A data-driven quality-score system for rating drug products and its implications for the health care industry.

The quality of drug products in the United States has been a matter of growing concern. Buyers and payers of pharmaceuticals have limited insight into measures of drug-product quality. Therefore, a quality-score system driven by data collection is proposed to differentiate between the qualities of drug products produced by different manufacturers. The quality scores derived using this proposed system would be based upon public regulatory data and independently-derived chemical data. A workflow for integrating the system into procurement decisions within health care organizations is also suggested. The implementation of such a quality-score system would benefit health care organizations by including the consideration of the quality of products while also considering price as a part of the drug procurement process. Such a system would also benefit the U.S. health care industry by bringing accountability and transparency into the drug supply chain and incentivizing manufacturers to place an increased emphasis on the quality and safety of their drug products.

Association of exposure to ambient particulate matter with maternal thyroid function in early pregnancy.

BACKGROUND: It is known that maternal thyroid dysfunction during early pregnancy can cause adverse pregnancy complications and birth outcomes. This study was designed to examine the association between ambient particulate matter with aerodynamic diameters ≤2.5 µm (PM2.5) and particulate matter with aerodynamic diameters ≤10 µm (PM10) exposure and maternal thyroid function during early pregnancy. METHODS: This study was based on data from a birth cohort study of 921 pregnant women in China. We estimated associations between ambient PM2.5 and PM10 exposure during the first trimester of pregnancy (estimated with land-use regression models) and maternal thyroid hormone concentrations (free thyroxine (FT4), free tri-iodothyronine (FT3), and thyroid-stimulating hormone (TSH)) collected between weeks 10 and 17 of gestation using linear regression models adjusting for potential confounders. Ambient PM2.5 and PM10 concentrations were modeled per interquartile range (IQR) increment and as tertiles based on the distribution of the exposure levels. RESULTS: An IQR increment (68 µg/m3) in PM2.5 exposure was associated with a significant decrease in maternal FT4 levels (ß = -0.60, 95% CI: -1.07, -0.12); and a significant decrease in FT4/FT3 ratio (ß = -0.13, 95% CI: -0.25, -0.02). Further analyses showed that, relative to the lowest tertile, women in both the middle and highest tertiles of PM2.5 had significantly lower concentrations of maternal FT4 and FT4/FT3 ratio. No significant associations were found between PM2.5 and FT3 or TSH levels. PM10 exposure was not significantly associated with maternal thyroid function. CONCLUSIONS: Our study suggested that higher ambient PM2.5, not PM10, exposed during the first trimester of pregnancy were associated with a significant decrease in maternal serum FT4 concentrations and FT4/FT3 ratio. Studies in populations with different exposure levels are needed to replicate our study results.

Successful Tobacco Dependence Treatment in Low-Income Emergency Department Patients: A Randomized Trial.

STUDY OBJECTIVE: Tobacco use is common among emergency department (ED) patients, many of whom have low income. Our objective is to study the efficacy of an intervention incorporating motivational interviewing, nicotine replacement, and quitline referral for adult smokers in an ED. METHODS: This was a 2-arm randomized clinical trial conducted from October 2010 to December 2012 in a northeastern urban US ED with 90,000 visits per year. Eligible subjects were aged 18 years or older, smoked, and were self-pay or had Medicaid insurance. Intervention subjects received a motivational interview by a trained research assistant, 6 weeks' worth of nicotine patches and gum initiated in the ED, a faxed referral to the state smokers' quitline, a booster call, and a brochure. Control subjects received the brochure, which provided quitline information. The primary outcome was biochemically confirmed tobacco abstinence at 3 months. Secondary endpoints included quitline use. RESULTS: Of 778 enrolled subjects, 774 (99.5%) were alive at 3 months. The prevalence of biochemically confirmed abstinence was 12.2% (47/386) in the intervention arm versus 4.9% (19/388) in the control arm, for a difference in quit rates of 7.3% (95% confidence interval 3.2% to 11.5%). In multivariable logistic modeling controlling for age, sex, and race or ethnicity, study subjects remained more likely to be abstinent than controls (odds ratio 2.72; 95% confidence interval 1.55 to 4.75). CONCLUSION: An intensive intervention improved tobacco abstinence rates in low-income ED smokers. Because approximately 20 million smokers, many of whom have low income, visit US EDs annually, these results suggest that ED-initiated treatment may be an effective technique to treat this group of smokers.

Heart rate dynamics and asymmetry during sympathetic activity stimulation and post-stimulation recovery in ski mountaineers-a pilot exploratory study.

There is a lack of studies on non-linear heart rate (HR) variability in athletes. We aimed to assess the usefulness of short-term HR dynamics and asymmetry parameters to evaluate the neural modulation of cardiac activity based on non-stationary RR interval series by studying their changes during sympathetic nervous system activity stimulation (isometric handgrip test) and post-stimulation recovery in professional ski mountaineers. The correlation between the changes in the parameters and the respiratory rate (RespRate) and also the duration of the career was analyzed. Short-term (5 min) and ultra-short-term (1 min) rates of patterns with no variations (0V), number of acceleration runs of length 1 (AR1), and short-term Porta's Index were greater, whereas Guzik's Index (GI) was smaller during sympathetic stimulation compared to rest. GI increased and the number of AR1 decreased during recovery. Greater increases in GI and RMSSD were associated with greater decreases in RespRate during recovery. Greater increases in RespRate from rest to short-term sympathetic stimulation were associated with greater increases in 0V (Max-min method) and AR1 but also with greater decreases in decelerations of short-term variance and accelerations and decelerations of long-term variance. Greater increases in 0V (Max-min method) and number of AR1 during sympathetic stimulation were associated with a shorter career duration. Greater decreases in these parameters during recovery were associated with a longer career duration. Changes in measures of HR dynamics and asymmetry, calculated based on short-term non-stationary RRi time series induced by sympathetic stimulation and post-stimulation recovery, reflected sympathovagal shift and were associated with condition-related alterations in RespRate and career duration in athletes who practice ski mountaineering.

Air Change Rate and SARS-CoV-2 Exposure in Hospitals and Residences: A Meta-Analysis.

As SARS-CoV-2 swept across the globe, increased ventilation and implementation of air cleaning were emphasized by the US CDC and WHO as important strategies to reduce the risk of inhalation exposure to the virus. To assess whether higher ventilation and air cleaning rates lead to lower exposure risk to SARS-CoV-2, 1274 manuscripts published between April 2020 and September 2022 were screened using key words "airborne SARS-CoV-2 or "SARS-CoV-2 aerosol". Ninety-three studies involved air sampling at locations with known sources (hospitals and residences) were selected and associated data were compiled. Two metrics were used to assess exposure risk: SARS-CoV-2 concentration and SARS-CoV-2 detection rate in air samples. Locations were categorized by type (hospital or residence) and proximity to the sampling location housing the isolated/quarantined patient (primary or secondary). The results showed that hospital wards had lower airborne virus concentrations than residential isolation rooms. A negative correlation was found between airborne virus concentrations in primary-occupancy areas and air changes per hour (ACH). In hospital settings, sample positivity rates were significantly reduced in secondary-occupancy areas compared to primary-occupancy areas, but they were similar across sampling locations in residential settings. ACH and sample positivity rates were negatively correlated, though the effect was diminished when ACH values exceeded 8. While limitations associated with diverse sampling protocols exist, data considered by this meta-analysis support the notion that higher ACH may reduce exposure risks to the virus in ambient air.

Aerobic Capacity in Relation to Selected Elements of Body Posture.

BACKGROUND: In the 21st century, with the rapid development of many human life areas, physical activity should be prevalent in health maintenance and promotion. Body posture is a motor habit characteristic of every individual. Its correctness depends on numerous aspects, e.g., physical activity, age, mental state, or eating habits. There are numerous reports in the literature on the impact of physical activity on body posture, correct foot arch development, and the level of aerobic capacity in children and adolescents, but there is a noticeable lack of assessments of these characteristics and their correlations in adults. AIM: To evaluate aerobic capacity in males and females in relation to selected body posture elements. METHODS: The study involved 45 females and 46 males aged 20-21 years. The inclusion criteria involved declared good health and no contraindications. Selected somatic traits, body posture, and physical capacity indicators were determined. RESULTS: Physical capacity shows a significant relationship with body mass in both sexes (female: r = -0.346; p = 0.020; male: r = -0.321; p = 0.030). A significant correlation was observed between aerobic capacity and lean body mass in females (r = -0.428; p = 0.003) and body mass (r = -0.461; p = 0.001) and body fat percentage in males (r = -0.443; p = 0.002). A significant correlation was demonstrated between maximal oxygen uptake and Clarke's angle (r = -0.300; p = 0.045) in females, between maximal oxygen uptake and the loaded area of the right foot (r = -0.247; p = 0.098) in the male group, and between maximal oxygen uptake and spine lateral deviation (r = 0.352; p = 0.018) in females. There was no dimorphism between body posture elements and physical capacity except for the level of foot longitudinal arches, feet loading surface, spine lateral deviation, and the range of spine mobility in the sagittal and frontal planes. Aerobic capacity significantly influenced lean body mass (ß = -0.379; p = 0.007) and spine deviation from the anatomical axis in the frontal plane in females (ß = 0.287; p = 0.039) and body fat percentage in males (ß = -0.443; p = 0.002). CONCLUSIONS: Selected body posture elements demonstrate relationships with physical capacity in both sexes. The results should find wide practical applications, e.g., in promoting a comprehensive assessment of body posture and physical capacity as determinants of health maintenance.

How do perceptions about cessation outcomes moderate the effectiveness of a gain-framed smoking cessation telephone counseling intervention?

The distinction between prevention and detection behaviors provides a useful guideline for appropriately framing health messages in terms of gains or losses. However, this guideline assumes that everyone perceives the outcomes associated with a behavior in a consistent manner, as prevention or detection. Individuals' perceptions of a behavior vary, and so the effects of framed messages may be optimized by considering individuals' perceptions rather than the prevention or detection function of the behavior. The authors tested this message-framing paradigm in a secondary analysis of data from a trial evaluating gain-framed smoking cessation counseling delivered through a state quitline (Toll et al., 2010 ). Smokers (N = 2,032) who called a state quitline received either gain-framed or standard care messages. Smokers' beliefs about the positive consequences of stopping smoking (outcome expectancies) were evaluated at baseline. Smoking status and self-efficacy were assessed at 3 months. Outcome expectancies moderated the framing effects among men but not among women. Men in the gain-framed counseling condition who had positive outcome expectancies were more likely to quit and had more confidence in their ability to quit or to remain abstinent than men who were uncertain of the positive outcome of smoking cessation. Among men, self-efficacy mediated the moderated framing effects of the intervention on quit status. These findings suggest that it may be useful to consider sex and individual differences in outcome expectancies when delivering gain-framed smoking cessation messages in the context of a state quitline.

Changes in blood rheological properties and biochemical markers after participation in the XTERRA Poland triathlon competition.

The importance of physical activity in preventing chronic cardiovascular and metabolic diseases and the role of exercise as an adjunct therapy are widely recognized. Triathlon is a typically endurance discipline. Prolonged and intensive exercise is known to cause changes in blood rheological properties and biochemical markers; sometimes athletes participating in strenuous competitions need medical attention. To understand the phenomena occurring in the body in such situations, we decided to study participants' biomarkers after the XTERRA Poland 2017 triathlon competition. The study involved 10 triathletes. The XTERRA Poland 2017 event comprised 1500-m swimming, 36-km cycling, and 10-km mountain running. Blood samples were collected 2 days before, immediately after, and 16 h after the competition. Immediately after the race, white blood cells count, platelets, and uric acid levels were significantly (P < 0.001) increased; haematocrit, Na+, Cl-, and IgA were decreased. On the following day, Na+, Cl-, and C-reactive protein levels were significantly (P < 0.001) increased; white blood cells count, red blood cells count, haemoglobin, haematocrit, mean corpuscular volume, platelets, IgG, and IgA were decreased. Assessing rheological parameters such as erythrocyte deformability and aggregation is useful for monitoring adverse effects of intensive and exhaustive exercise. The study illustrates the change in blood rheological properties and biochemical markers after intensive physical effort. Despite these differences, the indicators were within the reference range for the general population, which may demonstrate normal body function in the studied triathletes.

Preterm birth results in alterations in neural connectivity at age 16 years.

Very low birth weight preterm (PT) children are at high risk for brain injury. Employing diffusion tensor imaging (DTI), we tested the hypothesis that PT adolescents would demonstrate microstructural white matter disorganization relative to term controls at 16 years of age. Forty-four PT subjects (600-1250 g birth weight) without neonatal brain injury and 41 term controls were evaluated at age 16 years with DTI, the Wechsler Intelligence Scale for Children-III (WISC), the Peabody Picture Vocabulary Test-Revised (PPVT), and the Comprehensive Test of Phonological Processing (CTOPP). PT subjects scored lower than term subjects on WISC full scale (p=0.003), verbal (p=0.043), and performance IQ tests (p=0.001), as well as CTOPP phonological awareness (p=0.004), but scored comparably to term subjects on PPVT and CTOPP Rapid Naming tests. PT subjects had lower fractional anisotropy (FA) values in multiple regions including bilateral uncinate fasciculi (left: p=0.01; right: p=0.004), bilateral external capsules (left: p<0.001; right: p<0.001), the splenium of the corpus callosum (p=0.008), and white matter serving the inferior frontal gyrus bilaterally (left: p<0.001; right: p=0.011). FA values in both the left and right uncinate fasciculi correlated with PPVT scores (a semantic language task) in the PT subjects (left: r=0.314, p=0.038; right: r=0.336, p=0.026). FA values in the left and right arcuate fasciculi correlated with CTOPP Rapid Naming scores (a phonologic task) in the PT subjects (left: r=0.424, p=0.004; right: r=0.301, p=0.047). These data support for the first time that dual pathways underlying language function are present in PT adolescents. The striking bilateral dorsal correlations for the PT group suggest that prematurely born subjects rely more heavily on the right hemisphere than typically developing adults for performance of phonological language tasks. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain.

Functional connectivity to a right hemisphere language center in prematurely born adolescents.

Prematurely born children are at increased risk for language deficits at school age and beyond, but the neurobiological basis of these findings remains poorly understood. Thirty-one PT adolescents (600-1250g birth weight) and 36 T controls were evaluated using an fMRI passive language task and neurodevelopmental assessments including: the Wechsler Intelligence Scale for Children-III (WISC-III), the Peabody Picture Vocabulary Test-Revised (PPVT-R), the Comprehensive Test of Phonological Processing (CTOPP) and the Test of Word Reading Efficiency (TOWRE) at 16years of age. Neural activity was assessed for language processing and the data were evaluated for connectivity and correlations to cognitive outcomes. PT subjects scored significantly lower on all components of the WISC-III (p<0.05) compared to term subjects, but there was no significant difference in PPVT-R scores between the groups. Functional connectivity (fcMRI) between Wernicke's area (left BA 22) and the right supramarginal gyrus (BA 40) was increased in preterm subjects relative to term controls (p=0.03), and the strength of this connection was inversely related to performance on both the PPVT-R (R(2)=0.553, p=0.002), and the verbal comprehension index (R(2)=0.439, p=0.019). Preterm adolescents engage a dorsal right hemisphere region for language at age 16years. Those with the greatest cognitive deficits demonstrate increasing reliance on this alternate pathway.

Alterations in functional connectivity for language in prematurely born adolescents.

Recent data suggest recovery of language systems but persistent structural abnormalities in the prematurely born. We tested the hypothesis that subjects who were born prematurely develop alternative networks for processing language. Subjects who were born prematurely (n = 22; 600-1250 g birth weight), without neonatal brain injury on neonatal cranial ultrasound, and 26 term control subjects were examined with a functional magnetic resonance imaging (fMRI) semantic association task, the Wechsler Intelligence Scale for Children-III (WISC-III) and the Clinical Evaluation of Language Fundamentals (CELF). In-magnet task accuracy and response times were calculated, and fMRI data were evaluated for the effect of group on blood oxygen level dependent (BOLD) activation, the correlation between task accuracy and activation and the functional connectivity between regions activating to task. Although there were differences in verbal IQ and CELF scores between the preterm (PT) and term control groups, there were no significant differences for either accuracy or response time for the in-magnet task. Both groups activated classic semantic processing areas including the left superior and middle temporal gyri and inferior frontal gyrus, and there was no significant difference in activation patterns between groups. Clear differences between the groups were observed in the correlation between task accuracy and activation to task at P < 0.01, corrected for multiple comparisons. Left inferior frontal gyrus correlated with accuracy only for term controls and left sensory motor areas correlated with accuracy only for PT subjects. Left middle temporal gyri correlated with task accuracy for both groups. Connectivity analyses at P < 0.001 revealed the importance of a circuit between left middle temporal gyri and inferior frontal gyrus for both groups. In addition, the PT subjects evidenced greater connectivity between traditional language areas and sensory motor areas but significantly fewer correlated areas within the frontal lobes when compared to term controls. We conclude that at 12 years of age, children born prematurely and children born at term had no difference in performance on a simple lexical semantic processing task and activated similar areas. Connectivity analyses, however, suggested that PT subjects rely upon different neural pathways for lexical semantic processing when compared to term controls. Plasticity in network connections may provide the substrate for improving language skills in the prematurely born.

Sample size for post-marketing safety studies based on historical controls.

PURPOSE: As part of a drug's entire life cycle, post-marketing studies are an important part in the identification of rare, serious adverse events. Recently, the US Food and Drug Administration (FDA) has begun to implement new post-marketing safety mandates as a consequence of increased emphasis on safety. The purpose of this research is to provide exact sample size formula for the proposed hybrid design, based on a two-group cohort study with incorporation of historical external data. METHODS: Exact sample size formula based on the Poisson distribution is developed, because the detection of rare events is our outcome of interest. Performance of exact method is compared to its approximate large-sample theory counterpart. RESULTS: The proposed hybrid design requires a smaller sample size compared to the standard, two-group prospective study design. In addition, the exact method reduces the number of subjects required in the treatment group by up to 30% compared to the approximate method for the study scenarios examined. CONCLUSIONS: The proposed hybrid design satisfies the advantages and rationale of the two-group design with smaller sample sizes generally required.

Test-Retest Reliability of Handgrip Strength Measurement in Children and Preadolescents.

The reliability of handgrip strength (HGS) measurement has been confirmed in adults but has been sparsely addressed in pediatric populations. The aims of this study are twofold: to determine whether sex, age and/or hand-dominance influence the test-retest differences and to establish the reliability level of the HGS measurement in typical developing pediatric participants. A total of 338 participants aged 7-13 years were tested using a digital handgrip strength (HGS) dynamometer (Jamar Plus+ Dynamometer) by the same rater on two testing trials separated by a one-day interval between sessions. The HGS testing was conducted according to the American Society of Hand Therapists recommendations. Relative and absolute reliability statistics were calculated. Age influenced the test-retest difference of the HGS measurement as children compared to preadolescents had lower intraclass correlation coefficients (0.95 vs. 0.98), standard error of measurement (SEM) (0.74 vs. 0.78 kg), smallest detectable difference (SDD) (2.05 vs. 2.16 kg) and higher values of the percentage value of SEM (5.48 vs. 3.44%), normalized SDD (15.52 vs. 9.61%) and a mean difference between the test and retest values (0.50 vs. 0.02 kg) for the dominant hand. The results indicate that the protocol using the Jamar digital handgrip dynamometer is a reliable instrument to measure HGS in participants aged 7-13 years with typical development. Clinicians and researchers therefore can have confidence in determining the minimally clinical effect for HGS.

Alterations in neural connectivity in preterm children at school age.

Converging data suggest recovery from injury in the preterm brain. We used functional magnetic resonance imaging (fMRI) to test the hypothesis that cerebral connectivity involving Wernicke's area and other important cortical language regions would differ between preterm (PT) and term (T) control school age children during performance of an auditory language task. Fifty-four PT children (600-1250 g birth weight) and 24 T controls were evaluated using an fMRI passive language task and neurodevelopmental assessments including: the Wechsler Intelligence Scale for Children - III (WISC-III), the Peabody Individual Achievement Test - Revised (PIAT-R) and the Peabody Picture Vocabulary Test - Revised (PPVT-R) at 8 years of age. Neural activity was assessed for language processing and the data were evaluated for connectivity and correlations to cognitive outcomes. We found that PT subjects scored significantly lower on all components of the WISC-III (p<0.009), the PIAT-R Reading Comprehension test (p=0.013), and the PPVT-R (p=0.001) compared to term subjects. Connectivity analyses revealed significantly stronger neural circuits in PT children between Wernicke's area and the right inferior frontal gyrus (R IFG, Broca's area homologue) and both the left and the right supramarginal gyri (SMG) components of the inferior parietal lobules (p

Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis.

BACKGROUND/AIMS: A total of 213 patients with compensated cirrhosis, portal hypertension and no varices were included in a trial evaluating beta-blockers in preventing varices. Predictors of the development of hepatocellular carcinoma (HCC), including hepatic venous pressure gradient (HVPG) were analyzed. METHODS: Baseline laboratory tests, ultrasound and HVPG measurements were performed. Patients were followed prospectively every three months until development of varices or variceal bleeding or end of the study in 09/02. The endpoint was HCC development according to standard diagnostic criteria. Univariate and multivariate Cox regression models were developed to identify predictors of HCC. RESULTS: In a median follow-up of 58 months 26/213 (12.2%) patients developed HCC. Eight patients were transplanted and 28 patients died without HCC. Twenty-one (84%) HCC developed in patients with HCV. On multivariate analysis HVPG (HR 1.18; 95%CI 1.08-1.29), albumin (HR 0.34; 95%CI 0.14-0.83) and viral etiology (HR 4.59; 95%CI 1.51-13.92) were independent predictors of HCC development. ROC curves identified 10 mmHg of HVPG as the best cut-off; those who had an HVPG above this value had a 6-fold increase in the HCC incidence. CONCLUSIONS: Portal hypertension is an independent predictor of HCC development. An HVPG >10 mmHg is associated with a 6-fold increase of HCC risk.

Incidence, prevalence, and clinical significance of abnormal hematologic indices in compensated cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis develop abnormal hematologic indices (HI) from multiple factors, including hypersplenism. We aimed to analyze the sequence of events and determine whether abnormal HI has prognostic significance. METHODS: We analyzed a database of 213 subjects with compensated cirrhosis without esophageal varices. Subjects were followed for approximately 9 years until the development of varices or variceal bleeding or completion of the study; 84 subjects developed varices. Abnormal HI was defined as anemia at baseline (hemoglobin, < or =13.5 g/dL for men and 11.5 g/dL for women), leukopenia (white blood cell counts, < or =4000/mm3), or thrombocytopenia (platelet counts, < or =150,000/mm3). The primary end points were death or transplant surgery. RESULTS: Most subjects had thrombocytopenia at baseline. Kaplan-Meier analysis showed that leukopenia occurred by 30 months (95% confidence interval, 18.5-53.6), and anemia occurred by 39.6 months (95% confidence interval, 24.1-49.9). Baseline thrombocytopenia (P = .0191) and leukopenia (P = .0383) were predictors of death or transplant, after adjusting for baseline hepatic venous pressure gradient (HVPG), and Child-Pugh scores. After a median of 5 years, a significant difference in death or transplant, mortality, and clinical decompensation was observed in patients who had leukopenia combined with thrombocytopenia at baseline compared with patients with normal HI (P < .0001). HVPG correlated with hemoglobin and white blood cell count (hemoglobin, r = -0.35, P < .0001; white blood cell count, r = -0.31, P < .0001). CONCLUSIONS: Thrombocytopenia is the most common and first abnormal HI to occur in patients with cirrhosis, followed by leukopenia and anemia. A combination of leukopenia and thrombocytopenia at baseline predicted increased morbidity and mortality.

Platelet count is not a predictor of the presence or development of gastroesophageal varices in cirrhosis.

UNLABELLED: Current guidelines recommend esophagogastroduodenoscopy (EGD) in patients with cirrhosis to screen for gastroesophageal varices (GEV). Thrombocytopenia has been proposed as a noninvasive test to predict the presence of GEV. There is no agreement regarding a specific platelet count (PLT) that can reliably predict GEV. The present longitudinal study aims to (1) further investigate the relationship between varices and PLT at the time of endoscopy, (2) investigate whether changes in PLT from the baseline over time can predict the development of GEV, and (3) investigate whether changes in PLT correlate with the hepatic venous pressure gradient (HVPG). A secondary analysis was conducted for 213 subjects with compensated cirrhosis with portal hypertension but without GEV enrolled in a randomized, placebo-controlled, double-blind trial of a nonselective beta-blocker used to prevent GEV. PLTs were obtained every 3 months, and HVPG measurements and EGD were done annually. The PLTs were compared between subjects who did and did not develop GEV. In a median follow-up of 54.9 months, 84 patients developed GEV. PLT was greater than 150,000 in 15% of patients at the development of GEV. A receiver operating curve did not show any PLT with high sensitivity or specificity for the presence of GEV. Subjects with clinically insignificant portal hypertension (HVPG < 10 mm Hg) whose PLT remained greater than 100,000 had a 2-fold reduction in the occurrence of GEV (P = 0.0374). A significant correlation was found between HVPG and PLT at the baseline, year 1, and year 5 (P < 0.0001). CONCLUSION: Cross-sectional or longitudinal evaluations of PLTs are inadequate noninvasive markers for GEV. Patients with mild portal hypertension whose PLT remains greater than 100,000 have significantly less risk of GEV. Although HVPG correlates somewhat with PLT, changes in PLT cannot be used as a surrogate for HVPG changes.

Dose-dependent reduction of hazardous alcohol use in a placebo-controlled trial of naltrexone for smoking cessation.

The opiate antagonist naltrexone (Ntx) has demonstrated efficacy in the treatment of alcohol dependence and as a component of treatment to reduce heavy drinking. At present, there are no published dose-ranging clinical trials of the oral preparation for treatment of problem drinking. The present study evaluated the effects of Ntx on alcohol use among the subset of hazardous drinkers (n=102) who participated in a placebo-controlled, dose-ranging trial of oral Ntx (25-mg, 50-mg and 100-mg doses) combined with open-label transdermal nicotine patch for enhancing smoking cessation. On the primary outcome--no hazardous drinking (drinking that exceeded weekly or daily limits) during treatment--25 mg and 50 mg Ntx were superior to placebo (each p<0.05). These findings remained after controlling for baseline predictors or smoking abstinence during treatment. Time to remission of hazardous drinking was examined as a secondary outcome with definitions of hazardous drinking based on weekly limits, daily limits and the combination of weekly and daily limits and the results were consistent with the primary findings. In conclusion, the findings suggest that Ntx can reduce the risk of hazardous drinking in smokers who are not seeking or receiving alcohol treatment, providing strong evidence for the pharmacological effects of Ntx on drinking. This effect appears to favour lower doses that may be better tolerated and less expensive than the higher 100-mg dose. Given its efficacy and favourable side-effect profile, the 25-mg dose should be considered for future studies of combination therapy.

GABAA-benzodiazepine receptor availability in smokers and nonsmokers: relationship to subsyndromal anxiety and depression.

Many smokers experience subsyndromal anxiety symptoms while smoking and during acute abstinence, which may contribute to relapse. We hypothesized that cortical gamma aminobutyric acid(A)-benzodiazepine receptor (GABA(A)-BZR) availability in smokers and nonsmokers might be related to the expression of subsyndromal anxiety, depressive, and pain symptoms. Cortical GABA(A)-BZRs were imaged in 15 smokers (8 men and 7 women), and 15 healthy age and sex-matched nonsmokers, and 4 abstinent tobacco smokers (3 men; 1 woman) using [(123)I]iomazenil and single photon emission computed tomography (SPECT). Anxiety and depressive symptoms were measured using the Spielberger's State-Trait Anxiety Index (STAI) and the Center for Epidemiology Scale for Depressive Symptoms (CES-D). The cold pressor task was administered to assess pain tolerance and sensitivity. The relationship between cortical GABA(A)-BZR availability, smoking status, and subsyndromal depression and anxiety symptoms, as well as pain tolerance and sensitivity, were evaluated. Surprisingly, there were no statistically significant differences in overall GABA(A)-BZR availability between smokers and nonsmokers or between active and abstinent smokers; however, cortical GABA(A)-BZR availability negatively correlated with subsyndromal state anxiety symptoms in nonsmokers but not in smokers. In nonsmokers, the correlation was seen across many brain areas with state anxiety [parietal (r = -0.47, P = 0.03), frontal (r = -0.46, P = 0.03), anterior cingulate (r = -0.47, P = 0.04), temporal (r = -0.47, P = 0.03), occipital (r = -0.43, P = 0.05) cortices, and cerebellum (r = -0.46, P = 0.04)], trait anxiety [parietal (r = -0.72, P = 0.02), frontal (r = -0.72, P = 0.02), and occipital (r = -0.65, P = 0.04) cortices] and depressive symptoms [parietal (r = -0.68; P = 0.02), frontal (r = -0.65; P = 0.03), anterior cingulate (r = -0.61; P = 0.04), and temporal (r = -0.66; P = 0.02) cortices]. The finding that a similar relationship between GABA(A)-BZR availability and anxiety symptoms was not observed in smokers suggests that there is a difference in GABA(A)-BZR function, but not number, in smokers. Thus, while subsyndromal anxiety and depressive symptoms in nonsmokers may be determined in part by GABA(A)-BZR availability, smoking disrupts this relationship. Aberrant regulation of GABA(A)-BZR function in vulnerable smokers may explain why some smokers experience subsyndromal anxiety and depression.

Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.

BACKGROUND: Nonselective beta-adrenergic blockers decrease portal pressure and prevent variceal hemorrhage. Their effectiveness in preventing varices is unknown. METHODS: We randomly assigned 213 patients with cirrhosis and portal hypertension (minimal hepatic venous pressure gradient [HVPG] of 6 mm Hg) to receive timolol, a nonselective beta-blocker (108 patients), or placebo (105 patients). The primary end point was the development of gastroesophageal varices or variceal hemorrhage. Endoscopy and HVPG measurements were repeated yearly. RESULTS: During a median follow-up of 54.9 months, the rate of the primary end point did not differ significantly between the timolol group and the placebo group (39 percent and 40 percent, respectively; P=0.89), nor were there significant differences in the rates of ascites, encephalopathy, liver transplantation, or death. Serious adverse events were more common among patients in the timolol group than among those in the placebo group (18 percent vs. 6 percent, P=0.006). Varices developed less frequently among patients with a baseline HVPG of less than 10 mm Hg and among those in whom the HVPG decreased by more than 10 percent at one year and more frequently among those in whom the HVPG increased by more than 10 percent at one year. CONCLUSIONS: Nonselective beta-blockers are ineffective in preventing varices in unselected patients with cirrhosis and portal hypertension and are associated with an increased number of adverse events. (ClinicalTrials.gov number, NCT00006398.)