Background
Deutetrabenazine is approved in the USA, China, Australia, Israel, Brazil, and South Korea for the treatment of chorea associated with Huntington disease.
Objective
We aimed to evaluate ...the long-term safety and tolerability of deutetrabenazine for the treatment of Huntington disease.
Methods
This open-label, single-arm, multi-center study included patients who completed a double-blind study (Rollover) and patients who converted overnight from a stable tetrabenazine dose (Switch). Exposure-adjusted incidence rates (adverse events per person-year) were calculated. Efficacy was analyzed using a stable post-titration timepoint (8 weeks). Changes in the Unified Huntington’s Disease Rating Scale total motor score and total maximal chorea score from baseline to week 8, as well as those from week 8 to week 145 (or the last visit on the study drug if that occurred earlier), were evaluated as both efficacy and safety endpoints during the study.
Results
Of 119 patients (Rollover,
n
= 82; Switch,
n
= 37), 100 (84%) completed ≥ 1 year of treatment. End-of-study exposure-adjusted incidence rates for adverse events in Rollover and Switch, respectively, were: any, 2.57 and 4.02; serious, 0.11 and 0.14; leading to dose suspension, 0.05 and 0.04. Common adverse events (≥ 4% either cohort) included somnolence (Rollover, 20%; Switch, 30%), depression (32%; 22%), anxiety (27%; 35%), insomnia (23%; 16%), and akathisia (6%; 11%). Adverse events of interest included suicidality (9%; 5%) and parkinsonism (4%; 8%). Mean dose at week 8 was 38.1 mg (Rollover) and 36.5 mg (Switch). Mean dose across cohorts after titration was 37.6 mg; at the final visit, mean dose across cohorts was 45.7 mg. Patients showed minimal change in the Unified Huntington’s Disease Rating Scale total maximal chorea scores with stable dosing from weeks 8–145 or at the end of treatment, but total motor score increased versus week 8 (mean change standard deviation: 8.2 11.9). There were no unexpected adverse events upon drug withdrawal, and mean (standard deviation) total maximal chorea scores increased 4.7 (4.6) units from week 8 to 1-week follow-up.
Conclusions
Adverse events observed with long-term deutetrabenazine exposure were consistent with previous studies. Reductions in chorea persisted over time. Upon treatment cessation, there was no unexpected worsening of chorea.
Clinical Trial Registration
ClinicalTrials.gov identifier: NCT01897896.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Asian migrants that settle in countries like NZ learn English in the hope of accessing mainstream society. However, this process presents many challenges to their identities and their sense of self ...worth. This paper explores one migrant's journey. The case study of "Jessica" used a narrative approach to investigate her identity construction in trying to get entry to a degree programme. The study focuses on significant events collected from eight in-depth interviews over a period of eleven months. In the process of being originally denied entry to university, then later accepted, Jessica negotiated the negative and limited identity imposed on her, re-constructing her identity as a university student and successful language learner with increased self-value. The findings indicate the significance of imposed identities on self-value, the importance of identity negotiation and the close link to a sense of belonging in mainstream society. Journeys such as Jessica's hopefully make policy makers and language education providers aware of the importance of the sense of self when supporting migrants who are language learners.
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FFLJ, NUK, ODKLJ, UL, UM, UPUK
Asian migrants that settle in countries like NZ learn English in the hope of accessing mainstream society. However, this process presents many challenges to their identities and their sense of self ...worth. This paper explores one migrant’s journey. The case study of "Jessica" used a narrative approach to investigate her identity construction in trying to get entry to a degree programme. The study focuses on significant events collected from eight in-depth interviews over a period of eleven months. In the process of being originally denied entry to university, then later accepted, Jessica negotiated the negative and limited identity imposed on her, re-constructing her identity as a university student and successful language learner with increased self-value. The findings indicate the significance of imposed identities on self-value, the importance of identity negotiation and the close link to a sense of belonging in mainstream society. Journeys such as Jessica’s hopefully make policy makers and language education providers aware of the importance of the sense of self when supporting migrants who are language learners KCI Citation Count: 0
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FFLJ, NUK, ODKLJ, UL, UM, UPUK
Abstract only
3130
Background: IMpower150 is a phase 3 study measuring the effect of carboplatin and paclitaxel (CP) combined with atezolizumab (A) and/or bevacizumab (B) in patients with advanced ...nonsquamous NSCLC, testing the hypothesis that anti-PD-L1 therapy may be enhanced by the blockade of VEGF. Here, we apply a machine-learning based approach to quantify the tumor micro-environment (TME) and vasculature and identify associations with clinical outcome in IMpower150. Methods: Digitized H&E images were registered onto the PathAI research platform (n=1027). Over 200K annotations from 90 pathologists were used to train convolutional neural networks (CNNs) that classify human-interpretable features (HIFs) of cells and tissue structures from images. Blood vessel compression (BVC) indices were calculated using the long versus short axes for each predicted blood vessel. HIFs were clustered to reduce redundancy, and selected features were associated with progression free survival (PFS) within each arm (ABCP, ACP, and BCP) using Cox proportional hazard models. Results: We used the trained CNNs to generate 4,534 features summarizing each patient’s histopathology and TME. After association with survival and correction for multiple comparisons we identified clusters that were significantly associated with survival in at least one arm. Among patients receiving treatments that target PD-L1 (ABCP and ACP), high lymphocyte to fibroblast ratio (LFR) was associated with improved PFS (HR=0.64 (0.51, 0.81), p < 0.001) and showed no significant association with PFS among patients treated with BCP alone (HR=1.13 (0.85, 1.51), p=0.4). Among BCP treated patients, a higher average BVC within the tumor tissue was associated with improved PFS (HR=0.67 (0.50,0.90), p=0.01) and worse PFS among patients treated with ACP (HR=1.50 (1.10,2.06), p=0.009). Conclusions: We developed a deep learning-based assay for quantifying pathology features of the TME and vasculature from H&E images. Application of this system to Impower150 identified an association between high LFR and improved PFS among patients receiving PD-L1 targeting therapy, and between low BVC and improved PFS among patients receiving BCP. These findings support the importance of the TME and vasculature in determining response to PD-L1 and VEGF-targeting therapies.
Abstract only
e19152
Background: Cancer treatment is becoming more complex, necessitating subspecialty expertise and multidisciplinary approaches to treatment planning. Simultaneously, there is ...increasing demand to provide care as close to home as possible. While tumor boards have long been an institutional backbone to providing high-quality multidisciplinary care in tertiary facilities, connecting several hospitals and dozens of cancer specialists in a large integrated healthcare system is unique and potentially transformational for smaller facilities and communities. Methods: Using highly-secure, network firewall-protected Cisco Telepresence and WebEx capabilities, 11 disease specific tumor boards (Breast, GI, Sarcoma, GU, Thoracic, Head/Neck, Melanoma, Neuro, Heme, Hepatobiliary, Gyn) were organized across Intermountain Healthcare’s 24 geographically and medically diverse hospitals spanning over 500 miles. Meetings for each of these disease-specific tumor boards have been held at least every 1-2 weeks, at set times and days since July 2019. Cases are submitted to the appropriate tumor board by individual providers from anywhere in the system. Submitted cases are reviewed by a designated subspeciality leader. Cases are either added to the system-wide agenda, or at times, the clinical decision can be resolved immediately. Included cases’ records including pathology, radiology and pertinent medical history are obtained for display and discussion. After each tumor board, recommendations and conclusions are recorded by nurse navigators for future review and consultation. Results: From July 2019 to February 2020, 1,598 patient cases were discussed. Just as relevant, 293 unique oncology providers (surgeons, medical oncologists, radiation oncologists, genetic counselors, nurse navigators, and therapists) participated in tumor board discussions. These deliberations provided insight, experience and recommendations directly related to patient care. Conclusions: Our system-wide, disease-specific, multi-disciplinary tumor boards are useful in connecting oncology providers and subspecialists. This effort has led to better collaboration, coordination and delivery of high-quality cancer care to patients throughout a large healthcare system that includes thousands of patients and dozens of cancer providers in smaller/rural communities. In addition, provider engagement has improved. Work is ongoing to prospectively evaluate the effects on treatment decisions and clinical outcomes.
These recommendations for human immunodeficiency virus (HIV) testing are intended for all health-care providers in the public and private sectors, including those working in hospital emergency ...departments, urgent care clinics, inpatient services, substance abuse treatment clinics, public health clinics, community clinics, correctional health-care facilities, and primary care settings. The recommendations address HIV testing in health-care settings only. They do not modify existing guidelines concerning HIV counseling, testing, and referral for persons at high risk for HIV who seek or receive HIV testing in nonclinical settings (e.g., community-based organizations, outreach settings, or mobile vans). The objectives of these recommendations are to increase HIV screening of patients, including pregnant women, in health-care settings; foster earlier detection of HIV infection; identify and counsel persons with unrecognized HIV infection and link them to clinical and prevention services; and further reduce perinatal transmission of HIV in the United States. These revised recommendations update previous recommendations for HIV testing in health-care settings and for screening of pregnant women(CDC. Recommendations for HIV testing services for inpatients and outpatients in acute-care hospital settings. MMWR 1993;42No. RR-2:1–10; CDC. Revised guidelines for HIV counseling, testing, and referral. MMWR 2001;50No. RR-19:1–62; and CDC. Revised recommendations for HIV screening of pregnant women. MMWR 2001;50No. RR-19:63–85).
Major revisions from previously published guidelines are as follows:
For patients in all health-care settings
HIV screening is recommended for patients in all health-care settings after the patient is notified that testing will be performed unless the patient declines (opt-out screening).
Persons at high risk for HIV infection should be screened for HIV at least annually.
Separate written consent for HIV testing should not be required; general consent for medical care should be considered sufficient to encompass consent for HIV testing.
Prevention counseling should not be required with HIV diagnostic testing or as part of HIV screening programs in health-care settings.
For pregnant women
HIV screening should be included in the routine panel of prenatal screening tests for all pregnant women.
HIV screening is recommended after the patient is notified that testing will be performed unless the patient declines (opt-out screening).
Separate written consent for HIV testing should not be required; general consent for medical care should be considered sufficient to encompass consent for HIV testing.
Repeat screening in the third trimester is recommended in certain jurisdictions with elevated rates of HIV infection among pregnant women.
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BFBNIB, NMLJ, NUK, PNG, UL, UM, UPUK
The protein-kinase family is the most frequently mutated gene family found in human cancer and faulty kinase enzymes are being investigated as promising targets for the design of antitumour ...therapies. We have sequenced the gene encoding the transmembrane protein tyrosine kinase ERBB2 (also known as HER2 or Neu) from 120 primary lung tumours and identified 4% that have mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations. ERBB2 inhibitors, which have so far proved to be ineffective in treating lung cancer, should now be clinically re-evaluated in the specific subset of patients with lung cancer whose tumours carry ERBB2 mutations.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. Early antiretroviral therapy (ART) limits proviral reservoirs, a goal for human immunodeficiency virus type 1 (HIV-1) remission strategies. Whether this is an immediate or long-term ...effect of virologic suppression (VS) in perinatal infection is unknown. Methods. We quantified HIV-1 DNA longitudinally for up to 14 years in peripheral blood mononuclear cells (PBMCs) among 61 perinatally HIV-1–infected youths in the Pediatric HIV/AIDS Cohort Study who achieved VS at different ages. Participants in group 1 (n = 13) were <1 year of age and in group 2 (n = 48) from 1 through 5 years of age at VS. Piecewise linear mixed-effects regression models assessed the effect of age at VS on HIV-1 DNA trajectories during VS. Results. In the first 2 years following VS, HIV-1 DNA levels decreased by −0.25 (95% confidence interval CI, −.36 to −.13) log10 copies/million PBMCs per year and was faster with early VS by age 1 year compared with after age 1 (−0.50 and −0.15 log10 copies/million PBMCs per year, respectively). Between years 2 and 14 from VS, HIV-1 DNA decayed by −0.05 (95% CI, −.06 to −.03) log10 copies/million PBMCs per year and was no longer significantly different between groups. The estimated mean half-life of HIV-1 DNA from VS was 15.9 years and was shorter for group 1 compared to group 2 at 5.9 years and 18.8 years, respectively (P = .09). Adjusting for CD4 cell counts had no effect on decay estimates. Conclusions. Early effective, long-term ART initiated from infancy leads to decay of HIV-1–infected cells to exceedingly low concentrations desired for HIV-1 remission strategies.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Isopenicillin
synthase (IPNS) catalyzes the unique reaction of l-δ-(α-aminoadipoyl)-l-cysteinyl-d-valine (ACV) with dioxygen giving isopenicillin
(IPN), the precursor of all natural penicillins and ...cephalosporins. X-ray free-electron laser studies including time-resolved crystallography and emission spectroscopy reveal how reaction of IPNS:Fe(II):ACV with dioxygen to yield an Fe(III) superoxide causes differences in active site volume and unexpected conformational changes that propagate to structurally remote regions. Combined with solution studies, the results reveal the importance of protein dynamics in regulating intermediate conformations during conversion of ACV to IPN. The results have implications for catalysis by multiple IPNS-related oxygenases, including those involved in the human hypoxic response, and highlight the power of serial femtosecond crystallography to provide insight into long-range enzyme dynamics during reactions presently impossible for nonprotein catalysts.
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