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The current in vivo models for the utility and discovery of new potential anti-leishmanial drugs targeting Cutaneous Leishmaniasis (CL) differ vastly in their immunological responses to the disease and clinical presentation of symptoms. Animal models that show similarities to the human form of CL after infection with Leishmania should be more representative as to the effect of the parasite within a human. Thus, these models are used to evaluate the efficacy of new anti-leishmanial compounds before human clinical trials. Current animal models aim to investigate (i) host-parasite interactions, (ii) pathogenesis, (iii) biochemical changes/pathways, (iv) in vivo maintenance of parasites, and (v) clinical evaluation of drug candidates. This review focuses on the trends of infection observed between Leishmania parasites, the predictability of different strains, and the determination of parasite load. These factors were used to investigate the overall effectiveness of the current animal models. The main aim was to assess the efficacy and limitations of the various CL models and their potential for drug discovery and evaluation. In conclusion, we found that the following models are the most suitable for the assessment of anti-leishmanial drugs: L. major-C57BL/6 mice (or-vervet monkey, or-rhesus monkeys), L. tropica-CsS-16 mice, L. amazonensis-CBA mice, L. braziliensis-golden hamster (or-rhesus monkey). We also provide in-depth guidance for which models are not suitable for these investigations.

An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA-approved drugs (described in this paper) have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC50's) in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC50 of 0.4 µM), a selective serotonin reuptake inhibitor (fluoxetine, EC50 of 4.4 µM), and an antifolate drug (pyrimethamine, EC50 of 3.8 µM) and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease.

Few drugs are available for soil-transmitted helminthiasis (STH); the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment. While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura. In addition, drug resistance is a threat. It is therefore important to find alternatives.We searched the literature and the animal health marketed products and pipeline for potential drug development candidates. Recently registered veterinary products offer advantages in that they have undergone extensive and rigorous animal testing, thus reducing the risk, cost and time to approval for human trials. For selected compounds, we retrieved and summarised publicly available information (through US Freedom of Information (FoI) statements, European Public Assessment Reports (EPAR) and published literature). Concomitantly, we developed a target product profile (TPP) against which the products were compared.The paper summarizes the general findings including various classes of compounds, and more specific information on two veterinary anthelmintics (monepantel, emodepside) and nitazoxanide, an antiprotozoal drug, compiled from the EMA EPAR and FDA registration files.Few of the compounds already approved for use in human or animal medicine qualify for development track decision. Fast-tracking to approval for human studies may be possible for veterinary compounds like emodepside and monepantel, but additional information remains to be acquired before an informed decision can be made.

BACKGROUND: Human African trypanosomiasis (HAT) is an important public health problem in sub-Saharan Africa, affecting hundreds of thousands of individuals. An urgent need exists for the discovery and development of new, safe, and effective drugs to treat HAT, as existing therapies suffer from poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. We have discovered and optimized a novel class of small-molecule boron-containing compounds, benzoxaboroles, to identify SCYX-7158 as an effective, safe and orally active treatment for HAT. METHODOLOGY/PRINCIPAL FINDINGS: A drug discovery project employing integrated biological screening, medicinal chemistry and pharmacokinetic characterization identified SCYX-7158 as an optimized analog, as it is active in vitro against relevant strains of Trypanosoma brucei, including T. b. rhodesiense and T. b. gambiense, is efficacious in both stage 1 and stage 2 murine HAT models and has physicochemical and in vitro absorption, distribution, metabolism, elimination and toxicology (ADMET) properties consistent with the compound being orally available, metabolically stable and CNS permeable. In a murine stage 2 study, SCYX-7158 is effective orally at doses as low as 12.5 mg/kg (QD×7 days). In vivo pharmacokinetic characterization of SCYX-7158 demonstrates that the compound is highly bioavailable in rodents and non-human primates, has low intravenous plasma clearance and has a 24-h elimination half-life and a volume of distribution that indicate good tissue distribution. Most importantly, in rodents brain exposure of SCYX-7158 is high, with C(max) >10 µg/mL and AUC(0-24 hr) >100 µg*h/mL following a 25 mg/kg oral dose. Furthermore, SCYX-7158 readily distributes into cerebrospinal fluid to achieve therapeutically relevant concentrations in this compartment. CONCLUSIONS/SIGNIFICANCE: The biological and pharmacokinetic properties of SCYX-7158 suggest that this compound will be efficacious and safe to treat stage 2 HAT. SCYX-7158 has been selected to enter preclinical studies, with expected progression to phase 1 clinical trials in 2011.

BACKGROUND: There is an urgent need to develop new, safe and effective treatments for human African trypanosomiasis (HAT) because current drugs have extremely poor safety profiles and are difficult to administer. Here we report the discovery of 2,4-diaminopyrimidines, exemplified by 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid phenylamide (SCYX-5070), as potent inhibitors of Trypanosoma brucei and the related trypanosomatid protozoans Leishmania spp. METHODOLOGY/PRINCIPAL FINDINGS: In this work we show that loss of T. brucei viability following SCYX-5070 exposure was dependent on compound concentration and incubation time. Pulse incubation of T. brucei with SCYX-5070 demonstrates that a short period of exposure (10-12 hrs) is required to produce irreversible effects on survival or commit the parasites to death. SCYX-5070 cured an acute trypanosomiasis infection in mice without exhibiting signs of compound related acute or chronic toxicity. To identify the molecular target(s) responsible for the mechanism of action of 2,4-diaminopyrimidines against trypanosomatid protozoa, a representative analogue was immobilized on a solid matrix (sepharose) and used to isolate target proteins from parasite extracts. Mitogen-activated protein kinases (MAPKs) and cdc2-related kinases (CRKs) were identified as the major proteins specifically bound to the immobilized compound, suggesting their participation in the pharmacological effects of 2,4-diaminopyrimidines against trypanosomatid protozoan parasites. CONCLUSIONS/SIGNIFICANCE: Results show that 2,4-diaminopyrimidines have a good in vitro and in vivo pharmacological profile against trypanosomatid protozoans and that MAPKs and CRKs are potential molecular targets of these compounds. The 2,4-diminipyrimidines may serve as suitable leads for the development of novel treatments for HAT.

Abstract Key functions of antibodies, such as viral neutralisation, depend on high-affinity binding. However, viral neutralisation poorly correlates with antigen affinity for reasons that have been unclear. Here, we use a new mechanistic model of bivalent binding to study >45 patient-isolated IgG1 antibodies interacting with SARS-CoV-2 RBD surfaces. The model provides the standard monovalent affinity/kinetics and new bivalent parameters, including the molecular reach: the maximum antigen separation enabling bivalent binding. We find large variations in these parameters across antibodies, including reach variations (22–46 nm) that exceed the physical antibody size (~15 nm). By using antigens of different physical sizes, we show that these large molecular reaches are the result of both the antibody and antigen sizes. Although viral neutralisation correlates poorly with affinity, a striking correlation is observed with molecular reach. Indeed, the molecular reach explains differences in neutralisation for antibodies binding with the same affinity to the same RBD-epitope. Thus, antibodies within an isotype class binding the same antigen can display differences in molecular reach, substantially modulating their binding and functional properties.

Electroencephalography (EEG) is the gold standard for confirming epileptic seizures in both human and veterinary patients. Despite idiopathic epilepsy being one of the most common neurological conditions in dogs, our understanding of it in veterinary medicine lags that in human medicine. The relative underuse of EEG in dogs with seizures has potential causes including practical issues, financial concerns, lack of training/equipment, and questions of clinical value. This technological underuse may lead to, or result from, major gaps in our understanding of EEG in veterinary patients. This underutilization of EEG is of significant clinical relevance because the diagnosis of specific epilepsy syndromes in humans guides the treatment, namely pharmacological, dietary, or surgical. These epilepsy syndromes are diagnosed based on several factors, one of which is the characteristic electrical brain activity on EEG. The aim of this narrative literature review was to highlight the study of cortical brain activity to improve our understanding of EEG in veterinary medicine. Specifically, the utility of EEG with focus on the existing proposed electrode arrays and their current supporting evidence. A recent survey study confirmed that a variety of canine EEG protocols are concurrently in use, including diverse electrode arrays. By comparison, in humans there is a standardized 10–20 electrode array, with average localization error of 13–17 mm depending on the number of placed electrodes on the scalp. We offer a review of the factors that would contribute to the ideal canine EEG electrode array highlighting areas for improvement and future validation. This proposed level of understanding will facilitate the identification of cortical seizure foci with a known degree of error, paving the way for non-pharmaceutical interventions like epilepsy surgeries.

Background: Catheter ablation (CA) for ventricular tachycardia (VT) can be a useful treatment strategy, however, few studies have compared CA to medical therapy (MT) in the sarcoidosis population. Objective: To assess in-hospital outcomes and unplanned readmissions following CA for VT compared to MT in patients with sarcoidosis. Methods: Data was obtained from the Nationwide Readmissions Database between 2010 and 2019 to identify patients with sarcoidosis admitted for VT either undergoing CA or MT during elective and non-elective admission. Primary endpoints were a composite endpoint of inpatient mortality, cardiogenic shock, cardiac arrest and 30-day hospital readmissions. Procedural complications at index admission and causes of readmission were also identified. Results: Among 1581 patients, 1217 with sarcoidosis and VT underwent MT compared to 168 with CA during non-elective admission. 63 patients admitted electively underwent CA compared with 129 managed medically. There was no difference in the composite outcome for patients undergoing catheter ablation or medical therapy during both non-elective (9.0 % vs 12.0 %, p = 0.312) and elective admission (3.2 % vs. 7.8 %, p = 0.343). The most common cause of readmission were ventricular arrhythmias (VA) in both groups, however, those undergoing elective CA were less likely to be readmitted for VA compared to non-elective CA. The most common complication in the CA group was cardiac tamponade (4.8 %). Conclusion: VT ablation is associated with similar rates of 30-day readmission compared to MT and does not confer increased risk of harm with respect to inpatient mortality, cardiogenic shock or cardiac arrest. Further research is warranted to determine if a subgroup of sarcoidosis patients admitted with VT are better served with an initial conservative management strategy followed by VT ablation.

Obesity and chronic kidney disease are two ongoing progressive clinical pandemics of major public health and clinical care significance. Because of their growing prevalence, chronic indolent course and consequent complications both these conditions place significant burden on the health care delivery system especially in developed countries like the United States. Beyond the chance coexistence of both of these conditions in the same patient based on high prevalence it is now apparent that obesity is associated with and likely has a direct causal role in the onset, progression and severity of chronic kidney disease. The causes and underlying pathophysiology of this are myriad, complicated and multi-faceted. In this review, continuing the theme of this special edition of the journal on “ The Cross roads between Endocrinology and Nephrology” we review the epidemiology of obesity related chronic kidney disease (ORCKD), and its various underlying causes and pathophysiology. In addition, we delve into the consequent comorbidities and complications associated with ORCKD with particular emphasis on the cardio metabolic consequences and then review the current body of evidence for available strategies for chronic kidney disease modulation in ORCKD as well as the potential unique role of weight reduction and management strategies in its improvement and risk reduction.

Tissue dehydration is known to have adverse effects on health and is highly challenging to characterize in vitro due to the complexity of the cell/tissue organisation. There have been a large number of studies reporting the dielectric properties of animal and human tissue explants or bodily fluids such as urine or blood over a wide frequency range from 10 Hz to 100 GHz. However, variations in blood composition involving the cell type, haematocrit (HCT) protein levels, ionic conductivity, electrolyte or glucose concentration will affect the dielectric measurements. The present study examined the effects of physiological osmotic solutions with NaCl (280 mOsmol/kg to 300 mOsmol/kg), HCT (35% to 50%) and albumin (3.5 g/dl to 5.5 g/dl) isolated from bovine blood on the dielectric properties measured at frequencies spanning from 0.5 GHz to 20 GHz using an open-ended co-axial probe. Measurements demonstrated linear correlations between permittivity and loss factor of blood solutions with varying HCT levels, albumin or osmolality such that a high protein concentration reduced the dielectric response in a dose-dependent manner. Whilst the spectral trends for the permittivity response to HCT and albumin were similar in a concentration-dependent manner, the loss factor profile was influenced by osmolality of the solution. In summary, we characterized the dependence of the microwave dielectric properties of blood on HCT, albumin and osmolality. The dielectric measurement technique has the potential to determine hydration levels for future diagnostic and therapeutic devices.

Assisted breeding technology has important management implications for avian conservation and aviculture but species-specific reproductive information is lacking. This study aimed to develop a successful semen collection for the king quail (Synoicus chinesis) in order to establish baseline seminal characteristics and to explore the effect of flock density on seminal quality. A total of 19 quail consisting of 2 groups of 5 and 4 and 1 group of 10 were housed in 3 separate aviaries located at the University of Queensland, Gatton, Australia during Spring. Morphometrics and morphology (normal and abnormal) of the sperm cells were also described by phase contrast and differential interference microscopy. Semen was sucessfully collected by cloacal massage from 90 % of attempts with only minor evidence of faecal or urate contamination. No significant differences in seminal characteristics were found with respect to bird housing density. Mean ± SEM seminal characteristics for 103 ejaculates included volume (1.6 ± 0.02 μL), sperm concentration (8.1 ± 0.5 × 109 mL–1), progressive sperm motility (50.0 ± 0.04 %), rate of sperm motility, (2.9 ± 0.13), pH (6.7 ± 0.2), the percentage of live sperm (88.0 ± 0.01 %) and the percentage of total abnormal sperm morphology (21.0 ± 0.03 %). Cloacal massage proved to be a highly successful technique to collect king quail semen and the seminal characteristics reported here are the future basis of assessing fertility and the application of assisted breeding in the species.

This paper analyzes the causes of urban road flooding and evaluates the economic cost borne by the business houses on either side of Putalisadak road section of Kathmandu Metropolitan City, Nepal as a resultant of the flood during 2018 monsoon. The calculation of losses included direct, indirect, fixed and variable cost based on before-during-after flood framework through the in-person interview conducted with systematically selected business houses in flooded studied area. The storm water runoff quantity at extreme rainfall condition exceeds the drainage discharge capacity and further gutter clogging with waste triggered the overflow of sewer mixed water causing road flood. The annual economic cost of flooding was estimated to be USD 65,579.99. Result shows that the loss of businesses depend upon the extent of vulnerability of materials towards flood and the coping strategies of the business holders. The businesses with less material damage was found to be adopting coping strategies like elevating the ground level of shops and putting glasses in the front door to prevent damages caused by water. Ironically, such urban road flooding is underrated by the Government and concerned authorities as such flood seems to be smaller in front of big river floods in Nepal. But there are huge and unseen losses due to urban floods. It is recommended that the drainage capacity should be enhanced and regularly maintained to mitigate urban flood disaster.

Biomedical devices like microfluidic chips and externally triggered drug delivery devices can activate their drug release mechanisms using external triggers such as ultrasound, electric field, alternating magnetic field and electromagnetic radiation. This work proposes an electromagnetic triggering technique based on the interaction of electromagnetic waves with metallic microparticles that are placed under a temperatures sensitive hydrogel. The heating effect of the electromagnetic interaction results in a localized rise in temperature. The change in temperature manipulates the physical structure of the hydrogel which can be used for releasing drug particles in a drug delivery device or controlling fluid flow in a microfluidic chip. The design and operation of the device is explained with the help of Multiphysics simulations in COMSOL followed by experimental verification using sub-100-μm iron powder particles placed under 2 mm thick layer of a thermosensitive hydrogel. The primary experiments for the device operating at 2.4 GHz and 145 mW show a temperature increment of 2.7 °C after 50 min.

Abstract Background There are limited data describing adverse infant outcomes in infants born to women with a low risk of complications during pregnancy, such as those who may be enrolled in maternal immunization trials. This retrospective study estimated incidence proportions of infant outcomes in different cohorts of liveborn infants in England between 2005 and 2017. Methods The incidence proportions of 10 infant outcomes were calculated for liveborn infants from pregnancies represented in the Clinical Practice Research Datalink (CPRD) Mother-Baby Link (MBL) and linkage to Hospital Episode Statistics (HES). Three infant cohorts were designed: (1) the all pregnancies infants cohort (N = 185,119), (2) the all pregnancies with a gestational age (GA) ≥ 24 weeks infants cohort (N = 183,869), and (3) the low-risk pregnancies infants cohort (LR infants cohort, N = 121,871), which included pregnancies with a GA ≥ 24 weeks and no diagnosis of predefined high-risk medical conditions until 24 weeks GA. Results The most common adverse infant outcome in the three infant cohorts was macrosomia (e.g., 1,085.9/10,000 live births in the LR infants cohort), followed by minor congenital anomalies (e.g., 800.6/10,000 in the LR infants cohort), very low/low birth weight (e.g., 400.6/10,000 in the LR infants cohort), and major congenital anomalies (e.g., 270.4/10,000 in the LR infants cohort). The incidence proportions for early-onset sepsis, very low/low birth weight, and minor and major congenital anomalies were lower in the LR infants than in the other cohorts (non-overlapping confidence intervals [CIs]). The incidence proportions of neonatal death, infant death, late-onset sepsis, macrosomia, small for GA, and large for GA were similar between cohorts (overlapping CIs). Conclusions This study generated background rates of adverse infant outcomes from liveborn infants of all and low-risk pregnancies represented in the CPRD Pregnancy Register MBL and linkage to HES. The results indicate lower incidence proportions of several adverse infant outcomes in infants from low-risk pregnancies compared to all pregnancies, illustrating the importance of considering maternal risk factors. These background rates may facilitate the interpretation of safety data from maternal immunization trials and of pharmacovigilance data from maternal vaccines. They may also be of interest for other interventions studied in pregnant women.

Imaging from optical coherence tomography (OCT) is widely used for detecting retinal diseases, localization of intra-retinal boundaries, etc. It is, however, degraded by speckle noise. Deep learning models can aid with denoising, allowing clinicians to clearly diagnose retinal diseases. Deep learning models can be considered as an end-to-end framework. We selected denoising studies that used deep learning models with retinal OCT imagery. Each study was quality-assessed through image quality metrics (including the peak signal-to-noise ratio—PSNR, contrast-to-noise ratio—CNR, and structural similarity index metric—SSIM). Meta-analysis could not be performed due to heterogeneity in the methods of the studies and measurements of their performance. Multiple databases (including Medline via PubMed, Google Scholar, Scopus, Embase) and a repository (ArXiv) were screened for publications published after 2010, without any limitation on language. From the 95 potential studies identified, a total of 41 were evaluated thoroughly. Fifty-four of these studies were excluded after full text assessment depending on whether deep learning (DL) was utilized or the dataset and results were not effectively explained. Numerous types of OCT images are mentioned in this review consisting of public retinal image datasets utilized purposefully for denoising OCT images (n = 37) and the Optic Nerve Head (ONH) (n = 4). A wide range of image quality metrics was used; PSNR and SNR that ranged between 8 and 156 dB. The minority of studies (n = 8) showed a low risk of bias in all domains. Studies utilizing ONH images produced either a PSNR or SNR value varying from 8.1 to 25.7 dB, and that of public retinal datasets was 26.4 to 158.6 dB. Further analysis on denoising models was not possible due to discrepancies in reporting that did not allow useful pooling. An increasing number of studies have investigated denoising retinal OCT images using deep learning, with a range of architectures being implemented. The reported increase in image quality metrics seems promising, while study and reporting quality are currently low.

Abstract Background Maternal characteristics like medical history and health-related risk factors can influence the incidence of pregnancy outcomes and pregnancy-related events of interest (EIs). Data on the incidence of these endpoints in low-risk pregnant women are needed for appropriate external safety comparisons in maternal immunization trials. To address this need, this study estimated the incidence proportions of pregnancy outcomes and pregnancy-related EIs in different pregnancy cohorts (including low-risk pregnancies) in England, contained in the Clinical Practice Research Datalink (CPRD) Pregnancy Register linked to Hospital Episode Statistics (HES) between 2005 and 2017. Methods The incidence proportions of 7 pregnancy outcomes and 15 EIs were calculated for: (1) all pregnancies (AP) represented in the CPRD Pregnancy Register linked to HES (AP cohort; N = 298 155), (2) all pregnancies with a gestational age (GA) ≥ 24 weeks (AP24+ cohort; N = 208 328), and (3) low-risk pregnancies (LR cohort; N = 137 932) with a GA ≥ 24 weeks and no diagnosis of predefined high-risk medical conditions until 24 weeks GA. Results Miscarriage was the most common adverse pregnancy outcome in the AP cohort (1 379.5 per 10 000 pregnancies) but could not be assessed in the other cohorts because these only included pregnancies with a GA ≥ 24 weeks, and miscarriages with GA ≥ 24 weeks were reclassified as stillbirths. Preterm delivery (

This article is based upon autobiographical narratives of two students exploring their experiences in finding commonality through an institutionalized domestic and international student community. Both students' paths intersected at the East-West Center (EWC), an independent, public, nonprofit organization formed by the US Congress in 1960 with the goal of bringing people together through cooperative study, research, and dialogue. The co-authors describe various factors that facilitated cultivating inner peace and minimize imposed oppressive tendencies. In particular, they analyze the importance of a learning environment that motivates each student to deeply reexamine their relationship to cultural and disciplinary boundaries, through exposing them to multifaceted perspectives. Their conclusions highlight the importance of EWC as a place where both domestic and international students can build dialogue, debate, and learn from each other, across disciplinary sectors in a relaxed setting. EWC, with its unique diplomatic-building environment, is a learning prototype that has the potential to unify global diversity through developing unique partnerships of empowerment. [ABSTRACT FROM AUTHOR]

Optical coherence tomography (OCT) is an emerging imaging tool in healthcare with common applications in ophthalmology for the detection of retinal diseases and in dentistry for the early detection of tooth decay. Speckle noise is ubiquitous in OCT images, which can hinder diagnosis by clinicians. In this paper, a region-based, deep learning framework for the detection of anomalies is proposed for OCT-acquired images. The core of the framework is Transformer-Enhanced Detection (TED), which includes attention gates (AGs) to ensure focus is placed on the foreground while identifying and removing noise artifacts as anomalies. TED was designed to detect the different types of anomalies commonly present in OCT images for diagnostic purposes and thus aid clinical interpretation. Extensive quantitative evaluations were performed to measure the performance of TED against current, widely known, deep learning detection algorithms. Three different datasets were tested: two dental and one CT (hosting scans of lung nodules, livers, etc.). The results showed that the approach verifiably detected tooth decay and numerous lesions across two modalities, achieving superior performance compared to several well-known algorithms. The proposed method improved the accuracy of detection by 16–22% and the Intersection over Union (IOU) by 10% for both dentistry datasets. For the CT dataset, the performance metrics were similarly improved by 9% and 20%, respectively.