Ronghui Xu

Suspected Nonalcoholic Fatty Liver Disease and Mortality Risk in a Population-based Cohort Study

OBJECTIVE:Case series suggest that nonalcoholic fatty liver disease (NAFLD) is associated with increased all-cause and cardiovascular mortality. The current study compared the survival of subjects with and without suspected NAFLD in a population-based cohort, and placed the finding in the context of previously published case series.METHODS:Primary analysis assessed mortality for NHANES-III participants with and without suspected NAFLD using the National Death Index. Suspected NAFLD was based upon unexplained ALT elevation. The Olmsted County and Cleveland Clinic case series were also used for comparison. Survivals were compared using Proportional Hazards Model and direct age standardization.RESULTS:The NHANES cohort included 980 with and 6,594 subjects without suspected NAFLD. Over a mean of 8.7 yr, suspected NAFLD had a hazards ratio of 1.37 (95% CI 0.98–1.91) for all-cause mortality. In the 45–54 age group, suspected NAFLD had significantly higher all-cause (4.40 95% CI 1.27–13.23) and cardiovascular mortality (8.15, 95% CI 2.00–33.20) after adjusting for conventional cardiovascular risk factors. The age-standardized rate per 10,000 per year was 129 (95% CI 118–140) for the NHANES non-NAFLD cohort, 154 (95% CI 116–198) for the NHANES suspected NAFLD cohort, 214 (95% CI 157–279) for the Olmsted County series, and 426 (95% CI 298–573) for the Cleveland Clinic series.CONCLUSION:The magnitude of mortality risk in NAFLD depends on the setting and method of ascertainment. Suspected NAFLD in the 45–54 age group is a strong independent risk factor for cardiovascular death and warrants further cardiovascular risk management guidelines.

Pirfenidone for Diabetic Nephropathy

Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebo-controlled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m²). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (+3.3 ± 8.5 ml/min per 1.73 m²) whereas the mean eGFR decreased in the placebo group (-2.2 ± 4.8 ml/min per 1.73 m²; P = 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (-1.9 ± 6.7 ml/min per 1.73 m²). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P = 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.

Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease

People at risk for coronary heart disease are often at risk for nonalcoholic fatty liver disease (NAFLD). The association of modest wine consumption with NAFLD has not been studied and the recommendation of wine for patients at risk for both diseases is controversial. The aim is to test the hypothesis that modest wine consumption is associated with decreased prevalence of NAFLD. We included Third National Health and Nutrition Examination Survey participants who either reported no alcohol consumption or preferentially drinking wine with total alcohol consumption up to 10 g per day. Suspected NAFLD was based on unexplained serum alanine aminotransferase (ALT) elevation over the cut point of the reference laboratory (ALT > 43) and the cut point based on the 95th percentile of healthy subjects (ALT > 30 for men; ALT > 19 for women). Multivariate analysis was adjusted for age, gender, race, neighborhood, income, education, caffeine intake, and physical activity. A total of 7,211 nondrinkers and 945 modest wine drinkers comprised the study sample. Based on the reference laboratory cut point, suspected NAFLD was observed in 3.2% of nondrinkers and 0.4% of modest wine drinkers. The adjusted odds ratio was 0.15 (95% confidence interval, 0.05‐0.49). Using the healthy subject cut point, suspected NAFLD was observed in 14.3% of nondrinkers and 8.6% of wine drinkers. The adjusted odds ratio was 0.51 (95% confidence interval, 0.33‐0.79). Conclusion: Modest wine consumption is associated with reduced prevalence of suspected NAFLD. The current study supports the safety of one glass of wine per day for cardioprotection in patients at risk for both coronary heart disease and NAFLD. (HEPATOLOGY 2008.)

Birth outcomes in women who have taken leflunomide during pregnancy

OBJECTIVE In preclinical reproductive studies, leflunomide was found to be embryotoxic and teratogenic. Women treated with leflunomide are advised to avoid pregnancy; those who become pregnant are advised to reduce fetal exposure through a cholestyramine drug elimination procedure. The present study was undertaken to investigate pregnancy outcomes in women who received leflunomide and were treated with cholestyramine during pregnancy. METHODS Sixty-four pregnant women with rheumatoid arthritis (RA) who were treated with leflunomide during pregnancy (95.3% of whom received cholestyramine), 108 pregnant women with RA not treated with leflunomide, and 78 healthy pregnant women were enrolled in a prospective cohort study between 1999 and 2009. Information was collected via interview of the mothers, review of medical records, and specialized physical examination of infants. RESULTS There were no significant differences in the overall rate of major structural defects in the exposed group (3 of 56 live births [5.4%]) relative to either comparison group (each 4.2%)(P = 0.13). The rate was similar to the 3-4% expected in the general population. There was no specific pattern of major or minor anomalies. Infants in both the leflunomide-exposed and non-leflunomide-exposed RA groups were born smaller and earlier relative to infants of healthy mothers; however, after adjustment for confounding factors, there were no significant differences between the leflunomide-exposed and non-leflunomide-exposed RA groups. CONCLUSION Although the sample size is small, these data do not support the notion that there is a substantial increased risk of adverse pregnancy outcomes due to leflunomide exposure among women who undergo cholestyramine elimination procedure early in pregnancy. These findings can provide some reassurance to women who inadvertently become pregnant while taking leflunomide and undergo the washout procedure.

rTMS for Suppressing Neuropathic Pain: A Meta-Analysis

UNLABELLED This pooled individual data (PID)-based meta-analysis collectively assessed the analgesic effect of repetitive transcranial magnetic stimulation (rTMS) on various neuropathic pain states based on their neuroanatomical hierarchy. Available randomized controlled trials (RCTs) were screened. PID was coded for age, gender, pain neuroanatomical origins, pain duration, and treatment parameters analyses. Coded pain neuroanatomical origins consist of peripheral nerve (PN); nerve root (NR); spinal cord (SC); trigeminal nerve or ganglion (TGN); and post-stroke supraspinal related pain (PSP). Raw data of 149 patients were extracted from 5 (1 parallel, 4 cross-over) selected (from 235 articles) RCTs. A significant (P < .001) overall analgesic effect (mean percent difference in pain visual analog scale (VAS) score reduction with 95% confidence interval) was detected with greater reduction in VAS with rTMS in comparison to sham. Including the parallel study (Khedr et al), the TGN subgroup was found to have the greatest analgesic effect (28.8%), followed by PSP (16.7%), SC (14.7%), NR (10.0%), and PN (1.5%). The results were similar when we excluded the parallel study with the greatest analgesic effect observed in TGN (33.0%), followed by SC (14.7%), PSP (10.5%), NR (10.0%), and PN (1.5%). In addition, multiple (vs single, P = .003) sessions and lower (>1 and < or =10 Hz) treatment frequency range (vs >10 Hz) appears to generate better analgesic outcome. In short, rTMS appears to be more effective in suppressing centrally than peripherally originated neuropathic pain states. PERSPECTIVE This is the first PID-based meta-analysis to assess the differential analgesic effect of rTMS on neuropathic pain based on the neuroanatomical origins of the pain pathophysiology and treatment parameters. The derived information serves as a useful resource in regards to treatment parameters and patient population selection for future rTMS-pain studies.

RADIOSURGERY IN THE MANAGEMENT OF PEDIATRIC BRAIN TUMORS

OBJECTIVE To describe the outcome of pediatric brain tumor patients following stereotactic radiosurgery (SRS), and factors associated with progression-free survival. METHODS We reviewed the outcome of 90 children treated with SRS for recurrent (n = 62) or residual (n = 28) brain tumors over a 10-year period. Median follow-up from SRS was 24 months for all patients and 55.5 months for the 34 patients currently alive. RESULTS The median progression-free survival (PFS) for all patients was 13 months. Median PFS according to tumor histology was medulloblastoma = 11 months, ependymoma = 8.5 months, glioblastoma and anaplastic astrocytoma = 12 months. Median PFS in patients treated to a single lesion was 15.4 months. No patient undergoing SRS to more than 1 lesion survived disease free beyond 2 years. After adjusting for histology and other clinical factors, SRS for tumor recurrence (RR = 2.49) and the presence of > 1 lesion (RR = 2.3) were associated with a significantly increased rate of progression (p < 0.05). Three-year actuarial local control (LC) was as follows: medulloblastoma = 57%, ependymoma = 29%, anaplastic astrocytoma/glioblastoma = 60%, other histologies = 56%. Nineteen patients with radionecrosis and progressive neurologic symptoms underwent reoperation after an interval of 0.6-62 months following SRS. Pathology revealed necrosis with no evidence of tumor in 9 of these cases. CONCLUSION SRS can be given safely to selected children with brain tumors. SRS appears to reduce the proportion of first failures occurring locally and is associated with better outcome when given as a part of initial management. Some patients with unresectable relapsed disease can be salvaged with SRS. SRS to multiple lesions does not appear to be curative. Serious neurologic symptoms requiring reoperation is infrequently caused by radionecrosis alone.

Pregnancy outcome in women exposed to leflunomide before or during pregnancy

OBJECTIVE Findings from animal studies have suggested that leflunomide may be a human teratogen. In the only human cohort study published to date, an increase in adverse outcomes in pregnancies after exposure to leflunomide was not detected. The aim of the present analysis was to expand on the previously published data with a description of birth outcomes among women who did not meet the previous cohort study criteria but who were exposed to leflunomide either during pregnancy or prior to conception. METHODS Data on pregnancy exposures and outcomes were collected from 45 pregnant women who had contacted counseling services of the Organization of Teratology Information Specialists in the US or Canada between 1999 and 2009. Sixteen women were exposed to leflunomide during the first trimester of pregnancy and 29 women were exposed preconception. RESULTS All 16 of the pregnancies with leflunomide exposure during pregnancy and 27 (93%) of the pregnancies with exposure prior to conception resulted in liveborn infants. There were 2 infants with major malformations from mothers who were exposed during pregnancy, and no malformations reported in the preconception group. There was a potential known alternative etiology for at least some of the defects observed. CONCLUSION These data provide additional reassurance to women who inadvertently become pregnant while taking leflunomide and who undergo the washout procedure, as well as women who discontinue the medication prior to conception but have no prepregnancy documentation of drug clearance. However, until more conclusive data become available, women receiving leflunomide should be advised to use contraceptive methods and avoid pregnancy.

Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: birth defects, spontaneous abortion, preterm delivery, and small for gestational age infants.

INTRODUCTION There is a need for additional information on the fetal risks and relative safety of the pandemic H1N1 monovalent or trivalent influenza (pH1N1)-containing vaccines in women exposed during pregnancy. METHODS To assess risks and relative safety of the pH1N1-containing vaccines, we conducted a prospective cohort study of pH1N1-vaccine-exposed and unexposed comparison women residing in the U.S. or Canada who were recruited during pregnancy and followed to outcome between October 2009 and August 2012. For exposure to the pH1N1 vaccine, adjusted relative risks (RRs) and 95% confidence intervals (CIs) were estimated for major birth defects and infants small for gestational age. Adjusted hazard ratios (HRs) and 95% CIs were estimated for spontaneous abortion and preterm delivery for time-varying exposure. RESULTS There were 1032 subjects available for analysis; 841 women were exposed to a pH1N1-containing vaccine in pregnancy, and 191 women were unexposed to any influenza vaccine in pregnancy. Nine of 328 (2.7%) first-trimester-exposed pregnancies resulted in an infant with a major birth defect compared to 6/188 (3.2%) in the unexposed (adjusted RR 0.79, 95% CI 0.26-2.42). The HR for spontaneous abortion was not elevated (adjusted HR 0.92, 95% CI 0.31-2.72). Adjusted HRs for preterm delivery were elevated for exposure anytime in pregnancy (3.28, 95% CI 1.25-8.63), specifically with exposure in the 1st or 2nd trimester. However, the mean decrease in gestational age in the exposed pregnancies was approximately three days. Adjusted RRs for small for gestational age infants on weight and length approximated 1.0. CONCLUSIONS For the 2009-12 influenza seasons combined, we found no meaningful evidence of increased RR or HR for major birth defects, spontaneous abortion, or small for gestational age infants. There was some evidence of an increased HR for preterm delivery following pH1N1-influenza vaccine exposure; however the decrease in gestational age on average was approximately three days.

Modular Psychotherapy for Anxiety in Older Primary Care Patients

OBJECTIVE To develop and test a modular psychotherapy protocol in older primary care patients with anxiety disorders. DESIGN Randomized, controlled pilot study. SETTING University-based geriatric medicine clinics. PARTICIPANTS Thirty-one elderly primary care patients with generalized anxiety disorder or anxiety disorder not otherwise specified. INTERVENTION Modular form of psychotherapy compared with enhanced community treatment. MEASUREMENTS Self-reported, interviewer-rated, and qualitative assessments of anxiety, worry, depression, and mental health-related quality of life. RESULTS Both groups showed substantial improvements in anxiety symptoms, worry, depressive symptoms, and mental health-related quality of life. Most individuals in the enhanced community treatment condition reported receiving medications or some other form of professional treatment for anxiety. Across both conditions, individuals who reported major life events or stressors and those who used involvement in activities as a coping strategy made smaller gains than those who did not. CONCLUSIONS Results suggest that modular psychotherapy and other treatments can be effective for anxiety in older primary care patients. Results further suggest that life events and coping through increased activity may play a role in the maintenance of anxiety in older adults.

Changes on brief cognitive instruments over time in Parkinson's disease

Two hundred and twenty‐one subjects with Parkinsons disease (PD) were examined using the Mini–Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA), with a subset of these (n = 98) examined on repeat testing up to 3 years. The MoCA was more sensitive in identifying cognitive deficit, specifically in the domains of visuospatial abilities, language, and memory. In longitudinal study, the MMSE changed significantly over time, particularly in patients with disease duration of >10 years. The MoCA, however, did not change significantly, even when subjects were stratified by age, MMSE score, and disease duration. This suggests that the MoCA may be more sensitive for detecting early cognitive change in PD, but that the MMSE, and not the MoCA, may be better for tracking cognitive decline.