Abstract Adherence drives efficacy in PrEP clinical trials. We compared drug concentrations and self-reported adherence in HPTN069/ACTG5305, a double-blinded, randomized trial of the safety and ...tolerability of candidate PrEP regimens that included maraviroc (MVC), tenofovir (TDF), and emtricitabine (FTC). Plasma drug concentrations and self-reported adherence by computer-assisted self-interview (CASI) were assessed at study weeks 24 and 48. Descriptive statistics and a generalized linear model were used to assess the association between selected demographic factors, self-report of daily medication adherence and plasma drug concentrations consistent with daily adherence. Among 718 paired observations from 370 participants, 43% (306/718) reported daily adherence by CASI, 65% (467/718) had drug concentrations consistent with daily adherence and 11% (81/718) had CASI responses that reported daily adherence despite having drug concentrations consistent with less-than-daily adherence. In adjusted analyses, participants who were assigned male at birth (aOR 1.42 95% CI 1.02, 1.97), older (5-year increments aOR 1.10 95% CI 1.09, 1.11), White (aOR 2.2 95% CI 1.88, 2.56), had advanced education (aOR 3.89 95% CI 2.97, 5.09), were employed (aOR 1.89 95% CI 1.50, 2.40), or partnered/married (aOR 2 95% CI 1.72, 2.32) were more likely to have drug concentrations consistent with daily adherence. Participants who were not employed (aOR 2.7 95% CI 1.31, 5.55) or who were single/not partnered (aOR 2.33 CI 95% 1.25, 4.34) were more likely to have drug concentrations that did not reflect daily adherence despite self-reported PrEP adherence. These findings support the need for ongoing adherence counseling in clinical trials of new PrEP regimens.
Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun NH
-terminal kinase ...(JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulating myocardial JNK activity remain unclear. In this study, we sought to identify JNK-activating molecules as novel regulators of cardiac remodeling in HF. We investigated mixed lineage kinase-3 (MLK3), a master regulator of upstream JNK-activating kinases, whose role in the remodeling process had not previously been studied. We observed increased MLK3 protein expression in myocardium from patients with nonischemic and hypertrophic cardiomyopathy and in hearts of mice subjected to transverse aortic constriction (TAC). Mice with genetic deletion of MLK3 (MLK3
) exhibited baseline cardiac hypertrophy with preserved cardiac function. MLK3
mice subjected to chronic left ventricular (LV) pressure overload (TAC, 4 wk) developed worsened cardiac dysfunction and increased LV chamber size compared with MLK3
littermates ( n = 8). LV mass, pathological markers of hypertrophy ( Nppa, Nppb), and cardiomyocyte size were elevated in MLK3
TAC hearts. Phosphorylation of JNK, but not other MAPK pathways, was selectively impaired in MLK3
TAC hearts. In adult rat cardiomyocytes, pharmacological MLK3 kinase inhibition using URMC-099 blocked JNK phosphorylation induced by neurohormonal agents and oxidants. Sustained URMC-099 exposure induced cardiomyocyte hypertrophy. These data demonstrate that MLK3 prevents adverse cardiac remodeling in the setting of pressure overload. Mechanistically, MLK3 activates JNK, which in turn opposes cardiomyocyte hypertrophy. These results support modulation of MLK3 as a potential therapeutic approach in HF. NEW & NOTEWORTHY Here, we identified a role for mixed lineage kinase-3 (MLK3) as a novel antihypertrophic and antiremodeling molecule in response to cardiac pressure overload. MLK3 regulates phosphorylation of the stress-responsive JNK kinase in response to pressure overload and in cultured cardiomyocytes stimulated with hypertrophic agonists and oxidants. This study reveals MLK3-JNK signaling as a novel cardioprotective signaling axis in the setting of pressure overload.
African trypanosomes are unusual among pathogenic protozoa in that they can undergo their complete morphological life cycle in the tsetse fly vector with mating as a non-obligatory part of this ...development. Trypanosoma brucei rhodesiense, which infects humans and livestock in East and Southern Africa, has classically been described as a host-range variant of the non-human infective Trypanosoma brucei that occurs as stable clonal lineages. We have examined T. b. rhodesiense populations from East (Uganda) and Southern (Malawi) Africa using a panel of microsatellite markers, incorporating both spatial and temporal analyses. Our data demonstrate that Ugandan T. b. rhodesiense existed as clonal populations, with a small number of highly related genotypes and substantial linkage disequilibrium between pairs of loci. However, these populations were not stable as the dominant genotypes changed and the genetic diversity also reduced over time. Thus these populations do not conform to one of the criteria for strict clonality, namely stability of predominant genotypes over time, and our results show that, in a period in the mid 1990s, the previously predominant genotypes were not detected but were replaced by a novel clonal population with limited genetic relationship to the original population present between 1970 and 1990. In contrast, the Malawi T. b. rhodesiense population demonstrated significantly greater diversity and evidence for frequent genetic exchange. Therefore, the population genetics of T. b. rhodesiense is more complex than previously described. This has important implications for the spread of the single copy T. b. rhodesiense gene that allows human infectivity, and therefore the epidemiology of the human disease, as well as suggesting that these parasites represent an important organism to study the influence of optional recombination upon population genetic dynamics.
Trypanosoma brucei is the causative agent of African Sleeping Sickness in humans and contributes to the related veterinary disease, Nagana. T. brucei is segregated into three subspecies based on host ...specificity, geography and pathology. T. b. brucei is limited to animals (excluding some primates) throughout sub-Saharan Africa and is non-infective to humans due to trypanolytic factors found in human serum. T. b. gambiense and T. b. rhodesiense are human infective sub-species. T. b. gambiense is the more prevalent human, causing over 97% of human cases. Study of T. b. gambiense is complicated in that there are two distinct groups delineated by genetics and phenotype. The relationships between the two groups and local T. b. brucei are unclear and may have a bearing on the evolution of the human infectivity traits.
A collection of sympatric T. brucei isolates from Côte d'Ivoire, consisting of T. b. brucei and both groups of T. b. gambiense have previously been categorized by isoenzymes, RFLPs and Blood Incubation Infectivity Tests. These samples were further characterized using the group 1 specific marker, TgSGP, and seven microsatellites. The relationships between the T. b. brucei and T. b. gambiense isolates were determined using principal components analysis, neighbor-joining phylogenetics, STRUCTURE, FST, Hardy-Weinberg equilibrium and linkage disequilibrium.
Group 1 T. b. gambiense form a clonal genetic group, distinct from group 2 and T. b. brucei, whereas group 2 T. b. gambiense are genetically indistinguishable from local T. b. brucei. There is strong evidence for mating within and between group 2 T. b. gambiense and T. b. brucei. We found no evidence to support the hypothesis that group 2 T. b. gambiense are hybrids of group 1 and T. b. brucei, suggesting that human infectivity has evolved independently in groups 1 and 2 T. b. gambiense.
Background:
Limited ankle dorsiflexion (DF) range has been associated with knee injuries and altered biomechanics during functional squatting and landing tasks. Prior studies correlating ...weight-bearing DF with altered landing mechanics have primarily used advanced motion capture technology, with limited research using clinically validated scoring tools.
Hypothesis/Purpose:
To assess the relationship between decreased DF and functional testing performance in youth athletes who have undergone anterior cruciate ligament reconstruction (ACLR).
Methods:
A retrospective review of standardized data was conducted on patients who had undergone ACLR at a pediatric sports medicine practice that had completed functional testing between December 2017 and November 2020. Patients with testing completed at a minimum of five months post-operatively, and who planned to return-to-sport (RTS) were included. Functional testing included validated protocols for the Y-Balance Test (YBT) and the Landing Error Scoring System (LESS), as well as a modified Single-Leg Squat Endurance Test (SLSET) utilizing the VAIL sports test scoring criteria. DF was measured in a weight-bearing lunge position off the front foot. Subjects were categorized into a pass or fail group based on their YBT and LESS scores (YBT≥94%, LESS≤4), and t-tests were performed to identify significant differences in DF between groups (α=0.05). Lastly, Pearson correlations were performed to identify potential relationships between DF and SLSET total score as well as normalized anterior reach collected as a component of the YBT (α=0.05).
Results:
303 patients (148 (48.8%) males, 15.94±2.15 years, 7.46±2.11 months post-operative) were included for analysis. Significant correlations were identified between DF and YBT composite score (p <0.001) and LESS total score (p <0.001; Table 1). Additionally, positive relationships were found between DF and both SLSET total score (p <0.001, r = 0.296) and anterior reach (p <0.001; r =0.400). Average values for DF, YBT, and LESS can be found in Table 2.
Conclusion:
In this pediatric ACLR population, decreased ankle dorsiflexion is associated with high risk movement patterns during functional testing. This study adds to the literature by identifying clinically applicable DF thresholds associated with passing scores on the YBT and LESS functional tests. Clinical interventions aimed at improving ankle dorsiflexion to >36° may be an important component of ACL rehabilitation.
Table 1.
Ankle dorsiflexion (Mean ± SD) across patients and by functional test scores
Table 2.
Average values per measure (Note: Asymm = side-to-side differences)
The aim of this study was to describe the aetiology and severity of head injury in an infant (age<1 year) population presenting to a Scottish Paediatric Emergency Department (PED) and to discern ...preventable risk factors. The records of infants who presented to the PED of the Royal Aberdeen Children's Hospital between September 2010 and December 2011 with isolated head trauma were reviewed, patient demographics were extracted and information on aetiology, including nonaccidental injury (NAI), was recorded. Of 1574 attendances, 233 suffered isolated head injury. The majority (97%) were minor; six patients suffered skull fractures, three had traumatic intracranial haemorrhage and only three were considered to have sustained an NAI. The most common mode of injury was fall from a height (37%). Infants commonly present to the PED with head injury, many of which should be easily preventable. The number of cases because of NAI in our population is smaller than previously published figures.
Some of the most interesting and important questions in ecology require examination of the strength of different processes across environmental gradients and among organisms with different traits. ...Meta-analysis combines results from independent studies to examine patterns of effect across taxa or environments and, thus, may represent a powerful tool to test ecological theory. A meta-analysis requires that a common metric of effect size be extracted from each of the studies. Here, we focus on choosing a metric that best facilitates ecological inferences. We begin with a brief description of the standard definition of effect size in meta-analysis, as used in recent papers. We then discuss potential problems with this approach and suggest an alternative that is more explicitly tied to the dynamics of ecological systems. Using two examples drawn from predator-prey experiments, we then illustrate the limitations of the standard metric and the conceptual advantages of one ecologically based alternative. We conclude by discussing the link between metrics of effect size and ecological models.
Background:
Management of discoid meniscus in pediatric patients requires understanding of the presentation, associated risks, and appropriate techniques. Surgical treatment consists of ...saucerization, meniscus repair, meniscocapular stabilization, and, periodically, subtotal meniscectomy. The type of meniscal treatment is commonly determined during arthroscopy. Thus, surgeons, patients, and their parents/guardians must be prepared for a variety of surgical options.
Hypothesis/Purpose:
To compare intraoperative arthroscopic findings and treatment of discoid meniscus across pediatric age groups in a large multicenter quality improvement registry.
Methods:
A multi-center quality improvement registry (16 institutions, 26 surgeons) monitoring the safety of discoid meniscus surgery was reviewed. Audit processes using CPT codes were designed to ensure that all consecutive cases from 2018-2020 were prospectively entered on patients <19 years old into a HIPAA-compliant electronic platform. Patients were grouped into five groups based on age at time of surgery (<7, 7-10, 11-13, 14-16, >16). Demographic characteristics, discoid type, presence and type of tear, peripheral rim instability, repair technique, and partial meniscectomy/debridement beyond saucerization were reviewed. Chi-Square or Fisher’s exact tests were used for categorical comparisons and a Kruskal-Wallis test for continuous comparisons.
Results:
274 patients were identified (mean age 12.4 years, range 3-18; 47.3% females). Complete discoid meniscus and peripheral rim instability were found to be more prevalent in younger age groups (Table 1). Peripheral rim instability was noted in 55.5% of cases, most commonly in the posterior horn (24.8%). While a focal region of instability was most common, the youngest age group was more likely to have either multifocal instability or no instability. Repair was conducted more commonly in the younger cohorts, with a significant decrease in repair percentage (p=0.008) per age group. All-inside was the most common repair technique in all age groups. Partial meniscectomy/debridement beyond saucerization occurred more frequently in older age groups than younger age groups (p=.0002), including 38.4% of cases in the oldest age group (Table 2).
Conclusion:
Younger patients experienced a greater incidence of complete discoid menisci and meniscus repair in this age group and was more likely to have more than one area of rim instability. However, when meniscal resection beyond a saucerization was required, this was more likely to occur in older patients.
Table 1.
Age-Related Comparison of Discoid Meniscal Presentation and Treatment
Table 2.
Incidence of Additional Meniscal Resection Beyond Saucerization
In the last decade, there has been a wide range of studies using a series of molecular markers to investigate the genotypic diversity of some of the important species of African trypanosomes. Here, ...we review this work and provide an update of our current understanding of the mechanisms that generate this diversity based on population genetic analysis. In parallel with field based studies, our knowledge of the key features of the system of genetic exchange in
Trypanosoma brucei, based on laboratory analysis, has reached the point at which this system can be used as a tool to determine the genetic basis of a phenotype. In this context, we have outlined our current knowledge of the basis for phenotypic variation among strains of trypanosomes, and highlight that this is a relatively under researched area, except for work on drug resistance. There is clear evidence for ‘strain’-specific variation in tsetse transmission, a range of virulence/pathogenesis phenotypes and the ability to cross the blood brain barrier. The potential for using genetic analysis to dissect these phenotypes is illustrated by the recent work defining a locus determining organomegaly for
T. brucei. When these results are considered in relation to the body of research on the variability of the host response to infection, it is clear that there is a need to integrate the study of host and parasite diversity in relation to understanding infection outcome.
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