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"Hoch, T. L"
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Chasing Normal
High School sophmore Annie Smith is just hoping to live a normal life after she moves from Arkansas to the quiet little town of Reston, Texas. But it does not take long for her new friends to figure out that Annie is anything but normal. Annie's goal is to fly under the radar drawing as little attention to herself as possible. But she soon discovers that being normal does not always bring happiness.
Book
Assessing the performance of global hydrological models for capturing peak river flows in the Amazon basin
Extreme flooding impacts millions of people that live within the
Amazon floodplain. Global hydrological models (GHMs) are frequently used to
assess and inform the management of flood risk, but knowledge on the skill
of available models is required to inform their use and development. This
paper presents an intercomparison of eight different GHMs freely available
from collaborators of the Global Flood Partnership (GFP) for simulating
floods in the Amazon basin. To gain insight into the strengths and
shortcomings of each model, we assess their ability to reproduce daily and
annual peak river flows against gauged observations at 75 hydrological
stations over a 19-year period (1997–2015). As well as highlighting regional variability in the accuracy of simulated streamflow, these results indicate that (a) the meteorological input is the dominant control on the accuracy of both daily and annual maximum river flows, and (b) groundwater and routing calibration of Lisflood based on daily river flows has no impact on the ability to simulate flood peaks for the chosen river basin. These findings have important relevance for applications of large-scale hydrological models, including analysis of the impact of climate variability, assessment of the influence of long-term changes such as land-use and anthropogenic climate change, the assessment of flood likelihood, and for flood forecasting systems.
Journal Article
Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer
As the area of small molecules interacting with RNA advances, general routes to provide bioactive compounds are needed as ligands can bind RNA avidly to sites that will not affect function. Small-molecule targeted RNA degradation will thus provide a general route to affect RNA biology. A non–oligonucleotide-containing compound was designed from sequence to target the precursor to oncogenic microRNA-21 (pre–miR-21) for enzymatic destruction with selectivity that can exceed that for protein-targeted medicines. The compound specifically binds the target and contains a heterocycle that recruits and activates a ribonuclease to pre–miR-21 to substoichiometrically effect its cleavage and subsequently impede metastasis of breast cancer to lung in a mouse model. Transcriptomic and proteomic analyses demonstrate that the compound is potent and selective, specifically modulating oncogenic pathways. Thus, small molecules can be designed from sequence to have all of the functional repertoire of oligonucleotides, including inducing enzymatic degradation, and to selectively and potently modulate RNA function in vivo.
Journal Article
XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia
XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.
Journal Article
Molecular profiling of soft tissue sarcomas using next-generation sequencing: a pilot study toward precision therapeutics
Next-generation sequencing (NGS) can provide in-depth detection of numerous gene alterations. To date, there are very few reports describing the use of this technique in soft tissue sarcomas. Herein, we aim to test the utility of NGS in identifying targetable mutations in these tumors. NGS was performed using a clinically validated multiplexed gene sequencing panel interrogating the full coding sequence of 194 cancer-related genes. A custom bioinformatics pipeline was developed to detect all classes of mutations directly from the NGS data, including single-nucleotide variants, small insertions and deletions, copy number variation, and complex structural variations. Twenty-five soft tissue sarcomas were analyzed; 18 of these patients had metastatic disease and 7 primary locally advanced tumors. Targetable mutations for which clinical trials are available were identified in 60% of the cases.MAP2K4,AURKA,AURKB,andc-MYCamplification were recurrent events in leiomyosarcomas. Frequent non-targetable variants included copy losses of theTP53(24%), PTEN(16%), andCDKN2A(20%). Additional frameshift mutations, deletion mutations, and single-nucleotide variants involving numerous genes, includingRB1, NOTCH1, PIK3CA, PDGFRB, EPHA5, KDM6A, NF1,andFLT4genes, were also identified. NGS is useful in identifying targetable mutations in soft tissue sarcomas that can serve as a rationale for inclusion of patients with advanced disease in ongoing clinical trials and allow for better risk stratification.
Journal Article
Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial
This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS). There were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard ketamine dose ameliorated depression measured by the MADRS significantly more than placebo. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 h and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. This clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifier: NCT02655692.
Journal Article
Case 10-2023: A 27-Year-Old Man with Convulsions
A 27-year-old man was evaluated because of ongoing convulsive episodes that occurred despite the use of anticonvulsant medications. MRI of the head was normal. A diagnostic test was performed.
Journal Article
Effects of foot intensive rehabilitation (FIRE) on clinical outcomes for patients with chronic ankle instability: a randomized controlled trial protocol
Lateral ankle sprains account for a large proportion of musculoskeletal injuries among civilians and military service members, with up to 40% of patients developing chronic ankle instability (CAI). Although foot function is compromised in patients with CAI, these impairments are not routinely addressed by current standard of care (SOC) rehabilitation protocols, potentially limiting their effectiveness. The purpose of this randomized controlled trial is to determine if a Foot Intensive REhabilitation (FIRE) protocol is more effective compared to SOC rehabilitation for patients with CAI.
This study will use a three-site, single-blind, randomized controlled trial design with data collected over four data collection points (baseline and post-intervention with 6-, 12-, and 24-month follow-ups) to assess variables related to recurrent injury, sensorimotor function, and self-reported function. A total of 150 CAI patients (50 per site) will be randomly assigned to one of two rehabilitation groups (FIRE or SOC). Rehabilitation will consist of a 6-week intervention composed of supervised and home exercises. Patients assigned to SOC will complete exercises focused on ankle strengthening, balance training, and range of motion, while patients assigned to FIRE will complete a modified SOC program along with additional exercises focused on intrinsic foot muscle activation, dynamic foot stability, and plantar cutaneous stimulation.
The overall goal of this trial is to compare the effectiveness of a FIRE program versus a SOC program on near- and long-term functional outcomes in patients with CAI. We hypothesize the FIRE program will reduce the occurrence of future ankle sprains and ankle giving way episodes while creating clinically relevant improvements in sensorimotor function and self-reported disability beyond the SOC program alone. This study will also provide longitudinal outcome findings for both FIRE and SOC for up to two years. Enhancing the current SOC for CAI will improve the ability of rehabilitation to reduce subsequent ankle injuries, diminish CAI-related impairments, and improve patient-oriented measures of health, which are critical for the immediate and long-term health of civilians and service members with this condition. Trial Registration Clinicaltrials.gov Registry: NCT #NCT04493645 (7/29/20).
Journal Article
The effectiveness of 6 versus 12-months of dialectical behaviour therapy for borderline personality disorder: the feasibility of a shorter treatment and evaluating responses (FASTER) trial protocol
Although Dialectical Behaviour Therapy (DBT) is an evidence-based psychosocial treatment for borderline personality disorder (BPD), the demand for it exceeds available resources. The commonly researched 12-month version of DBT is lengthy; this can pose a barrier to its adoption in many health care settings. Further, there are no data on the optimal length of psychotherapy for BPD. The aim of this study is to examine the clinical and cost-effectiveness of 6 versus 12 months of DBT for chronically suicidal individuals with BPD. A second aim of this study is to determine which patients are as likely to benefit from shorter treatment as from longer treatment.
Powered for non-inferiority testing, this two-site single-blind trial involves the random assignment of 240 patients diagnosed with BPD to 6 or 12 months of standard DBT. The primary outcome is the frequency of suicidal or non-suicidal self-injurious episodes. Secondary outcomes include healthcare utilization, psychiatric and emotional symptoms, general and social functioning, and health status. Cost-effectiveness outcomes will include the cost of providing each treatment as well as health care and societal costs (e.g., missed work days and lost productivity). Assessments are scheduled at pretreatment and at 3-month intervals until 24 months.
This is the first study to directly examine the dose-effect of psychotherapy for chronically suicidal individuals diagnosed with BPD. Examining both clinical and cost effectiveness in 6 versus 12 months of DBT will produce answers to the question of how much treatment is good enough. Information from this study will help to guide decisions about the allocation of scarce treatment resources and recommendations about the benefits of briefer treatment.
NCT02387736 . Registered February 20, 2015.
Journal Article
The development of summary components for the Disablement in the Physically Active scale in collegiate athletes
Purpose The Disablement in the Physically Active scale (DPA) is a generic patient-reported outcome designed to evaluate constructs of disability in physically active populations. The purpose of this study was to analyze the DPA scale structure for summary components. Methods Four hundred and fifty-six collegiate athletes completed a demographic form and the DPA. A principal component analysis (PCA) was conducted with oblique rotation. Factors with eigenvalues >1 that explained >5 % of the variance were retained. Results The PCA revealed a two-factor structure consistent with paradigms used to develop the original DPA. Items 1-12 loaded on Factors 1 and Items 13-16 loaded on Factor 2. Items 1-12 pertain to impairment, activity limitations, and participation restrictions. Items 13-16 address psychosocial and emotional well-being. Consideration of item content suggested Factor 1 concerned physical function, while Factor 2 concerned mental wellbeing. Thus, items clustered around Factor 1 and 2 were identified as physical (DPA-PSC) and mental (DPA-MSC) summary components, respectively. Together, the factors accounted for 65.1 % of the variance. Conclusions The PCA revealed a two-factor structure for the DPA that resulted in DPA-PSC and DPA-MSC. Analyzing the DPA as separate constructs may provide distinct information that could help to prescribe treatment and rehabilitation strategies.
Journal Article