Body mass index and 20 specific cancers: re-analyses of dose-response meta-analyses of observational studies.

Background: Objectives were to provide an overview and understand the strength of evidence and extent of potential biases and validity of claimed associations between body mass index (BMI) and risk of developing cancer. Methods: We carried out an umbrella review and comprehensively re-analyzed the data of dose-response meta-analyses on associations between BMI and risk of 20 specific cancers (bladder, brain, breast, colonic, rectal, endometrial, gallbladder, gastric, leukemia, liver, lung, melanoma, multiple myeloma, non-Hodgkins lymphoma, esophagus, ovarian, pancreatic, prostate, renal, thyroid) by adding big data or missed individual studies. Convincing evidence for an association was defined as a strong statistical significance in fixed-effects and random-effects meta-analyses at P < 0.001, 95% prediction interval (PI) excluded null, there was no large between-study heterogeneity and no small study effects. Suggestive evidence was defined as meeting the significance threshold for the random summary effects of P < 0.05, but 95% PI included the null. Weak evidence was defined as meeting the significance threshold for the random summary effects at a P < 0.05, but 95% PI included the null and there was large between-study heterogeneity or there were small study effects. Results: Convincing evidence for an association with BMI was detectable for six cancers (leukemia, multiple myeloma, pancreatic, endometrial, rectal, and renal cell carcinoma). Suggestive evidence was detectable for malignant melanoma, non-Hodgkins lymphoma, and esophageal adenocarcinoma. Weak evidence was detectable for brain and central nervous system tumors, breast, colon, gall bladder, lung, liver, ovarian, and thyroid cancer. No evidence was detectable for bladder, gastric, and prostate cancer. Conclusions: The association of increased BMI and cancer is heterogeneous across cancer types. Leukemia, multiple myeloma, pancreatic, endometrial, rectal, and renal cell carcinoma are convincingly associated with an increased BMI by dose-response meta-analyses.

Statistical controversies in clinical research: overlap and errors in the meta-analyses of microRNA genetic association studies in cancers.

BACKGROUND: Various errors in the design, conduct, and analysis of medical and public health research studies can produce false results and waste valuable resources. While systematic reviews and meta-analyses are arguably considered the most dependable source of evidence-based medicine, increasing numbers of studies are indicating that, on the contrary to the public's belief, many of these investigations are redundant, erroneous, and even biased. METHODS: Ninety-four meta-analyses on microRNA polymorphism and risk of cancer were extracted from Pubmed database on August 2016. Two investigators independently extracted data (i.e. number of studies, ethnicity, number of cases/controls, bias, etc.) from each meta-analysis. PROSPERO registration status and reference status were also recorded. RESULTS: Among the 217 microRNA gene-variant cancer associations reported by 94 published meta-analyses, 37% had overlapping results and were extracted from the exact identical case-control studies. However, not one meta-analysis was registered into PROSPERO. Thirty-one percent of the overlapping associations referenced a previous meta-analysis investigating the same association; although only 36% of these overlapping associations referenced earlier meta-analysis that had the same overlapping results. Seventy-four percent of these references were limited to mere citations. Twenty-six percent of the overlapping associations from 16 meta-analyses showed discordant results, and of these, 87% of the genotype comparisons were found significant, contrary to the initial reports of being non-significant. However, no association was noteworthy in regards to false positive rate probability calculations at a given prior probability of 0.001 and 0.000001 and statistical power to detect an odds ratio (OR) of 1.1 and 1.5. CONCLUSIONS: Genetic association meta-analyses were by far more redundant, erroneous, and lacking references than initially expected. Careful search of similar studies, attention to small details, and inclination to reference previous works are needed. This paper proposes potential solutions for these problems in hopes of standardizing research efforts and in improving the quality of medical research.

Management of pinna haematoma study (MaPHaeS): A multicentre retrospective observational study.

OBJECTIVES: To assess current variation in the management of pinna haematoma (PH) and its effect on outcomes. DESIGN: Multicentre retrospective observational record-based study. SETTING: Eleven hospitals around the UK. PARTICIPANTS: Eighty-three patients above the age of 16 with PH. OUTCOME MEASURES: The primary outcome measure was recurrence rate of PH over a 6-month period post-treatment, assessed by treatment type (scalpel incision vs needle aspiration). Secondary outcome measures assessed the impact of other factors on recurrence, infection and cosmetic complications of PH over a period of 6 months. RESULTS: After adjusting for confounding factors, involvement of the whole ear, and management within an operating theatre were associated with a lower rate of recurrence of pinna haematoma. The drainage technique, suspected aetiology, choice of post-drainage management, grade and specialty of practitioner performing drainage, the use of antibiotic cover and hospital admission did not affect the rate of haematoma recurrence, infection or cosmetic complications. CONCLUSIONS: Where possible PH should be drained in an operating theatre. Multicentre randomized controlled trials are required to further investigate the impact of drainage technique and post-drainage management on outcome.

The bacterial-type [4Fe-4S] ferredoxin 7 has a regulatory function under photooxidative stress conditions in the cyanobacterium Synechocystis sp. PCC 6803.

Ferredoxins function as electron carrier in a wide range of metabolic and regulatory reactions. It is not clear yet, whether the multiplicity of ferredoxin proteins is also reflected in functional multiplicity in photosynthetic organisms. We addressed the biological function of the bacterial-type ferredoxin, Fed7 in the cyanobacterium Synechocystis sp. PCC 6803. The expression of fed7 is induced under low CO2 conditions and further enhanced by additional high light treatment. These conditions are considered as promoting photooxidative stress, and prompted us to investigate the biological function of Fed7 under these conditions. Loss of Fed7 did not inhibit growth of the mutant strain Δfed7 but significantly modulated photosynthesis parameters when the mutant was grown under low CO2 and high light conditions. Characteristics of the Δfed7 mutant included elevated chlorophyll and photosystem I levels as well as reduced abundance and activity of photosystem II. Transcriptional profiling of the mutant under low CO2 conditions demonstrated changes in gene regulation of the carbon concentrating mechanism and photoprotective mechanisms such as the Flv2/4 electron valve, the PSII dimer stabilizing protein Sll0218, and chlorophyll biosynthesis. We conclude that the function of Fed7 is connected to coping with photooxidative stress, possibly by constituting a redox-responsive regulatory element in photoprotection. In photosynthetic eukaryotes domains homologous to Fed7 are exclusively found in chloroplast DnaJ-like proteins that are likely involved in remodeling of regulator protein complexes. It is conceivable that the regulatory function of Fed7 evolved in cyanobacteria and was recruited by Viridiplantae as the controller for the chloroplast DnaJ-like proteins.

Comparison of PET/CT and PET/MRI hybrid systems using a 68Ga-labelled PSMA ligand for the diagnosis of recurrent prostate cancer: initial experience.

PURPOSE: (68)Ga-labelled HBED-CC-PSMA is a highly promising tracer for imaging recurrent prostate cancer (PCa). The intention of this study was to evaluate the feasibility of PET/MRI with this tracer. METHODS: Twenty patients underwent PET/CT 1 h after injection of the (68)Ga-PSMA ligand followed by PET/MRI 3 h after injection. Data from the two investigations were first analysed separately and then compared with respect to tumour detection rate and radiotracer uptake in various tissues. To evaluate the quantification accuracy of the PET/MRI system, differences in SUVs between PET/CT and corresponding PET/MRI were compared with differences in SUVs between PET/CT 1 h and 3 h after injection in another patient cohort. This cohort was investigated using the same PET/CT system. RESULTS: With PET/MRI, different diagnostic sequences, higher contrast of lesions and higher resolution of MRI enabled a subjectively easier evaluation of the images. In addition, four unclear findings on PET/CT could be clarified as characteristic of PCa metastases by PET/MRI. However, in PET images of the PET/MRI, a reduced signal was observed at the level of the kidneys (in 11 patients) and around the urinary bladder (in 15 patients). This led to reduced SUVs in six lesions. SUVmean values provided by the PET/MRI system were different in muscles, blood pool, liver and spleen. CONCLUSION: PCa was detected more easily and more accurately with Ga-PSMA PET/MRI than with PET/CT and with lower radiation exposure. Consequently, this new technique could clarify unclear findings on PET/CT. However, scatter correction was challenging when the specific (68)Ga-PSMA ligand was used. Moreover, direct comparison of SUVs from PET/CT and PET/MR needs to be conducted carefully.

PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a cell surface protein with high expression in prostate carcinoma (PC) cells. Recently, procedures have been developed to label PSMA ligands with (68)Ga, (99m)Tc and (123/124/131)I. Our initial experience with Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga(HBED-CC)]((68)Ga-PSMA) suggests that this novel tracer can detect PC relapses and metastases with high contrast. The aim of this study was to investigate its biodistribution in normal tissues and tumour lesions. METHODS: A total of 37 patients with PC and rising prostate-specific antigen (PSA) levels were subjected to (68)Ga-PSMA positron emission tomography (PET)/CT. Quantitative assessment of tracer uptake was performed 1 and 3 h post-injection (p.i.) by analysis of mean and maximum standardized uptake values (SUVmean/max) of several organs and 65 tumour lesions. Subsequently, tumour to background ratios were calculated. RESULTS: The PET/CT images showed intense tracer uptake in both kidneys and salivary glands. Moderate uptake was seen in lacrimal glands, liver, spleen and in small and large bowel. Quantitative assessment revealed excellent contrast between tumour lesions and most normal tissues. Of 37 patients, 31 (83.8 %) showed at least one lesion suspicious for cancer at a detection rate of 60 % at PSA <2.2 ng/ml and 100 % at PSA >2.2 ng/ml. Median tumour to background ratios were 18.8 (2.4-158.3) in early images and 28.3 (2.9-224.0) in late images. CONCLUSION: The biodistribution of the novel (68)Ga-PSMA tracer and its ability to detect PC lesions was analysed in 37 patients. Within healthy organs, kidneys and salivary glands demonstrated the highest radiotracer uptake. Lesions suspicious for PC presented with excellent contrast as early as 1 h p.i. with high detection rates even at low PSA levels.

Omega-3 fatty acids supplementation on major cardiovascular outcomes: an umbrella review of meta-analyses of observational studies and randomized controlled trials.

OBJECTIVE: Omega-3 fatty acids are commonly used as a lipid-lowering agent or dietary supplement for the purpose of prevention of cardiovascular diseases. However, even large-scale clinical trials have not shown significant results demonstrating clear clinical benefits in cardiovascular diseases. Thus, this umbrella review aims to summarize and evaluate the evidence of clinical effects of omega-3 fatty acids supplementation on cardiovascular outcomes through comprehensive analyses of previous randomized controlled trials (RCTs) or observational cohort studies. MATERIALS AND METHODS: We conducted relevant publication search in PubMed, Embase, and Cochrane Database of Systematic Reviews. We retrieved and analyzed 3,298 articles published until August 28th, 2019. RESULTS: We identified 29 relevant articles and analyzed 83 meta-analyses of RCTs or cohort studies therefrom. As a result, we identified 12 cardiovascular outcomes that are related to omega-3 fatty acids supplementation. Among them, total mortality from major cardiovascular causes (RR 0.92, 95% CI 0.86 to 0.98) had significant inverse associations, and moreover, statistical significances were maintained even in subgroup analysis of large-scale RCTs including more than 1,000 patients (RR 0.94, 95% CI 0.88 to 0.99). CONCLUSIONS: Our umbrella review study shows that omega-3 fatty acids supplementation have a clinical benefit in reducing mortality from cardiovascular causes. However, many studies still have shown conflicting results, and therefore, further studies will be needed to verify the clinical benefit of omega-3 supplementation.

Empirical assessment of biases in cerebrospinal fluid biomarkers of Alzheimer's disease: an umbrella review and re-analysis of data from meta-analyses.

OBJECTIVE: Alzheimer's disease (AD) is a leading cause of years lived with disability in older age, and several cerebrospinal fluid (CSF) markers have been proposed in individual meta-analyses to be associated with AD but field-wide evaluation and scrutiny of the literature is not available. MATERIALS AND METHODS: We performed an umbrella review for the reported associations between CSF biomarkers and AD. Data from available meta-analyses were reanalyzed using both random and fixed effects models. We also estimated between-study heterogeneity, small-study effects, excess significance, and prediction interval. RESULTS: A total of 38 meta-analyses on CSF markers from 11 eligible articles were identified and reanalyzed. In 14 (36%) of the meta-analyses, the summary estimate and the results of the largest study showed non-concordant results in terms of statistical significance. Large heterogeneity (I2≥75%) was observed in 73% and small-study effects under Egger's test were shown in 28% of CSF biomarkers. CONCLUSIONS: Our results suggest that there is an excess of statistically significant results and significant biases in the literature of CSF biomarkers for AD. Therefore, the results of CSF biomarkers should be interpreted with caution.

Benzamides as melanotropic carriers for radioisotopes, metals, cytotoxic agents and as enzyme inhibitors.

Benzamide derivatives are known as antipsychotic and antiemetic drugs. Owing to its neurotropic characteristic this class of compounds was found useful for imaging melanoma and melanoma metastases. [(123I)]BZA (N-(2-diethylaminoethyl)-4-[(123I)]iodobenzamide) was the first example which was clinically applied as an imaging agent demonstrating high tumor uptake. This finding initiated research efforts to further improve the affinity and pharmacological properties of this agent. In order to optimize the use of these molecules with respect to costs and wide spread distribution, (99m)Tc labeled benzamides have been developed. Indeed, several (99m)Tc complexes were found suitable for melanoma imaging; however, they were less eligible than radioiodinated benzamides. Besides their use as radiotracers benzamides have been evaluated for magnetic resonance imaging. Molecular imaging with paramagnetic metal contrast agents for magnetic resonance tomography (MRT) is hampered by the inferior sensitivity of MRT. Biochemical trapping was thought to overcome this problem using the polyamine transporter of melanoma cells. One of the neutral, DTPA based Gd complexes comprising 2-(diethylamino)ethylamine and bis-(2-aminoethyl)amine in the side chain led to intracellular uptake values well above the MRI detection limit. An overview about benzamides used for molecular imaging and as transporters for cytostatic agents as well as inhibitors for histone deacetylases concludes this review, demonstrating that benzamide derivatives represent a versatile class of compounds leading to novel imaging and therapeutic agents.

Why are HIV-positive mothers refusing to have their children screened for vertically transmitted HIV infection?

A previous audit showed that the HIV status of the majority (73%) of children of HIV-positive mothers attending a genitourinary clinic in the United Kingdom was unknown because mothers did not take up the offer of testing. The objectives of a re-audit were to establish the impact of the audit process on the uptake of testing and reasons for not taking up the offer of screening of offspring. One year after the previous audit, 13/92 (14%) of children not previously tested had their HIV status established. The reason for not testing was, in 43/52 (82%) mothers, the perception that a well child can not be infected with HIV. This was the only reason for not having their children tested in 16 mothers (31%). The next most common theme was fear of disclosure to others, in 29 (56%). The barriers for screening included fear of feeling guilty if the child was found to be positive.

Antibody-dendrimer conjugates: the number, not the size of the dendrimers, determines the immunoreactivity.

Radioimmunotherapy using antibodies with favorable tumor targeting properties and high binding affinity is increasingly applied in cancer therapy. The potential of this valuable cancer treatment modality could be further improved by increasing the specific activity of the labeled proteins. This can be done either by coupling a large number of chelators which leads to a decreased immunoreactivity or by conjugating a small number of multimeric chelators. In order to systematically investigate the influence of conjugations on immunoreactivity with respect to size and number of the conjugates, the anti-EGFR antibody hMAb425 was reacted with PAMAM dendrimers of different size containing up to 128 chelating agents per conjugation site. An improved dendrimer synthesis protocol was established to obtain compounds of high homogeneity suitable for the formation of defined protein conjugates. The quantitative derivatization of the PAMAM dendrimers with DOTA moieties and the characterization of the products by isotopic dilution titration using (111)In/(nat)In are shown. The DOTA-containing dendrimers were conjugated with high efficiency to hMAb425 by applying Sulfo-SMCC as cross-linking agent and a 10- to 25-fold excess of the thiol-containing dendrimers. The determination of the immunoreactivities of the antibody-dendrimer conjugates by FACS analysis revealed a median retained immunoreactivity of 62.3% for 1.7 derivatization sites per antibody molecule, 55.4% for 2.8, 27.9% for 5.3, and 17.1% for 10.0 derivatization sites per antibody but no significant differences in immunoreactivity for different dendrimer sizes. These results show that the dendrimer size does not influence the immunoreactivity of the derivatized antibody significantly over a wide molecular weight range, whereas the number of derivatization sites has a crucial effect.

Improved syntheses and applicability of different DOTA building blocks for multiply derivatized scaffolds.

DOTA (1,4,7,10-tetraazacyclodocecane-N,N',N'',N'''-tetraacetic acid), which forms extremely stable complexes with a large number of metal ions, is one of the most important and most commonly used chelators for in vivo applications such as cancer diagnosis and therapy. However, many of the published synthesis protocols for DOTA derivatives are complicated and give the products in low yields. Here we report improved synthesis routes for tris-tBu-DOTA, tris-benzyl-DOTA, and thiol-DOTA, and also describe the synthesis of the novel compound tris-4-nitro-benzyl-DOTA. In addition, we determined the applicability of the DOTA derivatives tris-tBu-DOTA, thiol-DOTA, tris-benzyl-DOTA, tris-4-nitrobenzyl-DOTA, tris-allyl-DOTA, DOTA-PFP-ester, and DOTA-PNP-ester for multimerization reactions using amino functionalized PAMAM dendrimers of different sizes. Thiol-DOTA was found to be the best compound for efficient reactions with dendritic scaffolds generating highly homogeneous DOTA-multimers. This DOTA derivative could be quantitatively conjugated to a 128-mer dendrimer.

Characteristic abnormalities in cerebrospinal fluid biochemistry in children with cerebral malaria compared to viral encephalitis.

BACKGROUND: In developing countries where Plasmodium falciparum malaria is endemic, viral encephalitis and cerebral malaria are found in the same population, and parasitemia with Plasmodium falciparum is common in asymptomatic children. The objective of this study was to investigate the cerebrospinal fluid (CSF) biochemistry in children with cerebral malaria compared to those with presumed viral encephalitis. METHODS: We studied the following CSF parameters: cell count, glucose, protein, lactic dehydrogenase (LDH) and adenosine deaminase (ADA) levels, in children with cerebral malaria, with presumed viral encephalitis, and in control subjects who had a lumbar puncture after a febrile convulsion with postictal coma. RESULTS: We recruited 12 children with cerebral malaria, 14 children with presumed viral encephalitis and 20 controls prospectively, over 2 years in the Government General Hospital in Kakinada, India. Patients with cerebral malaria had significantly lower CSF glucose, and higher protein, LDH, CSF/blood LDH ratio and CSF ADA levels but a lower CSF/serum ADA ratio compared to controls (p < 0.01). Patients with cerebral malaria had lower CSF white cell count, glucose, protein, LDH levels and CSF/serum ADA ratio compared to patients with presumed viral encephalitis. CSF/serum ADA ratio was lower in patients with cerebral malaria due to the fact that serum ADA levels were significantly higher in patients with cerebral malaria compared to the other two groups. A CSF/serum ADA ratio of <0.38 and a CSF glucose level of <3.4 mmol/l were selected as the cut-off values with the highest sensitivities and specificities for comparing the two conditions. CONCLUSION: CSF/serum ADA ratio and CSF glucose levels were the best discriminators of cerebral malaria from presumed viral encephalitis in our study. Further studies are needed to explore their usefulness in epidemiological studies.

[Comparison of diagnostic accuracy of (18)F-FDG PET, (123)I-IMT- and (99m)Tc-MIBI SPECT: evaluation of tumour progression in irradiated low grade astrocytomas]. / Vergleich der diagnostischen Genauigkeit von (18)F-FDG PET, (123)I-IMT- und (99m)Tc-MIBI SPECT zur Ermittlung des Progressionsstatus bestrahlter niedriggradiger Astrozytome.

AIM: To evaluates the diagnostic accuracy of the SPECT-tracers 3-(123)I-alpha-methyl-L-tyrosine (IMT) and (99m)Tc(I)- hexakis(2-methoxyisobutylisonitrile) (MIBI) as well as the PET-tracer 2-(18)F-2-deoxyglucose (FDG) for detecting tumour progression in irradiated low grade astrocytomas (LGA). PATIENTS, METHODS: We examined 91 patients (56 males; 35 females; 44.7 +/- 11.5 years), initially suffering from histologically proven LGAs (mean WHO grade II) and treated by stereotactic radiotherapy (59.0 +/- 4.6 Gy). On average 21.9 +/- 11.2 months after radiotherapy, patients presented new Gd-DTPA enhancing lesions on MRI, which did not allow a differentiation between progressive tumour (PT) and non-PT (nPT) at this point of time. PET scans (n = 82) were acquired 45 min after injection of 208 +/- 32 MBq FDG. SPECT scans started 10 min after injection of 269 +/- 73 MBq IMT (n = 68) and 15 min after injection of 706 +/- 63 MBq MIBI (n = 34). Lesions were classified as PT and nPT based on prospective follow-up (clinically, MRI) for 17.2 +/- 9.9 months after PET/SPECT. Lesion-to-normal ratios (L/N) were calculated using contra lateraly mirrored reference regions for the SPECT examinations and reference regions in the contra lateral grey (GM) and white matter (WM) for FDG PET. Ratios were evaluated by Receiver Operating Characteristic (ROC) analysis. RESULTS: In the patient groups nPT and PT, L/N ratios for FDG (GS) were 0.6 +/- 0.3 vs. 1.2 +/- 0.5 (p = 0.003), for FDG (WS) 1.2 +/- 0.4 vs. 2.6 +/- 0.4 (p < 0.001), for IMT 1.1 +/- 0.1 vs. 1.8 +/- 0.4 (p < 0.001) and for MIBI 1.6 +/- 0.7 vs. 2.6 +/- 2.2 (p = 0.554). Areas under the non-parametric ROC-curves were: 0.738 +/- 0.059 for FDG (GS), 0.790 +/- 0.057 for FDG (WS), 0.937 +/- 0.037 for IMT and 0.564 +/- 0.105 for MIBI. CONCLUSION: MIBI-SPECT examinations resulted in a low accuracy and especially in a poor sensitivity even at modest specificity values. A satisfying diagnostic accuracy was reached with FDG PET. Using WM as reference region for FDG PET, a slightly higher AUC as compared to GM was calculated. IMT yielded the best ROC characteristics and the highest diagnostic accuracy for differentiating between PT and nPT in irradiated LGA.

Inflammasome activation by cell volume regulation and inflammation-associated hyponatremia: A vicious cycle.

Inflammasomes are caspase-1-activating molecular platforms that produce active interleukin (IL)-1ß and are implicated in various central nervous system (CNS) diseases. These multi-protein complexes can be activated by exposure of cells to low osmolality. The inflammasome nucleotide-binding and oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) is hereby the main sensor of cellular osmolality. IL-1ß was found to stimulate the secretion of antidiuretic hormone (ADH) from the posterior pituitary gland either by action of prostaglandins or indirectly by causing the release of IL-6. Based on these findings, we hypothesize that the hyponatremia caused by a wide range of CNS diseases is able to induce significant cell swelling with induction of a hyposmotic intracellular environment, which activates the NLRP3 inflammasome, causing the release of IL-1ß and induced by IL-1ß, IL-6, which increases the production of ADH that leads to more profound hyponatremia. Supportive evidence for this hypothesis is the finding that IL-1 injection can induce ADH release and hyposmotic effect of ADH induced hyponatremia can, via the mechanical effect of cell swelling, activate transient receptor potential channels, which via transforming growth factor ß-activated kinase 1 activate NLRP3. Implications of this hypothesis, if confirmed, would include that hyponatremia can be exacerbated through this vicious cycle but also that the inflammasomes are key mediators of this process. Confirmation of this hypothesis would have implications for prevention and clinical management of changes in patients sodium levels related to syndrome of inappropriate antidiuretic hormone secretion (SIADH) with interventions targeting inflammatory mediator production and function of inflammasomes with the potential of prevention of permanent brain damage in a wide range of CNS diseases.

Intrarectal quinine for treating Plasmodium falciparum malaria.

BACKGROUND: In children with falciparum malaria, quinine administered rectally may be easier to use and less painful than intramuscular or intravenous administration. However, it may be less effective. OBJECTIVES: To compare intrarectal quinine with intravenous or intramuscular quinine for treating malaria caused by Plasmodium falciparum. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group Specialized Register (July 2004), CENTRAL (The Cochrane Library Issue 3, 2004), MEDLINE (1966 to July 2004), EMBASE (1974 to July 2004), LILACS (1982 to July 2004), and CINAHL (1982 to July 2004). We also searched conference proceedings, contacted individual researchers and a pharmaceutical company, and checked reference lists. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing intrarectal quinine with intramuscular and intravenous quinine for treating people with uncomplicated and severe falciparum malaria. DATA COLLECTION AND ANALYSIS: We independently assessed trial quality and extracted data, including adverse event data. We analysed dichotomous data using odds ratios and weighted mean difference for continuous data. MAIN RESULTS: Eight randomized controlled trials (involving 1247 children) fulfilled the inclusion criteria. The same principal investigator led seven of the trials. Five trials compared intrarectal with intravenous quinine, and six trials compared it with intramuscular treatment. We detected no statistically significant difference between intrarectal and intravenous or intramuscular routes for death, parasite clearance by 48 hours and 7 days, parasite clearance time, fever clearance time, coma recovery time, duration of hospitalization, and time to drinking. The trials reporting on these outcomes were small, which resulted in large confidence intervals for all outcomes apart from duration of hospitalization. One large trial (898 children) reported that intrarectal was less painful than intramuscular administration. AUTHORS' CONCLUSIONS: We detected no difference in the effect on parasites and clinical illness for intrarectal quinine, but most trials were small. Pain may be less with intrarectal quinine. Further larger trials, in patients with severe malaria and in adults, are required before the intrarectal route can be recommended.