Determination of precipitation return values in complex terrain and their evaluation

To determine return values at various return periods for extreme daily precipitation events over complex orography, an appropriate threshold value and distribution function are required. The return values are calculated using the peak-over-threshold approach in which only a reduced sample of precipitation events exceeding a predefined threshold is analyzed. To fit the distribution function to the sample, the L-moment method is used. It is found that the deviation between the fitted return values and the plotting positions of the ranked precipitation events is smaller for the kappa distribution than for the generalized Pareto distribution. As a second focus, the ability of regional climate models to realistically simulate extreme daily precipitation events is assessed. For this purpose the return values are derived using precipitation events exceeding the 90th percentile of the precipitation time series and a fit of a kappa distribution. The results of climate simulations with two different regional climate models are analyzed for the 30-yr period 1971-2000: the so-called consortium runs performed with the climate version of the Lokal Modell (referred to as the CLM-CR) at 18-km resolution and the Regional Model (REMO)-Umweltbundesamt (UBA) simulations at 10-km resolution. It was found that generally the return values are overestimated by both models. Averaged across the region the overestimation is higher for REMO-UBA compared to CLM-CR

Formulation and stabilization of a recombinant human Cytomegalovirus vector for use as a candidate vaccine for HIV-1

Vaccination using Cytomegalovirus (CMV) vectors have recently shown promising results in conferring protection in non-human primates against SIV and Mycobacterium tuberculosis infection (1-3). Since CMV vectors can stimulate the production of high concentrations of systemic effector memory T-cells, CMV vectors (containing the appropriate insert) have the potential to clear SIV/HIV and Mycobacterium tuberculosis infection, provided administration occurs at the onset of infection (1, 3). Despite the promising animal data, CMV vectors are prone to potency loss (i.e., degradation) by freeze-thaw and storage at 2-8°C. In this study, we wished to develop formulations with increased freeze-thaw and liquid stability for a recombinant human CMV vector (rHCMV-1) for use in initial clinical trials including i) reduce vector potency loss to \u3c0.5 log after 1 freeze-thaw cycle and ii) reduce vector potency loss to \u3c0.5 log after 4 hours at 2-8°C storage. To achieve these goals, we screened a library of ~50 pharmaceutical excipients and evaluated their effect on vector potency after 3 freeze-thaw cycles or incubation at 4°C for several days. We found that certain additives completely protected rHCMV-1 against freeze-thaw mediated potency loss. With regards to liquid stability, we found certain additives slowed the rate of rHCMV-1 titer loss when stored at 4°C. After screening various excipient combinations, we evaluated three candidate formulations and benchmarked them against the bulk drug substance (BDS) formulation buffer and another published formulation (4). The candidate formulations were significantly more stable than the formulations used for benchmarking in terms reducing rHCMV-1 titer loss due to freeze-thaw and incubation at 4°C for up to 30 days. Despite providing greater stability than the current BDS formulation buffer, rHCMV-1 titer loss was still observed at 4°C as a function of incubation time, which suggests further stabilization (i.e., lyophilization) is likely necessary for longer term development. This study highlights the utility of empirical design of a liquid formulation of a live viral vector where freeze-thaw and short-term liquid storage are necessary. References S. G. Hansen et al., Prevention of tuberculosis in rhesus macaques by a cytomegalovirus-based vaccine. Nat Med 24, 130-143 (2018). S. G. Hansen et al., Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473, 523-527 (2011). S. G. Hansen et al., Immune clearance of highly pathogenic SIV infection. Nature 502, 100-104 (2013). T.-M. Fu, D. Wang, M. B. Medi, M. S. D. Corp, Ed. (2013). Acknowledgements: This work was funded by the Bill and Melinda Gates Foundation. *Current affiliation: Bill and Melinda Gates Foundation

Rationale and design: telepsychology service delivery for depressed elderly veterans

BACKGROUND: Older adults who live in rural areas experience significant disparities in health status and access to mental health care. "Telepsychology," (also referred to as "telepsychiatry," or "telemental health") represents a potential strategy towards addressing this longstanding problem. Older adults may benefit from telepsychology due to its: (1) utility to address existing problematic access to care for rural residents; (2) capacity to reduce stigma associated with traditional mental health care; and (3) utility to overcome significant age-related problems in ambulation and transportation. Moreover, preliminary evidence indicates that telepsychiatry programs are often less expensive for patients, and reduce travel time, travel costs, and time off from work. Thus, telepsychology may provide a cost-efficient solution to access-to-care problems in rural areas. METHODS: We describe an ongoing four-year prospective, randomized clinical trial comparing the effectiveness of an empirically supported treatment for major depressive disorder, Behavioral Activation, delivered either via in-home videoconferencing technology ("Telepsychology") or traditional face-to-face services ("Same-Room"). Our hypothesis is that inhome Telepsychology service delivery will be equally effective as the traditional mode (Same-Room). Two-hundred twenty-four (224) male and female elderly participants will be administered protocol-driven individual Behavioral Activation therapy for depression over an 8-week period; and subjects will be followed for 12-months to ascertain longer-term effects of the treatment on three outcomes domains: (1) clinical outcomes (symptom severity, social functioning); (2) process variables (patient satisfaction, treatment credibility, attendance, adherence, dropout); and (3) economic outcomes (cost and resource use). DISCUSSION: Results from the proposed study will provide important insight into whether telepsychology service delivery is as effective as the traditional mode of service delivery, defined in terms of clinical, process, and economic outcomes, for elderly patients with depression residing in rural areas without adequate access to mental health services. TRIAL REGISTRATION: National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov identifier# NCT00324701)

Disseminating Evidence-Based Practices for Adults With PTSD and Severe Mental Illness in Public-Sector Mental Health Agencies

Posttraumatic stress disorder (PTSD) remains largely untreated among adults with severe mental illnesses (SMI). The treatment of psychotic symptoms usually takes precedence in the care of adults with SMI. Such oversight is problematic in that PTSD in SMI populations is common (19-43%), contributes a significant illness burden, and hinders mental health care. Yet, few public-sector mental health agencies routinely provide specialized services for PTSD. The purpose of the paper is to describe strategies and efforts to disseminate trauma-focused empirically-based practices (EBPs) in a public-sector mental health system. Identified challenges include limited resources and commitment; knowledge deficits, attitudes, and biases; and limited practice accountability at provider, facility, and system levels. Proposed strategies for overcoming these challenges are: set clear goals; nurture broad-based organizational commitment and key stakeholder involvement; implement specialty training efforts to provide information and change attitudes; provide on-going supervision; conduct fidelity monitoring; and ensure accountability to the extent possible

Aganirsen Antisense Oligonucleotide Eye Drops Inhibit Keratitis-Induced Corneal Neovascularization and Reduce Need for Transplantation: The I-CAN Study.

OBJECTIVE: Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation. DESIGN: Multicenter, double-masked, randomized, placebo-controlled phase III study. PARTICIPANTS: Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 μg/day/eye) or placebo twice daily for 90 days and were followed up to day 180. MAIN OUTCOME MEASURES: The primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL. RESULTS: Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment-related. CONCLUSIONS: This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated

Branched-Chain Amino Acids and Risk of Breast Cancer

Background Circulating branched-chain amino acid (BCAA) levels reflect metabolic health and dietary intake. However, associations with breast cancer are unclear. Methods We evaluated circulating BCAA levels and breast cancer risk within the Nurses’ Health Study (NHS) and NHSII (1997 cases and 1997 controls). A total of 592 NHS women donated 2 blood samples 10 years apart. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer risk in multivariable logistic regression models. We conducted an external validation in 1765 cases in the Women’s Health Study (WHS). All statistical tests were 2-sided. Results Among NHSII participants (predominantly premenopausal at blood collection), elevated circulating BCAA levels were associated with lower breast cancer risk (eg, isoleucine highest vs lowest quartile, multivariable OR = 0.86, 95% CI = 0.65 to 1.13, Ptrend = .20), with statistically significant linear trends among fasting samples (eg, isoleucine OR = 0.74, 95% CI = 0.53 to 1.05, Ptrend = .05). In contrast, among postmenopausal women, proximate measures (\u3c10 years from blood draw) were associated with increased breast cancer risk (eg, isoleucine OR = 1.63, 95% CI = 1.12 to 2.39, Ptrend = .01), with stronger associations among fasting samples (OR = 1.73, 95% CI = 1.15 to 2.61, Ptrend = .01). Distant measures (10-20 years since blood draw) were not associated with risk. In the WHS, a positive association was observed for distant measures of leucine among postmenopausal women (OR = 1.23, 95% CI = 0.96 to 1.58, Ptrend = .04). Conclusions No statistically significant associations between BCAA levels and breast cancer risk were consistent across NHS and WHS or NHSII and WHS. Elevated circulating BCAA levels were associated with lower breast cancer risk among predominantly premenopausal NHSII women and higher risk among postmenopausal women in NHS but not in the WHS. Additional studies are needed to understand this complex relationship