Changes in protein fluxes and gene expression in non-injured muscle tissue distant from an acute myotoxic injury in male mice.

The response to acute myotoxic injury requires stimulation of local repair mechanisms in the damaged tissue. However, satellite cells in muscle distant from acute injury have been reported to enter a functional state between quiescence and active proliferation. Here, we asked whether protein flux rates are altered in muscle distant from acute local myotoxic injury and how they compare to changes in gene expression from the same tissue. Broad and significant alterations in protein turnover were observed across the proteome in the limb contralateral to injury during the first 10 days after. Interestingly, mRNA changes had almost no correlation with directly measured protein turnover rates. In summary, we show consistent and striking changes in protein flux rates in muscle tissue contralateral to myotoxic injury, with no correlation between changes in mRNA levels and protein synthesis rates. This work motivates further investigation of the mechanisms, including potential neurological factors, responsible for this distant effect. KEY POINTS: Previous literature demonstrates that stem cells of uninjured muscle respond to local necrotic muscle tissue damage and regeneration. We show that muscle tissue that was distant from a model of local necrotic damage had functional changes at both the gene expression and the protein turnover level. However, these changes in distant tissue were more pronounced during the earlier stages of tissue regeneration and did not correlate well with each other. The results suggest communication between directly injured tissue and non-affected tissues that are distant from injury, which warrants further investigation into the potential of this mechanism as a proactive measure for tissue regeneration from damage.

Reductions in functional muscle mass and ability to ambulate in Duchenne muscular dystrophy from ages 4 to 24 years.

Duchenne muscular dystrophy (DMD) results in a progressive loss of functional skeletal muscle mass (MM) and replacement with fibrofatty tissue. Accurate evaluation of MM in DMD patients has not previously been available. Our objective was to measure MM using the D3creatine (D3Cr) dilution method and determine its relationship with strength and functional capacity in patients with DMD over a wide range of ages. Subjects were recruited for participation in a 12 month, longitudinal, observational study. Here, we report the baseline data. A 20 mg dose of D3Cr dissolved in water was ingested by 92 patients with DMD (ages 4-25 years) followed later with a fasting urine sample. Enrichment of D3creatinine was determined by liquid chromatography-mass spectrometry analysis. The North Star Ambulatory Assessment (NSAA) total score was determined for ambulatory participants, and the Performance of Upper Limb (PUL 2.0) total score and grip strength for all participants. We observed a significant age-associated increase in body weight along with a substantial decrease in MM/body weight (%MM). MM and %MM were associated with PUL score (r = 0.517, P < 0.0001 and r = 0.764, P < 0.0001 respectively). The age-associated decrease in MM and %MM was strongly associated with ambulatory status. We observed very little overlap in %MM between ambulant and non-ambulant subjects, suggesting a threshold of 18-22% associated with loss of ambulation. MM is substantially diminished with advancing age and is highly related to clinically meaningful functional status. The D3Cr dilution method may provide a biomarker of disease progression and therapeutic efficacy in patients with DMD or other neuromuscular disorders. KEY POINTS: The non-invasive D3creatine dilution method provides novel data on whole body functional muscle mass (MM) in a wide range of ages in patients with DMD and reveals profoundly low functional MM in older non-ambulant patients. The difference in %MM between ambulant and non-ambulant subjects suggests a threshold for loss of ambulatory ability between 18 and 22% MM. The data suggest that as functional MM declines with age, maintaining a lower body weight may help to conserve ambulatory ability.

Therapeutic efficacy and safety of artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria treatment in Metehara, Central-east Ethiopia.

BACKGROUND: Malaria remains a major global health problem although there was a remarkable achievement between 2000 and 2015. Malaria drug resistance, along with several other factors, presents a significant challenge to malaria control and elimination efforts. Numerous countries in sub-Saharan Africa have documented the presence of confirmed or potential markers of partial resistance against artemisinin, the drug of choice for the treatment of uncomplicated Plasmodium falciparum malaria. The World Health Organization (WHO) recommends regular surveillance of artemisinin therapeutic efficacy to inform policy decisions. METHODS: This study aimed to evaluate the therapeutic efficacy of artemether-lumefantrine (AL), which is the first-line treatment for uncomplicated P. falciparum malaria in Ethiopia since 2004. Using a single-arm prospective evaluation design, the study assessed the clinical and parasitological responses of patients with uncomplicated P. falciparum malaria in Metehara Health Centre, central-east Ethiopia. Out of 2332 malaria suspects (1187 males, 1145 females) screened, 80 (50 males, 30 females) were enrolled, followed up for 28 days, and 73 (44 males, 29 females) completed the follow up. The study was conducted and data was analysed by employing the per-protocol and Kaplan-Meier analyses following the WHO Malaria Therapeutic Efficacy Evaluation Guidelines 2009. RESULTS: The results indicated rapid parasite clearance and resolution of clinical symptoms, with all patients achieving complete recovery from asexual parasitaemia and fever by day (D) 3. The prevalence of gametocytes decreased from 6.3% on D0 to 2.5% on D2, D3, D7, and ultimately achieving complete clearance afterward. CONCLUSION: The overall cure rate for AL treatment was 100%, demonstrating its high efficacy in effectively eliminating malaria parasites in patients. No serious adverse events related to AL treatment were reported during the study, suggesting its safety and tolerability among the participants. These findings confirm that AL remains a highly efficacious treatment for uncomplicated P. falciparum malaria in the study site after 20 years of its introduction in Ethiopia.

Chloroquine has shown high therapeutic efficacy against uncomplicated Plasmodium vivax malaria in southern Ethiopia: seven decades after its introduction.

BACKGROUND: Plasmodium vivax malaria is a leading cause of morbidity in Ethiopia. The first-line treatment for P. vivax is chloroquine (CQ) and primaquine (PQ), but there have been local reports of CQ resistance. A clinical study was conducted to determine the efficacy of CQ for the treatment of P. vivax malaria in southern Ethiopia. METHODS: In 2021, patients with P. vivax mono-infection and uncomplicated malaria were enrolled and treated with 25 mg/kg CQ for 3 consecutive days. Patients were followed for 28 days according to WHO guidelines. The data were analysed using per-protocol (PP) and Kaplan‒Meier (K‒M) analyses to estimate the risk of recurrent P. vivax parasitaemia on day 28. RESULTS: A total of 88 patients were enrolled, 78 (88.6%) of whom completed the 28 days of follow-up. Overall, 76 (97.4%) patients had adequate clinical and parasitological responses, and two patients had late parasitological failures. The initial therapeutic response was rapid, with 100% clearance of asexual parasitaemia within 48 h. CONCLUSION: Despite previous reports of declining chloroquine efficacy against P. vivax, CQ retains high therapeutic efficacy in southern Ethiopia, supporting the current national treatment guidelines. Ongoing clinical monitoring of CQ efficacy supported by advanced molecular methods is warranted to inform national surveillance and ensure optimal treatment guidelines.

Evaluation of the effect of designed PLGA-arctiin nanoparticles modified with folic acid and chitosan on colon cancer cells.

In this study, we designed nanoparticles (NPs) based on polylactic acid glycolic acid modified with chitosan and folic acid to optimize the anti-cancer, anti-inflammatory, and antioxidant effects of arctiin (ARC), and we measured its effects on cancer cells, including colon cancer. NPs were synthesized using the W1/O/W2 double-emulsion solvent evaporation method. Physicochemical characteristics of synthesized NPs (ARC-PCF-NPs), including average particle size, dispersity index (PDI), zeta potential (ZP), field emission scanning electron microscope figures, and encapsulation efficiency (EE), were evaluated. 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) methods were carried out to determine the antioxidant properties of NPs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay was performed to investigate cytotoxicity effects on cancer cells and normal fibroblasts. Quantitative polymerase chain reaction was also performed on inflammatory and antioxidant genes. The obtained results indicated that the synthesized NPs have a size of 100 nm, a DPI of 0.36, a ZP of 26.30 mV, and EE was calculated at about 87.5%. The antioxidant influence of ARC-PCF-NPs was confirmed by inhibiting ABTS and DPPH free radicals and ferrous reduction in the FRAP method. Moreover, the reduction of inflammatory and antioxidant genes confirmed the anti-inflammatory and antioxidant properties of NPs. These results indicate the modification of the surface of NPs in order to increase the bioavailability, stability, and effectiveness of medicinal compounds in therapeutic applications.

Nutritional Value and in vitro Antigiardial Activity of Anise (Pimpinella anisum L.) Seeds.

The present study focused on evaluating the proximate analysis, mineral composition, and in vitro anti-giardial activity of Pimpinella anisum seed extracts, which are aromatic plants with a long history of usage in folk and conventional medicine, as well as pharmaceutical manufacturing. Standard methods were used to determine the proximate analysis of the powdered plant sample, including dry matter, ash, fat, protein, fiber, and carbohydrates. The mineral contents of Pimpinella anisum seed were analyzed using Inductively Coupled Plasma Mass Spectrometry (ICP-MS), revealing that the plant has a high fiber content (42.62%) followed by carbohydrates (38.79%). The seeds were also found to be a rich source of minerals, with notable amounts of Rubidium, Magnesium, and Calcium. The extracts showed a high mortality percentage compared to Metronidazole, with the chloroform extract exhibiting higher anti-giardial activity (78.71%) than the ethanolic extract (75.29%) at a concentration of 500 ppm. These findings support the traditional use of Anise in treating gastrointestinal issues and as a natural supplement. Further studies are needed to isolate the active ingredients and understand their mechanism of action.

Acetyl-CoA carboxylase inhibitor increases LDL-apoB production rate in NASH with cirrhosis: prevention by fenofibrate.

Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12 weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12 weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P = 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P = 0.03) and absolute synthesis rate (ASR) (30.4-45.2 mg/dl/day, P = 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17 mg/dl/day at week 12, P = 0.002, N = 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8 mg/dl/day, respectively, P = 0.51, N = 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy.

Safety and therapeutic efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria at Shecha health centre, Arba Minch, Ethiopia.

BACKGROUND: In 2004, Ethiopia adopted artemether-lumefantrine (AL, Coartem®) as first-line treatment for the management of uncomplicated Plasmodium falciparum malaria. Continuous monitoring of AL therapeutic efficacy is crucial in Ethiopia, as per the World Health Organization (WHO) recommendation. This study aimed to assess the therapeutic efficacy of AL in the treatment of uncomplicated P. falciparum infection. METHODS: A 28 day onearm, prospective evaluation of the clinical and parasitological response to AL was conducted at Shecha Health Centre, Arba Minch town, Southern Ethiopia. Patients were treated with six-dose regimen of AL over three days and monitored for 28 days with clinical and laboratory assessments. Participant recruitment and outcome classification was done in accordance with the 2009 WHO methods for surveillance of anti-malarial drug efficacy guidelines. RESULTS: A total of 88 study participants were enrolled and 69 of them completed the study with adequate clinical and parasitological response. Two late parasitological failures were observed, of which one was classified as a recrudescence by polymerase chain reaction (PCR). The PCRcorrected cure rate was 98.6% (95% CI 92.3-100). AL demonstrated a rapid parasite and fever clearance with no parasitaemia on day 2 and febrile cases on day 3. Gametocyte clearance was complete by day three. No serious adverse events were reported during the 28 days follow-up. CONCLUSION: The study demonstrated high therapeutic efficacy and good safety profile of AL. This suggests the continuation of AL as the first-line drug for the treatment of uncomplicated P. falciparum malaria in Ethiopia. Periodic therapeutic efficacy studies and monitoring of markers of resistance are recommended for early detection of resistant parasites.

Therapeutic efficacy of pyronaridine-artesunate (Pyramax®) against uncomplicated Plasmodium falciparum infection at Hamusit Health Centre, Northwest Ethiopia.

BACKGROUND: Early case detection and prompt treatment are important malaria control and elimination strategies. However, the emergence and rapid spread of drug-resistant strains present a major challenge. This study reports the first therapeutic efficacy profile of pyronaridine-artesunate against uncomplicated Plasmodium falciparum in Northwest Ethiopia. METHODS: This single-arm prospective study with 42-day follow-up period was conducted from March to May 2021 at Hamusit Health Centre using the World Health Organization (WHO) therapeutic efficacy study protocol. A total of 90 adults ages 18 and older with uncomplicated falciparum malaria consented and were enrolled in the study. A standard single-dose regimen of pyronaridine-artesunate was administered daily for 3 days, and clinical and parasitological outcomes were assessed over 42 days of follow-up. Thick and thin blood films were prepared from capillary blood and examined using light microscopy. Haemoglobin was measured and dried blood spots were collected on day 0 and on the day of failure. RESULTS: Out of 90 patients, 86/90 (95.6%) completed the 42-day follow-up study period. The overall PCR-corrected cure rate (adequate clinical and parasitological response) was very high at 86/87 (98.9%) (95% CI: 92.2-99.8%) with no serious adverse events. The parasite clearance rate was high with fast resolution of clinical symptoms; 86/90 (95.6%) and 100% of the study participants cleared parasitaemia and fever on day 3, respectively. CONCLUSION: Pyronaridine-artesunate was highly efficacious and safe against uncomplicated P. falciparum in this study population.

Mexiletine: Antiarrhythmic mechanisms, emerging clinical applications and mortality.

Mexiletine, a class Ib antiarrhythmic drug, exhibits its major antiarrhythmic effect via inhibition of the fast and late Na+ currents in myocardial tissues that are dependent on the opening of Na+ channels for their excitation. Through a comprehensive examination of mexiletine's therapeutic benefits and potential risks, we aim to provide valuable insights that reinforce its role as a vital therapeutic option for patients with ventricular arrhythmias, long QT syndrome, and other heart rhythm disorders. This review will highlight the current understandings of the antiarrhythmic effects and rationales for recent off-label use and address the mortality and proarrhythmic effects of mexiletine utilizing published basic and clinical studies over the past five decades.

Facial and body contouring with 1444 nm Nd:YAG laser-assisted lipolysis: Clinical evidence.

BACKGROUND: Body contouring is a significant area of dermatologic and plastic surgery. Surgical procedures, like surgical lipectomy, and less invasive procedures, such as various liposuction techniques, are the two main ways to reduce fat. AIM: Our study showed that 1444 nm Nd:YAG laser-assisted lipolysis used with appropriate and specific parameters effectively destroys adipose tissue avoiding these risks and determining a safe clinical application. METHOD: A subcutaneous, 1444 nm Nd:YAG laser was used on 132 patients (range, 18-73 years; 109 women and 23 men with Fitzpatrick skin phototypes ranging between II and V) requiring body and face contouring. All patients were photographed for documentation. Digital clinical photography was taken under as near identical conditions as possible at baseline (pre-treatment), and 16 weeks post-treatment. The 5-point Global Aesthetic Improvement Scale (GAIS) was recorded immediately after treatment and at their final assessment session (4 months). Adverse events were monitored. RESULTS: On the basis of the investigator-evaluated GAIS scale, the total GAIS scores showed satisfactory results. Clinician assessment from the clinical photography showed good efficacy and visible aesthetic results for body and face areas. No serious or unexpected adverse side effects were recorded, and transient pain, oedema, erythema and slight induration resolved within the first week of treatment. CONCLUSIONS: The 1444 nm Nd:YAG laser is a new tool for performing lipolysis, and this study reports its effectiveness and safety.

Molecular modeling investigation on mechanism of diazinon pesticide removal from water by single- and multi-walled carbon nanotubes.

In this study, the mechanism of diazinon adsorption on single-walled carbon nanotubes (SWNTs), as well as multi-walled carbon nanotubes (MWNTs), was investigated using molecular modelling. Determination of the lowest energy sites of different types of carbon nanotubes (CNTs) was demonstrated. The adsorption site locator module was used for this purpose. It was found that the 5-walled CNTs are the best MWNTs for diazinon elimination from water due to their higher interactions with diazinon. In addition, the adsorption mechanism in SWNT and MWNTs was determined to be wholly adsorption on the lateral surface. It is because the geometrical size of diazinon molecules is larger than the inner diameter of SWNT and MWNTs. Furthermore, the contribution of diazinon adsorption on the 5-wall MWNTs was the highest, for the lowest diazinon concentration in the mixture.

Effect of Achillea fragrantissima Extract on Excision Wound Biofilms of MRSA and Pseudomonas aeruginosa in Diabetic Mice.

Achillea fragrantissima, a desert plant commonly known as yarrow, is traditionally used as an antimicrobial agent in folklore medicine in Saudi Arabia. The current study was undertaken to determine its antibiofilm activity against methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug-resistant Pseudomonas aeruginosa (MDR-P. aeruginosa) using in vitro and in vivo studies. A biofilm model induced through an excision wound in diabetic mice was used to evaluate its effect in vivo. The skin irritation and cytotoxic effects of the extract were determined using mice and HaCaT cell lines, respectively. The Achillea fragrantissima methanolic extract was analyzed with LC-MS to detect different phytoconstituents, which revealed the presence of 47 different phytoconstituents. The extract inhibited the growth of both tested pathogens in vitro. It also increased the healing of biofilm-formed excision wounds, demonstrating its antibiofilm, antimicrobial, and wound-healing action in vivo. The effect of the extract was concentration-dependent, and its activity was stronger against MRSA than MDR-P. aeruginosa. The extract formulation was devoid of a skin irritation effect in vivo and cytotoxic effect on HaCaT cell lines in vitro.

Novel Management of Granuloma Formation Secondary to Dermal Filler with Intralesional 1444 nm Nd:YAG Laser Technique.

Background: Dermal fillers for soft tissue for the treatment of face sagging, volume loss, and wrinkles have become popular among patients of all ages and ethnicities, and their use is becoming increasingly widespread. Aim: the goal of this study was to evaluate the effectiveness and safety of a micro-pulsed, 1444 nm Nd:YAG laser on dermal filler complications, in particular on granuloma management. Methods: A subcutaneous, 1444 nm Nd:YAG laser was used on five female patients (range age 52-68 years) with hyaluronic filler granulomas located on the face (two on the cheek area and three on the lips); three patients had self-injected the filler, buying it online. Before and after the therapy, the patients received a skin ultrasound to determine the form and location of the granulomas and to determine if there had been a full or partial resolution. During this study, all possible adverse effects at the treatment site were monitored. The 5-point Global Aesthetic Improvement Scale (GAIS) (0 point-no change; 1 point-25%, mild improvement; 2 points-50%, moderate improvement; 3 points-75%, good improvement; 4 points-100%, excellent improvement) was recorded at a 3-month follow-up. Results: good results were obtained in the treatment of filler granulomas with the intralesional 1444 nm laser, even if just a single treatment was performed (one intervention was effective for curing granulomas up to 5 mm in diameter). Three patients were satisfied with excellent improvement, and two patients experienced good improvement. The results are functional and aesthetically satisfying, as shown by photographic assessment. At the last follow-up, the granuloma had reduced or completely disappeared in all cases, and no infections, burns, scarring or fibrosis, episodes of severe bleeding, or other serious adverse effects had been reported. All subjects tolerated the post-treatment period well. Conclusions: Our findings showed that granuloma treatment with an intralesional 1444 nm Nd:YAG laser is a minimally invasive, easy, fast, efficient, and low-risk procedure.

Spatial Distribution of Plasmodium falciparum and Plasmodium vivax in Northern Ethiopia by Microscopic, Rapid Diagnostic Test, Laboratory Antibody, and Antigen Data.

BACKGROUND: Determining malaria transmission within regions of low, heterogenous prevalence is difficult. A variety of malaria tests exist and range from identification of diagnostic infection to testing for prior exposure. This study describes the concordance of multiple malaria tests using data from a 2015 household survey conducted in Ethiopia. METHODS: Blood samples (n=2279) from 3 regions in northern Ethiopia were assessed for Plasmodium falciparum and Plasmodium vivax by means of microscopy, rapid diagnostic test, multiplex antigen assay, and multiplex assay for immunoglobulin G (IgG) antibodies. Geospatial analysis was conducted with spatial scan statistics and kernel density estimation to identify malaria hot spots by different test results. RESULTS: The prevalence of malaria infection was low (1.4% by rapid diagnostic test, 1.0% by microscopy, and 1.8% by laboratory antigen assay). For P. falciparum, overlapping spatial clusters for all tests and an additional 5 unique IgG clusters were identified. For P. vivax, clusters identified with bead antigen assay, microscopy, and IgG partially overlapped. CONCLUSIONS: Assessing the spatial distribution of malaria exposure using multiple metrics can improve the understanding of malaria transmission dynamics in a region. The relative abundance of antibody clusters indicates that in areas of low transmission, IgG antibodies are a more useful marker to assess malaria exposure.

What is needed to build a personalized recommender system for K-12 students' E-Learning? Recommendations for future systems and a conceptual framework.

Online learning has significantly expanded along with the spread of the coronavirus disease (COVID-19). Personalization becomes an essential component of learning systems due to students' different learning styles and abilities. Recommending materials that meet the needs and are tailored to learners' styles and abilities is necessary to ensure a personalized learning system. The study conducted a systematic literature review (SLR) of papers on recommendation systems for e-learning in the K12 setting published between 2017 and 2021 and aims to identify the most important component of a personalized recommender system for school students' e-learning. Recommendations for later studies were proposed based on the identified components, namely a personalized conceptual framework for providing materials to school students. The proposed framework comprised four stages: student profiling, material collection, material filtering, and validation.

The role of striated muscle Pik3r1 in glucose and protein metabolism following chronic glucocorticoid exposure.

Chronic glucocorticoid exposure causes insulin resistance and muscle atrophy in skeletal muscle. We previously identified phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1) as a primary target gene of skeletal muscle glucocorticoid receptors involved in the glucocorticoid-mediated suppression of insulin action. However, the in vivo functions of Pik3r1 remain unclear. Here, we generated striated muscle-specific Pik3r1 knockout (MKO) mice and treated them with a dexamethasone (DEX), a synthetic glucocorticoid. Treating wildtype (WT) mice with DEX attenuated insulin activated Akt activity in liver, epididymal white adipose tissue, and gastrocnemius (GA) muscle. This DEX effect was diminished in GA muscle of MKO mice, therefore, resulting in improved glucose and insulin tolerance in DEX-treated MKO mice. Stable isotope labeling techniques revealed that in WT mice, DEX treatment decreased protein fractional synthesis rates in GA muscle. Furthermore, histology showed that in WT mice, DEX treatment reduced GA myotube diameters. In MKO mice, myotube diameters were smaller than in WT mice, and there were more fast oxidative fibers. Importantly, DEX failed to further reduce myotube diameters. Pik3r1 knockout also decreased basal protein synthesis rate (likely caused by lower 4E-BP1 phosphorylation at Thr37/Thr46) and curbed the ability of DEX to attenuate protein synthesis rate. Finally, the ability of DEX to inhibit eIF2α phosphorylation and insulin-induced 4E-BP1 phosphorylation was reduced in MKO mice. Taken together, these results demonstrate the role of Pik3r1 in glucocorticoid-mediated effects on glucose and protein metabolism in skeletal muscle.

Temporal dynamics of Plasmodium falciparum population in Metehara, east-central Ethiopia.

BACKGROUND: Plasmodium falciparum is the most serious, genetically most complex and fastest-evolving malaria parasite. Information on genetic diversity of this parasite would guide policy decision and malaria elimination endeavors. This study explored the temporal dynamics of P. falciparum population in two time points in Metehara, east-central Ethiopia. METHODS: The participants were quantitative real-time polymerase chain reaction-confirmed patients who were recruited for uncomplicated falciparum malaria therapeutic efficacy test in 2015 and 2019. Dry blood spot samples were analysed by the nested PCR to genotype P. falciparum merozoite surface protein (msp1, msp2) and glutamate-rich protein (glurp) genes. RESULTS: While msp1, msp2 and glurp genotypes were successfully detected in 26(89.7%), 24(82.8%) and 14(48.3%) of 2015 samples (n = 29); the respective figures for 2019 (n = 41) were 31(68.3%), 39(95.1%), 25(61.0%). In 2015, the frequencies of K1, MAD20 and RO33 allelic families of msp1, and FC27 and IC/3D7 of msp2 were 19(73.1%), 8(30.6%), 14(53.8%), 21(87.5%), 12(50.5%); and in 2019 it was 15(48.4%), 19(61.3%), 15(48.4%), 30(76.9%), 27(69.2%) respectively. MAD20 has shown dominance over both K1 and RO33 in 2019 compared to the proportion in 2015. Similarly, although FC27 remained dominant, there was shifting trend in the frequency of IC/3D7 from 50.5% in 2015 to 69.2% in 2019. The multiplicity of infection (MOI) and expected heterozygosity index (He) in 2015 and 2019 were respectively [1.43 ± 0.84] and [1.15 ± 0.91], 0.3 and 0.03 for msp1. However, there was no significant association between MOI and age or parasitaemia in both time points. CONCLUSION: The lower genetic diversity in P. falciparum population in the two time points and overall declining trend as demonstrated by the lower MOI and He may suggest better progress in malaria control in Metehara. But, the driving force and selective advantage of switching to MAD20 dominance over the other two msp1 allelic families, and the dynamics within msp2 alleles needs further investigation.

Efficacy and safety of pyronaridine-artesunate (Pyramax®) for the treatment of uncomplicated Plasmodium vivax malaria in Northwest Ethiopia.

BACKGROUND: Declining efficacy of chloroquine for the treatment Plasmodium vivax malaria has been reported in different endemic settings in Ethiopia. This highlights the need to assess alternative options for P. vivax treatment with artemisinin-based combination therapy, such as pyronaridine-artesunate. This treatment regimen has shown high efficacy for uncomplicated malaria in both Africa and Asia. However, limited data are available from Ethiopia. This study was conducted to assess the efficacy and safety of pyronaridine-artesunate for the treatment of uncomplicated P. vivax malaria in Northwest Ethiopia. METHODS: A single arm prospective efficacy study was conducted in the Hamusite area, Northwest Ethiopia. Fifty-one febrile adult patients with uncomplicated P. vivax malaria were enrolled between March and July 2021. Patients were treated with pyronaridine-artesunate once daily for three days. Clinical and parasitological parameters were monitored over a 42-day follow-up period using the standard World Health Organization protocol for therapeutic efficacy studies. RESULTS: A total of 4372 febrile patients were screened with 51 patients enrolled and 49 completing the 42-day follow-up period. The PCR-uncorrected adequate clinical and parasitological response (ACPR) was 95.9% (47/49; 95% CI 84.9-99.0) on day 42. Two patients had recurrences [4.0% (2/49); 95% CI 0.7-12.1] on days 35 and 42. The parasite clearance rate was rapid with fast resolution of clinical symptoms; 100% of participants had cleared parasitaemia on day 1 and fever on day 2. All 16 (31.4%) patients with gametocyte carriage on day 0 had cleared by day 1. There were no serious adverse events. CONCLUSION: In this small study, pyronaridine-artesunate was efficacious and well-tolerated for the treatment of uncomplicated P. vivax malaria. In adults in the study setting, it would be a suitable alternative option for case management.

Investigation of Plasmodium falciparum pfhrp2 and pfhrp3 gene deletions and performance of a rapid diagnostic test for identifying asymptomatic malaria infection in northern Ethiopia, 2015.

BACKGROUND: Rapid diagnostic tests (RDTs) are widely used for malaria diagnosis of both symptomatic and asymptomatic infections. Although RDTs are a reliable and practical diagnostic tool, the sensitivity of histidine-rich protein 2 (HRP2)-based RDTs can be reduced if pfhrp2 or pfhrp3 (pfhrp2/3) gene deletions exist in the Plasmodium falciparum parasite population. This study evaluated dried blood spot (DBS) samples collected from a national household survey to investigate the presence of pfhrp2/3 deletions and the performance of the RDT used in the cross-sectional survey in a low transmission setting. METHODS: The 2015 Ethiopia Malaria Indicator Survey tested household members by RDT and collected DBS samples. DBS (n = 2648) from three regions in northern Ethiopia were tested by multiplex bead-based antigen detection assay after completion of the survey. The multiplex assay detected pan-Plasmodium lactate dehydrogenase (LDH), pAldolase, and HRP2 antigens in samples. Samples suspected for pfhrp2/3 gene deletions (pLDH and/or pAldolase positive but low or absent HRP2) were further investigated by molecular assays for gene deletions. Antigen results were also compared to each individual's RDT results. Dose-response logistic regression models were fit to estimate RDT level of detection (LOD) antigen concentrations at which 50, 75, 90, and 95% of the RDTs returned a positive result during this survey. RESULTS: Out of 2,648 samples assayed, 29 were positive for pLDH or pAldolase antigens but low or absent for HRP2 signal, and 15 of these samples (51.7%) were successfully genotyped for pfhrp2/3. Of these 15 P. falciparum infections, eight showed single deletions in pfhrp3, one showed a single pfhrp2 deletion, and six were pfhrp2/3 double-deletions. Six pfhrp2 deletions were observed in Tigray and one in Amhara. Twenty-five were positive for HRP2 by the survey RDT while the more sensitive bead assay detected 30 HRP2-positive samples. A lower concentration of HRP2 antigen generated a positive test result by RDT compared to pLDH (95% LOD: 16.9 ng/mL vs. 319.2 ng/mL, respectively). CONCLUSIONS: There is evidence of dual pfhrp2/3 gene deletions in the Tigray and Amhara regions of Ethiopia in 2015. As the prevalence of malaria was very low (< 2%), it is difficult to make strong conclusions on RDT performance, but these results challenge the utility of biomarkers in household surveys in very low transmission settings.