Background 
Human movement is a key behavioral factor in many vector-borne disease systems because it influences exposure to vectors and thus the transmission of pathogens. Human movement transcends spatial and temporal scales with different influences on disease dynamics. Here we develop a conceptual model to evaluate the importance of variation in exposure due to individual human movements for pathogen transmission, focusing on mosquito-borne dengue virus.


Methodology and Principal Findings 
We develop a model showing that the relevance of human movement at a particular scale depends on vector behavior. Focusing on the day-biting Aedes aegypti, we illustrate how vector biting behavior combined with fine-scale movements of individual humans engaged in their regular daily routine can influence transmission. Using a simple example, we estimate a transmission rate (R0) of 1.3 when exposure is assumed to occur only in the home versus 3.75 when exposure at multiple locations—e.g., market, friend's—due to movement is considered. Movement also influences for which sites and individuals risk is greatest. For the example considered, intriguingly, our model predicts little correspondence between vector abundance in a site and estimated R0 for that site when movement is considered. This illustrates the importance of human movement for understanding and predicting the dynamics of a disease like dengue. To encourage investigation of human movement and disease, we review methods currently available to study human movement and, based on our experience studying dengue in Peru, discuss several important questions to address when designing a study.


Conclusions/Significance 
Human movement is a critical, understudied behavioral component underlying the transmission dynamics of many vector-borne pathogens. Understanding movement will facilitate identification of key individuals and sites in the transmission of pathogens such as dengue, which then may provide targets for surveillance, intervention, and improved disease prevention.

/pdf/the-role-of-human-movement-in-the-transmission-of-vector-antjucqt2t.pdf

The Role of Human Movement in the Transmission of Vector-Borne Pathogens

In the pursuance of novel scaffolds with promising antiplasmodial and anti-inflammatory activity, a series of twenty-one compounds embraced with most promising penta-substituted pyrrole and biodynamic hydroxybutenolide in single skeleton was designed and synthesized. These pyrrole-hydroxybutenolide hybrids were evaluated against Plasmodium falciparum parasite. Four hybrids 5b, 5d, 5t and 5u exhibited good activity with IC50 of 0.60, 0.88, 0.97 and 0.96 μM for chloroquine sensitive (Pf3D7) strain and 3.92, 4.31, 4.21 and 1.67 μM for chloroquine resistant (PfK1) strain, respectively. In vivo efficacy of 5b, 5d, 5t and 5u was studied against the P. yoelii nigeriensis N67 (a chloroquine-resistant) parasite in Swiss mice at a dose of 100 mg/kg/day for 4 days via oral route. 5u was found to show maximum 100% parasite inhibition with considerably increased mean survival time. Simultaneously, the series of compounds was screened for anti-inflammatory potential. In preliminary assays, nine compounds showed more than 85% inhibition in hu-TNFα cytokine levels in LPS stimulated THP-1 monocytes and seven compounds showed more than 40% decrease in fold induction in reporter gene activity analyzed via Luciferase assay. 5p and 5t were found to be most promising amongst the series, thus were taken up for further in vivo studies. Wherein, mice pre-treated with them showed a dose dependent inhibition in carrageenan induced paw swelling. Moreover, the results of in vitro and in vivo pharmacokinetic parameters indicated that the synthesized pyrrole-hydroxybutenolide conjugates abide by the required criteria for the development of orally active drug and thus this scaffold can be used as pharmacologically active framework that should be considered for the development of potential antiplasmodial and anti-inflammatory agents. 

Design, synthesis and evaluation of novel pyrrole-hydroxybutenolide hybrids as promising antiplasmodial and anti-inflammatory agents.

In low- and middle-income countries (LMICs), inexpensive generic drugs like statins, ACE inhibitors, and ARBs, especially if used in combination, might be the only practical way to save the lives of patients with severe COVID-19. These drugs will already be available in all countries on the first pandemic day. Because they target the host response to infection instead of the virus, they could be used to save lives during any pandemic. Observational studies show that inpatient statin treatment reduces 28–30-day mortality but randomized controlled trials have failed to show this benefit. Combination treatment has been tested for antivirals and dexamethasone but, with the exception of one observational study in Belgium, not for inexpensive generic drugs. Future pandemic research must include testing combination generic drug treatments that could be used in LMICs.

/pdf/treating-covid-19-targeting-the-host-response-not-the-virus-2c8022uj.pdf

Treating COVID-19: Targeting the Host Response, Not the Virus

Background: Statins present a plethora of pleiotropic effects including anti-inflammatory and antimicrobial responses. A,α-difluorophenylacetamides, analogs of diclofenac, are potent pre-clinical anti-inflammatory non-steroidal drugs. Molecular hybridization based on the combination of pharmacophoric moieties has emerged as a strategy for the development of new candidates aiming to obtain multitarget ligands. Methods: Considering the anti-inflammatory activity of phenylacetamides and the potential microbicidal action of statins against obligate intracellular parasites, the objective of this work was to synthesize eight new hybrid compounds of α,α-difluorophenylacetamides with the moiety of statins and assess their phenotypic activity against in vitro models of Plasmodium falciparum and Trypanosoma cruzi infection besides exploring their genotoxicity safety profile. Results: None of the sodium salt compounds presented antiparasitic activity and two acetated compounds displayed mild anti-P. falciparum effect. Against T. cruzi, the acetate halogenated hybrids showed moderate effect against both parasite forms relevant for human infection. Despite the considerable trypanosomicidal activity, the brominated compound revealed a genotoxic profile impairing future in vivo testing. Conclusions: However, the chlorinated derivative was the most promising compound with chemical and biological profitable characteristics, without presenting genotoxicity in vitro, being eligible for further in vivo experiments.

/pdf/antiplasmodial-trypanocidal-and-genotoxicity-in-vitro-18y3shzd.pdf

Antiplasmodial, Trypanocidal, and Genotoxicity In Vitro Assessment of New Hybrid α,α-Difluorophenylacetamide-statin Derivatives

Les classifications et schemas actuels des syndromes secs oculaires ne rendent pas compte de maniere satisfaisante des liens physiopathologiques qui existent entre le film lacrymal et la surface oculaire. Ils presentent les syndromes secs oculaires comme provenant de maladies tres differentes, souvent disparates, qui peuvent entrainer, de maniere separee ou associee, une hyposecretion ou une instabilite du film lacrymal protecteur. Mais ils n’expliquent pas pourquoi certaines maladies peuvent declencher un syndrome sec qui pourra lui-meme evoluer de maniere autonome, independamment de son facteur causal meme lorsque celui-ci a disparu. Nous presentons ici une nouvelle approche physiopathologique de cette pathologie complexe dans laquelle les etiologies ne sont plus des maladies independantes responsables de syndromes secs autonomes, mais bien des points d’entree dans un veritable cercle vicieux biologique faisant intervenir tous les acteurs de la surface oculaire, film lacrymal, conjonctive, cornee, mucocytes, cellules inflammatoires et paupieres. La flore microbienne peut elle-meme jouer un role important par le biais de toxines et d’enzymes qui vont alterer la couche lipidique et contribuer a une instabilite supplementaire du film lacrymal. L’ensemble realise de veritables cercles auto-entretenus. Lorsque l’œil entre dans un tel cycle biologique, meme si la cause initiale a disparu (arret du port de lentilles de contact, suppression de conservateurs toxiques ou de medicaments entrainant une hyposecretion…), le cercle vicieux continue a tourner pour lui-meme et enferme les patients dans une souffrance et une inflammation chroniques. Le but de ce type de schema physiopathologique, dont l’approche mecanistique est tout a fait innovante par rapport aux schemas actuels, est de mieux comprendre pourquoi les patients aux yeux secs sont si souvent enfermes dans une pathologie chronique qui resiste autant a des traitements qui, s’ils ne sont que symptomatiques ou adaptes a un mecanisme isole, ne pourront etre que partiellement efficaces, voire totalement inoperants.

Iconography : Un nouveau schéma pour mieux comprendre les maladies de la surface oculaire

Cerebral malaria (CM) is the most severe neurological complication of malaria caused by Plasmodium falciparum infection. The available antimalarial drugs are effective at clearing the parasite, but the mortality rate remains as high as 20% of CM cases. At the vascular level, CM is characterized by endothelial activation and dysfunction. Several biomarkers of endothelial activation have been associated with CM severity and mortality, making the brain vascular endothelium a potential target for adjunctive therapies. Statins and Angiotensin II Receptor Blockers (ARBs) are drugs used to treat hypercholesterolemia and hypertension, respectively, that have shown endothelial protective activity in other diseases. Here, we used a combination of a statin (atorvastatin) and an ARB (irbesartan) as adjunctive therapy to conventional antimalarial drugs in a mouse experimental model of CM. We observed that administration of atorvastatin–irbesartan combination decreased the levels of biomarkers of endothelial activation, such as the von Willebrand factor and angiopoietin-1. After mice developed neurological signs of CM, treatment with the combination plus conventional antimalarial drugs increased survival rates of animals 3–4 times compared to treatment with antimalarial drugs alone, with animals presenting lower numbers and smaller hemorrhages in the brain. Taken together, our results support the hypothesis that inhibiting endothelial activation would greatly reduce the CM-associated pathology and mortality.

/pdf/treatment-reducing-endothelial-activation-protects-against-6mc074ld.pdf

Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria

Purpose: To evaluate the compliance with 0.1% cyclosporine A in dry eye patients with Sjögren's syndrome and identify factors affecting the compliance. Methods: This study included 67 dry eye patients with Sjögren's syndrome who had used 0.1% cyclosporine A for over 6 months. Clinical parameters including sex, age, the number of eye drops used, side effects, the use of steroid eye drops, and the visit interval were investigated. Additionally, the ocular surface disease index, tear break-up time (TBUT), Schirmer test score, and corneal fluorescein staining (CFS) score were assessed. Patients were classified into compliant and non-compliant groups, using a criterion of 50% compliance; relevant factors were evaluated accordingly. Results: Of the 67 patients, 36 (53.7%) were classified into the compliant group and 31 (46.3%) into the non-compliant group. Compared to the non-compliant group, the compliant group showed a longer TBUT (p = 0.03) and a lower CFS score (p = 0.04) at 6 months of follow-up. Altogether, 39 subjects (58.2%) experienced side effects, of which the most common was stinging pain (71.8%). In the multivariate analysis, severe dry-eye symptoms (p = 0.03), non-use of the steroid eye drops (p = 0.02), and longintervals between exam vitists (p = 0.02) were identified as factors reducing compliance. Conclusions: Factors related to a decrease in the compliance with 0.1% cyclosporine A in dry-eye patients with Sjögren's syndrome, included severe dry eye symptoms, long visit intervals, and non-use of steroid eye drops. Taking these factors into consideration may help increase patient compliance.

/pdf/assessment-of-the-compliance-with-0-1-cyclosporine-a-in-dry-1azgtdl4ki.pdf

Assessment of the Compliance with 0.1% Cyclosporine A in Dry-Eye Patients with Sjögren's Syndrome

Purpose: To evaluate the clinical efficacy of preservative-free 0.15% sodium hyaluronate eye drops on the ocular surface after upper eyelid surgery. Methods: This study included 43 patients who underwent upper eyelid surgery between December 2018 and May 2019. Patients were randomly assigned to group A (those treated with preservative-free 0.15% sodium hyaluronate eye drops) and group B (the control group). Ocular surface disease index score (OSDI), tear break up time (TBUT), Schirmer’s test, corneal staining score (CSS), meibomian gland (MG) quality, MG expressibility, and meiboscore were evaluated before surgery and at 1 week, 1 month, and 2 months after surgery. Results: In group A, OSDI and TBUT showed a significant increase at 1 week after surgery compared with baseline values (all p < 0.05). In group B, OSDI, TBUT, and CSS were significantly higher at 1 week and 1 month after surgery (all p < 0.05), whereas there were no significant changes at 2 months after surgery compared with baseline values. At 1 month after surgery, OSDI (p = 0.03) and CSS (p < 0.01) showed significant changes between group A and group B; however, there was no significant change in the TBUT. There were no significant within-group differences in Schirmer’s test values, MG quality, MG expressibility, or meiboscore, and there were no significant between-group differences over time. Conclusions: Preservative-free 0.15% sodium hyaluronate eye drops were shown to be an effective treatment for early dry-eye symptoms and ocular surface damage after upper eyelid surgery. J Korean Ophthalmol Soc 2021;62(5):612-620

/pdf/efficacy-of-0-15-sodium-hyaluronate-eye-drops-in-patients-1dft17m2rq.pdf

Efficacy of 0.15% Sodium Hyaluronate Eye Drops in Patients’ Ocular Surface after Upper Eyelid Surgery

Purpose: We evaluated the clinical manifestations and risk factors of fungal keratitis after penetrating keratoplasty (PKP). Methods: Eighteen patients who experienced fungal keratitis after PKP between January 2005 and January 2020 were included in this retrospective study. Clinical characteristics including sex, age, underlying disease, indication for PKP, symptom duration, visual acuity, graft state before infection, suture-related problems, size of epithelial defect, depth of infiltration, presence of hypopyon, use of eyedrops before infection, and the results of microbiological tests were analyzed. Patients were classified into the treatment success or failure group, and the risk factors were evaluated accordingly. Results: The mean age at diagnosis was 63.94 ± 15.53 years. Fungal infection occurred a mean of 55.31 ± 44.72 months after PKP. The mean symptom duration was 10.33 ± 7.36 days. Of the 18 patients, 5 (27.8%) and 13 (72.2%) were in the treatment success and failure groups, respectively. Of the treatment failure group, seven patients (38.9%) underwent surgical management. The graft state before infection, symptom duration, and size of epithelial defects had significant correlations with treatment failure (all p < 0.05). Multivariate analysis identified graft state (p = 0.046) as a significant risk factor for treatment failure. Conclusions: Graft state before infection, symptom duration, and size of epithelial defects were associated with the prognosis of fungal keratitis after PKP. Graft state before infection was a significant risk factor for treatment failure. J Korean Ophthalmol Soc 2021;62(4):472-478

/pdf/clinical-manifestations-of-fungal-keratitis-following-1aowdmfb36.pdf

Clinical Manifestations of Fungal Keratitis Following Penetrating Keratoplasty

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Papers

Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria

Assessment of the Compliance with 0.1% Cyclosporine A in Dry-Eye Patients with Sjögren's Syndrome

Efficacy of 0.15% Sodium Hyaluronate Eye Drops in Patients’ Ocular Surface after Upper Eyelid Surgery

Clinical Manifestations of Fungal Keratitis Following Penetrating Keratoplasty