Miracle-dz/UniFAR-FTUs huggingface dataset:
Topoisomerase I inhibition with topotecan: pharmacologic and clinical issues

Topoisomerase I (topo-I) inhibitors are a new class of anticancer agents with a mechanism of action aimed at interrupting DNA replication in cancer cells, the result of which is cell death. Most, if not all, topo-I inhibitors are derivatives of the plant extract camptothecin. Topotecan is a derivative of camptothecin which has been structurally modified to increase water solubility. The pharmacokinetic profile of topotecan is usually characterised by a two-compartment model and is linear in the dose range of 0.5 - 3.5 mg/m2. Current clinical trials suggest antitumour activity against a variety of human tumour types, including ovarian cancer, non-small cell lung cancer (NSCLC) and non-lymphocytic haematologic malignancies. The main dose-limiting toxicity (DLT) is non-cumulative myelosuppression. Non-haematologic toxicities are usually mild. Based on several Phase I studies, the recommended Phase II dose was 1.5 mg/m2/day iv. for 5 days. Current Phase I and Phase II trials are evaluating the combination of topotecan with other chemotherapeutic agents to increase the therapeutic benefits of topotecan. The DLT in these trials is mainly myelosuppression.
Development and Validation of an Instrument to Measure Patient Satisfaction with Pharmacy Services

A research program was undertaken to develop and validate a multidimensional measure of patient satisfaction with pharmacy services. A self-administered questionnaire consisting of 44 Likert-type attitudinal items was adapted from the Patient Satisfaction Questionnaire developed by Ware et al. In an iterative scale development process, the adapted questionnaire and its revisions were evaluated in three successive studies conducted on convenience samples (n = 30,313,489) of individuals in attendance at family practice clinics in a southwestern city. Methods used to construct multi-item scales measuring separate dimensions of service included principal components factor analysis and item analyses. Acquiescent response set (ARS), the tendency to agree with statements of opinion regardless of content, was measured by the method of matched pairs of items. A partial correlation matrix which controlled for ARS was used as the data in a principal components factor analysis in an effort to reduce the biasing effect of ARS on factor analytic outcomes. Dimensions of satisfaction identified were Explanation, Consideration, Technical Competence, Financial Aspects, Accessibility, Drug Efficacy, OTC (over-the-counter) Product Availability, and Quality of the Drug Product. Questionnaire revision is suggested to confirm the validity of the latter two dimensions. Future research should examine the relationship between separate dimensions of satisfaction and other patient attitudes and behaviors, and the convergence between this instrument and other measures of patient satisfaction with pharmacy services.
Circulating tocopherols and risk of coronary artery disease: A systematic review and meta-analysis

Background Circulating level of tocopherols was supposed to be associated with risk of coronary artery disease. However, the results from previous studies remain controversial. Therefore, we conducted a meta-analysis based on observational studies to evaluate the association between circulating tocopherols and coronary artery disease risk for the first time. Design Meta-analysis. Methods PubMed, Embase and Cochrane databases were searched to retrieve articles published during January 1995 and May 2015. Articles were included if they provided sufficient information to calculate the weighted mean difference and its corresponding 95% confidence interval. Results Circulating level of total tocopherols was significantly lower in coronary artery disease patients than that in controls (weighted mean difference −4.33 μmol/l, 95% confidence interval −6.74 to −1.91, P < 0.01). However, circulating α-tocopherol alone was not significantly associated with coronary artery disease risk. Results from subgroup analyses showed that a lower level of circulating total tocopherols was merely associated with higher coronary artery disease risk in studies with higher sex ratio in cases (<2, weighted mean difference −0.07 μmol/l, 95% confidence interval −1.15 to 1.00, P = 0.90; ≥ 2, weighted mean difference −6.00 μmol/l, 95% confidence interval −9.76 to −2.22, P < 0.01). Similarly, a lower level of circulating total tocopherols was associated with early onset coronary artery disease rather than late onset coronary artery disease (<60 years, weighted mean difference −5.40 μmol/l, 95% confidence interval −9.22 to −1.57, P < 0.01; ≥ 60 years, weighted mean difference −1.37 μmol/l, 95% confidence interval −3.48 to 0.74, P = 0.20). We also found some discrepancies in circulating total tocopherols when the studies were stratified by matching status and assay methods. Conclusions Our findings suggest that a deficiency in circulating total tocopherols might be associated with higher coronary artery disease risk. Whereas circulating α-tocopherol alone could not protect us from developing coronary artery disease. Further prospective studies were warranted to confirm our findings.
Implementing High‐Performance Work Practices in Healthcare Organizations: Qualitative and Conceptual Evidence

Studies across industries suggest that the systematic use of high-performance work practices (HPWPs) may be an effective but underused strategy to improve quality of care in healthcare organizations. Optimal use of HPWPs depends on how they are implemented, yet we know little about their implementation in healthcare. We conducted 67 key informant interviews in five healthcare organizations, each considered to have exemplary work practices in place and to deliver high-quality care, as part of an extensive study of HPWP use in healthcare. We analyzed interview transcripts inductively and deductively to examine why and how organizations implement HPWPs. We used an evidence-based model of complex innovation adoption to guide our exploration of factors that facilitate HPWP implementation. We found considerable variability in interviewees' reasons for implementing HPWPs, including macro-organizational (strategic level) and micro-organizational (individual level) reasons. This variability highlighted the complex context for HPWP implementation in many organizations. We also found that our application of an innovation implementation model helped clarify and categorize facilitators of HPWP implementation, thus providing insight on how these factors can contribute to implementation effectiveness. Focusing efforts on clarifying definitions, building commitment, and ensuring consistency in the application of work practices may be particularly important elements of successful implementation.
Violent Video Game Effects Remain a Societal Concern: Reply to Hilgard, Engelhardt, and Rouder (2017)

A large meta-analysis by Anderson et al. (2010) found that violent video games increased aggressive thoughts, angry feelings, physiological arousal, and aggressive behavior and decreased empathic feelings and helping behavior. Hilgard, Engelhardt, and Rouder (2017) reanalyzed the data of Anderson et al. (2010) using newer publication bias methods (i.e., precision-effect test, precision-effect estimate with standard error, p-uniform, p-curve). Based on their reanalysis, Hilgard, Engelhardt, and Rouder concluded that experimental studies examining the effect of violent video games on aggressive affect and aggressive behavior may be contaminated by publication bias, and these effects are very small when corrected for publication bias. However, the newer methods Hilgard, Engelhardt, and Rouder used may not be the most appropriate. Because publication bias is a potential a problem in any scientific domain, we used a comprehensive sensitivity analysis battery to examine the influence of publication bias and outliers on the experimental effects reported by Anderson et al. We used best meta-analytic practices and the triangulation approach to locate the likely position of the true mean effect size estimates. Using this methodological approach, we found that the combined adverse effects of outliers and publication bias was less severe than what Hilgard, Engelhardt, and Rouder found for publication bias alone. Moreover, the obtained mean effects using recommended methods and practices were not very small in size. The results of the methods used by Hilgard, Engelhardt, and Rouder tended to not converge well with the results of the methods we used, indicating potentially poor performance. We therefore conclude that violent video game effects should remain a societal concern.
Microstructural Morphology in the Transition Region Between Scar and Intact Residual Segments of a Healing Rat Medial Collateral Ligament

This study used a rat model to investigate the microstructural organization of collagen through the transition from scar to intact residual segments of a healing medial collateral ligament (MCL). Twenty-two male retired breeder Sprague-Dawley rats were randomly separated into two groups. Eleven underwent surgical transections of both MCLs and were allowed unrestricted cage activity until euthanized two weeks post surgery. The remaining eleven rats were used as normal controls. All 44 MCLs were harvested including intact femoral and tibial insertions and prepared for scanning electron microscopy (SEM) imaging. At harvest the scar region in the healing ligaments was more translucent than the normal tissue. Ligaments were viewed from femoral to tibial insertions at magnifications of 100X through 20,000X. Tissue away from the scar region in the transected MCLs was indistinguishable from normal tissue in uninjured ligaments. Collagen fibers and fibrils in these tissues were more aligned along the longitudinal axis of the ligament than in the scar tissue. Continuity of collagen fibers and fibrils were consistently observed from the residual portions of the transected ligament through the scar region. Bifurcations/fusions, but no anastomoses, in fibers and fibrils were observed in both normal and scar tissues of ligaments. Qualitatively, bifurcations were encountered more frequently in scar tissue. In the transition region, larger diameter fibers from the residual tissue bifurcated into smaller diameter fibrils in the scar. This connection between larger diameter and smaller diameter fibers and fibrils indicates that bifurcations/fusions are likely to be the dominant way in which force is transmitted from a region with larger fibrils (residual ligament) into and through a region with smaller fibrils (scar).
Spread of methicillin-resistant Staphylococcus aureus between the community and the hospitals in Asian countries: an ANSORP study.

OBJECTIVES Methicillin-resistant Staphylococcus aureus (MRSA) is highly prevalent in hospitals in many Asian countries. Recent emergence of community-associated (CA) MRSA worldwide has added another serious concern to the epidemiology of S. aureus infections. To understand the changing epidemiology of S. aureus infections in Asian countries, we performed a prospective, multinational surveillance study with molecular typing analysis. METHODS We evaluated the prevalence of methicillin resistance in S. aureus isolates in CA and healthcare-associated (HA) infections, and performed molecular characterization and antimicrobial susceptibility tests of MRSA isolates. RESULTS MRSA accounted for 25.5% of CA S. aureus infections and 67.4% of HA infections. Predominant clones of CA-MRSA isolates were ST59-MRSA-SCCmec type IV-spa type t437, ST30-MRSA-SCCmec type IV-spa type t019 and ST72-MRSA-SCCmec type IV-spa type t324. Previously established nosocomial MRSA strains including sequence type (ST) 239 and ST5 clones were found among CA-MRSA isolates from patients without any risk factors for HA-MRSA infection. CA-MRSA clones such as ST59, ST30 and ST72 were also isolated from patients with HA infections. CONCLUSIONS Our findings confirmed that MRSA infections in the community have been increasing in Asian countries. Data also suggest that various MRSA clones have spread between the community and hospitals as well as between countries.
In Vitro and In Vivo Antiviral Activity and Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450

ABSTRACT The development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219- and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log10 was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11-602 is registered at ClinicalTrials.gov under registration no. NCT01074008.)
Expression of mRNA encoding insulin‐like growth factors I and II by uterine tissues and placenta during pregnancy in the rat

The uterus and the placenta synthesize insulin‐like growth factors (IGFs) and insulin‐like binding proteins (IGFBPs). These growth factors are implicated in processes of proliferation and differentiation that occur in the uterus. To determine the patterns of expression of IGFs during rat pregnancy we used in situ hybridization with digoxigenin labeled probes on uterus from day 7 to day 16 of pregnancy. In early gestation days (7–8) both IGF mRNAs showed similar tissue distribution with relative abundance in the stroma and circular muscle layer. On days 11 and 12 expression for IGF‐I mRNA was found in the mesometrial decidua and metrial gland and in the ectoplacental cone while clear expression of IGF‐II mRNA could only be found in the latter. On days 13 and 14, expression for IGF‐I mRNA could be detected in the mesometrial decidua and metrial gland but no expression was observed for IGF‐II mRNA. A gradient of IGF‐I mRNA expression could be observed in the placenta on day 16, with the trophoblastic cells of the basal zone expressing the signal with stronger intensity than in the labyrinthine zone. For IGF‐II mRNA the highest expression was associated with the labyrinthine zone. Endovascular trophoblast was positive for both mRNAs. The spatial and temporal patterns of expression suggests a role for IGFs in the process of decidualization as well as in the establishment, growth and differentiation of the various trophoblast cells of the placenta. Mol. Reprod. Dev. 53:294–305, 1999. © 1999 Wiley‐Liss, Inc.
Effect of Irradiation on Mating Ability in the Male Sweetpotato Weevil (Coleoptera: Curculionidae)

Abstract The sterile insect technique (SIT) is widely used for suppressing or eradicating target pest insect populations. The effectiveness of SIT depends on the ability of released sterile males to mate with and inseminate wild females. Irradiation is the effective manner to sterilize mass-reared insects. The negative impacts of this procedure are not limited to damage on reproductive cells. Gamma-radiation damages the epithelial tissue of midgut, which affects the alimentation in insects. Irradiated males alter their mating behavior over time because of the depression of metabolic activity by sterilization. In this study, we evaluated the male mating performance and sexually compatibility of irradiated male Cylas formicarius elegantulus (Summers) (Coleoptera: Curculionidae) with a 200-Gy dose, as currently used in the SIT program in Okinawa Prefecture, throughout 16 d after irradiation in the laboratory. The mating ability of irradiated males did not differ from that of control males for about a week. However, the mating ability of irradiated male drastically decreased thereafter. We consider that irradiated male C. formicarius elegantulus with a 200-Gy dose had no major effect on male mating behavior approximately for a week after irradiation.
Complex organic molecules in comets C/2012 F6 (Lemmon) and C/2013 R1 (Lovejoy): detection of ethylene glycol and formamide

A spectral survey in the 1 mm wavelength range was undertaken in the long-period comets C/2012 F6 (Lemmon) and C/2013 R1 (Lovejoy) using the 30 m telescope of the Institut de radioastronomie millimetrique (IRAM) in April and November−December 2013. We report the detection of ethylene glycol (CH_2OH)_2 (aGg’ conformer) and formamide (NH_2CHO) in the two comets. The abundances relative to water of ethylene glycol and formamide are 0.2–0.3% and 0.02% in the two comets, similar to the values measured in comet C/1995 O1 (Hale-Bopp). We also report the detection of HCOOH and CH_3CHO in comet C/2013 R1 (Lovejoy), and a search for other complex species (methyl formate, glycolaldehyde).
Factors associated with pressure ulcers in patients with complete or sensory-only preserved spinal cord injury: is there any difference between traumatic and nontraumatic causes?

OBJECT Pressure ulcers (PUs) are common complications in patients with complete spinal cord injury (SCI) or incomplete SCI in which sensory function is spared. Most studies analyzing associated factors of PU and SCI have been performed in cases of traumatic SCI and in just a few cases of nontraumatic SCI. This study was designed to look specifically at the differences in causative factors of PU in cases of traumatic and nontraumatic SCIs. METHODS The authors performed a retrospective, cross-sectional study evaluating patients with complete and incomplete SCIs (American Spinal Injury Association Grades A and B) under the coverage of the financial, medicosocial, and rehabilitative support provided by the State Welfare Organization of Iran (SWOI). There were 3791 cases of traumatic SCI (63.2%) and 2110 cases of nontraumatic SCI (35.2%). For 94 patients (1.6%), sufficient data were not available. RESULTS A PU was detected in 39.2% of all patients with an SCI (71.8% of those with traumatic SCI vs 28.2% of those with nontraumatic SCI). A univariate analysis showed a significant association between occupation, education, and the presence of PU in patients with a traumatic SCI (p < 0.05). This contrasted with nontraumatic SCI in which an association between PU and age was noted (p < 0.05). Using logistic regression, traumatic cause, older age, an interval less than 1 year since the onset of SCI, male sex, and single status were found to significantly increase the risk of PU in all patients with an SCI. However, a higher education level had a preventive effect on PU. CONCLUSIONS This study revealed some risk factors for PU in the authors' setting. The authors' findings suggest a possible difference between the risk factors for PU in patients with both types of SCI. Further study on the pathoetiology of these differences is paramount in the future.
Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment A Pilot Clinical Trial

Objective : To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD). DiseaseCooperativeStudy–activitiesofdailyliving(ADCS-ADL)scale.Asubsetofparticipantsunderwentlumbar Results : Outcomemeasureswereanalyzedusingrepeated-measures 20 IU of in most cases. Our study examines the effects of longer-term insulin administration on primary outcome measures determined from the 3-week trial and on measures of global cognition and function used in traditional clinical trials in adults with aMCI or AD. In a subset of participants, we also examined changes in CSF-related AD biomarkers (A (cid:3) 42 level and tau protein–to–A (cid:3) 42 ratio) and changes in the cerebral metabolic rate of glucose (CMRGlc) utilization assessed by use of positron emission tomography (PET) with fludeoxyglucose F 18 (FDG). Our results showed that the administration of intranasal insulin stabilized or improved cognition and function and preserved CMRGlc in regions affected by AD.
DUAL-ENERGY X-RAY ABSORPTIOMETRY AND CALCULATED FRAX RISK SCORES MAY UNDERESTIMATE OSTEOPOROTIC FRACTURE RISK IN VITAMIN D-DEFICIENT VETERANS WITH HIV INFECTION.

OBJECTIVE We evaluated the utility of the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX) in assessing fracture risk in patients with human immunodeficiency virus (HIV) and vitamin D deficiency. METHODS This was a retrospective study of HIV-infected patients with co-existing vitamin D deficiency at the Atlanta Veterans Affairs Medical Center. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry (DEXA), and the 10-year fracture risk was calculated by the WHO FRAX algorithm. Two independent radiologists reviewed lateral chest radiographs for the presence of subclinical vertebral fractures. RESULTS We identified 232 patients with HIV and vitamin D deficiency. Overall, 15.5% of patients met diagnostic criteria for osteoporosis on DEXA, and 58% had low BMD (T-score between -1 and -2.5). The median risk of any major osteoporotic and hip fracture by FRAX score was 1.45 and 0.10%, respectively. Subclinical vertebral fractures were detected in 46.6% of patients. Compared to those without fractures, those with fractures had similar prevalence of osteoporosis (15.3% versus 15.7%; P>.999), low BMD (53.2% versus 59.3%; P = .419), and similar FRAX hip scores (0.10% versus 0.10%; P = .412). While the FRAX major score was lower in the nonfracture group versus fracture group (1.30% versus 1.60%; P = .025), this was not clinically significant. CONCLUSION We found a high prevalence of subclinical vertebral fractures among vitamin D-deficient HIV patients; however, DEXA and FRAX failed to predict those with fractures. Our results suggest that traditional screening tools for fragility fractures may not be applicable to this high-risk patient population.
Absence of Tobramycin Pharmacokinetic and Creatinine Clearance Variation During the Menstrual Cycle: Implied Absence of Variation in Glomerular Filtration Rate

During the menstrual cycle, a 20% increase in creatinine clearance (CLCR) has previously been reported between the menstrual (phase 1) and late luteal (phase 4) phases. Tobramycin pharmacokinetics and CLCR were studied in eight healthy women with documented, regular, ovulatory menses. During the first and fourth phases of the menstrual cycle (as determined by urinary luteinizing hormone peak and basal body temperature shift), subjects received tobramycin by intravenous bolus. Tobramycin half‐life, total body clearance, and volume of distribution were not significantly different between the two study phases. No significant change in total urinary creatinine excretion or CLCR was seen between phases. Total 24 hour urinary recovery of tobramycin was 98–99.7%. We conclude that no significant changes in renal function, as evaluated by tobramycin pharmacokinetics and CLCR, occur between these hormonally different phases of the menstrual cycle, and that urinary recovery of a single dose of tobramycin is nearly complete within 24 hours in premenopausal women with normal renal function.