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The 4-aminoquinoline drugs, such as chloroquine (CQ), amodiaquine or piperaquine, are still commonly used for malaria treatment, either alone (CQ) or in combination with artemisinin derivatives. We previously described the excellent in vitro activity of a novel pyrrolizidinylmethyl derivative of 4-amino-7-chloroquinoline, named MG3, against P. falciparum drug-resistant parasites. Here, we report the optimized and safer synthesis of MG3 , now suitable for a scale-up, and its additional in vitro and in vivo characterization. MG3 is active against a panel of P. vivax and P. falciparum field isolates, either alone or in combination with artemisinin derivatives. In vivo MG3 is orally active in the P. berghei, P. chabaudi, and P. yoelii models of rodent malaria with efficacy comparable, or better, than that of CQ and of other quinolines under development. The in vivo and in vitro ADME-Tox studies indicate that MG3 possesses a very good pre-clinical developability profile associated with an excellent oral bioavailability, and low toxicity in non-formal preclinical studies on rats, dogs, and non-human primates (NHP). In conclusion, the pharmacological profile of MG3 is in line with those obtained with CQ or the other quinolines in use and seems to possess all the requirements for a developmental candidate.

This study examines the potential utility of using continuous glucose monitoring (CGM) to prescribe an exercise time to target peak hyperglycaemia in people with type 2 diabetes (T2D). The main aim is to test the feasibility of prescribing an individualised daily exercise time, based on the time of CGM-derived peak glucose, for people with T2D. Thirty-five individuals with T2D (HbA1c: 7.2 ± 0.8%; age: 64 ± 7 y; BMI: 29.2 ± 5.2 kg/m 2 ) were recruited and randomised to one of two 14 d exercise interventions: i) ExPeak (daily exercise starting 30 min before peak hyperglycaemia) or placebo active control NonPeak (daily exercise starting 90 min after peak hyperglycaemia). The time of peak hyperglycaemia was determined via a two-week baseline CGM. A CGM, accelerometer, and heart rate monitor were worn during the free-living interventions to objectively measure glycaemic control outcomes, moderate-to-vigorous intensity physical activity (MVPA), and exercise adherence for future translation in a clinical trial. Participation in MVPA increased 26% when an exercise time was prescribed compared to habitual baseline ( p < 0.01), with no difference between intervention groups ( p > 0.26). The total MVPA increased by 10 min/day during the intervention compared to the baseline (baseline: 23 ± 14 min/d vs. intervention: 33 ± 16 min/d, main effect of time p = 0.03, no interaction). The change in peak blood glucose (mmol/L) was similar between the ExPeak (-0.44 ± 1.6 mmol/L, d = 0.21) and the NonPeak (-0.39 ± 1.5 mmol/L, d = 0.16) intervention groups ( p = 0.92). Prescribing an exercise time based on CGM may increase daily participation in physical activity in people with type 2 diabetes; however, further studies are needed to test the long-term impact of this approach.

Introduction: The benefits of physical activity for glycaemic control in type 2 diabetes (T2D) are well-known. However, whether established glycaemic and cardiovascular benefits can be maximised by exercising at a certain time of day is unknown. Given postprandial glucose peaks contribute to worsening glycated haemoglobin (HbA1c) and cardiovascular risk factors, and that exercise immediately lowers blood glucose, prescribing exercise at a specific time of day to attenuate peak hyperglycaemia may improve glycaemic control and reduce the burden of cardiovascular disease in people with T2D., Methods and Analysis: A single-centre randomised controlled trial will be conducted by the University of Wollongong, Australia. Individuals with T2D (n=70, aged 40-75 years, body mass index (BMI): 27-40 kg/m 2 ) will be recruited and randomly allocated (1:1), stratified for sex and insulin, to one of three groups: (1) exercise at time of peak hyperglycaemia (ExPeak, personalised), (2) exercise not at time of peak hyperglycaemia (NonPeak) or (3) waitlist control (WLC, standard care). The trial will be 5 months, comprising an 8-week intervention and 3-month follow-up. Primary outcome is the change in HbA1c preintervention to postintervention. Secondary outcomes include vascular function (endothelial function and arterial stiffness), metabolic control (blood lipids and inflammation) and body composition (anthropometrics and dual-energy X-ray absorptiometry (DEXA)). Tertiary outcomes will examine adherence., Ethics and Dissemination: The joint UOW and ISLHD Ethics Committee approved protocol (2019/ETH09856) prospectively registered at the Australian New Zealand Clinical Trials Registry. Written informed consent will be obtained from all eligible individuals prior to commencement of the trial. Study results will be published as peer-reviewed articles, presented at national/international conferences and media reports., Trial Registration Number: ACTRN12619001049167., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

New Findings: What is the central question of this study? Is the estrous cycle affected during disuse atrophies and if so, how do estrous cycle changes relate to musculoskeletal outcomes? What is the main finding and its importance? Rodent estrous cycles are altered during disuse atrophy, which corresponds to musculoskeletal outcomes. However, the estrous cycle does not appear changed in Lewis Lung Carcinoma, which corresponded to no differences in muscle size compared to healthy controls. These findings suggest a relationship between estrous cycle and muscle size during atrophic pathologies., Abstract: Hyperglycemia can cause disruptions in vascular function, whereas exercise has been shown to restore vascular function. The primary aim of this study is to investigate the effect of performing whole-body resistance exercise, 30-min before, immediately following, or 30- or 60-min after a high carbohydrate meal, on endothelial function, measured by flow-mediated dilation (FMD). Healthy adults will be recruited to this randomized crossover trial to compare the postprandial glycaemic and vascular responses to four different exercise timing conditions and a control: i) C- control, high carbohydrate meal/no exercise, ii) 30Pre- 30 min of resistance exercises (~30% of 1RM [Repetition Maximum]), 30 min before a high carbohydrate meal, iii) IP- 30 min of resistance exercises (~30% of 1RM), immediately following a high carbohydrate meal, iv) 30Post- 30 min of resistance exercises, 30 min after a high carbohydrate meal and v) 60Post- 30 min of resistance exercises, 60 min after a high carbohydrate meal. Measures of metabolic and vascular function will be assessed at baseline and for two hours following the carbohydrate-based breakfast meal., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.)

We investigated whether substituting the final half within 60-min bouts of exercise with passive warm or cold water immersion would provide similar or greater benefits for cardiometabolic health. Thirty healthy participants were randomized to two of three short-term training interventions in a partial crossover (12 sessions over 14-16 days, 4 week washout): (i) EXS: 60 min cycling 70% maximum heart rate (HRmax), (ii) WWI: 30 min cycling then 30 min warm water (38-40°C) immersion, and/or (iii) CWI: 30 min cycling then 30 min cold water (10-12°C) immersion. Before and after, participants completed a 20 min cycle work trial, V . O 2 max test, and an Oral Glucose Tolerance Test during which indirect calorimetry was used to measure substrate oxidation and metabolic flexibility (slope of fasting to post-prandial carbohydrate oxidation). Data from twenty two participants (25 ± 5 year, BMI 23 ± 3 kg/m 2 , Female = 11) were analyzed using a fixed-effects linear mixed model. V . O 2 max increased more in EXS (interaction p = 0.004) than CWI (95% CI: 1.1, 5.3 mL/kg/min, Cohen's d = 1.35), but not WWI (CI: -0.4, 3.9 mL/kg/min, d = 0.72). Work trial distance and power increased 383 ± 223 m and 20 ± 6 W, respectively, without differences between interventions (interaction both p > 0.68). WWI lowered post-prandial glucose ∼9% (CI -1.9, -0.5 mmol/L; d = 0.63), with no difference between interventions (interaction p = 0.469). Substituting the second half of exercise with WWI provides similar cardiometabolic health benefits to time matched exercise, however, substituting with CWI does not., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Russell, Chang, Hill, Cotter and Francois.)

Background: A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival., Methods and Findings: We examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted., Conclusions: Immature CD71+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen., Competing Interests: The authors have declared that no competing interests exist.

Malaria control and elimination are threatened by the emergence and spread of resistance to artemisinin-based combination therapies (ACTs). Experimental evidence suggests that when an artemisinin (ART)-sensitive (K13 wild-type) Plasmodium falciparum strain is exposed to ART derivatives such as dihydroartemisinin (DHA), a small population of the early ring-stage parasites can survive drug treatment by entering cell cycle arrest or dormancy. After drug removal, these parasites can resume growth. Dormancy has been hypothesized to be an adaptive physiological mechanism that has been linked to recrudescence of parasites after monotherapy with ART and, possibly contributes to ART resistance. Here, we evaluate the in vitro drug sensitivity profile of normally-developing P. falciparum ring stages and DHA-pretreated dormant rings (DP-rings) using a panel of antimalarial drugs, including the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691. We report that while KDU691 shows no activity against rings, it is highly inhibitory against DP-rings; a drug effect opposite to that of ART. Moreover, we provide evidence that KDU691 also kills DP-rings of P. falciparum ART-resistant strains expressing mutant K13.

Context: Data suggest that anorexia nervosa (AN) and obesity are complicated by elevated fracture risk, but skeletal site-specific data are lacking. Traditional bone mineral density (BMD) measurements are unsatisfactory at both weight extremes. Hip structural analysis (HSA) uses dual-energy X-ray absorptiometry data to estimate hip geometry and femoral strength. Factor of risk (φ) is the ratio of force applied to the hip from a fall with respect to femoral strength; higher values indicate higher hip fracture risk., Objective: The objective of the study was to investigate hip fracture risk in AN and overweight/obese women., Design: This was a cross-sectional study., Setting: The study was conducted at a Clinical Research Center., Patients: PATIENTS included 368 women (aged 19-45 y): 246 AN, 53 overweight/obese, and 69 lean controls., Main Outcome Measures: HSA-derived femoral geometry, peak factor of risk for hip fracture, and factor of risk for hip fracture attenuated by trochanteric soft tissue (φ(attenuated)) were measured., Results: Most HSA-derived parameters were impaired in AN and superior in obese/overweight women vs controls at the narrow neck, intertrochanteric, and femoral shaft (P ≤ .03). The φ(attenuated) was highest in AN and lowest in overweight/obese women (P < .0001). Lean mass was associated with superior, and duration of amenorrhea with inferior, HSA-derived parameters and φ(attenuated) (P < .05). Mean φ(attenuated) (P = .036), but not femoral neck BMD or HSA-estimated geometry, was impaired in women who had experienced fragility fractures., Conclusions: Femoral geometry by HSA, hip BMD, and factor of risk for hip fracture attenuated by soft tissue are impaired in AN and superior in obesity, suggesting higher and lower hip fracture risk, respectively. Only attenuated factor of risk was associated with fragility fracture prevalence, suggesting that variability in soft tissue padding may help explain site-specific fracture risk not captured by BMD.

Context: Obesity is associated with diminished GH secretion, which may result in the overdiagnosis of adult GH deficiency (GHD) in overweight/obese pituitary patients. However, there are no body mass index (BMI)-specific peak GH cutoffs for the glucagon stimulation test (GST), the favored dynamic test for assessing adult GHD in the United States., Objective: The objective of the study was to determine a peak GH cutoff level for the diagnosis of adult GHD in overweight/obese individuals using the GST., Design: This was a retrospective, cross-sectional study., Setting: The study was conducted at Massachusetts General Hospital and Oregon Health and Science University., Methods: A total of 108 subjects with a BMI ≥ 25 kg/m(2) were studied: healthy controls (n = 47), subjects with total pituitary deficiency (TPD) (n = 20, ≥ 3 non-GH pituitary hormone deficiencies), and subjects with partial pituitary deficiency (PPD) (n = 41, 1-2 non-GH pituitary hormone deficiencies)., Intervention: The intervention consisted of a standard 4-hour GST., Main Outcome Measures: The main outcome measure was peak GH level on GST., Results: Using the standard peak GH cutoff of 3 ng/mL, 95% of TPD cases (19 of 20), 80% of PPD (33 of 41), and 45% of controls (21 of 47) were classified as GHD. In receiver-operator characteristic curve analysis (controls vs TPD), a peak GH value of 0.94 ng/mL provided the greatest sensitivity (90%) and specificity (94%). Using a peak GH cutoff of 1 ng/mL, 6% of controls (3 of 47), 59% of PPDs (24 of 41), and 90% of TPDs (18 of 20) were classified as GHD. BMI (R = -0.35, P = .02) and visceral adipose tissue (R = -0.32, P = .03) negatively correlated with peak GH levels in controls., Conclusion: A large proportion of healthy overweight/obese individuals (45%) failed the GST using the standard 3 ng/mL GH cutoff. Overweight/obese pituitary patients are at risk of being misclassified as GHD using this cutoff level. A 1-ng/mL GH cutoff may reduce the overdiagnosis of adult GHD in overweight/obese patients.

Background: Human lung cancer patients exhibit different KRAS mutations depending on smoking status. In a mouse model of human cancer, A/J and BALB/cBy mice treated with the tobacco carcinogen, 3-methylcholanthrene (MCA), followed by butylated hydroxytoluene (BHT)-elicited chronic inflammation develop a high multiplicity of lung tumors., Methods: DNA was isolated from MCA-induced lung tumors in A/J and BALB/cByJ mice. Kras codon 12 sequences from these tumors were compared to those in human lung tumors from smokers and never-smokers., Results: The distribution of Kras codon 12 mutations in MCA-induced A/J lung tumors is strikingly similar to those found in adenocarcinomas from human smokers. In contrast, codon 12 mutations in BALB/cBy mice contain predominantly G --> D mutations, which is the most common mutation in never smokers., Conclusions: A single lung carcinogen induces different tumor initiating mutations in different strains of mice. This may be useful for investigating the role of specific KRAS mutations in adenocarcinoma pathogenesis in smokers versus never smokers, identifying mechanisms that select for certain KRAS mutations and developing new drugs that specifically target cells with different KRAS mutations.

The aim of this study was to develop a simple, field-practical, and effective in vitro method for determining the sensitivity of fresh erythrocytic Plasmodium vivax isolates to a range of antimalarials. The method used is a modification of the standard World Health Organization (WHO) microtest for determination of P. falciparum drug sensitivity. The WHO method was modified by removing leukocytes and using a growth medium supplemented with AB(+) serum. We successfully carried out 34 in vitro drug assays on 39 P. vivax isolates collected from the Mae Sod malaria clinic, Tak Province, Thailand. The mean percentage of parasites maturing to schizonts (six or more merozoites) in control wells was 66.5% +/- 5.9% (standard deviation). This level of growth in the control wells enabled rapid microscopic determination (5 min per isolate per drug) of the MICs of chloroquine, dihydroartemisinin, WR238605 (tafenoquine), and sulfadoxine. P. vivax was relatively sensitive to chloroquine (MIC = 160 ng/ml, 50% inhibitory concentration [IC(50)] = 49.8 ng/ml) and dihydroartemisinin (MIC = 0.5 ng/ml, IC(50) = 0.47 ng/ml). The poor response of P. vivax to both tafenoquine (MIC = 14,000 ng/ml, IC(50) = 9,739 ng/ml) and sulfadoxine (MIC = 500,000 ng/ml, IC(50) = 249,000 ng/ml) was due to the slow action of these drugs and the innate resistance of P. vivax to sulfadoxine. The in vitro assay developed in our study should be useful both for assessing the antimalarial sensitivity of P. vivax populations and for screening new antimalarials in the absence of long-term P. vivax cultures.