bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety, Tolerability, and Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Pediatric Patients
Authors: Seibel Nita L. , Shad Aziza T. , Bekersky Ihor , Groll Andreas H. , Gonzalez Corina , Wood Lauren V. , Jarosinski Paul , Buell Donald , Hope William W. , Walsh Thomas J. 
Published: November 2016

ABSTRACTThe safety, tolerability, and pharmacokinetics of the liposomal formulation of amphotericin B (L-AMB) were evaluated in 40 immunocompromised children and adolescents. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study with 10 to 13 patients in each of the four dosage cohorts. Each cohort received daily dosages of 2.5, 5.0, 7.5, or 10 mg of amphotericin B in the form of L-AMB per kg of body weight. Neutropenic patients between the ages of 1 and 17 years were enrolled to receive empirical antifungal therapy or treatment of documented invasive fungal infections. The pharmacokinetic parameters of L-AMB were measured as those of amphotericin B by high-performance liquid chromatography and calculated by noncompartmental methods. There were nine adverse-event-related discontinuations, four of which were related to infusions. Infusion-related side effects occurred for 63 (11%) of 565 infusions, with 5 patients experiencing acute infusion-related reactions (7.5- and 10-mg/kg dosage levels). Serum creatinine levels increased from 0.45 ± 0.04 mg/dl to 0.63 ± 0.06 mg/dl in the overall population (P= 0.003), with significant increases in dosage cohorts receiving 5.0 and 10 mg/kg/day. At the higher dosage level of 10 mg/kg, there was a trend toward greater hypokalemia and vomiting. The area under the concentration-time curve from 0 to 24 h (AUC0–24) values for L-AMB on day 1 increased from 54.7 ± 32.9 to 430 ± 566 μg · h/ml in patients receiving 2.5 and 10.0 mg/kg/day, respectively. These findings demonstrate that L-AMB can be administered to pediatric patients at dosages similar to those for adults and that azotemia may develop, especially in those receiving ≥5.0 mg/kg/day.
Long-Chain Fatty Acyl Coenzyme A Ligase FadD2 Mediates Intrinsic Pyrazinamide Resistance in Mycobacterium tuberculosis
Authors: Rosen Brandon C. , Dillon Nicholas A. , Peterson Nicholas D. , Minato Yusuke , Baughn Anthony D. 
Published: November 2016

ABSTRACT

Pyrazinamide (PZA) is a first-line tuberculosis (TB) drug that has been in clinical use for 60 years yet still has an unresolved mechanism of action. Based upon the observation that the minimum concentration of PZA required to inhibit the growth of
Mycobacterium tuberculosis
is approximately 1,000-fold higher than that of other first-line drugs, we hypothesized that
M. tuberculosis
expresses factors that mediate intrinsic resistance to PZA. To identify genes associated with intrinsic PZA resistance, a library of transposon-mutagenized
Mycobacterium bovis
BCG strains was screened for strains showing hypersusceptibility to the active form of PZA, pyrazinoic acid (POA). Disruption of the long-chain fatty acyl coenzyme A (CoA) ligase FadD2 enhanced POA susceptibility by 16-fold on agar medium, and the wild-type level of susceptibility was restored upon expression of
fadD2
from an integrating mycobacterial vector. Consistent with the recent observation that POA perturbs mycobacterial CoA metabolism, the
fadD2
mutant strain was more vulnerable to POA-mediated CoA depletion than the wild-type strain. Ectopic expression of the
M. tuberculosis
pyrazinamidase PncA, necessary for conversion of PZA to POA, in the
fadD2
transposon insertion mutant conferred at least a 16-fold increase in PZA susceptibility under active growth conditions in liquid culture at neutral pH. Importantly, deletion of
fadD2
in
M. tuberculosis
strain H37Rv also resulted in enhanced susceptibility to POA. These results indicate that FadD2 is associated with intrinsic PZA and POA resistance and provide a proof of concept for the target-based potentiation of PZA activity in
M. tuberculosis
.
Prevalence of
mcr-1
in the Cecal Contents of Food Animals in the United States
Authors: Meinersmann Richard J. , Ladely Scott R. , Plumblee Jodie R. , Cook Kimberly L. , Thacker Eileen 
Published: November 2016

ABSTRACT

A survey of 2,003 cecal content samples from chickens, turkeys, cattle, and swine at slaughter facilities in the United States was conducted to estimate the prevalence of the
mcr-1
gene conferring resistance to colistin in
Enterobacteriaceae
. Two cecal samples from swine had
Escherichia coli
with IncI2 plasmids bearing the
mcr-1
gene.
Modulation of Pertussis and Adenylate Cyclase Toxins by Sigma Factor RpoE in Bordetella pertussis
Authors: Barbier Mariette , Boehm Dylan T. , Sen-Kilic Emel , Bonnin Claire , Pinheiro Theo , Hoffman Casey , Gray Mary , Hewlett Erik , Damron F. Heath 
Published: November 2016

ABSTRACT

Bordetella pertussis
is a human pathogen that can infect the respiratory tract and cause the disease known as whooping cough.
B. pertussis
uses pertussis toxin (PT) and adenylate cyclase toxin (ACT) to kill and modulate host cells to allow the pathogen to survive and persist.
B. pertussis
encodes many uncharacterized transcription factors, and very little is known about their functions. RpoE is a sigma factor which, in other bacteria, responds to oxidative, heat, and other environmental stresses. RseA is a negative regulator of RpoE that sequesters the sigma factor to regulate gene expression based on conditions. In
B. pertussis
, deletion of the
rseA
gene results in high transcriptional activity of RpoE and large amounts of secretion of ACT. By comparing parental
B. pertussis
to an
rseA
gene deletion mutant (PM18), we sought to characterize the roles of RpoE in virulence and determine the regulon of genes controlled by RpoE. Despite high expression of ACT, the
rseA
mutant strain did not infect the murine airway as efficiently as the parental strain and PM18 was killed more readily when inside phagocytes. RNA sequencing analysis was performed and 263 genes were differentially regulated by RpoE, and surprisingly, the
rseA
mutant strain where RpoE activity was elevated expressed very little pertussis toxin. Western blots and proteomic analysis corroborated the inverse relationship of PT to ACT expression in the high-RpoE-activity
rseA
deletion strain. Our data suggest that RpoE can modulate PT and ACT expression indirectly through unidentified mechanisms in response to conditions.
Calcium Enhances Bile Salt-Dependent Virulence Activation in Vibrio cholerae
Authors: Hay Amanda J. , Yang Menghua , Xia Xiaoyun , Liu Zhi , Hammons Justin , Fenical William , Zhu Jun 
Published: November 2016

ABSTRACT

Vibrio cholerae
is the causative bacteria of the diarrheal disease cholera, but it also persists in aquatic environments, where it displays an expression profile that is distinct from that during infection. Upon entry into the host, a tightly regulated circuit coordinates the induction of two major virulence factors: cholera toxin and a toxin-coregulated pilus (TCP). It has been shown that a set of bile salts, including taurocholate, serve as host signals to activate
V. cholerae
virulence through inducing the activity of the transmembrane virulence regulator TcpP. In this study, we investigated the role of calcium, an abundant mental ion in the gut, in the regulation of virulence. We show that whereas Ca
2+
alone does not affect virulence, Ca
2+
enhances bile salt-dependent virulence activation for
V. cholerae
. The induction of TCP by murine intestinal contents is counteracted when Ca
2+
is depleted by the high-affinity calcium chelator EGTA, suggesting that the calcium present in the gut is a relevant signal for
V. cholerae
virulence induction
in vivo
. We further show that Ca
2+
enhances virulence by promoting bile salt-induced TcpP-TcpP interaction. Moreover, fluorescence recovery after photobleaching (FRAP) analysis demonstrated that exposure to bile salts and Ca
2+
together decreases the recovery rate for fluorescently labeled TcpP, but not for another inner membrane protein (TatA). Together, these data support a model in which physiological levels of Ca
2+
may result in altered bile salt-induced TcpP protein movement and activity, ultimately leading to an increased expression of virulence.
Contribution of Asparagine Catabolism to Salmonella Virulence
Authors: McLaughlin Patrick A. , McClelland Michael , Yang Hee-Jeong , Porwollik Steffen , Bogomolnaya Lydia , Chen Juei-Suei , Andrews-Polymenis Helene , van der Velden Adrianus W. M. 
Published: November 2016

ABSTRACT

Salmonellae are pathogenic bacteria that cause significant morbidity and mortality in humans worldwide. Salmonellae establish infection and avoid clearance by the immune system by mechanisms that are not well understood. We previously showed that
l
-asparaginase II produced by
Salmonella enterica
serovar Typhimurium (
S
. Typhimurium) inhibits T cell responses and mediates virulence. In addition, we previously showed that asparagine deprivation such as that mediated by
l
-asparaginase II of
S
. Typhimurium causes suppression of activation-induced T cell metabolic reprogramming. Here, we report that
STM3997
, which encodes a homolog of disulfide bond protein A (
dsbA
) of
Escherichia coli
, is required for
l
-asparaginase II stability and function. Furthermore, we report that
l
-asparaginase II localizes primarily to the periplasm and acts together with
l
-asparaginase I to provide
S
. Typhimurium the ability to catabolize asparagine and assimilate nitrogen. Importantly, we determined that, in a murine model of infection,
S
. Typhimurium lacking both
l
-asparaginase I and II genes competes poorly with wild-type
S
. Typhimurium for colonization of target tissues. Collectively, these results indicate that asparagine catabolism contributes to
S
. Typhimurium virulence, providing new insights into the competition for nutrients at the host-pathogen interface.
Two Isoforms of Clp Peptidase in Pseudomonas aeruginosa Control Distinct Aspects of Cellular Physiology
Authors: Hall Branwen M. , Breidenstein Elena B. M. , de la Fuente-Núñez César , Reffuveille Fany , Mawla Gina D. , Hancock Robert E. W. , Baker Tania A. 
Published: November 2016

ABSTRACT

Caseinolytic peptidases (ClpPs) regulate diverse aspects of cellular physiology in bacteria. Some species have multiple ClpPs, including the opportunistic pathogen
Pseudomonas aeruginosa
, in which there is an archetypical isoform, ClpP1, and a second isoform, ClpP2, about which little is known. Here, we use phenotypic assays to investigate the biological roles of ClpP1 and ClpP2 and biochemical assays to characterize purified ClpP1, ClpP2, ClpX, and ClpA. Interestingly, ClpP1 and ClpP2 have distinct intracellular roles for motility, pigment production, iron scavenging, and biofilm formation. Of particular interest, ClpP2, but not ClpP1, is required for microcolony organization, where multicellular organized structures first form on the pathway to biofilm production. We found that purified ClpP1 with ClpX or ClpA was enzymatically active, yet to our surprise, ClpP2 was inactive and not fully assembled
in vitro
; attempts to assist ClpP2 assembly and activation by mixing with the other Clp components failed to turn on ClpP2, as did solution conditions that have helped activate other ClpPs
in vitro
. We postulate that the active form of ClpP2 has yet to be discovered, and we present several potential models to explain its activation as well as the unique role ClpP2 plays in the development of the clinically important biofilms in
P. aeruginosa
.

IMPORTANCE
Pseudomonas aeruginosa
is responsible for severe infections of immunocompromised patients. Our work demonstrates that two different isoforms of the Clp peptidase, ClpP1 and ClpP2, control distinct aspects of cellular physiology for this organism. In particular, we identify ClpP2 as being necessary for microcolony organization. Pure active forms of ClpP1 and either ClpX or ClpA were characterized as assembled and active, and ClpP2 was incompletely assembled and inactive. By establishing both the unique biological roles of ClpP1 and ClpP2 and their initial biochemical assemblies, we have set the stage for important future work on the structure, function, and biological targets of Clp proteolytic enzymes in this important opportunistic pathogen.
Treating Primary Dysmenorrhoea with Acupuncture: A Narrative Review of the Relationship between Acupuncture ‘dose— and Menstrual Pain Outcomes
Authors: Armour Mike , Smith Caroline A 
Published: November 2016

Objective A number of randomised controlled trials have been performed to determine the effectiveness or efficacy of acupuncture in primary dysmenorrhoea. The objective of this review was to explore the relationship between the ‘dose’ of the acupuncture intervention and menstrual pain outcomes. Methods Eight databases were systematically searched for trials examining penetrating body acupuncture for primary dysmenorrhoea published in English up to September 2015. Dose components for each trial were extracted, assessed by the two authors and categorised by neurophysiological dose (number of needles, retention time and mode of stimulation), cumulative dose (total number and frequency of treatments), needle location and treatment timing. Results Eleven trials were included. Components of acupuncture dose were well reported across all trials. The relationship between needle location and menstrual pain demonstrated conflicting results. Treatment before the menses appeared to produce greater reductions in pain than treatment starting at the onset of menses. A single needle during menses may provide greater pain reduction compared to multiple needles. Conversely, multiple needles before menses were superior to a single needle. Electroacupuncture may provide more rapid pain reduction compared to manual acupuncture but may not have a significantly different effect on overall menstrual pain. Conclusions There appear to be relationships between treatment timing and mode of needle stimulation, and menstrual pain outcomes. Needle location, number of needles used and frequency of treatment show clear dose-response relationships with menstrual pain outcomes. Current research is insufficient to make definitive clinical recommendations regarding optimum dose parameters for treating primary dysmenorrhoea.
Pain, activities of daily living and sport function at different time points after hip arthroscopy in patients with femoroacetabular impingement: a systematic review with meta-analysis
Authors: Kierkegaard Signe , Langeskov-Christensen Martin , Lund Bent , Naal Florian D , Mechlenburg Inger , Dalgas Ulrik , Casartelli Nicola C 
Published: November 2016

AimTo investigate pain, activities of daily living (ADL) function, sport function, quality of life and satisfaction at different time points after hip arthroscopy in patients with femoroacetabular impingement (FAI).DesignSystematic review with meta-analysis. Weighted mean differences between preoperative and postoperative outcomes were calculated and used for meta-analysis.Data sourcesEMBASE, MEDLINE, SportsDiscus, CINAHL, Cochrane Library, and PEDro.Eligibility criteria for selecting studiesStudies that evaluated hip pain, ADL function, sport function and quality of life before and after hip arthroscopy and postoperative satisfaction in patients with symptomatic FAI.ResultsTwenty-six studies (22 case series, 3 cohort studies, 1 randomised controlled trial (RCT)) were included in the systematic review and 19 in the meta-analysis. Clinically relevant pain and ADL function improvements were first reported between 3 and 6 months, and sport function improvements between 6 months and 1 year after surgery. It is not clear when quality of life improvements were first achieved. On average, residual mild pain and ADL and sport function scores lower than their healthy counterparts were reported by patients following surgery. Postoperative patient satisfaction ranged from 68% to 100%.ConclusionsOn average, patients reported earlier pain and ADL function improvements, and slower sport function improvements after hip arthroscopy for FAI. However, average scores from patients indicate residual mild hip pain and/or hip function lower than their healthy counterparts after surgery. Owing to the current low level of evidence, future RCTs and cohort studies should investigate the effectiveness of hip arthroscopy in patients with FAI.Trial registration numberCRD42015019649.
Perspectives of host faculty and trainees on international visiting faculty to paediatric academic departments in East Africa
Authors: Russ Christiana M , Ganapathi Lakshmi , Marangu Diana , Silverman Melanie , Kija Edward , Bakeera-Kitaka Sabrina , Laving Ahmed 
Published: November 2016

BackgroundInvestments in faculty exchanges to build physician workforce capacity are increasing. Little attention has been paid to the expectations of host institution faculty and trainees. This prospective qualitative research study explored faculty and resident perspectives about guest faculty in paediatric departments in East Africa, asking (1) What are the benefits and challenges of hosting guest faculty, (2) What factors influence the effectiveness of faculty visits and (3) How do host institutions prepare for faculty visits?MethodsWe recruited 36 faculty members and residents from among four paediatric departments in East Africa to participate in semistructured interviews which were audio recorded and transcribed. Data were qualitatively analysed using principles of open coding and thematic analysis. We achieved saturation of themes.ResultsBenefits of faculty visits varied based on the size and needs of host institutions. Emergent themes included the importance of guest faculty time commitment, and mutual preparation to ensure that visit goals and scheduling met host needs. We documented conflicts that developed around guest emotional responses and ethical approaches to clinical resource limitations, which some hosts tried to prepare for and mitigate. Imbalance in resources led to power differentials; some hosts sought partnerships to re-establish control over the process of having guests.ConclusionsWe identified that guest faculty can assist paediatric institutions in building capacity; however, effective visits require: (1) mutually agreed on goals with appropriate scheduling, visit length and commitment to ensure that the visits meet the host's needs, (2) careful selection and preparation of guest faculty to meet the host's goals, (3) emotional preparation by prospective guests along with host orientation to clinical work in the host's setting and (4) attention to funding sources for the visit and mitigation of resulting power differentials.
External validation of the Probability of repeated admission (Pra) risk prediction tool in older community-dwelling people attending general practice: a prospective cohort study
Authors: Wallace Emma , McDowell Ronald , Bennett Kathleen , Fahey Tom , Smith Susan M 
Published: November 2016

ObjectivesEmergency admission is associated with the potential for adverse events in older people and risk prediction models are available to identify those at highest risk of admission. The aim of this study was to externally validate and compare the performance of the Probability of repeated admission (Pra) risk model and a modified version (incorporating a multimorbidity measure) in predicting emergency admission in older community-dwelling people.Setting15 general practices (GPs) in the Republic of Ireland.Participantsn=862, ≥70 years, community-dwelling people prospectively followed up for 2 years (2010–2012). Exposure: Pra risk model (original and modified) calculated for baseline year where ≥0.5 denoted high risk (patient questionnaire, GP medical record review) of future emergency admission.Primary outcomeEmergency admission over 1 year (GP medical record review). Statistical analysis: descriptive statistics, model discrimination (c-statistic) and calibration (Hosmer-Lemeshow statistic).ResultsOf 862 patients, a total of 154 (18%) had ≥1 emergency admission(s) in the follow-up year. 63 patients (7%) were classified as high risk by the original Pra and of these 26 (41%) were admitted. The modified Pra classified 391 (45%) patients as high risk and 103 (26%) were subsequently admitted. Both models demonstrated only poor discrimination (original Pra: c-statistic 0.65 (95% CI 0.61 to 0.70); modified Pra: c-statistic 0.67 (95% CI 0.62 to 0.72)). When categorised according to risk-category model, specificity was highest for the original Pra at cut-point of ≥0.5 denoting high risk (95%), and for the modified Pra at cut-point of ≥0.7 (95%). Both models overestimated the number of admissions across all risk strata.ConclusionsWhile the original Pra model demonstrated poor discrimination, model specificity was high and a small number of patients identified as high risk. Future validation studies should examine higher cut-points denoting high risk for the modified Pra, which has practical advantages in terms of application in GP. The original Pra tool may have a role in identifying higher-risk community-dwelling older people for inclusion in future trials aiming to reduce emergency admissions.
Narrowing mortality gap between men and women over two decades: a registry-based study in Ontario, Canada
Authors: Rosella Laura C , Calzavara Andrew , Frank John W , Fitzpatrick Tiffany , Donnelly Peter D , Henry David 
Published: November 2016

BackgroundHistorically, women have lower all-cause mortality than men. It is less understood that sex differences have been converging, particularly among certain subgroups and causes. This has implications for public health and health system planning. Our objective was to analyse contemporary sex differences over a 20-year period.MethodsWe analysed data from a population-based death registry, the Ontario Registrar's General Death file, which includes all deaths recorded in Canada's most populous province, from 1992 to 2012 (N=1 710 080 deaths). We calculated absolute and relative mortality sex differences for all-cause and cause-specific mortality, age-adjusted and age-specific, including the following causes: circulatory, cancers, respiratory and injuries. We used negative-binomial regression of mortality on socioeconomic status with direct age adjustment for the overall population.ResultsIn the 20-year period, age-adjusted mortality dropped 39.2% and 29.8%, respectively, among men and women. The age-adjusted male-to-female mortality ratio dropped 41.4%, falling from 1.47 to 1.28. From 2000 onwards, all-cause mortality rates of high-income men were lower than those seen among low-income women. Relative mortality declines were greater among men than women for cancer, respiratory and injury-related deaths. The absolute decline in circulatory deaths was greater among men, although relative deciles were similar to women. The largest absolute mortality gains were seen among men over the age of 85 years.ConclusionsThe large decline in mortality sex ratios in a Canadian province with universal healthcare over two decades signals an important population shift. These narrowing trends varied according to cause of death and age. In addition, persistent social inequalities in mortality exist and differentially affect men and women. The observed change in sex ratios has implications for healthcare and social systems.