bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined Bioinformatic and Rational Design Approach To Develop Antimicrobial Peptides against Mycobacterium tuberculosis
Authors: Pearson C. Seth , Kloos Zachary , Murray Brian , Tabe Ebot , Gupta Monica , Kwak Jun Ha , Karande Pankaj , McDonough Kathleen A. , Belfort Georges 
Published: February 2016

ABSTRACT

Drug-resistant pathogens are a growing problem, and novel strategies are needed to combat this threat. Among the most significant of these resistant pathogens is
Mycobacterium tuberculosis
, which is an unusually difficult microbial target due to its complex membrane. Here, we design peptides for specific activity against
M. tuberculosis
using a combination of “database filtering” bioinformatics, protein engineering, and
de novo
design. Several variants of these peptides are structurally characterized to validate the design process. The designed peptides exhibit potent activity (MIC values as low as 4 μM) against
M. tuberculosis
and also exhibit broad activity against a host of other clinically relevant pathogenic bacteria such as Gram-positive bacteria (
Streptococcus
) and Gram-negative bacteria (
Escherichia coli
). They also display excellent selectivity, with low cytotoxicity against cultured macrophages and lung epithelial cells. These first-generation antimicrobial peptides serve as a platform for the design of antibiotics and for investigating structure-activity relationships in the context of the
M. tuberculosis
membrane. The antimicrobial peptide design strategy is expected to be generalizable for any pathogen for which an activity database can be created.
Transmission-Blocking Potential of MEFAS, a Hybrid Compound Derived from Artesunate and Mefloquine
Authors: Penna-Coutinho Julia , Almela Maria Jesús , Miguel-Blanco Celia , Herreros Esperanza , Sá Paula M. , Boechat Núbia , Krettli Antoniana Ursine 
Published: February 2016

ABSTRACT

Most antimalarial drugs target asexual parasites without reducing gametocyte formation or development. Drugs with dual roles, i.e., those that can target both asexual parasites and gametocytes, would improve the control of malaria. In the current study, MEFAS, a hybrid drug derived from mefloquine and artesunate that has been shown to be an active blood schizonticidal drug, was assessed to determine its ability to block the infectivity of
Plasmodium falciparum
gametocytes. MEFAS was 280 and 15 times more effective than mefloquine alone and artesunate alone, respectively.
HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition
Authors: Kis Olena , Sankaran-Walters Sumathi , Hoque M. Tozammel , Walmsley Sharon L. , Dandekar Satya , Bendayan Reina 
Published: February 2016

ABSTRACT

This study investigated the effects of HIV-1 infection and antiretroviral therapy (ART) on the expression of intestinal drug efflux transporters, i.e., P-glycoprotein (Pgp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP), and metabolic enzymes, such as cytochrome P450s (CYPs), in the human upper intestinal tract. Intestinal biopsy specimens were obtained from HIV-negative healthy volunteers, ART-naive HIV-positive (HIV
+
) subjects, and HIV
+
subjects receiving ART (10 in each group). Intestinal tissue expression of drug transporters and metabolic enzymes was examined by microarray, real-time quantitative reverse transcription-PCR (qPCR), and immunohistochemistry analyses. Microarray analysis demonstrated significantly lower expression of
CYP3A4
and
ABCC2
/MRP2 in the HIV
+
ART-naive group than in uninfected subjects. qPCR analysis confirmed significantly lower expression of
ABCC2
/MRP2 in ART-naive subjects than in the control group, while
CYP3A4
and
ABCG2
/BCRP showed a trend toward decreased expression. Protein expression of MRP2 and BCRP was also significantly lower in the HIV
+
naive group than in the control group and was partially restored to baseline levels in HIV
+
subjects receiving ART. In contrast, gene and protein expression of
ABCB1
/Pgp was significantly increased in HIV
+
subjects on ART relative to HIV
+
ART-naive subjects. These data demonstrate that the expression of drug-metabolizing enzymes and efflux transporters is significantly altered in therapy-naive HIV
+
subjects and in those receiving ART. Since CYP3A4, Pgp, MRPs, and BCRP metabolize or transport many antiretroviral drugs, their altered expression with HIV infection may negatively impact drug pharmacokinetics in HIV
+
subjects. This has clinical implications when using data from healthy volunteers to guide ART.
An Open, Randomized, Single-Center, Crossover Pharmacokinetic Study of Meropenem after Intraperitoneal and Intravenous Administration in Patients Receiving Automated Peritoneal Dialysis
Authors: Wiesholzer Martin , Pichler Petra , Reznicek Gottfried , Wimmer Michaela , Kussmann Manuel , Balcke Peter , Burgmann Heinz , Zeitlinger Markus , Poeppl Wolfgang 
Published: February 2016

ABSTRACT

The objective of this study was to determine the pharmacokinetic profile of meropenem in automated peritoneal dialysis (APD) patients. In 6 patients without peritonitis, a single dose of 0.5 g of meropenem was applied intraperitoneally (i.p.) or intravenously (i.v.) and concentrations in serum and dialysate were measured at specified intervals over 24 h with high-performance liquid chromatography-mass spectrometry. The mean maximum concentrations of meropenem in serum (
C
max
) were 27.2 mg/liter (standard deviation [SD], ±6.9) and 10.1 mg/liter (SD, ±2.5) and in dialysate were 3.6 mg/liter (SD, ±2.3) and 185.8 mg/liter (SD, ±18.7) after i.v. and i.p. administrations, respectively. The mean areas under the curve from 0 to 24 (AUC
0–24
) of meropenem in serum were 173.5 mg · h/liter (SD, ±29.7) and 141.4 mg · h/liter (SD, ±37.5) (
P
= 0.046) and in dialysate were 42.6 mg · h/liter (SD, ±20.0) and 623.4 mg · h/liter (SD, ±84.1) (
P
= 0.028) after i.v. and i.p. administrations, respectively. The ratios for dialysate exposure over plasma exposure after i.v. and i.p. treatments were 0.2 (SD, ±0.1) and 4.6 (SD, ±0.9), respectively (
P
= 0.031). A mean target value of 40%
T
>MIC (time for which the free meropenem concentration exceeds the MIC) for clinically relevant pathogens with EUCAST susceptibility breakpoints of 2 mg/liter was reached in serum after i.p. and i.v. administrations and in dialysate after i.p. but not after i.v. administration. The present data indicate that low i.p. exposure limits the i.v. use of meropenem for PD-associated peritonitis. In contrast, i.p. administration not only results in superior concentrations in dialysate but also might be used to treat systemic infections.
The Protease Locus of Francisella tularensis LVS Is Required for Stress Tolerance and Infection in the Mammalian Host
Authors: He Lihong , Nair Manoj Kumar Mohan , Chen Yuling , Liu Xue , Zhang Mengyun , Hazlett Karsten R. O. , Deng Haiteng , Zhang Jing-Ren 
Published: February 2016

ABSTRACT

Francisella tularensis
is the causative agent of tularemia and a category A potential agent of bioterrorism, but the pathogenic mechanisms of
F. tularensis
are largely unknown. Our previous transposon mutagenesis screen identified 95 lung infectivity-associated
F. tularensis
genes, including those encoding the Lon and ClpP proteases. The present study validates the importance of Lon and ClpP in intramacrophage growth and infection of the mammalian host by using unmarked deletion mutants of the
F. tularensis
live vaccine strain (LVS). Further experiments revealed that
lon
and
clpP
are also required for
F. tularensis
tolerance to stressful conditions. A quantitative proteomic comparison between heat-stressed LVS and the isogenic Lon-deficient mutant identified 29 putative Lon substrate proteins. The follow-up protein degradation experiments identified five substrates of the
F. tularensis
Lon protease (FTL578, FTL663, FTL1217, FTL1228, and FTL1957). FTL578 (ornithine cyclodeaminase), FTL663 (heat shock protein), and FTL1228 (iron-sulfur activator complex subunit SufD) have been previously described as virulence-associated factors in
F. tularensis
. Identification of these Lon substrates has thus provided important clues for further understanding of the
F. tularensis
stress response and pathogenesis. The high-throughput approach developed in this study can be used for systematic identification of the Lon substrates in other prokaryotic and eukaryotic organisms.
International recommendations for national patient safety incident reporting systems: an expert Delphi consensus-building process
Authors: Howell Ann-Marie , Burns Elaine M , Hull Louise , Mayer Erik , Sevdalis Nick , Darzi Ara 
Published: February 2016

BackgroundPatient safety incident reporting systems (PSRS) have been established for over a decade, but uncertainty remains regarding the role that they can and ought to play in quantifying healthcare-related harm and improving care.ObjectiveTo establish international, expert consensus on the purpose of PSRS regarding monitoring and learning from incidents and developing recommendations for their future role.MethodsAfter a scoping review of the literature, semi-structured interviews with experts in PSRS were conducted. Based on these findings, a survey-based questionnaire was developed and subsequently completed by a larger expert panel. Using a Delphi approach, consensus was reached regarding the ideal role of PSRSs. Recommendations for best practice were devised.ResultsForty recommendations emerged from the Delphi procedure on the role and use of PSRS. Experts agreed reporting system should not be used as an epidemiological tool to monitor the rate of harm over time or to appraise the relative safety of hospitals. They agreed reporting is a valuable mechanism for identifying organisational safety needs. The benefit of a national system was clear with respect to medication error, device failures, hospital-acquired infections and never events as these problems often require solutions at a national level. Experts recommended training for senior healthcare professionals in incident investigation. Consensus recommendation was for hospitals to take responsibility for creating safety solutions locally that could be shared nationally.ConclusionsWe obtained reasonable consensus among experts on aims and specifications of PSRS. This information can be used to reflect on existing and future PSRS, and their role within the wider patient safety landscape. The role of PSRS as instruments for learning needs to be elaborated and developed further internationally.
Self-reported preparedness for clinical work has increased among recent cohorts of UK-trained first-year doctors
Authors: Lachish Shelly , Goldacre Michael J , Lambert Trevor 
Published: February 2016

AbstractIntroductionUK medical schools have made considerable efforts to ensure that graduates are well prepared for their first year of clinical work. We report the views of two recent cohorts of UK-trained doctors 1 year after graduation about whether their medical school prepared them well, and compare responses with earlier cohorts.MethodsWe surveyed doctors who qualified in 2011 and 2012 from all UK medical schools. We obtained their responses to the statement ‘My experience at medical school prepared me well for the jobs I have undertaken so far’ on a 5-point scale from ‘Strongly Agree’ to ‘Strongly Disagree’. Responses were compared with those of the UK graduates of 1999, 2000, 2002, 2005, 2008 and 2009, surveyed in the same way 1 year after graduation.ResultsThe percentage of doctors who either ‘Agreed’ or ‘Strongly Agreed’ that they were well prepared doubled from 35% in 1999 to 70% in 2012, while the percentage who ‘Strongly Agreed’ with the statement increased fourfold. Perceptions of being well prepared have increased in graduates from almost every medical school. Variation between medical schools in self-reported preparedness of their graduates has decreased in recent cohorts. However, some large differences between medical schools remain. Significant differences in perceived preparedness remain between white and non-white doctors, but have diminished between men and women.ConclusionsOur work contributes to growing evidence suggesting that changes to medical education in the UK are producing doctors who feel well prepared for the challenges of being a doctor, though further improvements could be made.
Temporal bone partial ostectomy via the temporomandibular joint to treat osteosarcoma of the caudal zygoma in a three‐year‐old Labrador retriever
Authors: Dean Barnaby Luke , Nicholson Ian 
Published: February 2016

A three years, seven‐month‐old male entire Labrador retriever was referred with a one‐month history of pain when yawning and eating. CT revealed a 20×10×10 mm mass in the region of the left caudal zygoma. CT‐guided biopsy results identified a florid periosteal reaction but were otherwise inconclusive. Surgery was performed to resect the left caudal zygoma via the temporomandibular joint. Further histopathological results confirmed completely resected osteogenic osteosarcoma with narrow margins. No other treatment modalities were pursued. The dog remained free from clinical signs until 28 months following surgery when local tumour growth and thoracic metastases were diagnosed.
Sex Differences in the Incidence of Peripheral Artery Disease in the Chronic Renal Insufficiency Cohort
Authors: Wang Grace J. , Shaw Pamela A. , Townsend Raymond R. , Anderson Amanda H. , Xie Dawei , Wang Xue , Nessel Lisa C. , Mohler Emile R. , Sozio Stephen M. , Jaar Bernard G. , Chen Jing , Wright Jackson , Taliercio Jonathan J. , Ojo Akinlolu , Ricardo Ana C. , Lustigova Eva , Fairman Ronald M. , Feldman Harold I. , Ky Bonnie 
Published: February 2016

Background—
To define how the incidence of peripheral artery disease (PAD) in chronic kidney disease differs according to sex and age.

Methods and Results—

The Chronic Renal Insufficiency Cohort (CRIC) is a multicenter, prospective cohort study of chronic kidney disease participants. Fine and Gray methods were used to determine the cumulative incidence of PAD, defined by an ankle brachial index <0.90 or a confirmed PAD event, with death as a competing event. Adjusted subdistribution hazard ratios from the Fine and Gray model determined the risk of PAD according to sex. A priori, we hypothesized that the relationship between sex and cumulative incidence of PAD differed according to age. The mean age of the 3174 participants in this study was 56.6 years and consisted of 55% males. During a median follow-up of 5.9 years, 17.8% developed PAD, 13.0% were lost to follow-up and 11.1% died. Females had a 1.53-fold greater adjusted PAD risk compared with males (95% confidence interval, 1.27–1.84;
P
<0.001). These sex-related differences in PAD risk also differed by age (
P
=0.013). Women, compared with men were at a markedly increased risk for PAD at younger ages; however, at ages >70 years, the risk was similar across both the sexes. Older men had a substantially greater PAD risk compared with younger men. In women, PAD risk did not vary with age.

Conclusions—
Females with chronic kidney disease have a higher PAD risk compared with males at younger ages. There is an important need to improve our understanding of the biological and clinical basis for these differences.
Sex Differences in Outcomes Following Percutaneous Coronary Intervention According to Age
Authors: Epps Kelly C. , Holper Elizabeth M. , Selzer Faith , Vlachos Helen A. , Gualano Sarah K. , Abbott J. Dawn , Jacobs Alice K. , Marroquin Oscar C. , Naidu Srihari S. , Groeneveld Peter W. , Wilensky Robert L. 
Published: February 2016

Background—
Women <50 years of age with coronary artery disease may represent a group at higher risk for recurrent ischemic events after percutaneous coronary intervention (PCI); however, no long-term, multicenter outcomes assessment exists in this population.

Methods and Results—

Using the National Heart, Lung, and Blood Institute Dynamic Registry, we evaluated the association of sex and age on cardiovascular-related outcomes in10 963 patients (3797 women, 394 <50 years) undergoing PCI and followed for 5 years. Death, myocardial infarction, coronary artery bypass graft surgery, and repeat PCI were primary outcomes comprising major adverse cardiovascular events. Although procedural success rates were similar by sex, the cumulative rate of major adverse cardiovascular events at 1 year was higher in young women (27.8 versus 19.9%;
P
=0.003), driven largely by higher rates of repeat revascularizations for target vessel or target lesion failure (coronary artery bypass graft surgery: 8.9% versus 3.9%,
P
<0.001, adjusted hazard ratio 2.4, 95% confidence interval 1.5–4.0; PCI: 19.0% versus 13.0%,
P
=0.005, adjusted hazard ratio 1.6, 95% confidence interval 1.2–2.2). At 5 years, young women remained at higher risk for repeat procedures (coronary artery bypass graft surgery: 10.7% versus 6.8%,
P
=0.04, adjusted hazard ratio 1.71, 95% confidence interval 1.01–2.88; repeat PCI [target vessel]: 19.7% versus 11.8%,
P
=0.002, adjusted hazard ratio 1.8, 95% confidence interval 1.24–2.82). Compared with older women, younger women remained at increased risk of major adverse cardiovascular events, whereas all outcome rates were similar in older women and men.

Conclusions—
Young women, despite having less severe angiographic coronary artery disease, have an increased risk of target vessel and target lesion failure. The causes of this difference deserve further investigation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00005677.
Sex and Ethnic Differences in Outcomes of Acute Coronary Syndrome and Stable Angina Patients With Obstructive Coronary Artery Disease
Authors: Izadnegahdar Mona , Mackay Martha , Lee May K. , Sedlak Tara L. , Gao Min , Bairey Merz C. Noel , Humphries Karin H. 
Published: February 2016

Background—
The joint contribution of sex, ethnicity, and initial clinical presentation to the long-term outcomes of patients undergoing coronary angiography for acute coronary syndrome (ACS) or stable angina, in whom there is angiographic evidence for obstructive coronary artery disease, remains unknown.

Methods and Results—

We conducted a population-based cohort study on 49 556 adult ACS or stable angina patients with angiographic evidence of obstructive coronary artery disease (≥50% stenosis) in British Columbia. The 2-year composite outcome was all-cause death and hospital readmissions for myocardial infarction, heart failure, cerebrovascular accident, or angina after the index angiography. Sex and ethnic differences in the composite outcome were examined by clinical presentation using the Cox proportional-hazards and logistic regression models. Overall, 25.6% were women, 9.5% were South Asians, 3.0% were Chinese, and 65.9% presented with ACS. Regardless of ethnicity, women were more likely than men to have adverse outcomes, but the magnitude of the sex difference was greater in the ACS patients (
P
interaction
for sex and clinical presentation=0.03). Angina readmission accounted for 45% of the composite outcome and was the main component for all groups with the exception of Chinese women with ACS. Furthermore, women were more likely than men to be readmitted for angina (odds ratio [95% confidence interval], 1.13 [1.04–1.22]).

Conclusions—
Higher rates of adverse events among women with obstructive coronary artery disease, regardless of ethnicity, as well as high rates of angina readmission, highlight the need for more targeted interventions to reduce the burden of angina because this presentation is clearly not benign.
Sex Differences in Clinical Profiles and Quality of Care Among Patients With ST‐Segment Elevation Myocardial Infarction From 2001 to 2011: Insights From the China Patient‐Centered Evaluative Assessment of Cardiac Events (PEACE)‐Retrospective Study
Authors: Du Xue , Spatz Erica S. , Dreyer Rachel P. , Hu Shuang , Wu Chaoqun , Li Xi , Li Jing , Wang Sisi , Masoudi Frederick A. , Spertus John A. , Nasir Khurram , Krumholz Harlan M. , Jiang Lixin ,   for the China PEACE Collaborative Group
Published: February 2016

Background

China is experiencing a marked increase in
ST
‐segment elevation myocardial infarction hospitalizations, with 30% occurring among women and higher risk of in‐hospital death in relatively younger age groups (<70). Yet, little is known about sex differences in
ST
‐segment elevation myocardial infarction presentation and management.

Methods and Results

In a nationally representative sample of patients with
ST
‐segment elevation myocardial infarction admitted to 162 Chinese hospitals in 2001, 2006, and 2011, we examined sex differences in hospitalization rates, clinical profiles, and quality of care. Among 11 986 patients, the proportion of women was unchanged between 2001 and 2011. The estimated national rates of hospital admission per 100 000 people increased from 4.6 in 2001 to 18.0 in 2011 among men (3.9‐fold increase) and from 1.9 to 8.0 among women (4.2‐fold increase) (
P
trend
<0.0001). The median age of women increased from 68 years in 2001 to 72 years in 2011 (
P
trend
<0.001); however, there was no age change in men (63 years in 2011) (
P
trend
=0.48). After accounting for age, women had a higher frequency of comorbidities. Although there were significant sex differences in the time interval of >12 hours between symptom onset and admission time in 2001, since 2006 delays in presentation were comparable between women and men. Fewer women without contraindications received evidence‐based therapies than men, including reperfusion (57.5% versus 44.2%), early aspirin (88.8% versus 85.9%), and clopidogrel (56.9% versus 52.5%,
P
<0.001 for all) and the differences were largely unchanged over time.

Conclusions

Women experienced a higher increase in hospitalization rates for
ST
‐segment elevation myocardial infarction in China between 2001 and 2011 and were less likely to receive evidence‐based therapies, especially reperfusion. In addition to efforts to improve quality of care generally, understanding the reasons for this sex disparity and addressing these differences in care should be a priority.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
01624883.