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"Thurman, Mark"
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Snow amazing : cool facts and warm tales
Read about what snow brings to our world and its animals.
Book
Randomized, placebo controlled phase I trial of the safety, pharmacokinetics, pharmacodynamics and acceptability of a 90 day tenofovir plus levonorgestrel vaginal ring used continuously or cyclically in women: The CONRAD 138 study
Multipurpose prevention technologies (MPTs), which prevent sexually transmitted infection(s) and unintended pregnancy, are highly desirable to women. In this randomized, placebo-controlled, phase I study, women used a placebo or tenofovir (TFV) and levonorgestrel (LNG) intravaginal ring (IVR), either continuously or cyclically (three, 28-day cycles with a 3 day interruption in between each cycle), for 90 days. Sixty-eight women were screened; 47 were randomized to 4 arms: TFV/LNG or placebo IVRs used continuously or cyclically (4:4:1:1). Safety was assessed by adverse events and changes from baseline in mucosal histology and immune mediators. TFV concentrations were evaluated in multiple compartments. LNG concentration was determined in serum. Modeled TFV pharmacodynamic antiviral activity was evaluated in vaginal and rectal fluids and cervicovaginal tissue ex vivo . LNG pharmacodynamics was assessed with cervical mucus quality and anovulation. All IVRs were safe with no serious adverse events nor significant changes in genital tract histology, immune cell density or secreted soluble proteins from baseline. Median vaginal fluid TFV concentrations were >500 ng/mg throughout 90d. TFV-diphosphate tissue concentrations exceeded 1,000 fmol/mg within 72hrs of IVR insertion. Mean serum LNG concentrations exceeded 200 pg/mL within 2h of TFV/LNG use, decreasing quickly after IVR removal. Vaginal fluid of women using TFV-containing IVRs had significantly greater inhibitory activity (87–98% versus 10% at baseline; p<0.01) against HIV replication in vitro . There was a >10-fold reduction in HIV p24 antigen production from ectocervical tissues after TFV/LNG exposure. TFV/LNG IVR users had significantly higher rates of anovulation, lower Insler scores and poorer/abnormal cervical mucus sperm penetration. Most TFV/LNG IVR users reported no change in menstrual cycles or fewer days of and/or lighter bleeding. All IVRs were safe. Active rings delivered high TFV concentrations locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. Trial registration: ClinicalTrials.gov #NCT03279120 .
Journal Article
Alien invaders : species that threaten our world
Explores the history of alien invaders--plants, animals, bacteria, or viruses that are deliberately or accidentally introduced to a new habitat, and subsequently explode in numbers causing harm to property and wildlife; features case studies of such species; and discusses what can be done to halt the progress of alien invaders.
Book
An expansive human regulatory lexicon encoded in transcription factor footprints
Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human
cis
–regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNase I cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of protein–DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50-base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation and pluripotency.
DNase I footprinting in 41 cell and tissue types reveals millions of short sequence elements encoding an expansive repertoire of conserved recognition sequences for DNA-binding proteins.
ENCODE: transcription-factor footprints
DNaseI footprinting detects DNA sequences that are protected from cleavage by DNaseI because they are bound by regulatory factors. Studying these footprints in 41 diverse cell and tissue types, the authors describe millions of short sequence elements that are conserved recognition sequences for DNA-binding proteins. The effort nearly doubles the size of the human
cis
-regulatory lexicon and provides insight into chromatin states and levels of evolutionary conservation. A large collection of novel regulatory-factor recognition motifs that closely parallel major regulators of development, differentiation and pluripotency is also described.
Journal Article
Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women
To prevent the global health burdens of human immunodeficiency virus [HIV] and unintended/mistimed pregnancies, we developed an intravaginal ring [IVR] that delivers tenofovir [TFV] at ~10mg/day alone or with levonorgestrel [LNG] at ~20μg/day for 90 days. We present safety, pharmacokinetics, pharmacodynamics, acceptability and drug release data in healthy women. CONRAD A13-128 was a randomized, placebo controlled phase I study. We screened 86 women; 51 were randomized to TFV, TFV/LNG or placebo IVR [2:2:1] and 50 completed all visits, using the IVR for approximately 15 days. We assessed safety by adverse events, colposcopy, vaginal microbiota, epithelial integrity, mucosal histology and immune cell numbers and phenotype, cervicovaginal [CV] cytokines and antimicrobial proteins and changes in systemic laboratory measurements, and LNG and TFV pharmacokinetics in multiple compartments. TFV pharmacodynamic activity was measured by evaluating CV fluid [CVF] and tissue for antiviral activity using in vitro models. LNG pharmacodynamic assessments were timed based on peak urinary luteinizing hormone levels. All IVRs were safe with no significant colposcopic, mucosal, immune and microbiota changes and were acceptable. Among TFV containing IVR users, median and mean CV aspirate TFV concentrations remained above 100,000 ng/mL 4 hours post IVR insertion and mean TFV-diphosphate [DP] concentrations in vaginal tissue remained above 1,000 fmol/mg even 3 days post IVR removal. CVF of women using TFV-containing IVRs completely inhibited [94-100%] HIV infection in vitro. TFV/LNG IVR users had mean serum LNG concentrations exceeding 300 pg/mL within 1 hour, remaining high throughout IVR use. All LNG IVR users had a cervical mucus Insler score <10 and the majority [95%] were anovulatory or had abnormal cervical mucus sperm penetration. Estimated in vivo TFV and LNG release rates were within expected ranges. All IVRs were safe with the active ones delivering sustained high concentrations of TFV locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. The TFV and TFV/LNG rings are ready for expanded 90 day clinical testing. Trial registration ClinicalTrials.gov #NCT02235662.
Journal Article
Conservation of trans-acting circuitry during mammalian regulatory evolution
The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ∼8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ∼95% similar with that derived from human TF footprints. However, only ∼20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity.
Mouse genomic footprinting reveals conservation of transcription factor (TF) recognition repertoires and trans-regulatory circuitry despite massive turnover of DNA elements that contact TFs in vivo.
Trans-acting networks in the mouse epigenome
Having generated genomic DNase I footprinting data of the mouse genome across 25 cell and tissue types, these authors use these data to quantify cis-versus-trans regulatory contributions to mammalian regulatory evolution. They describe more than 600 motifs that collectively are over 95% similar to that recognized
in vivo
by human transcription factors (TFs). Despite substantial turnover of the cis-regulatory landscape around each TF gene, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Conservation between mouse and human TF regulatory networks is particularly similar at the highest organization level. The work was performed as part of the mouse ENCODE project.
Journal Article
Vaginal microbiota and mucosal pharmacokinetics of tenofovir in healthy women using tenofovir and tenofovir/levonorgestrel vaginal rings
Recent data support that the vaginal microbiota may alter mucosal pharmacokinetics (PK) of topically delivered microbicides. Our team developed an intravaginal ring (IVR) that delivers tenofovir (TFV) (8-10 mg/day) alone or with levonorgestrel (LNG) (20 ug/day). We evaluated the effect of IVRs on the vaginal microbiota, and describe how the vaginal microbiota impacts mucosal PK of TFV. CONRAD A13-128 was a randomized, placebo controlled phase I study. We randomized 51 women to TFV, TFV/LNG or placebo IVR. We assessed the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and after approximately 15 days of use. We measured the concentration of TFV in the cervicovaginal (CV) aspirate, and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue at the end of IVR use. The change in relative or absolute abundance of vaginal bacterial phylotypes was similar among active and placebo IVR users (all q values >0.13). TFV concentrations in CV aspirate and vaginal tissue, and TFV-DP concentrations in vaginal tissue were not significantly different among users with community state type (CST) 4 versus those with Lactobacillus dominated microbiota (all p values >0.07). The proportions of participants with CV aspirate concentrations of TFV >200,000 ng/mL and those with tissue TFV-DP concentrations >1,000 fmol/mg were similar among women with anaerobe versus Lactobacillus dominated microbiota (p = 0.43, 0.95 respectively). There were no significant correlations between the CV aspirate concentration of TFV and the relative abundances of Gardnerella vaginalis or Prevotella species. Tissue concentrations of TFV-DP did not correlate with any the relative abundances of any species, including Gardnerella vaginalis. In conclusion, active IVRs did not differ from the placebo IVR on the effect on the vaginal microbiota. Local TFV and TFV-DP concentrations were high and similar among IVR users with Lactobacillus dominated microbiota versus CST IV vaginal microbiota. Trial registration: ClinicalTrials.gov NCT02235662.
Journal Article
Vaginal Microbiota and Mucosal Pharmacokinetics of Tenofovir in Healthy Women Using a 90-Day Tenofovir/Levonorgestrel Vaginal Ring
A relationship between the vaginal microbiota and tenofovir (TFV) concentrations and activity after topical administration has been previously reported.
CONRAD A15-138 was a randomized, placebo-controlled Phase I study aimed at characterizing the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TFV and levonorgestrel (LNG) administered through a vaginal ring (IVR) for 90 days. Herein, we describe changes from baseline in the vaginal microbiota with IVR use and the impact of the vaginal microbiota on mucosal TFV PK.
The study screened 68 participants and randomized 47 (37 TFV/LNG, 10 placebo), assessing the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and monthly for 3 months. Concentrations of TFV in vaginal fluid (VF), and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue, and modeled PD against HIV-1
were measured before and after treatment.
There were no clinically significant changes in relative abundance of vaginal bacterial phylotypes from pre-insertion baseline at any month among active and placebo IVR users. There were no significant changes in community state type (CST) with IVR use. Participants with diverse, anaerobic CST IVA/B microbiota had higher
release of TFV from the IVR compared to women with
-dominated (LbD) microbiota, who had expected
TFV release rates. Median VF TFV concentrations were significantly higher among women with CST IVA/B microbiota in months 1 (3,135 ng/mg VF) and 2 (3,800 ng/mg). Women with LbD microbiota had significantly higher median VF TFV concentration (1,423 ng/mg) and median TFV (103 ng/mg) and TFV-DP (5,877 fmol/mg) tissue concentrations versus women with CST IVA/B microbiota at month 3. All women demonstrated a significant increase from pre-insertion baseline of
HIV-1 inhibition by VF (p values <0.05). PD differences in tissue according to CST, however, were not statistically significant.
TFV/LNG IVR use did not change the vaginal microbiota nor increase the incidence of CST IVA/B. Vaginal microbiota, and in particular CST IVA/B, possibly through increased vaginal pH, impacted
TFV release and cervicovaginal (CV) PK, but both PK and PD data suggest CV protection against HIV-1.
ClinicalTrials.gov (#NCT03279120).
Journal Article
Smartphone Technology to Empower People Experiencing Homelessness: Secondary Analysis
In the United States, the number of people experiencing homelessness has continually increased over the last 3 years. Homelessness is associated with poor health, and people experiencing homelessness are often burdened with high rates of chronic and mental health conditions, functional limitations, and cognitive impairment. Despite the high burden of chronic illness and functional limitations, there is limited literature exploring self-management among homeless populations.
This study aims to investigate how access to smartphone technology facilitates self-management, including the attainment of social needs within the context of homelessness.
A secondary analysis of 33 exit interviews from 2 feasibility studies related to mobile health interventions among people experiencing homelessness was conducted. Iterative thematic analysis was used to identify themes representative of participants' experiences using smartphone technology.
Collectively, participants revealed not only how the context of homelessness constrained their ability to engage in activities necessary to self-manage health and meet social needs but also how consistent and predictable access to the tools available through a smartphone changed their behaviors and outlook. The global theme of empowered by technology was identified and defined as how having a smartphone with a plan for unlimited text, calling, data, and transportation allowed participants to navigate homelessness and facilitated self-management.
People experiencing homelessness used the tools on a smartphone to make decisions, take action, solve problems, and use the resources-skills necessary for fulfilling tasks required for effective self-management. Further, consistent access to smartphone technology and transportation empowered participants to meet the requirements for the attainment of social needs.
Journal Article
Neurally triggered breaths reduce trigger delay and improve ventilator response times in ventilated infants with bronchiolitis
Purpose
Neurally adjusted ventilatory assist (NAVA) is a mode of ventilation designed to improve patient–ventilator interaction by interpreting a neural signal from the diaphragm to trigger a supported breath. We hypothesized that neurally triggered breaths would reduce trigger delay, ventilator response times, and work of breathing in pediatric patients with bronchiolitis.
Methods
Subjects with a clinical diagnosis of bronchiolitis were studied in volume support (pneumatic trigger) and NAVA (pneumatic and neural trigger) in a crossover design. Airway flow and pressure waveforms were obtained with a pneumotachograph and computerized digital recorder and were recorded for 120 s for each experiment.
Results
Neurally triggered breaths had less trigger delay (ms) (40 ± 27 vs. 98 ± 34;
p
< 0.001) and reduced ventilator response times (ms) (15 ± 7 vs. 36 ± 25;
p
< 0.001) compared with pneumatically triggered breaths. Neurally triggered breaths had reduced pressure–time product (PTP) area A (cmH
2
O * s), the area of the pressure curve from initiation of breath to start of ventilator pressurization (0.013 ± 0.010;
p
< 0.001), and reduced PTP area B (cmH
2
O * s), the area of the pressure curve from start of ventilator pressurization to return of baseline pressure (0.008 ± 0.006 vs. 0.023 ± 0.009;
p
= 0.003). Reduced PTP may indicate decreased work of breathing.
Conclusion
Neurally triggered breaths reduce trigger delay, improve ventilator response times, and may decrease work of breathing in children with bronchiolitis. Further analysis is required to determine if neurally triggered breaths will improve patient–ventilator synchrony.
Journal Article