A mathematical model for malaria disease dynamics with vaccination and infected immigrants.

The world is aiming to eliminate malaria by 2030. The introduction of the pilot project on malaria vaccination for children in Kenya, Ghana, and Malawi presents a significant thrust to the elimination efforts. In this work, a susceptible, infectious and recovered (SIR) human-vector interaction mathematical model for malaria was formulated. The model was extended to include a compartment of vaccinated humans and an influx of infected immigrants. Qualitative and quantitative analysis was performed on the model. When there was no influx of infected immigrants, the model had a disease-free equilibrium point that was globally asymptotically stable when a threshold known as the basic reproductive number denoted by $ R_0 $ was less than one. When there was an influx of infected immigrants, the model had endemic equilibrium points only. Parameter sensitivity analysis on $ R_0 $ was performed and results showed that strategies must be implemented to reduce contact between mosquitoes and humans. Results from different vaccine coverage indicated that in the absence of an influx of infected immigrants, it is possible to achieve a malaria-free society when more children get vaccinated and the influx of infected humans is avoided. The analysis of the optimal control model showed that the combined use of vaccination, personal protective equipment, and treatment is the best way to curb malaria incidence, provided the influx of infected humans is completely stopped.

Use of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, in chronic kidney disease-associated anemia in cats.

BACKGROUND: Erythropoietic effects of molidustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, were previously demonstrated in healthy cats. OBJECTIVE: To evaluate the safety and erythropoietic effects of daily PO administration of molidustat in anemic cats with chronic kidney disease (CKD). ANIMALS: Twenty-one client-owned CKD cats (4-17 years old) with anemia. METHODS: Multicenter field study; randomized, masked, and placebo-controlled. Cats were treated PO once daily for 28 days with suspensions of control product (CP; n = 6) or 5 mg/kg of molidustat (n = 15). Hematocrit (HCT) was evaluated at weekly intervals. Individual cat treatment success was defined as a ≥4% point increase in HCT compared to baseline. RESULTS: Control group mean HCT remained low throughout the study (20.1%-23.4%). Mean HCT of molidustat-treated cats increased weekly, and a significant increase compared to baseline (23.6%) was first observed on Day 21 (27.3%; P < .001; 95% confidence interval [CI], 1.69-5.67). Compared to CP group, mean HCT was significantly higher on Day 21 (27.3% vs 20.1%; P < .001; 95% CI, 2.91-10.75) but not significantly higher on Day 28 (27.8% vs 23.4%; P = .06; 95% CI, -0.23 to 9.88). The number of individual treatment successes on Day 28 was higher among remaining molidustat-treated cats (7/14) compared to remaining control cats (1/5), but there was no significant difference between groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Daily PO molidustat administration may stimulate a clinically relevant erythropoietic response in anemic cats with CKD. This HIF-PH inhibitor may be an alternative for managing anemia in cats compared to recombinant EPO treatment.

First record of rainbow shrimp, exotic species Mierspenaeopsis sculptilis (Heller, 1862), in the Brazilian coastal amazon, validated by DNA barcode.

BACKGROUND: This is the first record of the alien shrimp Mierspenaeopsis sculptilis in Brazil. The invasion was detected within Marine Extractive Reserves based on eight specimens accidentally caught by local fishermen using trawlnets focused on fisheries of native species. These specimens were transported to the Laboratory of Applied Genetics and morphologically identified as Mierspenaeopsis sculptilis (rainbow shrimp). The taxonomic status of analyzed samples was confirmed by DNA barcoding using a 627-bp fragment of the Cytochrome C Oxidase Subunit I (COI) gene. RESULTS: A single haplotype was recovered from the eight specimens, being identical to a haplotype reported in India, where this species naturally occurs, and in Mozambique, where the rainbow shrimp is considered an invasive species. The present analyses indicated a putative invasive route (i.e., India-Mozambique-Brazil) mediated by shipping trade. CONCLUSIONS: This study presents the first record of Mierspenaeopsis sculptilis in Brazil, in areas of extractive reserves on the Amazon coast. Notably exotic species can cause imbalance in the ecosystem, harming native species. In view of this, the registration of new invasions is essential as they contribute to the implementation of control plans.

Efficacy evaluation of anthelmintic products against an infection with the canine hookworm (Ancylostoma caninum) isolate Worthy 4.1F3P in dogs.

Ancylostoma caninum is the most prevalent intestinal nematode of dogs, and has a zoonotic potential. Multiple-drug resistance (MDR) has been confirmed in a number of A. caninum isolates, including isolate Worthy 4.1F3P, against all anthelmintic drug classes approved for hookworm treatment in dogs in the United States (US). The cyclooctadepsipeptide emodepside is not registered to use in dogs in the US, but in a number of other countries/regions. The objective of this study was to evaluate the efficacy of emodepside + praziquantel, as well as three commercial products that are commonly used in the US for treatment of hookworms, against a suspected (subsequently confirmed) MDR A. caninum isolate Worthy 4.1F3P. 40 dogs infected on study day (SD) 0 with 300 third-stage larvae, were randomly allocated to one of five treatment groups with eight dogs each: pyrantel pamoate (Nemex®-2), fenbendazole (Panacur® C), milbemycin oxime (Interceptor®), emodepside + praziquantel tablets and non-treated control. Fecal egg counts (FEC) were performed on SDs 19, 20, 22, 27, 31 and 34. All treatments were administered as per label requirements on SD 24 to dogs in Groups 1 through 4. Two additional treatments were administered on SDs 25 and 26 to dogs in Group 2 as per label requirements. Dogs were necropsied on SD 34 and the digestive tract was removed/processed for worm recovery and enumeration. The geometric mean (GM) worm counts for the control group was 97.4, and for the pyrantel pamoate, fenbendazole, milbemycin oxime, and emodepside + praziquantel groups were 74.8, 72.0, 88.9, and 0.4, respectively. These yielded efficacies of 23.2%, 26.1%, and 8.8%, and 99.6%, respectively. These data support previous findings of the MDR status of Worthy 4.1F3P as treatments with pyrantel pamoate, fenbendazole and milbemycin oxime lacked efficacy. In sharp contrast, Worthy 4.1F3P was highly susceptible to treatment with emodepside + praziquantel.

Lysines residing in putative Small Ubiquitin-like MOdifier (SUMO) motifs regulate fate and function of 37 KDa laminin receptor.

There is a putative precursor to mature receptor relationship between 37 Laminin Receptor (LR) and 67 LR. As such, the pair are frequently referred to as a single entity, the 37/67 kDa Laminin Receptor (37/67 LR) and 67 LR was identified as a laminin binding entity. 37/67 LR has been of clinical interest for many years, as 37/67 LR is a prognostic indicator for many cancers including breast, lung, colon, and prostate. However, the genesis of 67 LR is controversial, and confounded by its stability under SDS-PAGE conditions, a lack of splice variants, and the existence of post-translational modifications that cannot account for the mass discrepancy between 37 and 67 LR. In the present work, we mutated potential SUMO motif sites (Lysine residues) in 37 LR and generated a series of 37 LR-expressing plasmids with a C-terminal histidine tag. We report an inability to detect 67 LR formation, suggesting that SUMOylation does not appear to directly occur at the lysine residues proposed. However, the work revealed that these lysine mutations still appear to be important and can impact the fate and function of 37 LR, by impairing half-life and steady state pre-mRNA levels. These results suggest that the Lys residues within putative SUMO motifs of 37 LR are important for 37 LR function.

A dock derived compound against laminin receptor (37 LR) exhibits anti-cancer properties in a prostate cancer cell line model.

Laminin receptor (67 LR) is a 67 kDa protein derived from a 37 kDa precursor (37 LR). 37/67 LR is a strong clinical correlate for progression, aggression, and chemotherapeutic relapse of several cancers including breast, prostate, and colon. The ability of 37/67 LR to promote cancer cell aggressiveness is further increased by its ability to transduce physiochemical and mechanosensing signals in endothelial cells and modulate angiogenesis. Recently, it was demonstrated that 37/67 LR modulates the anti-angiogenic potential of the secreted glycoprotein pigment epithelium-derived factor (PEDF). Restoration of PEDF balance is a desirable therapeutic outcome, and we sought to identify a small molecule that could recapitulate known signaling properties of PEDF but without the additional complications of peptide formulation or gene delivery safety validation. We used an in silico drug discovery approach to target the interaction interface between PEDF and 37 LR. Following cell based counter screening and binding validation, we characterized a hit compound's anti-viability, activation of PEDF signaling-related genes, anti-wound healing, and anti-cancer signaling properties. This hit compound has potential for future development as a lead compound for treating tumor growth and inhibiting angiogenesis.

Efficacy of 10% imidacloprid + 2.5% moxidectin topical solution (Advantage Multi® for Dogs) for the prevention of heartworm disease and infection all month long.

BACKGROUND: Prior work has shown that the levels of moxidectin in dogs treated with Advantage Multi® for Dogs (Bayer Animal Health) remain at a high plasma concentration for the full month after application. The objective of this study was to demonstrate the efficacy of 10% imidacloprid + 2.5% moxidectin topical solution (Advantage Multi® for Dogs, also known as Advocate® for Dogs) for the prevention of heartworm infection and disease 30 days after just one application. METHODS: Two groups of eight dogs each were included. Dogs in Group 1 received the product (Advantage Multi® for Dogs) while those in Group 2 remained as nontreated controls. All dogs entering the study completed a physical examination including examination for Dirofilaria immitis antigen and circulating microfilariae. Dogs in Group 1 were treated on Study Day (SD) -30 as per the label recommendation. Thirty days later (SD 0) dogs in Groups 1 and 2 were subcutaneously infected in the inguinal region with approximately 50 infective third-stage D. immitis larvae ("Missouri" isolate). Blood was collected on SDs 120 and 147 for examination for D. immitis antigen and circulating microfilariae. On SD 148, all animals were euthanized and necropsied for recovery of adult heartworms. All procedures were performed in accordance with the VICH GL9 guidelines. RESULTS: Examination and worm counts made at necropsy showed no heartworms in the treated dogs (Group 1) compared with six of eight nontreated dogs (Group 2) with heartworms (range of 2-33). The treated dogs (Group 1) had significantly fewer heartworms (p < 0.05) compared with the nontreated controls (Group 2). CONCLUSION: The results demonstrated that 10% imidacloprid + 2.5% moxidectin topical solution (Advantage Multi® for Dogs) is efficacious for the prevention of heartworm infection and disease all month long with no observation of treatment-related adverse events.

Novel pectin-based carriers for colonic drug delivery.

Pectin-based hydrogel carriers have been studied and shown to have promising applications for drug delivery to the lower GI tract, especially to the colonic region. However, making sure these hydrogel carriers can pass through the upper GI tract and reach the targeted regions, after oral administration, still remains a challenge to overcome. A solution to this problem is to promote stronger cross-linking interactions within the pectin-based hydrogel network. The combined usage of a divalent cation (Ca(2+)) and the cationic biopolymer oligochitosan has shown to improve the stability of pectin-based hydrogel systems - suggesting that these two cross-linkers may be used to eventually help improve pectin-based hydrogel systems for colonic drug delivery methods.

Laboratory Evaluation of the Efficacy of 10 % Imidacloprid + 2.5 % Moxidectin Topical Solution (Advantage® Multi, Advocate®) for the Treatment of Dirofilaria immitis Circulating Microfilariae in Dogs.

This study examined the efficacy of 10 % imidacloprid + 2.5 % moxidectin topical solution (Advantage ® Multi, Advocate®, Bayer) for the treatment of circulating microfilariae from dogs naturally infected with Dirofilaria immitis. The study included two groups of 11 dogs each that consisted of two replicates. Replicate 1 contained 12 dogs (6 treated and 6 controls) and replicate 2 contained 10 dogs (5 treated and 5 controls). Six of the 10 dogs in replicate 2 were the controls from replicate 1. All dogs entering the study completed a physical examination including chest radiographs, blood collections for examination of Dirofilaria immitis circulating microfilariae, serum chemistry, complete blood counts and urinalysis. To qualify for the study each dog was required to have a geometric mean ≥ 300 microfilariae per ml of blood from 3 consecutive samples collected during the 8 day acclimation period and a heartworm disease classification of 1 or 2. Dogs were treated on study days 0 and 28. Post-treatment microfilarial counts were performed on study days 1, 2, 3, 7, 14, 21, 28, 29, 35, and 42. Percent microfilarial reduction was determined by comparing the geometric mean number of circulating microfilaria remaining in treated dogs with those remaining in the control dogs post-treatment. Seven days after the first treatment, the geometric mean microfilarial counts in treated dogs were reduced by > 99 % compared to the control dogs. Reduction remained at > 99 % through the end of the study at 42 days after the first treatment (14 days after the second treatment). The results of this study demonstrated that Advantage® Multi for dogs is efficacious for treatment of circulating D. immitis microfilariae in naturally infected heartworm-positive dogs with no treatment-related adverse events observed.

Observational study and estimate of cost savings from use of a health information exchange in an academic emergency department.

BACKGROUND: Federal initiatives to improve health care information sharing have led to the development of a new type of regional electronic medical record known as a health information exchange (HIE). OBJECTIVE: Our aim was to investigate the ability of an HIE to decrease health services use for emergency department (ED) patients. METHODS: We performed an observational, prospective study using a voluntary, anonymous survey among clinicians at an urban academic ED. All ED clinicians were eligible to participate. Survey items addressed clinician perception of whether information from the HIE avoided the use of hospital resources, improved quality of care, and reduced length of stay (LOS). Cost savings were estimated by multiplying the number of services the clinicians completing our survey reported they avoided through use of the HIE by the costs of those services at our facility. The study was approved by the Institutional Review Board at the study site. RESULTS: The study was conducted between August and December of 2011. There were 18,529 patient encounters during the study period and 60 clinicians at the study site who were eligible to participate. The clinicians consulted the HIE for 5.39% of these encounters (998 patients). Surveys were completed by the clinicians caring for 13.8% (n = 138) of these patients. Of the completed surveys, 76% (105 surveys) referenced patients for whom the HIE was found to contain information on the patient under care by the clinician participant. These 105 patients formed the sample on which our analysis was based. Within this sample of patients, the following studies were reported to have been avoided by the clinicians participating in our survey: values are percent of patients for whom a study was reported to have been avoided (actual number of studies avoided): laboratory/microbiology: 30.5% (32 studies); radiologic studies: 47.6% (50 studies); consultations: 19% (20 consultations); and admissions: 11.4% (12 admissions). Calculated cost savings based on these estimates were as follows: laboratory/microbiology: $462.85; radiologic studies: $160,893.00; consultations: $3,990.00; and admissions: $118,131.84. Total savings: $283,477. Clinicians participating in the study reported improved quality of care for 86.7% of their patients, as well as a mean time savings of 120.8 minutes. CONCLUSIONS: According to clinician estimates, use of an HIE in this urban academic ED resulted in reduced use of hospital resources, noteworthy cost savings, decreased LOS, and improved quality of care. Limitations included the observational nature of the study, selection bias, the Hawthorne effect, and cost estimates being from a single institution. Allowance was not made for additional services used because of information obtained from the HIE.

Anticipating and managing opioid side effects in the elderly.

Pain is a common complaint in the elderly, and opioids are useful agents for management of both acute and chronic pain. Opioids are known to cause a variety of adverse effects, and these adverse effects can be particularly problematic for the frail elderly patient and may limit their use. As a result, this can lead to undertreatment of pain and poor patient outcome. Understanding, anticipating, and managing opioid side effects is an important component of care for the elderly patient.

Efficacy of emodepside plus toltrazuril (Procox(®) oral suspension for dogs) against Toxocara canis, Uncinaria stenocephala and Ancylostoma caninum in dogs.

The efficacy of emodepside plus toltrazuril (Procox® oral suspension for dogs) against different species of gastrointestinal nematodes (Toxocara canis, Ancylostoma caninum, Uncinaria stenocephala) was evaluated in nine randomised,blinded and placebo-controlled laboratory studies in naturally or experimentally infected dogs. The product was used at the proposed minimum dose of 0.45 mg emodepside and 9 mg toltrazuril per kg body weight. Efficacy was calculated based on worm counts after necropsy. Worm burdens in the control dogs ranged between 0 and 409 worms of the respective stage for T. canis and between 4 and 655 worms for hookworms. The studies demonstrated 100 % efficacy of emodepside/toltrazuril suspension against mature adult, ≥ 94.7 %efficacy against immature adult and 99.3 % efficacy against the L4 larval stage of T. canis. The efficacy against mature adult A. caninum was ≥ 99.5 % and the efficacy against mature adult U. stenocephala was 100 %. All differences between treatment and control groups were statistically significant and no gender effect was found. It can be concluded that the emodepside/toltrazuril suspension represents a safe and highly effective product in dogs with nematode (T. canis, hookworms) infection.

Efficacy of emodepside plus praziquantel tablets (Profender tablets for dogs) against mature and immature adult Ancylostoma caninum and Uncinaria stenocephala infections in dogs.

This paper reports the efficacy of a novel flavoured tablet formulation of emodepside plus praziquantel (Profender tablets for dogs) against mature and immature adult hookworms (Ancylostoma caninum and Uncinaria stenocephala) in dogs. The tablets were used at the minimum recommended dose of 1 mg emodepside and 5 mg praziquantel per kg body weight. Four randomised, blinded and controlled laboratory studies demonstrated >95% efficacy against mature and immature adult stages of U. stenocephala and four randomised, blinded and controlled laboratory studies demonstrated >98% efficacy against mature and immature adult stages of A. caninum. No side effects of the treatment were observed. It is concluded that the emodepside plus praziquantel tablet is an effective and safe treatment against mature and immature hookworms.

Efficacy of emodepside plus praziquantel tablets (Profender tablets for dogs) against mature and immature infections with Toxocara canis and Toxascaris leonina in dogs.

The efficacy of emodepside plus praziquantel tablets (Profender tablets for dogs) against mature adult, immature adult and larval stages of Toxocara canis and Toxascaris leonina was evaluated in ten randomised, blinded and placebo-controlled dose confirmation studies in naturally or experimentally infected dogs. The tablets were used at the proposed minimum dose of 1 mg emodepside and 5 mg praziquantel per kg body weight. Efficacy was calculated based on worm counts after necropsy. Five studies demonstrated >99% efficacy against mature adult, >92% efficacy against immature adult, >98% efficacy against L4 and >94% efficacy against L3 larval stages of T. canis. Another five studies demonstrated >99% efficacy against mature and immature adult and >95% efficacy against L4 larval stages of T. leonina. No side effects of the treatment were observed. Emodepside plus praziquantel tablets thus provide a comprehensive new treatment option for ascarid infections in the dog.

Efficacy of emodepside plus praziquantel tablets (Profender tablets for dogs) against mature and immature adult Trichuris vulpis infections in dogs.

This paper reports on the efficacy of a novel flavoured tablet formulation of emodepside plus praziquantel (Profender tablets for dogs) against mature and immature adult whipworms (Trichuris vulpis) at the proposed minimum dose of 1 mg emodepside and 5 mg praziquantel per kg body weight in dogs. Three randomised, blinded and controlled laboratory studies with naturally or experimentally infected dogs were performed. The first study was conducted as a dose determination study in experimentally infected dogs using three different dose levels, i.e., 0.5x, 1x and 2x the minimum therapeutic dose. Two further studies confirmed the efficacy of emodepside plus praziquantel tablets against mature and immature adult T. vulpis at the recommended minimum dose. In all three studies, the efficacy against mature and immature adult T. vulpis was >99%. No side effects of the treatment were observed. It is concluded that the emodepside plus praziquantel tablet is an effective and safe treatment against mature and immature adult stages of T. vulpis in dogs.