rotational constants and ab initio MP2(full)/6-311+G(d,p) predicted structural values, adjusted r(0) parameters are reported with distances (Å): rCC=1.343 (3), rC-C=1.496 (3), rC-S=1.827 (3) and angles (°) ∠CCC=123.4 (5), ∠CCS=112.5 (5), and τC(γ)C(ß)C(α)S=118.7 (5). Variable temperature (-55 to -100°C) infrared spectra (3600-400cm(-1)) were recorded of allyl thiol in liquid xenon and the Gg conformer was determined to be the most stable form. The enthalpy differences relative to the Gg form are for Cg 120±9cm(-1) (1.44±0.11kJ/mol), for Gg' 337±34cm(-1) (4.03±0.41kJ/mol), and for Gt 360±36cm(-1) (4.31±0.43kJ/mol). The relative amounts present at ambient temperature are Gg 52±1%, Cg 29±1%, Gg' 10±1%, and Gt 9±1%. The conformational stabilities have been predicted from ab initio calculations with many basis sets up to aug-cc-pVTZ and the predicted stabilities are in agreement with the experimentally determined order. Vibrational assignments are reported with support by ab initio predictions and results are discussed.

Rotational spectra and computational analysis of two conformers of leucinamide.

Rotational spectra were recorded for two isotopic species of two conformers of the amide derivative of leucine in the range of 10.5-21 GHz and fit to a rigid rotor Hamiltonian. Ab initio calculations at the MP2/6-311++G(d,p) level identified the low energy conformations with different side chain configurations; the rotational spectra were assigned to the two lowest energy ab initio structures. We recorded 16 a- and b-type rotational transitions for conformer 1; the rotational constants of the normal species are A = 2275.6(2), B = 1033.37(2) and C = 911.71(5) MHz. We recorded 23 a- and b-type rotational transitions for conformer 2; the rotational constants of the normal species are A = 2752.775(8), B = 843.502(1) and C = 796.721(1) MHz. The rotational spectra of the (15)N(amide) isotopomer of each conformer were recorded and the atomic coordinates of the amide nitrogen were determined by Kraitchman's method of isotopic substitution. The experimentally observed structures are significantly different from the crystal structures of leucinamide and the gas-phase structures of leucine, and a natural bond orbital analysis revealed the donor-acceptor interactions governing side chain configuration.

Decision making for the extent of thyroidectomy in the patient with atypical cytologic results.

OBJECTIVE: to identify additional preoperative factors that could reliably be used to aid in determining the appropriate extent of thyroidectomy. DESIGN: retrospective chart review. SETTING: tertiary care academic hospital. PATIENTS: two hundred consecutively treated patients who underwent thyroid surgery after having a fine-needle aspiration biopsy procedure yielding a specimen that met the criteria for atypical cytologic features. MAIN OUTCOME MEASURE: final histopathologic diagnosis of malignant vs benign disease. RESULTS: the final diagnosis was benign in 42.5% of patients and malignant in 57.5%. The presence of microcalcifications within the nodule on ultrasonography (US) was significantly associated with a higher risk of malignant disease (relative risk = 1.31, P = .04). When examined individually, age, sex, family history of thyroid malignant disease, exposure to head and neck irradiation, nodule size, rim enhancement on US, and intranodular vascularity on US were not significantly associated with an increased risk of malignant disease. Mulivariate stepwise logistic regression modeling was used to identify a model that could reliably predict a higher probability of malignant disease. The final model determined that patients with microcalcifications on US and a nodule of 2.0 cm or larger had a 74.3% risk of malignant disease vs a 47.5% risk in patients with no microcalcifications and a nodule smaller than 2.0 cm. This difference was statistically significant. When the predicted probabilities of malignant disease were compared with the observed probabilities, the goodness-of-fit test revealed no significant difference (P = .95). CONCLUSION: microcalcifications and nodule size can be used to risk-stratify patients with an atypical fine-needle aspiration biopsy result and aid in determining the appropriate extent of thyroidectomy.

Microwave, Raman, and infrared spectra; adjusted r(0) structural parameters; conformational stability; and vibrational assignment of germylcyclohexane.

The FT-microwave spectrum of germylcyclohexane, c-C(6)H(11)GeH(3), has been recorded, and more than 40 transitions for the (70)Ge, (72)Ge, and (74)Ge isotopomers (isotopologues) have been assigned for the chair-equatorial conformer. The heavy atom adjusted r(0) structural parameters have been determined [distances, C(gamma)-C(delta) = 1.533(3) A, C(gamma)-C(beta) = 1.532(3) A, C(alpha)-C(beta) = 1.540(3) A, C(alpha)-Ge = 1.957(3) A; angles, angleC(gamma)C(delta)C(beta) = 111.2(5) degrees , angleGeC(alpha)C(beta) = 111.1(5) degrees , with the dihedral angle angleC(gamma)C(delta)C(beta)C(alpha) = 55.6(10) degrees ]. Raman and/or infrared spectra of gas, liquid, and solid germylcyclohexane have been recorded. The temperature dependency of the Raman spectrum of the conformer pair 712 (equatorial)/683 (axial) cm(-1) gives an enthalpy difference of 453 +/- 38 cm(-1) (1.30 +/- 0.11 kcal/mol) with the chair-equatorial conformer the more stable form. At ambient temperature, the abundance of the axial conformer is 11 +/- 1%. Substituent effects on the enthalpy difference and structure of monosubstituted cyclohexanes are discussed for a number of molecules.

Infrared spectra of CF(2)=CHD and CF(2)=CD(2): scaled quantum-chemical force fields and an equilibrium structure for 1,1-difluoroethylene.

Infrared (IR) spectra in the gas phase are reported for CF(2)=CHD and CF(2)=CD(2) in the region 350-4000 cm(-1). Ab initio calculations of an harmonic force-field and anharmonicity constants have been made with an MP2/aug-cc-pVTZ model. These enable a number of Fermi resonances in each species to be analyzed and a complete set of "observed" harmonic frequencies to be derived. The latter are combined with similar data for CF(2)=CH(2) in a scaling of the model harmonic force field to both anharmonic and harmonic frequencies. Inspection of the scale factors reveals minor defects of the model, evident in the out-of-plane wagging modes and in the CF stretch/CF stretch interaction force constant. Fermi resonance treatments involved in all isotopomers studied are compatible with the overall force-field refinement results. The treatment leaves a small anomaly in the (13)C shift on nu(1). Improved microwave spectra are reported for five isotopic species, and a semiexperimental equilibrium structure for F(2)C=CH(2) is determined and compared favorably with the structure obtained from new high-level ab initio calculations. Centrifugal distortion constants are predicted for the five isotopic species, and those for F(2)C=CH(2) are compared with values fit to microwave spectra.

Rotational spectra of o-, m-, and p-cyanophenol and internal rotation of p-cyanophenol.

Rotational spectra of p-, m-, and o-cyanophenol have been measured in the range of 10.5-21 GHz and fit using Watson's A-reduction Hamiltonian coupled with nuclear quadrupole coupling interaction terms for the (14)N nuclei. Ab initio calculations at the MP2/6-311++G(d,p) and CCSD(T)/6-311++G(d,p) levels predict the cis conformers of m- and o-cyanophenol to be more stable than the corresponding trans conformers. A natural bond orbital analysis of the hydrogen bonding interaction in o- and m-cyanophenol revealed an intramolecular hydrogen bond that preferentially stabilizes the cis conformer of o-cyanophenol but there was no evidence of hydrogen bonding interactions in cis m-cyanophenol. We recorded 25 a- and b-type rotational transitions for cis o-cyanophenol; the rotational constants are A = 3053.758(2) MHz, B = 1511.2760(3) MHz, and C = 1010.7989(2) MHz. The trans conformer of o-cyanophenol was not observed. We recorded 14 a- and b-type rotational transitions for cis m-cyanophenol and 16 a- and b-type rotational transitions for trans m-cyanophenol. The rotational constants are A = 3408.9200(2) MHz, B = 1205.8269(2) MHz, and C = 890.6672(1) MHz and A = 3403.1196(3) MHz, B = 1208.4903(2) MHz, and C = 891.7241(2) MHz for the cis and trans species, respectively. Rotational transitions of the p-cyanophenol monomer are split due to the internal rotation of the hydroxyl group with respect to the aromatic ring. We recorded 25 a- and b-type rotational transitions for p-cyanophenol; the b-type transitions are split by 40 MHz. The rotational constants are A = 5612.96(2) MHz, B = 990.4283(6) MHz, and C = 841.9363(6) MHz. The ground state spitting DeltaE is 20.1608(6) MHz and the barrier to internal rotation, V(2), is 1413(2) cm(-1) from a fit of the rotational transitions to an internal axis system Hamiltonian. The barrier to internal rotation was modeled at the MP2/6-311++G(d,p) level and the effects of substituents on the phenolic ring and the barriers to internal rotation are discussed.

Favorable outcomes of autoimmune hepatitis in a community clinic setting.

BACKGROUND AND AIM: Autoimmune hepatitis (AIH) is an idiopathic disease with diverse clinical manifestations. The aims of the present study were: (i) to describe the clinical characteristics of AIH patients in a community clinic setting; and (ii) to determine factors which were associated with poor clinical outcomes. METHODS: A retrospective review was performed on 72 AIH patients who: (i) had pretreatment sera: (ii) were treatment-naïve at presentation; and (iii) had a minimum of 24 months of follow up. RESULTS: On initial presentation, 22 (30%) had an acute onset of symptoms simulating acute viral hepatitis, 34 (47%) had chronic symptoms of greater than 6 months duration, and the remaining 16 (22%) were asymptomatic. Twenty-six (36%) had coexisting autoimmune diseases. Anti-nuclear antibody (ANA) was positive in 73% of the patients, and antismooth muscle antibody was positive in 15% of ANA-negative patients. Those few patients who tested positive for soluble liver antigen, anti-liver-kidney, microsomal antibody type-1, and anti-mitochondrial antibody were all also ANA positive. The median (range) duration of follow up was 98 (24-331) months. After immunosuppressive therapy, 26 of 72 (36%) remained in remission without further treatment. However, 46 (64%) required maintenance immunosuppression. Three patients who presented under the age of 20 years progressed to liver failure while on therapy and died while waiting for liver transplantation. Two other patients developed hepatocellular carcinoma (HCC) while on therapy and died. CONCLUSIONS: A majority of AIH patients have an excellent prognosis. However, presentation at a younger age is a predictor of poor disease outcome and, although uncommon, HCC may develop during the late stages of cirrhosis.

Feeding the open abdomen.

BACKGROUND: The purpose of this study was to determine if early enteral nutrition improves outcome for trauma patients with an open abdomen (OA). METHODS: Retrospective review was used to identify 78 patients who required an OA for >or=4 hospital days, survived, and had available nutrition data. Demographic data and nutrition data comprising enteral nutrition initiation day and daily % target goal were collected. Patients were divided into 2 groups: early enteral feeding (EEN), initiated 4 days). Outcomes included infectious complications, early closure of the abdominal cavity (<8 days from original celiotomy), and fistula formation. RESULTS: Fifty-three of 78 (68%) patients were men, with a mean age of 35 years; 74% had blunt trauma. Forty-three of 78 (55%) patients had EEN, whereas 35 of 78 (45%) had LEN. There was no difference with respect to demographics, injury severity, or infectious complication rates. Thirty-two of 43 (74%) patients with EEN had early closure of the abdominal cavity, whereas 17 of 35 (49%) patients with late feeding had early closure (p = .02). Four of 43 (9%) patients with EEN demonstrated fistula formation, whereas 9 of 35 (26%) patients with late feeding formed fistulae (p = .05). The EEN group had lower hospital charges (p = .04) by more than $50,000. CONCLUSIONS: EEN in the OA was associated with (1) earlier primary abdominal closure, (2) lower fistula rate, (3) lower hospital charges.

Does the heterozygous state of alpha-1 antitrypsin deficiency have a role in chronic liver diseases? Interim results of a large case-control study.

BACKGROUND: The role of the heterozygous PiZ state of alpha-1 antitrypsin deficiency (alpha1ATD) in the pathogenesis of chronic liver disease (LD) is still a matter of controversy. AIM: To determine the prevalence of alpha1ATD heterozygote states in a large population of patients with established LD compared with individuals with no LD, and to determine whether the prevalence of PiZ is increased in patients with more severe LD. METHODS: A cross sectional case-control study among patients with and without LD. Blood samples were tested for alpha1AT levels and alpha1AT phenotype. The severity of LD was determined by clinical evaluation, lab tests, imaging studies and histopathology. RESULTS: In total, 1405 patients were enrolled; 651 with, and 754 without LD. Out of them, 173 patients had decompensated cirrhosis requiring liver transplantation. PiMZ was significantly more prevalent in White patients (3.5%) compared with Hispanics (1.7%; P = 0.029). There was no difference in PiMZ prevalence between the total LD group and the group with no LD (2.1% vs. 1.7%; P = 0.64). Within the LD group, 5.7% of 173 patients with decompensated LD, listed for liver transplantation, had PiMZ, compared with 2.1% of 478 patients with less severe LD (P = 0.016). Similarly, there was a disproportionately higher prevalence of PiZ among hepatitis C virus (HCV) patients (5.6%) and patients with nonalcoholic fatty liver disease (NAFLD) (5.0%) with decompensated LD, compared with HCV patients (1.2%) and NAFLD patients (1.9%) with less severe LD (P = 0.044 and 0.017, respectively). Patients with cryptogenic cirrhosis, who were not considered NAFLD patients, did not have a higher prevalence of PiMZ compared with patients with LD of known etiologies (1.9% vs. 2.3%; P = 0.12). CONCLUSIONS: We found no association between the heterozygous PiZ state of alpha1ATD and the presence of chronic LD in-general or the presence of cryptogenic cirrhosis. In contrast, patients with decompensated LD of any etiology had a significantly higher prevalence of PiMZ compared with patients with compensated LD. Furthermore, in patients with chronic LD due to HCV or NAFLD there was a significant association between the PiMZ heterozygous state and increased severity of LD and the need for liver transplantation. These interim results suggest that the PiMZ alpha1ATD heterozygous state may have a role in worsening LD due to HCV or NAFLD.

Prospective multi-institutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma.

PURPOSE: To evaluate the prognostic significance of molecular staging using reverse transcriptase polymerase chain reaction (RT-PCR) in detecting occult melanoma cells in sentinel lymph nodes (SLNs) and circulating bloodstream. PATIENTS AND METHODS: In this multicenter study, eligibility criteria included patient age 18 to 71 years, invasive melanoma > or = 1.0 mm Breslow thickness, and no clinical evidence of metastasis. SLN biopsy and wide excision of the primary tumor were performed. SLNs were examined by serial-section histopathology and S-100 immunohistochemistry. A portion of each SLN was frozen for RT-PCR. In addition, RT-PCR was performed on peripheral-blood mononuclear cells (PBMCs). RT-PCR analysis was performed using four markers: tyrosinase, MART1, MAGE3, and GP-100. Disease-free survival (DFS), distant-DFS (DDFS), and overall survival (OS) were analyzed. RESULTS: A total of 1,446 patients with histologically negative SLNs underwent RT-PCR analysis. At a median follow-up of 30 months, there was no difference in DFS, DDFS, or OS between the RT-PCR-positive (n = 620) and RT-PCR-negative (n = 826) patients. Analysis of PBMC from 820 patients revealed significant differences in DFS and DDFS, but not OS, for patients with detection of more than one RT-PCR marker in peripheral blood. CONCLUSION: In this large, prospective, multi-institutional study, RT-PCR analysis on SLNs and PBMCs provides no additional prognostic information beyond standard histopathologic analysis of SLNs. Detection of more than one marker in PBMC is associated with a worse prognosis. RT-PCR remains investigational and should not be used to direct adjuvant therapy at this time.

Relationship of smoking and fibrosis in patients with chronic hepatitis C.

BACKGROUND & AIMS: Preliminary studies have suggested that in patients with chronic hepatitis C (CHC), cigarette smoking increases the risk for developing liver fibrosis. Hypoxia caused by smoking may induce expression of the cytokines' vascular endothelial growth factor (VEGF) and VEGF-D and their corresponding soluble tyrosine kinase receptors fms-like tyrosine kinase receptor (s-Flt) and kinase insert domain receptor (s-KDR). These cytokine levels are increased in animals with cirrhosis and in human beings with CHC. We studied whether the concentrations of VEGF, VEGF-D, s-Flt, and s-KDR were increased in CHC smokers with and without hepatic fibrosis. METHODS: A total of 170 CHC patients were identified retrospectively from a single center's database. In 59 patients, serum levels of VEGF, VEGF-D, s-Flt, and s-KDR were measured using an enzyme-linked immunosorbent assay. RESULTS: All 170 patients were hepatitis C virus RNA positive, 117 (69%) were men, 43 (25%) were smokers, and their mean (+/-SD) age was 47 (+/-6) years. Overall, 21% of smokers had Metavir fibrosis scores of 3 and 4 compared with 14% of nonsmokers (P < .01). In an age-weighted multivariate model using step-wise logistic regression, smoking, infection with hepatitis C virus genotype 1, male sex, and increased VEGF-D concentration all were significant independent predictors of more severe liver fibrosis (P < .05 for all observations). CONCLUSIONS: These data suggest that CHC patients who smoke may have more hepatic fibrosis. The data also suggest that increased VEGF and VEGF-D concentrations are associated with smoking and may be involved in the molecular mechanisms of fibrogenesis.

Kinetics of hepatitis C virus reinfection after liver transplantation.

Improved understanding of hepatitis C virus (HCV) dynamics during and after liver transplantation can be useful in optimizing antiviral therapy in transplant recipients. We analyzed serum HCV ribonucleic acid (RNA) levels during and after cadaveric liver transplantation in 6 HCV patients. After removal of the liver and before the new liver started producing virions, HCV RNA levels dropped with an average half-life (t(1/2)) of 0.8 hours. Viral loads then continued to drop up to 23 hours postimplantation (t(1/2) = 3.4 hours), and began to rise (doubling-time = 2.0 days) as soon as 15 hours after the anhepatic phase. In 3 patients the viral load reached a plateau before rising, suggesting that a nonhepatic source supplied virions and balanced their intrinsic clearance. However, from the decline in viral load over the first 24 hours of the postanhepatic phase, we estimate that nonhepatic sources can at most correspond to 4% of total viral production, 96% of which occurs in the liver, even after we corrected for fluid exchanges during surgery. As the new liver was reinfected, production increased and viral load rose to a new steady state. Using nonlinear regression, we were able to fit the patients' HCV RNA data to a viral dynamic model and estimate the de novo infection rate (mean 1.5 x 10(-6) mL/virion/day), as well as the average percentage of hepatocytes infected at the posttransplantation steady state (19%). In conclusion, we have quantified liver reinfection dynamics in the absence of posttransplantation antiviral therapy. Our findings support the notion that early antiviral therapy may delay or prevent reinfection.

HLA class I allelic diversity and progression of fibrosis in patients with chronic hepatitis C.

Patients infected with HIV-1 who are heterozygous at HLA class I loci present greater variety of antigenic peptides to CD8+ cytotoxic T lymphocytes, slowing progression to AIDS. A similar broad immune response in chronic hepatitis C (CHC) infection could result in greater hepatic injury. Although specific HLA class II alleles may influence outcome in CHC patients, the role of HLA class I heterogeneity is generally less clearly defined. Our aims were to determine whether HLA class I allelic diversity is associated with disease severity and progression of fibrosis in CHC. The study population consisted of 670 adults with CHC, including 155 with advanced cirrhosis, and 237 non-HCV-infected controls. Serological testing for HLA class I antigens was performed via microlymphocytotoxicity assay. Peptide expression was defined as heterozygous (i.e., a different allele at each locus) or homozygous. Fibrosis staging was determined using METAVIR classification. Heterozygosity at the B locus (fibrosis progression rate [FPR] 0.08 vs. 0.06 units/yr; P = .04) and homozygosity at the A locus (FPR 0.10 vs. 0.08 units/yr; P = .04) predicted a higher median FPR. Age at infection, genotype, and duration of infection were also predictors of FPR. A higher proportion of patients with stage F2-F4 expressed HLA-B18 compared with controls (OR 2.2, 95% CI 1.17-4.23; P = .02). These differences were not observed in patients with advanced cirrhosis. HLA zygosity at 1, 2, or 3 alleles was not associated with fibrosis stage, liver inflammation, or treatment outcome. In conclusion, HLA class I allelic diversity has a minor influence on FPRs and disease severity in CHC.