Rainfall and sentinel chicken seroconversions predict human cases of Murray Valley encephalitis in the north of Western Australia

Background Murray Valley encephalitis virus (MVEV) is a flavivirus that occurs in Australia and New Guinea. While clinical cases are uncommon, MVEV can cause severe encephalitis with high mortality. Sentinel chicken surveillance is used at many sites around Australia to provide an early warning system for risk of human infection in areas that have low population density and geographical remoteness. MVEV in Western Australia occurs in areas of low population density and geographical remoteness, resulting in logistical challenges with surveillance systems and few human cases. While epidemiological data has suggested an association between rainfall and MVEV activity in outbreak years, it has not been quantified, and the association between rainfall and sporadic cases is less clear. In this study we analysed 22 years of sentinel chicken and human case data from Western Australia in order to evaluate the effectiveness of sentinel chicken surveillance for MVEV and assess the association between rainfall and MVEV activity. Methods Sentinel chicken seroconversion, human case and rainfall data from the Kimberley and Pilbara regions of Western Australia from 1990 to 2011 were analysed using negative binomial regression. Sentinel chicken seroconversion and human cases were used as dependent variables in the model. The model was then tested against sentinel chicken and rainfall data from 2012 and 2013.Results Sentinel chicken seroconversion preceded all human cases except two in March 1993. Rainfall in the prior three months was significantly associated with both sentinel chicken seroconversion and human cases across the regions of interest. Sentinel chicken seroconversion was also predictive of human cases in the models. The model predicted sentinel chicken seroconversion in the Kimberley but not in the Pilbara, where seroconversions early in 2012 were not predicted. The latter may be due to localised MVEV activity in isolated foci at dams, which do not reflect broader virus activity in the region. Conclusions We showed that rainfall and sentinel chickens provide a useful early warning of MVEV risk to humans across endemic and epidemic areas, and that a combination of the two indicators improves the ability to assess MVEV risk and inform risk management measures

Contributions to Statistical Testing, Prediction, and Modeling

1. Parametric Bootstrap (PB) and Objective Bayesian (OB) Testing with Applications to Heteroscedastic ANOVA : For one-way heteroscedastic ANOVA, we show a close relationship between the PB and OB approaches to significance testing, demonstrating the conditions for which the two approaches are equivalent. Using a simulation study, PB and OB performance is compared to a test based on the predictive distribution as well as the unweighted test of Akritas & Papadatos (2004). We extend this work to the RCBD with subsampling model, and prove a repeated sampling property and large sample property for general OB significance testing. 2. Early Identification of Binswanger\u27s Disease Patients Using Random Forests : We use cross validation to compare several methods for predicting if vascular dementia patients are of the Binswanger type or if they more likely suffer from some other small vessel disease. We investigate which biomarkers are most important for classification, and see that a random forest algorithm accurately identifies Binswanger\u27s patients years before a clinical diagnosis can be ascertained. 3. High-Throughput Gene Expression Analysis Under the Case-Cohort Study Design : The case-cohort study design blends the efficiency of case control studies with the philosophical soundness of full cohort studies, and presents an efficient way to analyze survival data, particularly for large cohorts with low failure rates. Using a tandem of real data examples and simulation studies, we investigate the performance of the most popular case-cohort analysis approaches in the context of high-dimensional biomarker evaluation

Covid-19 Mortality and Contemporaneous Air Pollution

We examine the relationship between contemporaneous fine particulate matter exposure and COVID-19 morbidity and mortality using an instrumental variable approach based on wind direction. Harnessing daily changes in county-level wind direction, we show that arguably exogenous fluctuations in local air quality impact the rate of confirmed cases and deaths from COVID-19. In our preferred high dimensional fixed effects specification with state-level policy and social distancing controls, we find that a one μg/m3 increase in PM 2.5 increases the number of confirmed cases by roughly 2% from the mean case rate in a county. These effects tend to increase in magnitude over longer time horizons, being twice as large over a 3-day period. Meanwhile, a one μg/m3 increase in PM 2.5 increases the same-day death rate by 3% from the mean. Our estimates are robust to a host of sensitivity tests. These results suggest that air pollution plays an important role in mediating the severity of respiratory syndromes such as COVID-19, for which progressive respiratory failure is the primary cause of death, and that policy levers to improve air quality may lead to improvements in COVID-19 outcomes

The effects of contemporaneous air pollution on COVID-19 morbidity and mortality

We examine the relationship between contemporaneous fine particulate matter exposure and COVID-19 morbidity and mortality using an instrumental variable approach. Harnessing daily changes in county-level wind direction, we show that arguably exogenous fluctuations in local air quality impact the incidence of confirmed COVID-19 cases and deaths. We find that a one μg/m3 increase in PM 2.5, or 15% of the average PM 2.5 concentration in a county, increases the number of same-day confirmed cases by 1.8% from the mean case incidence in a county. A one μg/m3 increase in PM 2.5 increases the same-day death rate by just over 4% from the mean. These effects tend to increase in magnitude over longer time horizons and are robust to a host of sensitivity tests. When analyzing potential mechanisms, we also demonstrate that an additional unit of PM 2.5 increases COVID-19-related hospitalizations by 0.8% and use of intensive care units by 0.5% on the same day. Using individual case records, we also show that higher PM 2.5 exposure at the time of case confirmation increases risk of later mechanical ventilation and mortality. These results suggest that air pollution plays an important role in mediating the severity of respiratory syndromes such as COVID-19

MMP-9 inhibitors impair learning in spontaneously hypertensive rats.

Vascular cognitive impairment dementia (VCID) is a major cause of cognitive loss in the elderly. Matrix metalloproteinases (MMPs) are a family of proteases involved in remodeling the extracellular matrix in development, injury and repair. Blood-brain barrier (BBB) disruption due to inflammation mediated by MMPs is a mechanism of white matter injury. Currently there are no treatments besides the control of vascular risk factors. We tested two MMP-9 inhibitors that improved outcome in acute stroke: DP-460 and SB-3CT. We hypothesized that these inhibitors would have a beneficial effect in chronic stroke by reducing edema in white matter and improving behavioral outcomes. Spontaneously hypertensive stroke-prone rats (SHRSPs) with unilateral carotid artery occlusion (UCAO) fed a Japanese Permissive Diet (JPD) were used as a model of VCID. JPD was begun in the 12th week of life. Rats were treated with DP-460 (500 mg/kg) for 4 weeks, or SB-3CT (10 mg/kg) for 8 weeks, beginning at the UCAO/JPD onset. Rats treated with a dextrose or DMSO solution served as vehicle controls. Naïve SHRSPs on a standard diet served as sham control. Magnetic resonance imaging (MRI) analyses of the corpus callosum, external capsule, hippocampus and Morris water maze behavioral tests were conducted. We found an increase in body weight (p = 0.004) and blood pressure (p = 0.007) at 15 weeks with the DP-460 drug. SB-3CT increased body weight at 14 weeks (p = 0.015) and had significant but variable effects on blood pressure. Neither drug affected imaging parameters. Behavioral studies showed an impaired ability to learn with DP-460 (p<0.001) and no effect on learning with SB-3CT. Unchanged MMP-9 levels were detected in DP-460-treated rats via gel zymography. Our findings suggest that MMPs are not major factors in white matter damage in the SHRSP model of VCID and that drugs that are relatively selective for MMP-9 can interfere with learning

Long-term Follow-up of Patients with Relapsed or Refractory Non–Hodgkin Lymphoma Treated with Venetoclax in a Phase I, First-in-Human StudyLong-term Outcomes of R/R NHL Pts Treated with Venetoclax

PurposeWe previously reported a 44% overall response rate (ORR) with the oral BCL-2 inhibitor venetoclax in a phase I study of relapsed/refractory non-Hodgkin lymphoma (NHL). Complete response (CR) was observed in patients with mantle cell lymphoma [(MCL), 21%, n = 6/28] and follicular lymphoma [(FL), 17%, n = 5/29], and partial response (PR) noted in several patients with Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). Here, we report the long-term outcomes of these four cohorts.Patients and methodsAll patients (n = 106) received venetoclax monotherapy in dose cohorts of 200 to 1,200 mg daily until disease progression or unacceptable toxicity. ORR, progression-free survival (PFS), duration of response (DoR), and adverse events (AEs) were evaluated.ResultsAt a median follow-up of 38.5 months (range, 30.0-46.5), the median PFS for all 106 patients was 5.4 [95% confidence interval (CI), 3.5-8.4] months (FL, 10.8; MCL, 11.3; MZL, 21.2; and WM, 30.4). The median DoR was 14.9 (95% CI, 9.7-27.6) months (FL, 26.6; MCL, 15.7; MZL, 20.1; and WM, 25.3). Achievement of CR versus PR predicted longer DoR in both MCL (31.5 vs. 10.1 months) and FL (37.6 vs. 9.7 months). All grade hematologic AEs were infrequent: neutropenia (19%), anemia (19%), and thrombocytopenia (17%), with no new cytopenias after 2 years on therapy. Nonhematologic AEs included nausea (49%), diarrhea (46%), fatigue (44%), with decreased incidence after 1 year.ConclusionsVenetoclax monotherapy has a manageable safety profile and achieves durable responses in a subset of patients with FL, MCL, WM, and MZL, particularly in those who achieve CR. Further research is warranted on combination strategies to enhance the durability of response to venetoclax

Targeting BCL ‐2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma

International audienceVenetoclax (Ven) is a selective small-molecule inhibitor of BCL-2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open-label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21-day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL-2) and BCL2L1 (BCL-XL ) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow-up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF-kB. VenDex demonstrated efficacy and manageable safety in heavily-pre-treated patients with t(11;14) R/R MM