This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data.
The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes.
Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual.
This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus.

BACKGROUND: Emergence of Plasmodium falciparum resistance to artemether-lumefantrine in Africa prompted the pilot introduction of multiple first-line therapies (MFT) against malaria in Kenya, potentially exposing women-of-childbearing-age (WOCBAs) to anti-malarials with unknown safety profiles in the first trimester. This qualitative study explored knowledge and perceptions among healthcare providers providing malaria treatment to WOCBAs and pregnant women.
METHODS: In-depth interviews were conducted with purposively selected public and private health facility (HF) and drug outlet (DO) providers within and outside the pilot-MFT area. County health managers were interviewed about their knowledge of the national treatment guidelines. Transcripts were coded by content analysis using the World Health Organization health system building blocks (leadership/governance, financing, health workforce, health information systems, access to medicines, and service delivery).
RESULTS: Thirty providers (HF:21, DO:9) and three health managers were interviewed. Eighteen providers were from HFs in the pilot-MFT area; the remaining three and all nine DOs were outside the pilot-MFT area. The analysis revealed that providers had not been trained in malaria case management in the previous twelve months. DO providers were unfamiliar with national treatment guidelines in pregnancy and reported having no pregnancy tests. Health managers were unable to supervise DOs due to resource limitations. Providers from HFs and DOs noted poor sensitivity of malaria rapid diagnostic tests (RDTs) and hesitancy among patients who associated malaria-RDTs with HIV testing. Almost all providers reported anti-malarial stock-outs, with quinine most affected. Patient preference was a major factor in prescribing anti-malarials. Providers in HFs and DOs reported preferentially using artemether-lumefantrine in the first trimester due to the side effects and unavailability of quinine.
CONCLUSIONS: Knowledge of malaria case management in drug outlets and health facilities remains poor. Improved regulation of DO providers is warranted. Optimizing treatment of malaria in pregnancy requires training, availability of malaria commodities, and pregnancy tests.

BACKGROUND: Concerns about emerging resistance to artemether-lumefantrine (AL) in Africa prompted the pilot introduction of multiple first-line therapies (MFT) in Western Kenya, potentially exposing women-of-childbearing-age (WOCBA) to anti-malarials with unknown safety profiles in the first trimester. The study assessed healthcare provider knowledge and adherence to national guidelines for managing malaria in pregnancy in the context of the MFT pilot.
METHODS: From March to April 2022, a cross-sectional study was conducted in 50 health facilities (HF) and 40 drug outlets (DO) using structured questionnaires to assess pregnancy detection, malaria diagnosis, and treatment choices by trimester. Differences between HF and DO providers and between MFT and non-MFT HFs were assessed using Chi-square tests.
RESULTS: Of 174 providers (77% HF, 23% DO), 56% were from MFT pilot facilities. Most providers had tertiary education; 5% HF and 20% DO had only primary or secondary education. More HF than DO providers had knowledge of malaria treatment guidelines (62% vs. 40%, p = 0.023), received training in malaria in pregnancy (49% vs. 20%, p = 0.002), and reported assessing for pregnancy in WOCBA (98% vs. 78%, p < 0.001). Most providers insisted on parasitological diagnosis, with 59% HF using microscopy and 85% DO using rapid diagnostic tests. More HF than DO providers could correctly name the drugs for treating uncomplicated malaria in the first trimester (oral quinine, or AL if quinine is unavailable) (90% vs. 58%, p < 0.001), second and third trimesters (artemisinin-based combination therapy) (84% vs. 70%, p = 0.07), and for severe malaria (parenteral artesunate/artemether) (94% vs. 60%, p < 0.001). Among HF providers, those in the MFT pilot had more knowledge of malaria treatment guidelines (67% vs. 49%, p = 0.08) and had received training on treatment of malaria in pregnancy (56% vs. 32%, p = 0.03). Few providers (10% HF and 12% DO) had adequate knowledge of malaria treatment in pregnancy, defined as the correct drug and dose for uncomplicated and severe malaria in all trimesters.
CONCLUSIONS: Knowledge of national malaria in pregnancy treatment guidelines among providers in Western Kenya is suboptimal. Robust training on appropriate anti-malarial and dosage is needed, particularly given the recent change in recommendation for artemether-lumefantrine use in the first trimester. Supervision of DO and HF practices is essential for correct treatment of malaria in pregnancy in the context of MFT programmes.

Owing to its life cycle involving multiple hosts and species-specific biological complexities, a vaccine against Plasmodium, the causative agent of Malaria remains elusive. This makes chemotherapy the only viable means to address the clinical manifestations and spread of this deadly disease. However, rapid surge in antimalarial resistance poses significant challenges to our efforts to eliminate Malaria since the best drug available to-date; Artemisinin and its combinations are also rapidly losing efficacy. Sodium ATPase (PfATP4) of Plasmodium has been recently explored as a suitable target for new antimalarials such as Cipargamin. Prior studies showed that multiple compounds from the Medicines for Malaria Venture (MMV) chemical libraries were efficient PfATP4 inhibitors. In this context, we undertook a structure- based virtual screening approach combined to Molecular Dynamic (MD) simulations to evaluate whether new molecules with binding affinity towards PfATP4 could be identified from the Pandemic Response Box (PRB), a 400-compound library of small molecules launched in 2019 by MMV. Our analysis identified new molecules from the PRB library that showed affinity for distinct binding sites including the previously known G358 site, several of which are clinically used anti-bacterial (MMV1634383, MMV1634402), antiviral (MMV010036, MMV394033) or antifungal (MMV1634494) agents. Therefore, this study highlights the possibility of exploiting PRB molecules against Malaria through abrogation of PfATP4 activity.Communicated by Ramaswamy H. Sarma.

BACKGROUND: It has been observed that most malaria patients especially G6PD-deficient patients usually experience oxidative stress and severe anemia when treated with primaquine. This calls for the need to search for a treatment option that will ameliorate these side effects.
OBJECTIVE: The effect of co-treatment of malaria with aqueous extract of Ocimum gratissimum leaves (AEOGL) and primaquine on G6PD activity, antioxidant indices and hematological parameters in Plasmodium berghei-infected mice was investigated.
METHODS: Thirty mice divided into six groups of five mice each were recruited for this study. Whilst Group 1 (G1) served as the negative control (group not infected with plasmodium parasite), Groups 2 to 6 (G2-G6) were inoculated intraperitoneally with 0.2 ml of 1 × 105/ml Plasmodium berghei (NK 65 strain) infected erythrocytes. G2 (parasite control) received no treatment. Groups 3,4,5 and 6 were administered 0.25 mg/kg bw of primaquine only; 100 mg/kg b. w of AEOGL +0.25 mg/kg bw of primaquine; 200 mg/kg b. w of AEOGL +0.25 mg/kg bw of primaquine; 200 mg/kg b. w of AEOGL respectively, for 14 days.
RESULTS: Treatment with only primaquine gave the highest mean malaria parasite clearance (82.10 ± 0.45 percent), followed by 100 mg/kg b. w of AEOGL + Primaquine (75.59 ± 0.47 percent), 200 mg/kg b. w of AEOGL + Primaquine (67.35 ± 0.67 percent), and AEOGL alone (55 ± 0.56 percent). In comparison with the untreated malaria groups, co-treatment with AEOGL + Primaquine produced a significant (p < 0.05) increase in G6PD activity, serum ascorbate, reduced glutathione, catalase activity, and a significant (p < 0.05) decrease in malondialdehyde level in a dose-dependent pattern and also a significant (p < 0.05) rise in packed cell volume, haemoglobin, and red blood cell count, unlike treatment with only primaquine which resulted in a non-significant (P > 0.05) difference in these parameters.
CONCLUSIONS: Co-treatment of Plasmodium berghei-infected mice with AEOGL and primaquine improved the G6PD activity, hematological parameters and antioxidant status relative to treatment with only primaquine.

Background: The emergence of artemisinin resistance in South East Asia calls for urgent discovery of new drug compounds that have antiplasmodial activity. Unlike the classical compound screening drug discovery methods, the rational approach involving targeted drug discovery is less cumbersome and therefore key for innovation of new antiplasmodial compounds.  Plasmodium falciparum (Pf) utilizes the process of host erythrocyte remodeling using Plasmodium-helical interspersed sub-telomeric domain (PHIST) containing proteins, which are amenable drug targets. The aim of this study is to identify inhibitors of PHIST from sulfated polysaccharides as new antimalarials. Methods: 251 samples from an ongoing study of epidemiology of malaria and drug resistance sensitivity patterns in Kenya were sequenced for PHISTb/RLP1 gene using Sanger sequencing. The sequenced reads were mapped to the reference Pf3D7 protein sequence of PHISTb/RLP1 using CLC Main Workbench. Homology modeling of both reference and mutant protein structures was achieved using the LOMETs tool. The models were refined using ModRefiner for energy minimization. Ramachandran plot was generated by ProCheck to assess the conformation of amino acids in the protein model. Protein binding sites predictions were assessed using FT SITE software. We searched for prospective antimalarials from PubChem. Docking experiments were achieved using AutoDock Vina and analysis results visualized in PyMOL. Results: Sanger sequencing generated 86 complete sequences. Upon mapping of the sequences to the reference, 12 non-synonymous single nucleotide polymorphisms were considered for mutant protein structure analysis. Eleven drug compounds with antiplasmodial activity were identified. Both modeled PHISTb/RLP1 reference and mutant structures had a Ramachandran score of >90% of the amino acids in the favored region. Ten of the drug compounds interacted with amino acid residues in PHISTb and RESA domains, showing potential activity against these proteins. Conclusion: This research identifies inhibitors of exported proteins that can be used in in vitro tests against the Plasmodium parasite.

Malaria remains one of the most prominent and dangerous tropical diseases. While artemisinin and analogs have been used as first-line drugs for the past decades, due to the high mutational rate and rapid adaptation to the environment of the parasite, it remains urgent to develop new antimalarials. The pyrimidine biosynthesis pathway plays an important role in cell growth and proliferation. Unlike human host cells, the malarial parasite lacks a functional pyrimidine salvage pathway, meaning that RNA and DNA synthesis is highly dependent on the de novo synthesis pathway. Thus, direct or indirect blockage of the pyrimidine biosynthesis pathway can be lethal to the parasite. Aspartate transcarbamoylase (ATCase), catalyzes the second step of the pyrimidine biosynthesis pathway, the condensation of L-aspartate and carbamoyl phosphate to form N-carbamoyl aspartate and inorganic phosphate, and has been demonstrated to be a promising target both for anti-malaria and anti-cancer drug development. This is highlighted by the discovery that at least one of the targets of Torin2 - a potent, yet unselective, antimalarial - is the activity of the parasite transcarbamoylase. Additionally, the recent discovery of an allosteric pocket of the human homology raises the intriguing possibility of species selective ATCase inhibitors. We recently exploited the available crystal structures of the malarial aspartate transcarbamoylase to perform a fragment-based screening to identify hits. In this review, we summarize studies on the structure of Plasmodium falciparum ATCase by focusing on an allosteric pocket that supports the catalytic mechanisms.

Malaria is one of the prevalent tropical diseases caused by the parasitic protozoan of the genus Plasmodium spp. With an estimated 228 million cases, it is a major public health concern with high incidence of morbidity and mortality worldwide. The emergence of drug-resistant parasites, inadequate vector control measures, and the non-availability of effective vaccine(s) against malaria pose a serious challenge to malaria eradication especially in underdeveloped and developing countries. Malaria treatment and control comprehensively relies on chemical compounds, which encompass various complications, including severe toxic effects, emergence of drug resistance, and high cost of therapy. To overcome the clinical failures of anti-malarial chemotherapy, a new drug development is of an immediate need. However, the drug discovery and development process is expensive and time consuming. In such a scenario, nanotechnological strategies may offer promising alternative approach for the treatment and control of malaria, with improved efficacy and safety. Nanotechnology based formulations of existing anti-malarial chemotherapeutic agents prove to exceed the limitations of existing therapies in relation to optimum therapeutic benefits, safety, and cost effectiveness, which indeed advances the patient\'s compliance in treatment. In this review, the shortcomings of malaria therapeutics and necessity of nanotechnological strategies for treating malaria were discussed.

BACKGROUND: The role of Accredited Social Health Activist (ASHA) in the health care delivery services at the periphery level is crucial for achieving disease prevention, control and elimination goals. The objective of the study was to assess the knowledge, attitude, practices, priorities and capability of ASHA related to malaria diagnosis and treatment as part of the Malaria Elimination Demonstration Project in 1233 villages of district Mandla, Madhya Pradesh.
METHODS: A cross sectional study was conducted using a fully structured, pre-tested interview schedule during June and July 2017 (before the field operations of MEDP were started). Two hundred twenty (17%) of the total ASHAs were selected for the interview from the 9 developmental blocks of Mandla district.
RESULTS: Knowledge, Attitude and Practices (KAP) study revealed that most ASHAs knew that mosquitoes are the main agent for spread of malaria (97.7%). They mostly used Rapid Diagnostic Test (RDT) for diagnosis (91.8%). The majority (87.3%) correctly identified negative RDT result while only 15% and 10.5%, respectively, identified Plasmodium vivax and Plasmodium falciparum positive cases correctly. Further analysis showed that 85% ASHAs used chloroquine, 44.5% used artemisinin-based combination therapy (ACT), and 55.5% used primaquine for treatment of malaria. It was also found that only 38.2% ASHA gave PQ for 14 days in cases of P. vivax. At the time of the interview, 19.1% ASHAs did not have any RDTs for diagnosis and 47.7% reported not having ACT for treatment of P. falciparum malaria.
CONCLUSIONS: This study has revealed that ASHAs in the test district were not adequately trained or stocked for malaria parasite species identification and treatment, which are the major components of malaria elimination programme. This study has, therefore, revealed a need for training ASHAs on testing by RDT and proper treatment regimen for P. vivax and P. falciparum.

The Malaria burden was an escalating global encumbrance and need to be addressed with critical care. Anti-malarial drug discovery was integrated with supervised machine learning (ML) models to identify potent thiazolyl-traizine derivatives. This assimilated approach of Direct Kernel-based Partial Least Squares regression (DKPLS) with molprint 2D fingerprints in Quantitative Structure Activity Relationship models was utilized to map the knowledge of known actives and to design novel molecules. This QSAR study had revealed the structural features required for better antimalarial activity. Two of the molecules which were designed based on the results of this QSAR study, had shown good percentage of parasitemia against both chloroquine sensitive (3D7) and chloroquine resistant (Dd2) strains of Plasmodium falciparum respectively. The IC50 of 201D and 204D was 3.02 and 2.17 µM against chloroquine resistant Dd2 strain of Plasmodium falciparum. This result had proved the efficiency of a multidisciplinary approach of medicinal chemistry and machine learning for the design of novel potent anti-malarial compounds.