ELUCIDATING THE ROLE OF NIDOGEN IN THE FUSION OF THE CHOROID FISSURE

In the developing embryo, the timely fusion of opposing epithelial sheets into one uniform layer denotes the completion of several developmental events. Failure of this epithelial sheet fusion event (ESF) within the choroid fissure (CF) is associated with the congenital disorder Ocular Coloboma, and is one of the leading causes of pediatric blindness. A requirement for a highly coordinated dismantling of the basement membrane (BM) to allow for fusion to occur is undoubted, however the underlying mechanisms of this process are poorly understood. Due to its BM crosslinking capabilities, I have hypothesized that the regulation of nidogen plays a crucial role in the disassembly of the BM prior to ESF. Whole mount in situ hybridization for all four BM components has revealed that expression of nidogen decreases prior to that of other BM components. Additionally, preliminary IHC data has revealed nidogen and collagenIV deposition within the CF. Further, knock-down of nidogen1a and 1b, or the expression of dominant negative nidogen1b resulted in gross morphological, as well as BM organization defects in developing eyes. Together, these data suggest that nidogen plays a role in regulating the integrity of the BM of the eye and may play a role in its disassembly prior to ESF

The foundations of inference and its application to fundamental physics

This thesis concerns the foundations of inference – probability theory,entropic inference, information geometry, etc. – and its application to the Entropic Dynamics (ED) approach to Quantum Mechanics (QM) [21, 22, 41, 53, 56–61, 150–153, 165, 195, 196, 268]. The first half of this thesis, chapters 2-6, concern the development of the inference framework. We begin in chapter 2 by discussing de- ductive inference, which involves formal logic and it’s role in access- ing the truth of propositions. We eventually discover that deductive inference is incomplete, in that it can’t address situations in which we have incomplete information. This necessitates a theory of inductive inference (probability theory), which is developed in chapter 3. Prob- ability theory is derived as a framework for manipulating degrees of belief of propositions, in a way which is consistent with its deduc- tive counterpart [47]. In chapter 4 we review the construction of en- tropic inference as a means for updating our beliefs in the presence of new information. The entropy functional is designed through the pro- cess of eliminative induction by imposing a principle of minimal updating (PMU) and various constraints [47, 238, 242, 266, 267]. Chapter 5 con- siders the design of another entropic functional, the total correlation and all its variants, for the purposes of ranking join distributions with respect to their correlations [46]. Finally, in chapter 6, we discuss the application of a special case of the correlation functionals from chap- ter 5, the mutual information, to problems in experimental physics and machine learning [42–45]. The second half of this thesis, chapters 7-9, concerns the ED ap- proach to QM. In particular, chapters 8 and 9 involve the inclusion of particles with spin 1/2 into the framework [41, 61]. These devel- opments are the main contribution of this thesis to the body of work in the ED approach. The problem is defined as an application of in- ference to the dynamics of quantum particles which have definite yet unknown positions and follow continuous trajectories. Through the method of maximum entropy developed in chapter 4, we can deter- mine the transition probability that these particles will move from one location to another. Geometric algebra (GA) [90, 140] is chosen as the preferred representation for the algebra of spin, which is then introduced through constraints in the maximum entropy method. A quantum mechanics is subsequently developed by constructing an epistemic phase space of probabilities and constraints and imposing that the physically relevant flows in this space are those which preserve a particular metric and symplectic form. These flows lead to a linear Pauli equation for one and two particles with spin

Plasmodium vivax relapse rates following plasmodium falciparum malaria reflect previous transmission intensity

From 2003 through 2009, 687 of 2885 patients (23.8%) treated for Plasmodium falciparum malaria in clinical studies in Myanmar or on the Thailand-Myanmar border had recurrent Plasmodium vivax malaria within 63 days, compared with 18 of 429 patients (4.2%) from 2010 onward (risk ratio [RR], 0.176; 95% confidence interval, .112–.278; P < .0001). Corresponding data from 42 days of follow-up revealed that 820 of 3883 patients (21.1%) had recurrent P. vivax malaria before 2010, compared with 22 of 886 (2.5%) from 2010 onward (RR, 0.117; 95% CI, .077–.177; P < .0001). This 6-fold reduction suggests a recent decline in P. vivax transmission intensity and, thus, a substantial reduction in the proportion of individuals harboring hypnozoites

Declining efficacy of artemisinin combination therapy against P. falciparum malaria on the Thai-Myanmar border (2003-2013): The role of parasite genetic factors.

Background Deployment of mefloquine–artesunate (MAS3) on the Thailand–Myanmar border has led to a sustained reduction in falciparum malaria, although antimalarial efficacy has declined substantially in recent years. The role of Plasmodium falciparum K13 mutations (a marker of artemisinin resistance) in reducing treatment efficacy remains controversial. Methods Between 2003 and 2013, we studied the efficacy of MAS3 in 1005 patients with uncomplicated P. falciparum malaria in relation to molecular markers of resistance. Results Polymerase chain reaction (PCR)–adjusted cure rates declined from 100% in 2003 to 81.1% in 2013 as the proportions of isolates with multiple Pfmdr1 copies doubled from 32.4% to 64.7% and those with K13 mutations increased from 6.7% to 83.4%. K13 mutations conferring moderate artemisinin resistance (notably E252Q) predominated initially but were later overtaken by propeller mutations associated with slower parasite clearance (notably C580Y). Those infected with both multiple Pfmdr1 copy number and a K13 propeller mutation were 14 times more likely to fail treatment. The PCR-adjusted cure rate was 57.8% (95% confidence interval [CI], 45.4, 68.3) compared with 97.8% (95% CI, 93.3, 99.3) in patients with K13 wild type and Pfmdr1 single copy. K13 propeller mutation alone was a strong risk factor for recrudescence (P = .009). The combined population attributable fraction of recrudescence associated with K13 mutation and Pfmdr1 amplification was 82%. Conclusions The increasing prevalence of K13 mutations was the decisive factor for the recent and rapid decline in efficacy of artemisinin-based combination (MAS3) on the Thailand–Myanmar border

Comparison of the cumulative efficacy and safety of chloroquine, artesunate, and chloroquine-primaquine in plasmodium vivax malaria

Background: Chloroquine has been recommended for Plasmodium vivax infections for >60 years, but resistance is increasing. To guide future therapies, the cumulative benefits of using slowly eliminated (chloroquine) vs rapidly eliminated (artesunate) antimalarials, and the risks and benefits of adding radical cure (primaquine) were assessed in a 3-way randomized comparison conducted on the Thailand-Myanmar border. Methods: Patients with uncomplicated P. vivax malaria were given artesunate (2 mg/kg/day for 5 days), chloroquine (25 mg base/kg over 3 days), or chloroquine-primaquine (0.5 mg/kg/day for 14 days) and were followed for 1 year. Recurrence rates and their effects on anemia were compared. Results: Between May 2010 and October 2012, 644 patients were enrolled. Artesunate cleared parasitemia significantly faster than chloroquine. Day 28 recurrence rates were 50% with artesunate (112/224), 8% with chloroquine (18/222; P < .001), and 0.5% with chloroquine-primaquine (1/198; P < .001). Median times to first recurrence were 28 days (interquartile range [IQR], 21–42) with artesunate, 49 days (IQR, 35–74) with chloroquine, and 195 days (IQR, 82–281) with chloroquine-primaquine. Recurrence by day 28, was associated with a mean absolute reduction in hematocrit of 1% (95% confidence interval [CI], .3%–2.0%; P = .009). Primaquine radical cure reduced the total recurrences by 92.4%. One-year recurrence rates were 4.51 (95% CI, 4.19–4.85) per person-year with artesunate, 3.45 (95% CI, 3.18–3.75) with chloroquine (P = .002), and 0.26 (95% CI, .19–.36) with chloroquine-primaquine (P < .001). Conclusions: Vivax malaria relapses are predominantly delayed by chloroquine but prevented by primaquine. Clinical Trials Registration: NCT01074905

A Comparative Analysis of OpenET for Evaluating Evapotranspiration in California Almond Orchards

The almond industry in California faces water management challenges that are being exacerbated by droughts, climate change, and groundwater sustainability legislation. The Tree-crop Remote sensing of Evapotranspiration eXperiment (T-REX) aims to explore opportunities to improve precision irrigation management for woody perennial cropping systems. Almond orchards in the California Central Valley were equipped with eddy covariance flux measurements to evaluate satellite remote sensing-based evapotranspiration (RSET) models. OpenET provides high-resolution (30-m spatial and daily temporal) RSET data, synthesizing decades of research for practical water management. This study provides an evaluation of OpenET performance at six almond sites covering a large range in soils, age, and variety. It also compares OpenET ensemble evapotranspiration (ET) data with applied irrigation and precipitation records over an additional 148 almond orchards located in the Central Valley of California. Results show OpenET models, including the ensemble ET value, produced reasonable and actionable ET values, with overall coefficient of determination (R2) and mean absolute error values of 0.73- and 0.95-mm d−1 at the daily time step, respectively. However, given the temporal sampling of Landsat (8-day revisit) and the interpolation methods used, the assessed ET models had difficulty in capturing short-term variability in almond ET; for example, the rapid decline in measured ET observed as a response to lack of irrigation preceding and during almond harvest. The study also drew attention to the spatial complexity in scenarios where irrigated orchards are surrounded by hot/dry areas, causing discrepancies between measured and modeled ET values. In comparison with irrigation records, OpenET ensemble ET was capable of quantifying water input (applied irrigation + precipitation) in almond orchards to within 13 % when evaluating monthly data. Initial results presented here reinforce the idea that RSET models, such as in OpenET, are powerful tools, yet their application requires nuanced understanding and careful consideration of local conditions

Submicroscopic malaria in pregnancy and associated adverse pregnancy events: A case-cohort study of 4,352 women on the Thailand–Myanmar border

Background: Malaria in pregnancy detected by microscopy is associated with maternal anaemia, reduced fetal growth, and preterm birth, but the effects of lower density (i.e., submicroscopic) malaria infections are poorly characterised. This analysis was undertaken to investigate associations between submicroscopic malaria at the first antenatal care (ANC) visit and these adverse pregnancy events on the Thailand–Myanmar border. Methods: Blood samples taken from refugee and migrant pregnant women presenting for their first ANC visit were analysed retrospectively for malaria using ultrasensitive PCR (uPCR, limit of detection 22 parasites/mL). The relationships between submicroscopic malaria and subsequent microscopically detectable malaria, anaemia, birth weight, and preterm birth were evaluated using inverse probability weighting for stratified random sampling. Results: First ANC visit samples from 4,352 asymptomatic women (median gestational age 16.5 weeks) attending between October 1st 2012 and December 31st 2015 were analysed. The weighted proportion of women with submicroscopic malaria infection was 4.6% (95% CI 3.9–5.6), comprising 59.8% (49.5–69.4) Plasmodium vivax, 6.5% (4.0–10.5) Plasmodium falciparum, 1.8% (0.9–3.6) mixed, and 31.9% (22.2–43.5) infections which could not be speciated. Submicroscopic parasitaemia at first ANC visit was associated with subsequent microscopically detected malaria (adjusted hazard ratio [HR] 12.9, 95% CI 8.8–18.8, p < 0.001) and lower birth weight (adjusted predicted mean difference −275 g, 95% CI −510 to −40, p = 0.022). There was no association with preterm birth. Submicroscopic P. falciparum mono-infection (adjusted HR 2.8, 95% CI 1.2–6.6, p = 0.023) and coinfection with P. falciparum and P. vivax (adjusted HR 10.3, 95% CI 2.6–40.4, p = 0.001) was associated with increased risk of maternal anaemia, but submicroscopic P. vivax mono-infection was not. That uPCR was conducted for only a part of the cohort due to cost constraints is a limitation. Conclusions: In low transmission settings, uPCR identifies substantially more malaria infections at antenatal screening than conventional diagnostic methods. On the Thailand–Myanmar border, submicroscopic malaria at first antenatal consultation was associated with higher risks of microscopically diagnosed malaria later in pregnancy, anaemia, and reduced birth weight

The role of anti-malarial drugs in eliminating malaria

Abstract Effective anti-malarial drug treatment reduces malaria transmission. This alone can reduce the incidence and prevalence of malaria, although the effects are greater in areas of low transmission where a greater proportion of the infectious reservoir is symptomatic and receives anti-malarial treatment. Effective treatment has greater effects on the transmission of falciparum malaria, where gametocytogenesis is delayed, compared with the other human malarias in which peak gametocytaemia and transmissibility coincides with peak asexual parasite densities. Mature Plasmodium falciparum gametocytes are more drug resistant and affected only by artemisinins and 8-aminoquinolines. The key operational question now is whether primaquine should be added to artemisinin combination treatments for the treatment of falciparum malaria to reduce further the transmissibility of the treated infection. Radical treatment with primaquine plays a key role in the eradication of vivax and ovale malaria. More evidence is needed on the safety of primaquine when administered without screening for G6PD deficiency to inform individual and mass treatment approaches in the context of malaria elimination programmes.</p