MATERIALS AND METHODS: Seventy-five participants underwent MRE as an initial investigation or follow-up for inflammatory bowel disease. A systematic sampling method was used to divide the participants into three different groups: group 1 received 6.7% mannitol concentration, group 2 received 3.3% mannitol concentration and group 3 received pineapple juice as an oral contrast agent during their MRE examination. The degree of bowel distension on MRE images was assessed by a radiologist by measuring the bowel diameter from inner wall to inner wall at specified levels, while qualitative analysis was evaluated based on the presence of artefacts. All patients were asked to score their acceptance of the oral contrast and were asked about side effects such as diarrhoea, abdominal discomfort and vomiting.

RESULTS: All patients were able to completely ingest 1.5L of oral contrast. The mean diameter of bowel distension was 2.1cm in patients who received 6.7% mannitol concentration, 2.0cm in patients who received 3.3% mannitol concentration and 1.6 cm in patients who received pineapple juice. Twothirds of patients who received 6.7% mannitol and 3.3% mannitol solutions had good-quality MRE images, but 68% of patients who received pineapple juice had poor-quality MRE images. Twenty-four patients (96%) who received pineapple juice rated it as slightly acceptable and acceptable but only 12 patients (48%) who received 6.7% mannitol solution rated it as slightly acceptable and acceptable. Eighty-eight percent of patients who received 6.7% mannitol solution experienced at least one form of side effect as compared to 44% of patients who received 3.3% mannitol solution and 18% of patients who received pineapple juice.

METHODS: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate-mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876.

FINDINGS: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate-mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76-91]) of 115 patients in the artesunate-mefloquine group versus 61 (55% [45-64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0-40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate-mefloquine than in those given chloroquine (18·0 h [range 6·0-48·0] vs 24·0 h [6·0-60·0]; p<0·0001), with faster clearance of ring stages in the artesunate-mefloquine group (mean time to 50% clearance of baseline parasites 8·6 h [95% CI 7·9-9·4] vs 13·8 h [12·1-15·4]; p<0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate-mefloquine group (71 [62%; 95% CI 52·2-70·6]) than in those in the chloroquine group (83 [75%; 65·6-82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate-mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate-mefloquine group (mean 11·5 h [95% CI 8·3-14·6]) than in the chloroquine group (14·8 h [11·7-17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate-mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812-0·906]; p<0·0001). One (<1%) patient in the artesunate-mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug.

INTERPRETATION: Artesunate-mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas.

METHODS: Crude Eurycoma longifolia extract was chromatographed into a DHY-enriched extract (DHY-F) and an EN-enriched extract (EN-F). Male Sprague-Dawley rats were administered intravenously and orally with both extracts and their plasma levels of both quassinoids were determined. The extracts were then tested for their spermatogenesis augmentation ability in normal rats and an andrographolide-induced oligospermia model.

KEY FINDINGS: Chromatographic enrichment resulted in a 28-fold increase of DHY in DHY-F and a 5-fold increase of EN in EN-F compared with non-chromatographed crude extracts. DHY showed better oral bioavailability (1.04 ± 0.58%) than EN (0.31 ± 0.19%). At 5 mg/kg, EN exhibited higher efficacy in spermatogenesis enhancement in normal rats and restoration of oligospermia to normal sperm profile versus DHY.

METHODS: This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase.

RESULTS: Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]).

CONCLUSIONS: Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD.

OBJECTIVES: To investigate the effects of vitamin D supplementation in children and adults with SCD and to compare different dose regimens. To determine the effects of vitamin D supplementation on general health (e.g. growth status and health-related quality of life), on musculoskeletal health (including bone mineral density, pain crises, bone fracture and muscle health), on respiratory health (including lung function, acute chest syndrome, acute exacerbation of asthma and respiratory infections) and the safety of vitamin D supplementation.

SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last search: 19 March 2020. We also searched database such as PubMed, clinical trial registries and the reference lists of relevant articles and reviews. Date of last search: 14 January 2020.

SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing oral administration of any form of vitamin D supplementation at any dose and for any duration to another type or dose of vitamin D or placebo or no supplementation in people with SCD, of all ages, gender, and phenotypes.

DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and assessed the risk of bias of the included studies. They used the GRADE guidelines to assess the quality of the evidence.

MAIN RESULTS: Vitamin D versus placebo One double-blind RCT (n = 39) compared oral vitamin D3 (cholecalciferol) supplementation (20 participants) to placebo (19 participants) for six weeks. Only 25 participants completed the full six months of follow-up. The study had a high risk of bias due to incomplete outcome data, but a low risk of bias for randomisation, allocation concealment, blinding (of participants, personnel and outcome assessors) and selective outcome reporting; and an unclear risk of other biases. Vitamin D supplementation probably led to higher serum 25(OH)D levels at eight weeks, mean difference (MD) 29.79 (95% confidence interval (CI) 26.63 to 32.95); at 16 weeks, MD 12.67 (95% CI 10.43 to 14.90); and at 24 weeks, MD 15.52 (95% CI 13.50 to 17.54) (moderate-quality evidence). There was little or no difference in adverse events (tingling of lips or hands) between the vitamin D and placebo groups, risk ratio 3.16 (95% CI 0.14 to 72.84) (low-quality evidence). Vitamin D supplementation probably caused fewer pain days compared to the placebo group at eight weeks, MD -10.00 (95% CI -16.47 to -3.53) (low-quality evidence), but probably led to a lower (worse) health-related quality of life score (change from baseline in physical functioning PedsQL scores); at both 16 weeks, MD -12.56 (95% CI -16.44 to -8.69) and 24 weeks, MD -12.59 (95% CI -17.43 to -7.76), although this may not be the case at eight weeks (low-quality evidence). Vitamin D supplementation regimens compared Two double-blind RCTs (83 participants) compared different regimens of vitamin D. One RCT (n = 62) compared oral vitamin D3 7000 IU/day to 4000 IU/day for 12 weeks, while the second RCT (n = 21) compared oral vitamin D3 100,000 IU/month to 12,000 IU/month for 24 months. Both RCTs had low risk of bias for blinding (of participants, personnel and outcome assessors) and incomplete outcome data, but the risk of selective outcome reporting bias was high. The bias from randomisation and allocation concealment was low in one study but not in the second. There was an unclear risk of other biases. When comparing oral vitamin D 100,000 IU/month to 12,000 IU/month, the higher dose may have resulted in higher serum 25(OH)D levels at one year, MD 16.40 (95% CI 12.59 to 20.21) and at two years, MD 18.96 (95% CI 15.20 to 22.72) (low-quality evidence). There was little or no difference in adverse events between doses (low-quality evidence). There were more episodes of acute chest syndrome in the high-dose group, at one year, MD 0.27 (95% CI 0.02 to 0.52) but there was little or no difference at two years, MD 0.09 (95% CI -0.04 to 0.22) (moderate-quality evidence). At one year and two years there was also little or no difference between the doses in the presence of pain (moderate-quality evidence) or forced expiratory volume in one second % predicted. However, the high-dose group had lower values for % predicted forced vital capacity at both one and two years, MD -7.20% predicted (95% CI -14.15 to -0.25) and MD -7.10% predicted (95% CI -14.03 to -0.17), respectively. There were little or no differences between dose regimens in the muscle health of either hand or the dominant hand. The study comparing oral vitamin D3 7000 IU/day to 4000 IU/day (21 participants) did not provide data for analysis, but median serum 25(OH)D levels were reported to be lower in the low-dose group at both six and 12 weeks. At 12 weeks the median serum parathyroid hormone level was lower in the high-dose group.

OBJECTIVES: To evaluate the effects of short-term intravenous magnesium on the length of hospital stay and quality of life in children and adults with sickle cell disease. To determine the effects of long-term oral magnesium therapy on the frequency of painful crises and the quality of life in children and adults with sickle cell disease.

SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 01 December 2016.Date of last search of other resources (clinical trials registries): 29 March 2017.

SELECTION CRITERIA: We searched for published and unpublished randomized controlled studies of oral or intravenous magnesium compared to placebo or no magnesium.

DATA COLLECTION AND ANALYSIS: Authors independently assessed the study quality and extracted the data using standard Cochrane methodologies.

MAIN RESULTS: We included five randomized placebo-controlled studies with a total of 386 participants (aged three to 53 years). Two shorter parallel studies (n = 306) compared intravenous magnesium sulphate to placebo (normal saline) for admission to hospital due to a vaso-occlusive crisis, for which we were able to analyse data. The quality of evidence was moderate for studies presenting this comparison mainly due to limitations due to risk of bias and imprecision. Two of the three longer-term studies comparing oral magnesium pidolate to placebo had a cross-over design. The third was a parallel factorial study which compared hydroxyurea and oral magnesium to each other and to placebo over a longer period of time; we only present the comparison of oral magnesium to placebo from this study. The quality of evidence was very low with uncertainty of the estimation.The eight-hourly dose levels in the two studies of intravenous magnesium were different; one used 100 mg/kg while the second used 40 mg/kg. Only one of these studies (n = 104) reported the mean daily pain score while hospitalised (a non-significant difference between groups, moderate quality evidence). The second study (n = 202) reported a number of child- and parent-reported quality of life scores. None of the scores showed any difference between treatment groups (low quality evidence). Data from one study (n = 106) showed no difference in length of stay in hospital between groups (low quality evidence). Both studies reported on adverse events, but not defined by severity as we had planned. One study showed significantly more participants receiving intravenous magnesium experienced warmth at infusion site compared to placebo; there were no differences between groups for other adverse events (low quality evidence).Three studies (n = 80) compared oral magnesium pidolate to placebo. None of them reported data which we were able to analyse. One study (n = 24) reported on the number of painful days and stated there was no difference between two groups (low quality evidence). None of the studies reported on quality of life or length of hospital stay. Two studies (n = 68) reported there were no differences in levels of magnesium in either plasma or red blood cells (moderate quality evidence). Two studies (n = 56) reported adverse events. One reported episodes of mild diarrhoea and headache, all of which resolved without stopping treatment. The second study reported adverse events as gastrointestinal disorders, headache or migraine, upper respiratory infections and rash; which were all evenly distributed across treatment groups (moderate quality evidence).

OBJECTIVES: To assess the effectiveness and adverse effects of chloral hydrate as a sedative agent for non-invasive neurodiagnostic procedures in children.

SEARCH METHODS: We used the standard search strategy of the Cochrane Epilepsy Group. We searched MEDLINE (OVID SP) (1950 to July 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 7, 2017), Embase (1980 to July 2017), and the Cochrane Epilepsy Group Specialized Register (via CENTRAL) using a combination of keywords and MeSH headings.

SELECTION CRITERIA: We included randomised controlled trials that assessed chloral hydrate agent against other sedative agent(s), non-drug agent(s), or placebo for children undergoing non-invasive neurodiagnostic procedures.

DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for their eligibility, extracted data, and assessed risk of bias. Results were expressed in terms of risk ratio (RR) for dichotomous data, mean difference (MD) for continuous data, with 95% confidence intervals (CIs).

MAIN RESULTS: We included 13 studies with a total of 2390 children. The studies were all conducted in hospitals that provided neurodiagnostic services. Most studies assessed the proportion of sedation failure during the neurodiagnostic procedure, time for adequate sedation, and potential adverse effects associated with the sedative agent.The methodological quality of the included studies was mixed, as reflected by a wide variation in their 'Risk of bias' profiles. Blinding of the participants and personnel was not achieved in most of the included studies, and three of the 13 studies had high risk of bias for selective reporting. Evaluation of the efficacy of the sedative agents was also underpowered, with all the comparisons performed in single small studies.Children who received oral chloral hydrate had lower sedation failure when compared with oral promethazine (RR 0.11, 95% CI 0.01 to 0.82; 1 study, moderate-quality evidence). Children who received oral chloral hydrate had a higher risk of sedation failure after one dose compared to those who received intravenous pentobarbital (RR 4.33, 95% CI 1.35 to 13.89; 1 study, low-quality evidence), but after two doses there was no evidence of a significant difference between the two groups (RR 3.00, 95% CI 0.33 to 27.46; 1 study, very low-quality evidence). Children who received oral chloral hydrate appeared to have more sedation failure when compared with music therapy, but the quality of evidence was very low for this outcome (RR 17.00, 95% CI 2.37 to 122.14; 1 study). Sedation failure rates were similar between oral chloral hydrate, oral dexmedetomidine, oral hydroxyzine hydrochloride, and oral midazolam.Children who received oral chloral hydrate had a shorter time to achieve adequate sedation when compared with those who received oral dexmedetomidine (MD -3.86, 95% CI -5.12 to -2.6; 1 study, moderate-quality evidence), oral hydroxyzine hydrochloride (MD -7.5, 95% CI -7.85 to -7.15; 1 study, moderate-quality evidence), oral promethazine (MD -12.11, 95% CI -18.48 to -5.74; 1 study, moderate-quality evidence), and rectal midazolam (MD -95.70, 95% CI -114.51 to -76.89; 1 study). However, children with oral chloral hydrate took longer to achieve adequate sedation when compared with intravenous pentobarbital (MD 19, 95% CI 16.61 to 21.39; 1 study, low-quality evidence) and intranasal midazolam (MD 12.83, 95% CI 7.22 to 18.44; 1 study, moderate-quality evidence).No data were available to assess the proportion of children with successful completion of neurodiagnostic procedure without interruption by the child awakening. Most trials did not assess adequate sedation as measured by specific validated scales, except in the comparison of chloral hydrate versus intranasal midazolam and oral promethazine.Compared to dexmedetomidine, chloral hydrate was associated with a higher risk of nausea and vomiting (RR 12.04 95% CI 1.58 to 91.96). No other adverse events were significantly associated with chloral hydrate (including behavioural change, oxygen desaturation) although there was an increased risk of adverse events overall (RR 7.66, 95% CI 1.78 to 32.91; 1 study, low-quality evidence).