Correlation of severity & clinical outcomes of COVID-19 with virus variants: A prospective, multicentre hospital network study.

BACKGROUND OBJECTIVES: The clinical course of COVID-19 and its prognosis are influenced by both viral and host factors. The objectives of this study were to develop a nationwide platform to investigate the molecular epidemiology of SARS-CoV-2 (Severe acute respiratory syndrome Corona virus 2) and correlate the severity and clinical outcomes of COVID-19 with virus variants. METHODS: A nationwide, longitudinal, prospective cohort study was conducted from September 2021 to December 2022 at 14 hospitals across the country that were linked to a viral sequencing laboratory under the Indian SARS-CoV-2 Genomics Consortium. All participants (18 yr and above) who attended the hospital with a suspicion of SARS-CoV-2 infection and tested positive by the reverse transcription-PCR method were included. The participant population consisted of both hospitalized as well as outpatients. Their clinical course and outcomes were studied prospectively. Nasopharyngeal samples collected were subjected to whole genome sequencing to detect SARS-CoV-2 variants. RESULTS: Of the 4972 participants enrolled, 3397 provided samples for viral sequencing and 2723 samples were successfully sequenced. From this, the evolution of virus variants of concern including Omicron subvariants which emerged over time was observed and the same reported here. The mean age of the study participants was 41 yr and overall 49.3 per cent were female. The common symptoms were fever and cough and 32.5 per cent had comorbidities. Infection with the Delta variant evidently increased the risk of severe COVID-19 (adjusted odds ratio: 2.53, 95% confidence interval: 1.52, 4.2), while Omicron was milder independent of vaccination status. The independent risk factors for mortality were age >65 yr, presence of comorbidities and no vaccination. INTERPRETATION CONCLUSIONS: The authors believe that this is a first-of-its-kind study in the country that provides real-time data of virus evolution from a pan-India network of hospitals closely linked to the genome sequencing laboratories. The severity of COVID-19 could be correlated with virus variants with Omicron being the milder variant.

Parent and child influence in body image dissatisfaction: The moderating effect of parent acceptance of the COVID-19 pandemic.

The present study investigated the influence of parent and child-driven effects on body image dissatisfaction during the COVID-19 pandemic. The moderating effect of parents' acceptance of the COVID-19 pandemic and child gender were also investigated. The participants were 175 Canadian parents (mothers = 87.4%, fathers = 12%, unspecified = 0.6%) of children aged between 7 and 12 years old (M = 9.2; boys = 48.9%, girls = 51.1%). Two cohorts of parents were asked to complete a questionnaire in June 2020 and January 2021, respectively, followed by a second questionnaire approximately five months later. At both time points, the questionnaires addressed the parents' body image dissatisfaction and acceptance of the COVID-19 pandemic. In addition, parents reported on their child's body image dissatisfaction at both time points. Path analysis models were used to examine parent-driven and child-driven effects. Parents' acceptance of the pandemic significantly moderated both parent and child-driven effects such that parents with low levels of acceptance were more likely to negatively influence, and be negatively influenced by, their perception of their child's body image dissatisfaction. Child gender significantly moderated child-driven effects, as mothers' perception of their son's body image dissatisfaction predicted their own dissatisfaction over time. Our findings suggest that child-driven effects should be considered in future studies on body image dissatisfaction.

Clever pest control? The role of cognition in biological pest regulation.

Crop pest management is a global challenge. Increases in agricultural intensity due to anthropogenic demands, alongside the need to reduce the reliance on pesticides to minimize environmental harm, have resulted in an urgent need to improve and expand other methods of pest control. One increasingly utilized method is biological pest control, in which natural pest predators are used to regulating crop pests. Current approaches to biological pest regulation assess the importance of a pest controller by examining its ability to maintain pest populations over an extended period. However, this approach lacks efficiency, specificity, and efficacy because it does not take into account crucial factors which determine how predators find, evaluate and remember food sources-the cognitive processes underlying their behavior. This review will investigate the cognitive factors involved in biological pest control and examine how these factors may be manipulated to impact pest behavior and pest controller performance.

COVID-19-related anxiety and trauma symptoms predict decreases in body image satisfaction in children.

The present study investigated short-term longitudinal effects of COVID-19-related trauma and separation, social, and generalized anxiety symptoms on children's body image satisfaction. Participants were 247 Canadian children (121 boys, 123 girls) aged between 7 and 12 years (M = 9.04). Two cohorts of parents were recruited to complete a questionnaire at two time points on their children's body image satisfaction and COVID-19-related trauma and anxiety symptoms. The first cohort (n = 136 children) was recruited in Summer 2020 and the second cohort (n = 111 children) was recruited in Winter 2021. For each cohort, follow-up surveys were completed approximately five months later, therefore covering an entire year with both cohorts. Multilevel regression analyses showed that children's trauma and anxiety at Time 1 predicted significant decreases in body image satisfaction at Time 2. Older children were especially at risk of decreased body image satisfaction as a result of their COVID-19-related trauma, social anxiety and generalized anxiety symptoms. Younger girls were susceptible to decreased body image satisfaction as a result of their separation anxiety symptoms. Given that children's body image dissatisfaction is a precursor to the development of eating disorders, these findings shed light on potential targets for early intervention with children who are at-risk of developing such difficulties.

Construction of 5-(Alkylamino)-6-aryl/alkylpyrazine-2,3-dicarbonitriles via the One-Pot Reaction of Alkyl Isocyanides with Aryl/Alkyl Carbonyl Chlorides and Diaminomaleonitrile: Fluorescence and Antimicrobial Activity Evaluation.

5-(Alkylamino)-6-aryl/alkylpyrazine-2,3-dicarbonitriles were successfully synthesized in good to moderate yields by reacting alkyl isocyanides with aryl/alkyl carbonyl chlorides, followed by the addition of diaminomaleonitrile. The synthesized pyrazines were fully characterized in this investigation, and X-ray crystal structure analysis was performed on some derivatives. The antibacterial and antifungal activities of the newly synthesized pyrazine-2,3-dicarbonitriles were assessed in addition to their UV and fluorescence results. All the compounds showed similar UV-Vis spectral features with absorption peaks (λmax) around 267, 303, and 373 nm.

Safety and efficacy of endoscopic sleeve gastroplasty for obesity management in new bariatric endoscopy programs: a multicenter international study.

Background: Endoscopic sleeve gastroplasty (ESG) is an incisionless procedure that reduces the size of the gastric cavity. In prior studies, it has been proven to be a safe and effective treatment for obesity. In this study, we performed a collaborative study to evaluate the effectiveness of ESG among new endobariatric programs. Methods: This was an international, multicenter study reviewing the outcomes of ESG in centers starting ESG programs. Total body weight loss, change of body mass index (BMI), excess body weight loss (EBWL), technical success, duration of hospitalization, and immediate and delayed adverse events and complications at 24 h, 1 week, and 1, 3, and 6 months post-procedure were evaluated. Results: A total of 91 patients (35 males) from six centers were included. The patients' mean BMI before the procedure was 38.7 kg/m2. BMI reduction at 3 months was 7.3 (p < 0.000), at 6 months 9.3 (p < 0.000), and at 12 months 8.6 (p < 0.000) from baseline. EBWL was 17.3% at 1 month (p < 0.000), 29.2% at 3 months (p < 0.000), and 35.6% at 6 months (p < 0.000). The mean procedure duration was 85.1 min. The mean length of hospital stay post-procedure was 27 h. Conclusion: ESG provides EBWL percentage sustained up to 12 months. These results are equivalent among the new ESG centers compared to previous studies by expert centers. Lay title: Endoscopic sleeve gastroplasty in new bariatric endoscopy programs. Plain Language Summary: This article is the result of a collaborative international study on new endoscopic programs offering endoscopic sleeve gastroplasty.The minimally invasiveness and increasing accessibility of this technique makes it very attractive for patients with obesity while being poor candidate for surgery or refusing surgery.This study will also provide valuable information regarding this rising technique of endobariatric treatment.

Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the pharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drug development.

BACKGROUND: SJ733, a newly developed inhibitor of P. falciparum ATP4, has a favorable safety profile and rapid antiparasitic effect but insufficient duration to deliver a single-dose cure of malaria. We investigated the safety, tolerability, and pharmacokinetics of a multidose SJ733 regimen and a single-dose pharmacoboost approach using cobicistat to inhibit CYP3A4, thereby increasing exposure. METHODS: Two multidose unboosted cohorts (n = 9) (SJ733, 300 mg and 600 mg daily for 3 days) followed by three single-dose boosted cohorts combining SJ733 (n = 18) (75-, 300-, or 600-mg single dose) with cobicistat (150-mg single dose) as a pharmacokinetic booster were evaluated in healthy volunteers (ClinicalTrials.gov: NCT02661373). FINDINGS: All participants tolerated SJ733 well, with no serious adverse events (AEs), dose-limiting toxicity, or clinically significant electrocardiogram or laboratory test findings. All reported AEs were Grade 1, clinically insignificant, and considered unlikely or unrelated to SJ733. Compared to unboosted cohorts, the SJ733/cobicistat-boosted cohorts showed a median increase in area under the curve and maximum concentration of 3·9 × and 2·6 ×, respectively, and a median decrease in the ratio of the major CYP3A-produced metabolite SJ506 to parent drug of 4·6 × . Incorporating these data in a model of parasite dynamics indicated that a 3-day regimen of SJ733/cobicistat (600 mg/150 mg daily) relative to a single 600-mg dose ± cobicistat would increase parasite clearance from 106 to 1012 parasites/µL. INTERPRETATION: The multidose and pharmacoboosted approaches to delivering SJ733 were well-tolerated and significantly increased drug exposure and prediction of cure. This study supports the further development of SJ733 and demonstrates an innovative pharmacoboost approach for an antimalarial. FUNDING: Global Health Innovative Technology Fund, Medicines for Malaria Venture, National Institutes of Health, and American Lebanese Syrian Associated Charities.

Gender Disparity in Academic Gastroenterology: Beginning of the End of the Underrepresentation of Women?

BACKGROUND: Though there are an increasing number of female medical graduates, women remain underrepresented in academic medicine. There have been several reasons to explain this gender disparity, including marital status, number of children, number of hours worked, job flexibility, perceptions of women as inferior leaders, gender bias, sexual harassment, and unsupportive academic climates. AIMS: This study aimed to investigate the relationship between scholarly productivity and the representation of female gastroenterologists in academia. Specifically, scholarly productivity measured by the h-index and academic rank were explored to determine if there were gender disparities in academic productivity and rank in gastroenterology. METHODS: Gastroenterology departmental listings were obtained from the Fellowship and Residency Interactive Database of the American Medical Association. The Scopus database was used to record each physician's h-index. Statistical analyses were conducted with Wilcoxon rank-sum test, which compared matched samples by academic rank, and ANOVA tests, which compared multiple academic ranks. RESULTS: Out of 1703 academic gastroenterologists, women account for 25% of academic physicians. Women have statistically lower h-indices at the level of Assistant Professor (p = 0.0012), and at the level of Chair (p = 0.01). There was no difference in h-indices between male and female at the rank of Associate Professor and Professor. CONCLUSIONS: While these results mirror patterns appreciated in other fields of medicine, the results at the rank of Chair may suggest that despite the lower h-index compared to their male counterparts, females are perceived as having strong inherent leadership skills outside of academic productivity that are also conducive to leading a department and may be contributing to their rise to Chair.

Ablative therapies of the biliary tree.

Cholangiocarcinoma, a malignancy of the epithelial cells in the intrahepatic or extrahepatic biliary tree, is often diagnosed at later stages. Median survival duration ranges from 3 to 9 months with a less than ten percent 5-year survival rate. Thus, often treatment strategies are aimed more towards palliation instead of cure. With the majority of patients presenting with unresectable disease at the time of diagnosis, surgical intervention is not feasible, making less invasive endoscopic therapies more suitable. Initially, biliary stents were utilized for biliary decompression to mitigate cholestatic symptoms and prevent cholangitis; however, this strategy did not prove to provide significant survival benefit. Therefore, efforts to treat the tumor burden itself in addition to maintaining biliary patency became a focus of innovation and research in the endoscopic field. This study has led to the advent of therapies such as photodynamic therapy, radiofrequency ablation, and intraluminal brachytherapy. These options combined with biliary stenting have shown to not only offer the benefit of biliary decompression, but also to potentially improve stent patency and survival. Further, there is an anti-tumor effect of each of these modalities, portending an additional benefit in this subset of patients. Despite numerous retrospective and prospective studies assessing these ablative therapies, there is still a paucity of appropriately powered randomized controlled trials, and further research has yet to be done in the field. This review details the current literature entailing endobiliary ablative strategies.

The Value of Managing Acute Pancreatitis With Standardized Order Sets to Achieve "Perfect Care".

OBJECTIVES: We aimed to define perfect care index (PCI) metrics and to evaluate whether implementation of standardized order sets would improve outcomes without increasing hospital-based charges in patients with acute pancreatitis (AP). METHODS: This is a retrospective, pre-post, observational study measuring clinical quality, processes of care, and hospital-based charges at a single tertiary care center. The first data set included AP patients from August 2011 to December 2014 (n = 219) before the implementation of a standardized order set (Methodist Acute Pancreatitis Protocol [MAPP]) and AP patients after MAPP implementation from January 2015 to September 2018 (n = 417). The second data set included AP patients (n = 150 in each group) from January 2013 to September 2014 (pre-MAPP) and January 2018 to September 2019 (post-MAPP) to evaluate perfect care between the 2 cohorts after controlling for systemic inflammatory response syndrome at baseline. Length of stay, PCI, and hospital-based charges were measured. RESULTS: The post-MAPP cohort had a significantly shorter length of stay (median, 3 days vs 4 days; P = 0.01). In the second data set, PCI significantly increased after implementation of MAPP order sets (5.3%-35.3%, P < 0.0001). CONCLUSIONS: The MAPP order sets increased the value of care by improving clinical outcomes without increasing hospital-based charges.

Synthesis and characterization of novel tricyanofuran hydrazone probe: solvatochromism, density-functional theory calculation and selective fluorescence, and colorimetric determination of iron (III).

A tricyanofuran hydrazone (TCFH) spectroscopic probe was produced to visually recognize Fe(III) ions in aqueous environments. The synthesis was started by reacting tricyanofuran with 4-aminophenol diazonium chloride. All the synthesized compounds were characterized by spectroscopic analyses. TCFH showed distinctive solvatochromic behaviour in various organic polar solvents due to intramolecular charge transfer. Its behaviour towards sensing Fe(III) was studied using ultraviolet-visible spectrophotometry. The sensing behaviours of the proposed probe for other metal ions, namely Co(II), Cr(III), Mg(II), Pb(II), Cd(II), Ba(II), Hg(II), Mn(II), Ni(II), Cu(II), Zn(II), Ca(II), Al(III), Na(I) and K(I), were also investigated, but no spectral changes were observed, indicating the probe's potential use as a highly selective and Fe(III)-sensitive colorimetric and fluorescent chemical sensor. The TCFH probe using EtOH/H2 O (5:1; v/v) served as a colorimetric and fluorescent chemosensor for identification of Fe(III) by the naked eye owing to both its high sensitivity and selectivity towards Fe(III) compared with the other examined metal ions. The proposed TCFH probe can therefore be utilized as an effective spectroscopic sensor for Fe(III). Both colorimetric and fluorescence recognition of the analyte depended on the concentration of Fe(III) ions and was accomplished at a pH of 7. A rapid colour change from yellow to red occurred when an aqueous solution of Fe(III) ions was added. The intensity of the colour increased at higher Fe(III) concentrations. Cyclic voltammetry measurements in the dimethylformamide solvent indicated a nonreversible redox potential. This study also explained the possible mechanisms for both solvatochromism and the detection of Fe(III) through TCFH-Fe(III) complex formation. The binding constant of the generated TCFH-Fe(III) complex was explored. Computational modelling was conducted to explain the deprotonation-triggered changes that occur in the photophysical properties of TCFH dyes.

BPA and BPS Affect Connexin 37 in Bovine Cumulus Cells.

Bisphenol S (BPS) is used as an alternative plasticizer to Bisphenol A (BPA), despite limited knowledge of potential adverse effects. BPA exhibits endocrine disrupting effects during development. This article focuses on the impact of bisphenols during oocyte maturation. Connexins (Cx) are gap junctional proteins that may be affected by bisphenols, providing insight into their mechanism during development. Cxs 37 and 43 are crucial in facilitating cell communication between cumulus cells and oocytes. Cumulus-oocyte complexes (COCs), denuded oocytes, and cumulus cells were exposed to 0.05 mg/mL BPA or BPS for 24 h. Both compounds had no effect on Cx43. Cumulus cells exhibited a significant increase in Cx37 expression following BPA (p = 0.001) and BPS (p = 0.017) exposure. COCs treated with BPA had increased Cx37 protein expression, whilst BPS showed no effects, suggesting BPA and BPS act through different mechanisms. Experiments conducted in in vitro cultured cumulus cells, obtained by stripping germinal vesicle oocytes, showed significantly increased expression of Cx37 in BPA, but not the BPS, treated group. BPA significantly increased Cx37 protein expression, while BPS did not. Disrupted Cx37 following BPA exposure provides an indication of possible effects of bisphenols on connexins during the early stages of development.

What Will Happen to This Dog? A Qualitative Analysis of Rehoming Organisations' Pre-adoption Dog Behaviour Screening Policies and Procedures.

Rehoming organisations often undertake some type of behaviour evaluation to determine dogs' suitability for rehoming and/or the type of suitable home. Assessments can carry considerable weight in determining dogs' fates. Although evaluation of the validity and reliability of any test is important, a more fundamental consideration is if the nature of the information sought and the weight given to this in organisations' decision making is of more than anecdotal value. Therefore, this study's aim was to conduct a qualitative analysis of organisations' pre-adoption dog behaviour screenings and potential justifications, comparing this with the available scientific evidence. A written enquiry was sent electronically to rehoming organisations in the UK and US from February 2016-July 2017. Of 73 respondents, the majority conducted assessments for all dogs. Using a thematic analysis, nine themes and 71 sub-themes emerged concerning the types of information respondents aim to gather from assessments. The majority of respondents used, at least partially, pass/fail scoring, i.e., certain outcomes would lead to dogs being deemed unadoptable. Forty-one sub-themes and one theme were identified as potentially leading to a dog being deemed unadoptable. The evidence base for these factors was identified from the scientific literature relating to: increased risk for relinquishment, impact on a dog's quality of life, and human safety risk. Evidence supported 10 factors: "aggression towards people", "aggression towards cats or other animals", "aggression towards dogs", "biting or snapping", "resource guarding", "activity level or exercise needs", "destructiveness", "housetrained", "fearfulness", and "knowledge of basic commands and/or general training". Of those, seven were associated only with relinquishment risk, two ("resource guarding", "knowledge of basic commands") with human safety risk, and one ("fearfulness") with both. Thus, for >85% of characteristics organisations deemed important for dogs' adoptability, scientific evidence to support this is lacking. More research is needed to investigate the value of behaviour assessments, especially concerning the assessment of factors that could pose a public safety risk. However, given the current lack of scientific support for many decisions regarding dogs' rehoming suitability and recognised pressure on resources, it is suggested that organisations should focus on pre-adoption adopter education and post-adoption support.

Highly efficient Ru(ii)-alkylidene based Hoveyda-Grubbs catalysts for ring-closing metathesis reactions.

Three novel phosphine-free Ru-alkylidenes (7a-7c) have been synthesized and utilized as efficient catalysts for ring closing metathesis (RCM) reaction. Spectroscopic data, i.e. NMR and HRMS, along with single crystal X-ray diffraction analysis, were used to confirm their chemical structures. The tosylated carbenoid 7b showed the highest efficiency in cyclizing different acyclic diene substrates. RCM of various (un)substituted N,N-diallylaniline derivatives and stereoselective RCM of different macromolecular dienes were well tolerated using only a catalytic amount (0.5-2.0 mol%) of the additive catalyst (7b) as compared to the well-known Grubbs (II) and Hoveyda-Grubbs (II) catalysts.

Superior Specimen and Diagnostic Accuracy with Endoscopic Ultrasound-Guided Liver Biopsies Using 19-Gauge versus 22-Gauge Core Needles.

BACKGROUND/AIMS: Endoscopic ultrasound-guided liver biopsy (EUS-LB) is an effective and safe method of procuring liver tissue. The aims of this study were to assess and compare the outcomes and tissue adequacy of a single-pass, single-actuation, wet suction technique between 19 G and 22 G needles in patients undergoing EUS-LB. METHODS: We performed a prospective case series study of 20 patients undergoing EUS-LB at a single center between September 2017 and April 2020. The primary objective was to evaluate differences in sample adequacy via a single actuation wet suction technique between a 19 G core needle and a 22 G core needle. Adequacy was gauged by cumulative core biopsy length and the number of portal tracts visualized. RESULTS: The 19 G needle provided a longer core length (2.5 cm vs. 1.2 cm, p<0.0001), more complete portal tracts (5.8 vs. 1.7, p<0.0001), more total tracts (8.8 vs. 3, p<0.0001), and a longer, intact, fragment length (0.75 cm vs. 0.32 cm, p<0.0006). The 19 G needle was superior in providing adequate (60% vs. 5%, p<0.001) and diagnostic pathologic samples (85% vs. 10%, p<0.001). CONCLUSION: A single-pass, single-actuation, wet suction technique using a 19 G needle is superior to that using a 22 G needle for tissue acquisition and sample adequacy in EUS-LB.

Plasmid-Mediated Biodegradation of Chlorpyrifos and Analysis of Its Metabolic By-Products.

Organophosphate pesticide persistence is an emerging menace to the environment and despite this fact, its use has been enhanced due to its high efficiency. Bioremediation using microorganisms would be the only means by which these hazardous compounds could be wiped out without disturbing the environmental harmony. The current work studied the molecular mechanism of degradation of Chlorpyrifos (CP) by a bacterial consortium C5 comprising of three soil isolates Staphylococcus warneri (CPI 2), Pseudomonas putida (CPI 9) and Stenotrophomonas maltophilia (CPI 15), which unveiled that the property is plasmid borne. All the isolates were found to possess a 4 kb plasmid which could be cured only by using sodium azide. The Escherichia coli JM109 cells when transformed individually with the plasmid of the isolates showed CP degradation in mineral salts medium (MSM) that contained CP as the sole carbon source. The degradative enzyme organophosphorus hydrolase (~ 60 KDa) of the isolates was extracted and purified to 31.85, 26 and 37.74 fold, respectively. The possible metabolic by-products of CP degradation by the consortium C5, were also analysed. The LC-Q-Tof MS analysis revealed the presence of the major metabolite 3, 5, 6 -trichloropyridine (TCP) with the formation of chlorpyrifos oxon as the intermediate. The isolates also showed trichloropyridine degradation (> 80%) individually in MSM-TCP medium proving its efficiency to remediate both CP and TCP.

Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: a first-in-human and induced blood-stage malaria phase 1a/b trial.

BACKGROUND: (+)-SJ000557733 (SJ733) is a novel, orally bioavailable inhibitor of Plasmodium falciparum ATP4. In this first-in-human and induced blood-stage malaria phase 1a/b trial, we investigated the safety, tolerability, pharmacokinetics, and antimalarial activity of SJ733 in humans. METHODS: The phase 1a was a single-centre, dose-escalation, first-in-human study of SJ733 allowing modifications to dose increments and dose-cohort size on the basis of safety and pharmacokinetic results. The phase 1a took place at St Jude Children's Research Hospital and at the University of Tennessee Clinical Research Center (Memphis, TN, USA). Enrolment in more than one non-consecutive dose cohort was allowed with at least 14 days required between doses. Participants were fasted in seven dose cohorts and fed in one 600 mg dose cohort. Single ascending doses of SJ733 (75, 150, 300, 600, 900, or 1200 mg) were administered to participants, who were followed up for 14 days after SJ733 dosing. Phase 1a primary endpoints were safety, tolerability, and pharmacokinetics of SJ733, and identification of an SJ733 dose to test in the induced blood-stage malaria model. The phase 1b was a single-centre, open-label, volunteer infection study using the induced blood-stage malaria model in which fasted participants were intravenously infected with blood-stage P falciparum and subsequently treated with a single dose of SJ733. Phase 1b took place at Q-Pharm (Herston, QLD, Australia) and was initiated only after phase 1a showed that exposure exceeding the threshold minimum exposure could be safely achieved in humans. Participants were inoculated on day 0 with P falciparum-infected human erythrocytes (around 2800 parasites in the 150 mg dose cohort and around 2300 parasites in the 600 mg dose cohort), and parasitaemia was monitored before malaria inoculation, after inoculation, immediately before SJ733 dosing, and then post-dose. Participants were treated with SJ733 within 24 h of reaching 5000 parasites per mL or at a clinical score higher than 6. Phase 1b primary endpoints were calculation of a parasite reduction ratio (PRR48) and parasite clearance half-life, and safety and tolerability of SJ733 (incidence, severity, and drug-relatedness of adverse events). In both phases of the trial, SJ733 hydrochloride salt was formulated as a powder blend in capsules containing 75 mg or 300 mg for oral administration. Healthy men and women (of non-childbearing potential) aged 18-55 years were eligible for both studies. Both studies are registered with ClinicalTrials.gov (NCT02661373 for the phase 1a and NCT02867059 for the phase 1b). FINDINGS: In the phase 1a, 23 healthy participants were enrolled and received one to three non-consecutive doses of SJ733 between March 14 and Dec 7, 2016. SJ733 was safe and well tolerated at all doses and in fasted and fed conditions. 119 adverse events were recorded: 54 (45%) were unrelated, 63 (53%) unlikely to be related, and two (2%) possibly related to SJ733. In the phase 1b, 17 malaria-naive, healthy participants were enrolled. Seven participants in the 150 mg dose cohort were inoculated and dosed with SJ733. Eight participants in the 600 mg dose cohort were inoculated, but two participants could not be dosed with SJ733. Two additional participants were subsequently inoculated and dosed with SJ733. SJ733 exposure increased proportional to the dose through to the 600 mg dose, then was saturable at higher doses. Fasted participants receiving 600 mg exceeded the target area under the concentration curve extrapolated to infinity (AUC0-∞) of 13 000 µg × h/L (median AUC0-∞ 24 283 [IQR 16 135-31 311] µg × h/L, median terminal half-life 17·4 h [IQR 16·1-24·0], and median timepoint at which peak plasma concentration is reached 1·0 h [0·6-1·3]), and this dose was tested in the phase 1b. All 15 participants dosed with SJ733 had at least one adverse event. Of the 172 adverse events recorded, 128 (74%) were mild. The only adverse event attributed to SJ733 was mild bilateral foot paraesthesia that lasted 3·75 h and resolved spontaneously. The most common adverse events were related to malaria. Based on parasite clearance half-life, the derived log10PRR48 and corresponding parasite clearance half-lives were 2·2 (95% CI 2·0-2·5) and 6·47 h (95% CI 5·88-7·18) for 150 mg, and 4·1 (3·7-4·4) and 3·56 h (3·29-3·88) for 600 mg. INTERPRETATION: The favourable pharmacokinetic, tolerability, and safety profile of SJ733, and rapid antiparasitic effect support its development as a fast-acting component of combination antimalarial therapy. FUNDING: Global Health Innovative Technology Fund, Medicines for Malaria Venture, and the American Lebanese Syrian Associated Charities.