A multisite study of performance drivers among institutional review boards.

Introduction:The time required to obtain Institutional Review Board (IRB) approval is a frequent subject of efforts to reduce unnecessary delays in initiating clinical trials. This study was conducted by and for IRB directors to better understand factors affecting approval times as a first step in developing a quality improvement framework. Methods:807 IRB-approved clinical trials from 5 University of California campuses were analyzed to identify operational and clinical trial characteristics influencing IRB approval times. Results:High workloads, low staff ratios, limited training, and the number and types of ancillary reviews resulted in longer approval times. Biosafety reviews and the need for billing coverage analysis were ancillary reviews that contributed to the longest delays. Federally funded and multisite clinical trials had shorter approval times. Variability in between individual committees at each institution reviewing phase 3 multisite clinical trials also contributed to delays for some protocols. Accreditation was not associated with shorter approval times. Conclusions:Reducing unnecessary delays in obtaining IRB approval will require a quality improvement framework that considers operational and study characteristics as well as the larger institutional regulatory environment

Changing the malaria treatment protocol policy in Timor-Leste: an examination of context, process, and actors’ involvement

In 2007 Timor-Leste, a malaria endemic country, changed its Malaria Treatment Protocol for uncomplicated falciparum malaria from sulphadoxine-pyrimethamine to artemether-lumefantrine. The change in treatment policy was based on the rise in morbidity due to malaria and perception of increasing drug resistance. Despite a lack of nationally available evidence on drug resistance, the Ministry of Health decided to change the protocol. The policy process leading to this change was examined through a qualitative study on how the country developed its revised treatment protocol for malaria. This process involved many actors and was led by the Timor-Leste Ministry of Health and the WHO country office. This paper examines the challenges and opportunities identified during this period of treatment protocol change

Spin polarized transport current in n-type co-doped ZnO thin films measured by Andreev spectroscopy

We use point contact Andreev reflection measurements to determine the spin polarization of the transport current in pulse laser deposited thin films of ZnO with 1% Al and with and without 2%Mn. Only films with Mn are ferromagnetic and show spin polarization of the transport current of up to 55 $\pm$ 0.5% at 4.2 K, in sharp contrast to measurements of the nonmagnetic films without Mn where the polarization is consistent with zero. Our results imply strongly that ferromagnetism in these Al doped ZnO films requires the presence of Mn.Comment: Published versio

The use of remotely sensed environmental parameters for spatial and temporal schistosomiasis prediction across climate zones in Ghana

Schistosomiasis control in sub-Saharan Africa is enacted primarily through preventive chemotherapy. Predictive models can play an important role in filling knowledge gaps in the distribution of the disease and help guide the allocation of limited resources. Previous modeling approaches have used localized cross-sectional survey data and environmental data typically collected at a discrete point in time. In this analysis, 8 years (2008-2015) of monthly schistosomiasis cases reported into Ghana's national surveillance system were used to assess temporal and spatial relationships between disease rates and three remotely sensed environmental variables: land surface temperature (LST), normalized difference vegetation index (NDVI), and accumulated precipitation (AP). Furthermore, the analysis was stratified by three major and nine minor climate zones, defined using a new climate classification method. Results showed a downward trend in reported disease rates (~ 1% per month) for all climate zones. Seasonality was present in the north with two peaks (March and September), and in the middle of the country with a single peak (July). Lowest disease rates were observed in December/January across climate zones. Seasonal patterns in the environmental variables and their associations with reported schistosomiasis infection rates varied across climate zones. Precipitation consistently demonstrated a positive association with disease outcome, with a 1-cm increase in rainfall contributing a 0.3-1.6% increase in monthly reported schistosomiasis infection rates. Generally, surveillance of neglected tropical diseases (NTDs) in low-income countries continues to suffer from data quality issues. However, with systematic improvements, our approach demonstrates a way for health departments to use routine surveillance data in combination with publicly available remote sensing data to analyze disease patterns with wide geographic coverage and varying levels of spatial and temporal aggregation.Accepted manuscrip

ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects.

BackgroundDolutegravir (DTG), a once-daily, human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF).MethodsING116070 is an ongoing, single-arm, open-label, multicenter study in antiretroviral therapy-naive, HIV-1-infected adults. Subjects received DTG (50 mg) plus abacavir/lamivudine (600/300 mg) once daily. The CSF and plasma (total and unbound) DTG concentrations were measured at weeks 2 and 16. The HIV-1 RNA levels were measured in CSF at baseline and weeks 2 and 16 and in plasma at baseline and weeks 2, 4, 8, 12, and 16.ResultsThirteen white men enrolled in the study; 2 withdrew prematurely, 1 because of a non-drug-related serious adverse event (pharyngitis) and 1 because of lack of treatment efficacy. The median DTG concentrations in CSF were 18 ng/mL (range, 4-23 ng/mL) at week 2 and 13 ng/mL (4-18 ng/mL) at week 16. Ratios of DTG CSF to total plasma concentration were similar to the unbound fraction of DTG in plasma. Median changes from baseline in CSF (n = 11) and plasma (n = 12) HIV-1 RNA were -3.42 and -3.04 log10 copies/mL, respectively. Nine of 11 subjects (82%) had plasma and CSF HIV-1 RNA levels <50 copies/mL and 10 of 11 (91%) had CSF HIV-1 RNA levels <2 copies/mL at week 16.ConclusionsThe DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/mL), suggesting that DTG achieves therapeutic concentrations in the central nervous system. The HIV-1 RNA reductions were similar in CSF and plasma. Clinical Trials Registration. NCT01499199

Melanoma LAMP-2C Modulates Tumor Growth and Autophagy

Autophagy plays critical but diverse roles in cellular quality control and homeostasis potentially checking tumor development by removing mutated or damaged macromolecules, while conversely fostering tumor survival by supplying essential nutrients during cancer progression. This report documents a novel inhibitory role for a lysosome-associated membrane protein, LAMP-2C in modulating autophagy and melanoma cell growth in vitro and in vivo. Solid tumors such as melanomas encounter a variety of stresses in vivo including inflammatory cytokines produced by infiltrating lymphocytes directed at limiting tumor growth and spread. Here, we report that in response to the anti-tumor, pro-inflammatory cytokine interferon-gamma, melanoma cell expression of LAMP2C mRNA significantly increased. These results prompted an investigation of whether increased melanoma cell expression of LAMP-2C might represent a mechanism to control or limit human melanoma growth and survival. In this study, enhanced expression of human LAMP-2C in melanoma cells perturbed macroautophagy and chaperone-mediated autophagy in several human melanoma lines. In vitro analysis showed increasing LAMP-2C expression in a melanoma cell line, triggered reduced cellular LAMP-2A and LAMP-2B protein expression. Melanoma cells with enhanced LAMP-2C expression displayed increased cell cycle arrest, increased expression of the cell cycle regulators Chk1 and p21, and greater apoptosis and necrosis in several cell lines tested. The increased abundance of Chk1 protein in melanoma cells with increased LAMP-2C expression was not due to higher CHEK1 mRNA levels, but rather an increase in Chk1 protein abundance including Chk1 molecules phosphorylated at Ser345. Human melanoma cell xenografts with increased LAMP-2C expression, displayed reduced growth in immune compromised murine hosts. Melanomas with high LAMP-2C expression showed increased necrosis and reduced cell density upon histological analysis. These results reveal a novel role for LAMP-2C in negatively regulating melanoma growth and survival

The Stargazin-Related Protein {gamma}7 Interacts with the mRNA-Binding Protein Heterogeneous Nuclear Ribonucleoprotein A2 and Regulates the Stability of Specific mRNAs, Including CaV2.2

The role(s) of the novel stargazin-like {gamma}-subunit proteins remain controversial. We have shown previously that the neuron-specific {gamma}7 suppresses the expression of certain calcium channels, particularly CaV2.2, and is therefore unlikely to operate as a calcium channel subunit. We now show that the effect of {gamma}7 on CaV2.2 expression is via an increase in the degradation rate of CaV2.2 mRNA and hence a reduction of CaV2.2 protein level. Furthermore, exogenous expression of {gamma}7 in PC12 cells also decreased the endogenous CaV2.2 mRNA level. Conversely, knockdown of endogenous {gamma}7 with short-hairpin RNAs produced a reciprocal enhancement of CaV2.2 mRNA stability and an increase in endogenous calcium currents in PC12 cells. Moreover, both endogenous and expressed {gamma}7 are present on intracellular membranes, rather than the plasma membrane. The cytoplasmic C terminus of {gamma}7 is essential for all its effects, and we show that {gamma}7 binds directly via its C terminus to a heterogeneous nuclear ribonucleoprotein (hnRNP A2), which also binds to a motif in CaV2.2 mRNA, and is associated with native CaV2.2 mRNA in PC12 cells. The expression of hnRNP A2 enhances CaV2.2 IBa, and this enhancement is prevented by a concentration of {gamma}7 that alone has no effect on IBa. The effect of {gamma}7 is selective for certain mRNAs because it had no effect on {alpha}2{delta}-2 mRNA stability, but it decreased the mRNA stability for the potassium-chloride cotransporter, KCC1, which contains a similar hnRNP A2 binding motif to that in CaV2.2 mRNA. Our results indicate that {gamma}7 plays a role in stabilizing CaV2.2 mRNA

Safety and pharmacokinetics of MM-302, a HER2-targeted antibody–liposomal doxorubicin conjugate, in patients with advanced HER2-positive breast cancer: A phase 1 dose-escalation study

BackgroundThis phase 1 dose-escalation trial studied MM-302, a novel HER2-targeted PEGylated antibody-liposomal doxorubicin conjugate, in HER2-positive locally advanced/metastatic breast cancer.MethodsPatients were enrolled in four cohorts: MM-302 monotherapy (8, 16, 30, 40, and 50 mg/m2 every 4 weeks [q4w]); MM-302 (30 or 40 mg/m2 q4w) plus trastuzumab (4 mg/kg q2w); MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) q3w; MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) and cyclophosphamide (450 mg/m2) q3w.ResultsSixty-nine patients were treated. The most common adverse events (AEs) were fatigue and nausea. Grade 3/4 AEs of special interest included neutropenia, fatigue, mucosal inflammation, anemia, thrombocytopenia, febrile neutropenia, and palmar-plantar erythrodysesthesia. The MTD was not reached. With MM-302 ≥ 30 mg/m2, overall response rate (ORR) was 13% and median progression-free survival (mPFS) 7.4 months (95% CI: 3·5-10·9) in all arms. In 25 anthracycline-naïve patients, ORR was 28·0% and mPFS 10·9 months (95% CI: 1·8-15·3). Imaging with 64Cu-labeled MM-302 visualized tumor-drug penetrance in tumors throughout the body, including the brain.ConclusionMM-302 monotherapy, in combination with trastuzumab, or trastuzumab plus cyclophosphamide, was well tolerated and showed promising efficacy. The selected phase 2 MM-302 dose was 30 mg/m2 plus 6 mg/kg trastuzumab q3w