Miracle-dz/UniFAR-FTUs huggingface dataset:
Promises and partnership: FDA's Critical Path Initiative and its intersection with pharmacology: an ASPET 2011 annual meeting symposium

The Critical Path Initiative (CPI) is a 2004 white paper of the US FDA, which fosters long-term strategies for incorporating 21st-century scientific advances into development, assessment, manufacture and use of medical products. Its ongoing implementation is paced by the outcome of numerous ad hoc, FDA-sponsored research projects and consortia in areas of major concern, some of which were discussed in this symposium. Of paramount importance is Tox21 program the aim of which is to identify novel predictive, cost-effective, mechanism-based investigational tools mainly of soft- and wet (in vitro)-ware nature firmly grounded in human biology for easily detecting xenobiotic-induced adverse reactions in humans and the environment. Additionally, the intelligent application of holistic approaches (e.g., systems biology and systems pharmacology) to the drug development process will also greatly help in predicting, avoiding and appropriately managing potential risks inherent in medical product use. Optimization of clinical investigations, another crucial objective of CPI, may be partly achieved by adopting targeted enrichment provisions (individual, pathophysiological, genomic (e.g., biomarkers)) for recruiting patients that would most likely respond to a treatment, as sought after. However, for regulatory purposes, drug development tools, such as biomarkers for demonstrating the value or the risk of a treatment, require an appropriate qualification that can be obtained following a recently released FDA guidance. In conclusion, a current major FDA commitment is the rejuvenation of drug ‘Critical Path’ platforms with the introduction of 21st-century best science tools and methods for rapidly turning ‘discoveries into medical miracles' for the benefit of people in need.
Role of aramchol in steatohepatitis and fibrosis in mice

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) that sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits, including oxidative stress, mitochondrial dysfunction, inflammation, and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Arachidyl‐amido cholanoic acid (Aramchol) is presently in a phase IIb NASH study. The aim of the present study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine‐ and choline‐deficient (MCD) diet model of NASH. We collected liver and serum from mice fed an MCD diet containing 0.1% methionine (0.1MCD) for 4 weeks; these mice developed steatohepatitis and fibrosis. We also collected liver and serum from mice receiving a control diet, and metabolomes and proteomes were determined for both groups. The 0.1MCD‐fed mice were given Aramchol (5 mg/kg/day for the last 2 weeks), and liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD‐fed mice. Aramchol down‐regulated stearoyl‐coenyzme A desaturase 1, a key enzyme involved in triglyceride biosynthesis and the loss of which enhances fatty acid β‐oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and the GSH/oxidized GSH ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of the serum metabolomic pattern between 0.1MCD‐fed mice and patients with NAFLD showed a substantial overlap. Conclusion: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing stearoyl‐coenyzme A desaturase 1 and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype observed in about 50% of patients with NAFLD, which supports the potential use of Aramchol in NASH treatment. (Hepatology Communications 2017;1:911–927)
Liver transplantation for small hepatocellular carcinoma: The tumor‐node‐metastasis classification does not have prognostic power

Tumoral recurrence rate and survival of patients with hepatocellular carcinoma (HCC) treated by orthotopic liver transplantation (OLT) depend on tumor stage. Thereby, from the beginning of our program, we selected only patients with solitary tumors ≤5 cm without vascular invasion, thus avoiding the use of the tumor‐node‐metastasis (TNM) staging system as a selection tool. The present study reports the results obtained in 58 consecutive patients (52 ± 8 years, 47 males) with HCC (7 incidentals) transplanted between 1989 and 1995. Transplantation was indicated because of tumor diagnosis in 40 cases and advanced liver failure in 18. Mean tumor size at staging was 28.2 ± 12.1 mm. No adjuvant treatment was applied during the waiting period (58.9 ± 45.1 days). The pathological tumor‐node‐metastasis (pTNM) classification allocated 15 patients to stage I, 19 to stage II, 11 to stage IIIA, and 13 to stage IVA showing preoperative understaging in 43% of the cases with known tumor. After a median follow up of 31 months, only two patients have shown tumor recurrence and fifteen have died, the 1‐, 3‐, and 5‐year survival being 84%, 74%, and 74%. All HCV+ patients remain infected and 94% showed significant liver disease (6 cirrhosis). Six patients have had a second transplant. In conclusion, the application of restrictive criteria not following the TNM staging system prompts excellent results for liver transplantation in patients with HCC, both in terms of survival and disease recurrence, even without applying adjuvant treatment; however, the survival data should be tempered by the appearance of complications that may worsen the long‐term prognosis.
Initiation of remote hepatic injury in the rat: Interactions between Kupffer cells, tumor necrosis factor‐α, and microvascular perfusion

Severe trauma may initiate a systemic inflammatory response, which in turn may result in remote organ injury. After limb ischemia/reperfusion (I/R), intravital fluorescence microscopy was applied to the livers of normotensive rats to investigate the initiation of remote injury to the liver. Additionally, we determined whether Kupffer cell activation and tumor necrosis factor‐α (TNF‐α) were involved, via perfusion deficits, in such injury. TNF‐α, measured by immunoassay, peaked at 30 minutes of reperfusion, but returned to baseline within 60 minutes. Limb I/R resulted in significant increases to global hepatocellular injury measured by alanine transaminase (ALT) and lethal hepatocyte injury as seen with intravital fluorescence microscopy. Although the number of perfused sinusoids went unchanged, a significantly augmented perfusion heterogeneity was measured. After 1.5 hours of reperfusion, both TNF‐α and Kupffer cells were shown to contribute to global hepatocellular injury (e.g., ALT). After 3 hours, TNF‐α was no longer essential for this injury, suggesting that some other mechanism(s) activated Kupffer cells and initiated hepatocellular injury. Using propidium iodide and fluorescence microscopy, we found that both TNF‐α and Kupffer cell activation were necessary to drive hepatocytes toward lethal injury. No additional benefits were observed with a combination of TNF‐α inhibition and Kupffer cell suppression. These results not only implicate both Kupffer cells and TNF‐α in the initiation of remote hepatic injury, but suggest that sinusoidal perfusion deficits are not essential for the initiation of such injury. Other mechanism(s) are likely involved in the pathogenesis of remote hepatic parenchymal injury.
‘Without a plan’ but ‘keeping on track’: Views on contraception, pregnancy and abortion in Mexico City

Despite increased use of modern contraception among Mexican women, there has been a significant increase in abortions. Little is known about the experiences behind these trends. This study examines decision-making around contraception, pregnancy, childbearing and abortion. We carried out 26 in-depth interviews with 23- to 35-year-old females and males in Mexico City. Interviewees described reproductive planning ‘without a plan’ and sporadic contraceptive use. Linking of reproductive preferences and contraceptive use occurred only after raising a child for a few years or after experiencing an abortion. Interviewees described side effects of hormonal contraceptives and the intrauterine device (IUD) and problems with condoms. Only 8% of participants disagreed with abortion completely. Those with mixed views opposed abortion for pregnancies resulting from lack of responsibility or due to personal problems or concerns about one's future. However, these more controversial reasons were the primary motivations for terminating pregnancies. Females and males expressed that females made most decisions related to contraception, pregnancy and abortion. Further research could explore the reasons behind reproductive planning ‘without a plan’, ‘on and off’ contraceptive use and abortion beliefs and experiences that are somewhat contradictory.
Apolipoprotein E ε4 allele and the lifetime risk of Alzheimer's disease : what physicians know, and what they should know

Background: Published studies now show a clear association between Alzheimer's disease (AD) and the apolipoprotein E e4 allele (APOE*e4). The clinical value of this information to estimate a healthy individual's lifetime risk of AD has not been well delineated. Physicians dealing with AD may not know either the lifetime risk of developing AD or the effect of theAPOEgenotype on this risk. Because the lifetime risk of AD depends in part on life expectancy, and available figures onAPOEare not population based, a computation is necessary to derive risk estimates useful to physicians. Objectives: To estimate the lifetime risk of AD and the effect ofAPOEgenotype information on that risk and to assess the knowledge of these risks among physicians who manage patients with dementia. Design: Estimation of risk of AD and survey of physician awareness. The lifetime risk of developing AD withoutAPOEgenotype information was first computed for 65-year-olds from existing epidemiologic studies of age-related AD incidence and an actuarial life-table analysis. Using this computed a priori risk of AD and published studies ofAPOEgenotypes in individuals with and without AD, we used a Bayesian analysis to determine the risk of developing AD, with and without anAPOE*e4 allele, for unaffected 65-year-olds. To assess physician knowledge of the lifetime risk of AD and the effect ofAPOEgenotyping on the risk, 50 neurologists, internists, geriatricians, geriatric psychiatrists, and family physicians who manage patients with dementia were randomly selected to participate in a questionnaire-driven telephone survey. Results: In a person with no family history of AD, the epidemiologic/actuarial lifetime risk of AD is approximately 15%. Based on a Bayesian calculation and publishedAPOEdata, the lifetime risk of AD is 29% for individuals with oneAPOE*e4 allele and it is 9% if noAPOE*e4 allele is present. Physician awareness survey results were as follows: 42% of physicians correctly estimated the approximate lifetime risk of AD; of these, only one third were moderately sure of their response. Only three physicians correctly estimated the change in risk given theAPOE*e4 genotype; only one of these was at least moderately sure. Conclusions: Determining theAPOE*e4 status of healthy adults with no family history of AD approximately doubles (for the e4 allele) or reduces by 40% (for the non-e4 allele) the uninformed lifetime risk of developing AD. Even with anAPOE*e4 allele, the lifetime risk remains below 30%. Most physicians managing patients with AD do not know the lifetime risk of AD, and very few know howAPOE*e4 status modifies the risk. These clinically relevant risk figures should be more widely disseminated among physicians.
Bilateral NMDA lesions centered on the postrhinal cortex have minimal effects on hippocampal place cell firing

The postrhinal cortex (POR) receives input from parietal cortex and sends output to the hippocampus. It may, therefore, relay spatial information to the hippocampus and as a result, lesions of POR may disturb the spatial firing patterns of hippocampal place cells. To test this hypothesis, the firing of hippocampal CA1 place cells in rats with bilateral N‐methyl‐D‐aspartic acid lesions centered on the POR (n = 83 cells) and rats with sham lesions (n = 77 cells) was compared, while animals foraged freely. The main effect of postrhinal lesions on the basic firing properties of hippocampal place cells was to decrease the coherence of their firing fields. In contrast to the previously reported effects of lesions of neighboring perirhinal cortex, however, there was no effect of postrhinal lesions on the location stability of the fields over time or in the response of these cells to the animal's movement. These data indicate that information originating from the POR has relatively little influence on hippocampal place cell firing while an animal is engaged in foraging behavior. This also suggests that perirhinal and postrhinal cortices make distinct contributions to hippocampal functioning. © 2008 Wiley‐Liss, Inc.
Communicable disease control in Afghanistan

Among public health challenges in Afghanistan, communicable diseases still predominate because the epidemiologic transition to chronic disease has not yet occurred. Afghanistan's 10-year journey to improve its response to communicable disease is reflected in varying degrees of progress and innovation, all while long-standing conflict and geographic inaccessibility limit outreach and effective service delivery to vulnerable populations. Although Afghanistan is close to achieving polio elimination, other reportable communicable diseases are only slowly achieving their goals and objectives through targeted, sustained programmatic efforts. The introduction of disease early warning systems has allowed for identification and investigation of outbreaks within 48 hours. Tuberculosis case detection has risen over the last 10 years, and treatment success rates have been sustained at World Health Organization targets over the last 5 years at 85%. These successes are in large part due to increased government commitment, Global Fund support, training of community health workers and improved laboratory capabilities. Malaria cases dropped between 2002 and 2010. HIV/AIDS has been kept at low levels except in only certain sub-sectors of the population. In order to build on these achievements, Afghanistan will need a comprehensive strategy for all communicable diseases, with better human and infrastructure development, better multi-sectoral development and international collaboration.
After the Global Fund: Who can sustain the HIV/AIDS response in Peru and how?

Peru has received around $70 million from Global Fund to fight AIDS, Tuberculosis and Malaria (Global Fund). Recent economic growth resulted in grant ineligibility, enabling greater government funding, yet doubts remain concerning programme continuity. This study examines the transition from Global Fund support to increasing national HIV/AIDS funding in Peru (2004–2012) by analysing actor roles, motivations and effects on policies, identifying recommendations to inform decision-makers on priority areas. A conceptual framework, which informed data collection, was developed. Thirty-five in-depth interviews were conducted from October to December 2011 in Lima, Peru, among key stakeholders involved in HIV/AIDS work. Findings show that Global Fund involvement led to important breakthroughs in the HIV/AIDS response, primarily concerning treatment access, focus on vulnerable populations and development of a coordination body. Nevertheless, reliance on Global Fund financing for prevention activities via non-governmental organisations, compounded by lack of government direction and weak regional governance, diluted power and caused role uncertainty. Strengthening government and regional capacity and fostering accountability mechanisms will facilitate an effective transition to government-led financing. Only then can achievements gained from the Global Fund presence be maintained, providing lessons for countries seeking to sustain programmes following donor exit.
Political commitment to tuberculosis control in Ghana

As part of expanding and sustaining tuberculosis (TB) control, the Stop TB Partnership of the World Health Organization initiative has called for strong political commitment to TB control, particularly in developing countries. Framing political commitment within the theoretical imperatives of the political economy of health, this study explores the existing and the expected dimensions of political commitment to TB control in Ghana. Semi-structured in-depth interviews were conducted with 29 purposively selected staff members of the Ghana Health Service and some political officeholders. In addition, the study analysed laws, policies and regulations relevant to TB control. Four dimensions of political commitment emerged from the interviews: provision of adequate resources (financial, human and infrastructural); political authorities' participation in advocacy for TB; laws and policies' promulgation and social protection interventions. Particularly in respect to financial resources, donors such as the Global Fund to Fight AIDS, Tuberculosis and Malaria presently give more than 60% of the working budget of the programme. The documentary review showed that laws, policies and regulations existed that were relevant to TB control, albeit they were not clearly linked.
Generating political priority for newborn survival in three low-income countries

Deaths to babies in their first 28 days of life now account for more than 40% of global under-5 child mortality. High neonatal mortality poses a significant barrier to achieving the child survival Millennium Development Goal. Surmounting the problem requires national-level political commitment, yet only a few nation-states have prioritised this issue. We compare Bolivia, Malawi and Nepal, three low-income countries with high neonatal mortality, with a view to understanding why countries prioritise or neglect the issue. The three have had markedly different trajectories since 2000: attention grew steadily in Nepal, stagnated then grew in Malawi and grew then stagnated in Bolivia. The comparison suggests three implications for proponents seeking to advance attention to neglected health issues in low-income countries: the value of (1) advancing solutions with demonstrated efficacy in low-resource settings, (2) building on existing and emerging national priorities and (3) developing a strong network of domestic and international allies. Such actions help policy communities to weather political storms and take advantage of policy windows.
Demographic, environmental, access, and attitude factors that influence walking to school by elementary school-aged children.

BACKGROUND Walking to school has been identified as an activity that contributes to children's daily exercise requirements. The purpose of this study was to better understand factors that influence walking to school by elementary school-aged children. METHODS A sample of 1,897 elementary school-aged children (84% response rate; 3rd-5th graders) throughout Michigan completed the Michigan Safe Routes to School Student Survey. The survey measures environmental, access, and attitudinal perceptions toward school routes and transportation methods. RESULTS Using logistic regression, the results indicate that the odds of walking to school increase the older children are (odds ratio (OR) = 1.80, 95% confidence interval (CI) = 1.20-2.70) and if students perceive that walking to school saves time (OR = 3.32, 95% CI = 1.44-7.66) or is safe (OR = 2.60, 95% CI = 1.06-6.39). The odds of a student walking to school decrease the farther a student lives from his or her school (OR = 0.11, 95% CI = 0.04-0.37), if his or her parents have a car (OR = 0.07, 95% CI = 0.02-0.22), and if the student has access to a school bus (OR = 0.07, 95% CI = 0.03-0.18). These factors are significant (p < .05) predictors of walking to school after controlling for other demographic, environmental, access, and attitude factors. CONCLUSIONS The study results support research indicating that environmental and access factors influence whether elementary school-aged children walk to school. In addition, when children perceive walking to school to be convenient (ie, saves time), their odds of walking to school increase. Future school- and community-based programs promoting walking to school should continue to focus on making walking to school not only safer, but also more convenient.
The velocity‐related firing property of hippocampal place cells is dependent on self‐movement

Hippocampal place cells have the interesting property of increasing their firing rate when a freely moving animal increases its running speed through the cell's place field. A previous study from this laboratory showed that this movement‐related firing property is disrupted by lesions of the perirhinal cortex (PrhC). It is possible, therefore, that PrhC lesions disrupt speed‐modulated sensory information such as optic flow or motor efferent or proprioceptive input that might be available to the hippocampus from the PrhC. To test this hypothesis, rats with single unit recording electrodes implanted in the CA1 region of the hippocampus received different levels of optic flow stimulation in both a freely moving and a passive movement condition. The effects of PrhC lesions were also tested. Although increasing the amount of optic flow information available decreased place field size, it had no discernable effect on the movement‐firing rate relationship in the place cells of control animals run in the free‐movement condition. In lesioned animals the relationship was disrupted, replicating our previous results. In the passive movement condition many place cells stopped firing. In those cells that did fire, however, the movement‐firing rate relationship was no longer evident. These data indicate that the movement‐firing rate relationship is not driven by vestibular or optic flow cues, but rather depends on either motor efferent or proprioceptive input, or that it results from some other form of input that may be modulated by self‐motion, such as from the vibrissae. © 2009 Wiley‐Liss, Inc.