Miracle-dz/UniFAR-FTUs huggingface dataset:
Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial

Objective To evaluate the long-term effect of cumulative time exposed to Helicobacter pylori infection on the progression of gastric lesions. Design 795 adults with precancerous gastric lesions were randomised to receive anti-H. pylori treatment at baseline. Gastric biopsies were obtained at baseline and at 3, 6, 12 and 16 years. A total of 456 individuals attended the 16-year visit. Cumulative time of H. pylori exposure was calculated as the number of years infected during follow-up. Multivariable logistic regression models were used to estimate the risk of progression to a more advanced diagnosis (versus no change/regression) as well as gastric cancer risk by intestinal metaplasia (IM) subtype. For a more detailed analysis of progression, we also used a histopathology score assessing both severity and extension of the gastric lesions (range 1–6). The score difference between baseline and 16 years was modelled by generalised linear models. Results Individuals who were continuously infected with H. pylori for 16 years had a higher probability of progression to a more advanced diagnosis than those who cleared the infection and remained negative after baseline (p=0.001). Incomplete-type IM was associated with higher risk of progression to cancer than complete-type (OR, 11.3; 95% CI 1.4 to 91.4). The average histopathology score increased by 0.20 units/year (95% CI 0.12 to 0.28) among individuals continuously infected with H. pylori. The effect of cumulative time of infection on progression in the histopathology score was significantly higher for individuals with atrophy (without IM) than for individuals with IM (p<0.001). Conclusions Long-term exposure to H. pylori infection was associated with progression of precancerous lesions. Individuals infected with H. pylori with these lesions may benefit from eradication, particularly those with atrophic gastritis without IM. Incomplete-type IM may be a useful marker for the identification of individuals at higher risk for cancer.
Ethnic drinking cultures, gender, and socioeconomic status in Asian American and Latino drinking.

BACKGROUND Heterogeneity in drinking across national groups is well documented, but what explains such heterogeneity is less clear. To improve understanding of the underlying cultural conditions that may lead to diverse drinking outcomes, we investigate whether 3 dimensions of ethnic drinking culture (EDC)-alcohol consumption level, drinking prevalence, and detrimental drinking pattern (DDP) in the country of origin (COO)-are significantly associated with alcohol consumption in Asian Americans and Latina/os, and whether the associations vary by gender and socioeconomic status (SES) as assessed by educational level. METHODS A nationally representative sample of 1,012 Asian American and 4,831 Latino adults extracted from the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions data was used. A series of multiple logistic and linear regression models were fitted separately for Asian Americans and for Latinos. Analyses were also stratified by gender and educational level. RESULTS Overall, the associations between EDC variables and drinking outcomes were more pronounced for all Asian Americans than for all Latina/os, for males than for females among Asian Americans, and for Latinas than for Latinos. In analyses simultaneously stratifying on gender and education level, however, there was a clear pattern of COO DDP associated with heavier drinking and alcohol consumption volume only for Latinos without a college degree. CONCLUSIONS Ethnic drinking cultures may influence drinking in Asian American and Latino subgroups, albeit to a varying degree. Low-SES Latinos may be at disproportionate risk of harmful drinking patterns pervasive in their COO. Future research might investigate the complex interplay between socioeconomic disadvantage and cultural conditions to inform targeted interventions for subgroups at high risk of alcohol-related harms.
Genetic absence of nNOS worsens fetal alcohol effects in mice. II: microencephaly and neuronal losses.

BACKGROUND Prenatal alcohol exposure can kill developing neurons, leading to microencephaly and mental retardation. However, not all fetuses are equally vulnerable to alcohol's neurotoxic effects. While some fetuses are severely affected and are ultimately diagnosed with fetal alcohol syndrome (FAS), others have no evidence of neuropathology and are behaviorally normal. These widely different outcomes among alcohol-exposed fetuses are likely due, in part, to genetic differences. Some fetuses possess genotypes that make them much more vulnerable than others to alcohol's teratogenic effects. However, to date, only 1 gene has been identified whose mutation can worsen alcohol-induced behavioral deficits in an animal model of FAS. That gene is neuronal nitric oxide synthase (nNOS). The purpose of this study was to determine whether mutation of nNOS can likewise worsen alcohol-induced microencephaly and lead to permanent neuronal deficits. METHODS Wild-type and nNOS(-/-) mice received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days (PDs) 4 to 9. Beginning on PD 85, the mice underwent a series of behavioral tests; the results of which are reported in the companion paper. The brains were then weighed, and stereological cell counts were performed on the cerebral cortex and hippocampal formation, which are the brain regions that mediate the aforementioned behavioral tasks. RESULTS Alcohol caused dose-dependent microencephaly, but only in the nNOS(-/-) mice and not in wild-type mice. Alcohol-induced neuronal losses were more severe in the nNOS(-/-) mice than in the wild-type mice in all of the brain regions examined, including the cerebral cortex, hippocampal CA3 subregion, hippocampal CA1 subregion, and dentate gyrus. CONCLUSIONS Targeted mutation of the nNOS gene increases the vulnerability of the developing brain to alcohol-induced growth restriction and neuronal losses. This increased neuropathology is associated with worsened behavioral dysfunction. The results demonstrate the critical importance of genotype in determining the outcome of developmental alcohol exposure.
Refining measures of alcohol problems for general population surveys.

BACKGROUND There is a need to improve classification of alcohol use disorders (AUDs) in general population surveys. We developed and tested follow-up questions for 2 commonly reported symptom domains (withdrawal and larger/longer) to assess effects on Diagnostic and Statistical Manual-5 AUD classification. METHODS Telephone interviews recontacted a selective follow-up sample of respondents under age 46 from the 2010 National Alcohol Survey with at least 1 lifetime AUD symptom (n = 244). Items included detailed questions about past-year AUD symptoms. Three items (vomiting, sweating, irritability) were recoded as acute intoxication rather than withdrawal if they most recently occurred within 8 hours of stopping drinking. The larger/longer criterion was recoded as socially motivated if respondents endorsed "got caught up in drinking with a group of friends" and not "feel compelled to drink and just can't stop" as a reason for drinking more than intended. RESULTS Of 225 current drinkers, 11% reported past-year withdrawal, with 28% of those reporting acute intoxication instead of physical withdrawal. Adjusting past-year withdrawal classification reduced AUD prevalence by 6%. A minority (12%) reported the past-year larger/longer criterion. Of those, 50% indicated social reasons for drinking more than intended, rather than compulsion to drink. Adjusting the past-year larger/longer criterion reduced AUD prevalence by 8%. Accounting for both adjustments reduced AUD prevalence by 13%. Cases that met AUD criteria after both adjustments were substantially heavier drinkers than those that were reclassified. CONCLUSIONS Follow-up items could be implemented in epidemiologic studies with minimal response burden and may help reduce misclassification of AUD.
Plausibility criteria for putative pathophysiological mechanisms in functional gastrointestinal disorders: a consensus of experts

Background and aims The functional gastrointestinal disorders (FGIDs) are extremely common conditions associated with a considerable personal, social and health economic burden. Managing FGIDs in clinical practice is challenging because of the uncertainty of symptom-based diagnosis, the high frequency of overlap between these conditions and the limited efficacy of available therapies. It has often been argued that successful drug development and management of FGIDs requires knowledge of the underlying pathophysiology. Numerous and highly variable candidate pathophysiological mechanisms have been implicated in the generation of FGID symptoms, but there is no current consensus on how to best define the relevance of these disturbances. Methods A group of international experts on FGIDs developed plausibility criteria that should be fulfilled by relevant pathophysiological mechanisms in FGIDs. Results Five criteria are proposed: (1) the presence of the abnormality in a subset of patients, (2) temporal association between proposed mechanism and symptom(s), (3) correlation between the level of impairment of the mechanism and symptom(s), (4) induction of the symptom(s) by provoking the pathophysiological abnormality in healthy subjects and (5) treatment response by a therapy specifically correcting the underlying disorder or congruent natural history of symptoms and dysfunction in the absence of specific therapy. Based on strength of evidence for these five criteria according to the Grading of Recommendations Assessment, Development and Evaluation system, a plausibility score can be calculated for each mechanism. Conclusion Evaluation of the strength of evidence for candidate pathophysiological abnormalities fulfilling these five plausibility criteria will help to identify the most relevant mechanisms to target for novel diagnostic approaches and for the development of new therapies.
Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma

Objective Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC. Design The effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo. The mechanisms of intrinsic and acquired resistance to palbociclib were assessed in human liver cancer cell lines and human HCC samples by protein and gene expression analyses. Results Palbociclib suppressed cell proliferation in human liver cancer cell lines by promoting a reversible cell cycle arrest. Intrinsic and acquired resistance to palbociclib was determined by loss of RB1. A signature of ‘RB1 loss of function’ was found in <30% of HCC samples. Palbociclib, alone or combined with sorafenib, the standard of care for HCC, impaired tumour growth in vivo and significantly increased survival. Conclusions Palbociclib shows encouraging results in preclinical models of HCC and represents a novel therapeutic strategy for HCC treatment, alone or particularly in combination with sorafenib. Palbociclib could potentially benefit patients with RB1-proficient tumours, which account for 70% of all patients with HCC.
Adolescent alcohol use before and after the high school transition.

BACKGROUND An important question is whether the high school (HS) entry is a critical developmental event associated with escalation of alcohol use. This study examined trajectories of adolescent alcohol use as a function of a normative developmental event-the HS entry. In addition, given that at-risk youth may be particularly vulnerable to the stress associated with this transition, we examined how these alcohol use trajectories may be shaped by a measure of early behavioral risk, early adolescent delinquency. METHODS Participants included 891 twelve-year-olds from the prospective National Longitudinal Survey of Youth 1997 for whom relevant longitudinal school data were available (51.2% boys; 61.4% White). RESULTS Alcohol use after HS entry increased at a significantly greater rate than did use during the middle school years, even after accounting for students' age at transition. In addition, early delinquency emerged as a risk factor such that differences in alcohol use existed prior to the transition. That is, children with early delinquency characteristics displayed more rapid progression in alcohol use, but this effect was evident only during middle school. CONCLUSIONS HS entry appears to be a critical developmental event associated with increased social risk for greater alcohol use that goes beyond the simple maturational (i.e., aging) factors. Youth with behavioral problems appears to be at greater risk in middle school, in contrast to lower risk youth for whom HS entry may be a more critical event, in part because HS may be a less restrictive environment and/or because alcohol use becomes more normative at that time. Adolescent substance use may be described as a series of distinct developmental stages that closely correspond to school transitions and suggest a critical period for targeted intervention that may differ as a function of preexisting risk.
MoCA as a Screening Tool of Neuropsychological Deficits in Alcohol-Dependent Patients.

BACKGROUND Alcoholism is known to be associated with cognitive deficits mainly concerning visuospatial capacity, executive function, memory, and attention. These impairments may affect treatment efficacy which should therefore be adapted. We evaluated the potential utility of the Montreal Cognitive Assessment (MoCA) to evaluate cognitive impairment in a large series of alcoholic patients hospitalized for withdrawal and rehabilitation. METHODS Consecutive recruitment during a time period of patients admitted to an addiction treatment unit of a teaching hospital. Administration of the MoCA test on admission by trained staff members. RESULTS A total of 166 patients aged 49.9 ± 9.2 years were included. Mean duration of administration was 20 minutes. The mean MoCA score was 23.5 ± 3.5 and 68.1% had an impaired value (<26). Age was negatively and education was positively associated with the MoCA score. Significant cognitive deficits concerned visuospatial capacity, attention, fluency, abstraction, and delayed recall. Neither age nor sex was significantly related to the MoCA score, while having a high education level (>12 years) significantly increased the likelihood of having a high MoCA score. CONCLUSIONS Owing to their severity and frequency, screening for cognitive deficits is necessary in alcoholics during rehabilitation. MoCA is an appropriate tool for this purpose.
The Biology of Bronchial Premalignancy

The observation that invasive cancer is the result of stepwise accumulation of progressively more severe abnormalities in precursor in situ lesions has become a commonplace in the cancer literature. This concept implies that a stage during carcinogenesis exists in which precursor cells have begun to accumulate changes that may ultimately lead to invasive carcinoma, but in which these cells have not yet acquired the capacity to invade normal tissue or to metastasize. In this article, the term "premalignancy" will be used to refer to the aggregate of changes that occur in precursor cell populations prior to the development of invasive cancer. The concept of premalignancy is particularly important as applied to lung carcinogenesis since high mortality from lung cancer is, at least in part, the result of late clinical presentation. Elucidation of premalignant changes may help to identify those patients in whom earlier intervention may reduce morbidity and mortality from this highly lethal tumor. This article will discuss the historical development of the concept of multistep carcinogenesis, the current state of our understanding of how this concept applies to lung cancer and premalignant changes in bronchial epithelium, and the prospects for future application of this concept to the management of people at risk for lung cancer.
Postmarketing migraine survey of frovatriptan: effectiveness and tolerability vs previous triptans, NSAIDs or a combination

Abstract Objective: Compare the effectiveness and tolerability of current therapy with frovatriptan 2.5-mg tablets (in 1–3 migraines) in patients with migraine previously using other triptans, analgesics/nonsteroidal anti-inflammatory drugs (NSAIDs), or triptans and NSAIDs (T+NSAIDs). Research design and methods: Subanalysis of a postmarketing survey study in patients with migraine managed at primary care facilities in Germany. Main outcome measures: A total of 5025 patients rated the effectiveness and tolerability of previous therapy (triptans; T+NSAIDs; NSAIDs) and current therapy with frovatriptan; physicians rated only frovatriptan effectiveness and tolerability (1 = Very Good, 2 = Good, 3 = Satisfactory, 4 = Poor). Results: Of 7107 patients initially surveyed, 5025 were identified for this subanalysis as previously using NSAIDs (n = 2890), triptans (n = 1418) or T + NSAIDs (n = 717). The mean (SD) age was 42.3 (11.9) years. At baseline, patients who previously used NSAIDs reported significantly fewer migraines per month, lower migraine severity, shorter migraine duration, and poorer ratings for effectiveness and tolerability versus responses from patients previously using triptans or T + NSAIDs (P < 0. 001 for each). Patient effectiveness ratings of Very Good or Good for previous therapy occurred in 49% (n = 691 of 1411) of patients using triptans, 27% (n = 195 of 716) of patients using T + NSAIDs, and 11% (n = 303 of 2866) of patients using NSAIDs (P < 0.04 between each group). Most patients rated current therapy with frovatriptan as Very Good or Good for effectiveness (86%, triptans; 83%, T + NSAIDs; 94%, NSAIDs) and tolerability (95%; 95%; 97%). Most physicians rated frovatriptan as Very Good or Good for effectiveness (87%; 86%; 95%) and tolerability (96%; 96%; 98%). Within-patient comparisons confirmed that frovatriptan had improved effectiveness (P < 0.001) and tolerability ratings (P < 0.001) in all three groups versus previous therapies. Conclusions: Intrapatient comparisons showed that most patients with migraine reported significantly improved effectiveness and tolerability ratings with frovatriptan versus previous acute therapies.
Risk Factors for Sudden Cardiac Death Among Patients with Alcohol Dependence: A Nested Case-Control Study.

BACKGROUND Excessive alcohol consumption causes a broad range of health problems, including premature mortality and sudden cardiac death (SCD). We identified potential clinical characteristics and laboratory indices associated with SCD among patients with alcohol dependence. METHODS Patients with alcohol dependence (n = 2,793) admitted to a psychiatric center in northern Taiwan between 1985 and 2008 were linked with a national mortality database for causes of death. Of the 2,793 patients in the cohort, 67 cases died of SCD. The standardized mortality ratio (SMR) of SCD relative to the general population was calculated. Based on a nested case-control design, we selected a set of sex-, age-, and year-of-admission-matched two control subjects for each case derived from the cohort. We collated the clinical information through a standardized review of patients' medical records. Conditional logistic regressions were then conducted to explore potential exposures associated with SCD. RESULTS The sample had substantially higher SCD mortality (SMR 12.8) compared to the general population. After adjustments in the multivariate analyses for the clinical profiles at the index (earliest) admission, both abnormal electrocardiography (ECG) (adjusted risk ratio = 16.97, 95% confidence interval (CI) 1.60 to 179.58, p = 0.019) and elevated aspartate aminotransferase levels (adjusted risk ratio = 1.01, 95% CI 1.00 to 1.02, p = 0.046) were significantly associated with SCD. CONCLUSIONS This study raises the question of whether intensive follow-up of patients with elevated AST and abnormal ECG findings should be evaluated as a strategy to prevent SCD in patients with alcohol dependence.
Histone Deacetylase Gene Expression Following Binge Alcohol Consumption in Rats and Humans.

BACKGROUND Alcohol binge drinking is one of the most common patterns of excessive alcohol use and recent data would suggest that histone deacetylases (HDACs) gene expression profiling could be useful as a biomarker for psychiatric disorders. METHODS This study aimed to characterize the gene expression patterns of Hdac 1-11 in samples of rat peripheral blood, liver, heart, prefrontal cortex, and amygdala following repeated binge alcohol consumption and to determine the parallelism of Hdac gene expression between rats and humans in peripheral blood. To accomplish this goal, we examined Hdac gene expression following 1, 4, or 8 alcohol binges (3 g/kg, orally) in the rat, in patients who were admitted to the hospital emergency department for acute alcohol intoxication, and in rats trained in daily operant alcohol self-administration. RESULTS We primarily found that acute alcohol binging reduced gene expression (Hdac1-10) in the peripheral blood of alcohol-naïve rats and that this effect was attenuated following repeated alcohol binges. There was also a reduction of Hdac gene expression in the liver (Hdac2,4,5), whereas there was increased expression in the heart (Hdac1,7,8) and amygdala (Hdac1,2,5). Additionally, increased blood alcohol concentrations were measured in rat blood at 1 to 4 hours following repeated alcohol binging, and the only group that developed hepatic steotosis (fatty liver) were those animals exposed to 8 alcohol binge events. Finally, both binge consumption of alcohol in humans and daily operant alcohol self-administration in rats increased Hdac gene expression in peripheral blood. CONCLUSIONS Our results suggest that increases in HDAC gene expression within the peripheral blood are associated with chronic alcohol consumption, whereas HDAC gene expression is reduced following initial exposure to alcohol.