Safety and Efficacy of Dihydroartemisinin-Piperaquine in Falciparum Malaria: A Prospective Multi-Centre Individual Patient Data Analysis

BACKGROUND: The fixed dose antimalarial combination of dihydroartemisinin-piperaquine (DP) is a promising new artemisinin-based combination therapy (ACT). We present an individual patient data analysis of efficacy and tolerability in acute uncomplicated falciparum malaria, from seven published randomized clinical trials conducted in Africa and South East Asia using a predefined in-vivo protocol. Comparator drugs were mefloquine-artesunate (MAS3) in Thailand, Myanmar, Laos and Cambodia; artemether-lumefantrine in Uganda; and amodiaquine+sulfadoxine-pyrimethamine and artesunate+amodiaquine in Rwanda. METHODS AND FINDINGS: In total 3,547 patients were enrolled: 1,814 patients (32% children under five years) received DP and 1,733 received a comparator antimalarial at 12 different sites and were followed for 28-63 days. There was no significant heterogeneity between trials. DP was well tolerated with 1.7% early vomiting. There were less adverse events with DP in children and adults compared to MAS3 except for diarrhea; ORs (95%CI) 2.74 (2.13 to 3.51) and 3.11 (2.31 to 4.18), respectively. DP treatment resulted in a rapid clearance of fever and parasitaemia. The PCR genotype corrected efficacy at Day 28 of DP assessed by survival analysis was 98.7% (95%CI 97.6-99.8). DP was superior to the comparator drugs in protecting against both P.falciparum recurrence and recrudescence (P = 0.001, weighted by site). There was no difference between DP and MAS3 in treating P. vivax co-infections and in suppressing the first relapse (median interval to P. vivax recurrence: 6 weeks). Children under 5 y were at higher risk of recurrence for both infections. The proportion of patients developing gametocytaemia (P = 0.002, weighted by site) and the subsequent gametocyte carriage rates were higher with DP (11/1000 person gametocyte week, PGW) than MAS3 (6/1000 PGW, P = 0.001, weighted by site). CONCLUSIONS: DP proved a safe, well tolerated, and highly effective treatment of P.falciparum malaria in Asia and Africa, but the effect on gametocyte carriage was inferior to that of MAS3

Deep brain and cortical stimulation for epilepsy

Background : Despite optimal medical treatment, including epilepsy surgery, many epilepsy patients have uncontrolled seizures. In the last decades, interest has grown in invasive intracranial neurostimulation as a treatment for these patients. Intracranial stimulation includes both deep brain stimulation (DBS) (stimulation through depth electrodes) and cortical stimulation (subdural electrodes). Objectives : To assess the efficacy, safety and tolerability of deep brain and cortical stimulation for refractory epilepsy based on randomized controlled trials. Search methods : We searched PubMed (6 August 2013), the Cochrane Epilepsy Group Specialized Register (31 August 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 7 of 12) and reference lists of retrieved articles. We also contacted device manufacturers and other researchers in the field. No language restrictions were imposed. Selection criteria : Randomized controlled trials (RCTs) comparing deep brain or cortical stimulation to sham stimulation, resective surgery or further treatment with antiepileptic drugs. Data collection and analysis : Four review authors independently selected trials for inclusion. Two review authors independently extracted the relevant data and assessed trial quality and overall quality of evidence. The outcomes investigated were seizure freedom, responder rate, percentage seizure frequency reduction, adverse events, neuropsychological outcome and quality of life. If additional data were needed, the study investigators were contacted. Results were analysed and reported separately for different intracranial targets for reasons of clinical heterogeneity. Main results : Ten RCTs comparing one to three months of intracranial neurostimulation to sham stimulation were identified. One trial was on anterior thalamic DBS (n = 109; 109 treatment periods); two trials on centromedian thalamic DBS (n = 20; 40 treatment periods), but only one of the trials (n = 7; 14 treatment periods) reported sufficient information for inclusion in the quantitative meta-analysis; three trials on cerebellar stimulation (n = 22; 39 treatment periods); three trials on hippocampal DBS (n = 15; 21 treatment periods); and one trial on responsive ictal onset zone stimulation (n = 191; 191 treatment periods). Evidence of selective reporting was present in four trials and the possibility of a carryover effect complicating interpretation of the results could not be excluded in 4 cross-over trials without any washout period. Moderate-quality evidence could not demonstrate statistically or clinically significant changes in the proportion of patients who were seizure-free or experienced a 50% or greater reduction in seizure frequency (primary outcome measures) after 1 to 3 months of anterior thalamic DBS in (multi) focal epilepsy, responsive ictal onset zone stimulation in (multi) focal epilepsy patients and hippocampal DBS in (medial) temporal lobe epilepsy. However, a statistically significant reduction in seizure frequency was found for anterior thalamic DBS (-17.4% compared to sham stimulation; 95% confidence interval (CI) -32.1 to -1.0; high-quality evidence), responsive ictal onset zone stimulation (-24.9%; 95% CI -40.1 to 6.0; high-quality evidence)) and hippocampal DBS (-28.1%; 95% CI -34.1 to -22.2; moderate-quality evidence). Both anterior thalamic DBS and responsive ictal onset zone stimulation do not have a clinically meaningful impact on quality life after three months of stimulation (high-quality evidence). Electrode implantation resulted in asymptomatic intracranial haemorrhage in 3% to 4% of the patients included in the two largest trials and 5% to 13% had soft tissue infections; no patient reported permanent symptomatic sequelae. Anterior thalamic DBS was associated with fewer epilepsy-associated injuries (7.4 versus 25.5%; P = 0.01) but higher rates of self-reported depression (14.8 versus 1.8%; P = 0.02) and subjective memory impairment (13.8 versus 1.8%; P = 0.03); there were no significant differences in formal neuropsychological testing results between the groups. Responsive ictal-onset zone stimulation was well tolerated with few side effects but SUDEP rate should be closely monitored in the future (4 per 340 [= 11.8 per 1000] patient-years; literature: 2.2-10 per 1000 patient-years). The limited number of patients preclude firm statements on safety and tolerability of hippocampal DBS. With regards to centromedian thalamic DBS and cerebellar stimulation, no statistically significant effects could be demonstrated but evidence is of only low to very low quality. Authors' conclusions : Only short term RCTs on intracranial neurostimulation for epilepsy are available. Compared to sham stimulation, one to three months of anterior thalamic DBS ((multi) focal epilepsy), responsive ictal onset zone stimulation ((multi) focal epilepsy) and hippocampal DBS (temporal lobe epilepsy) moderately reduce seizure frequency in refractory epilepsy patients. Anterior thalamic DBS is associated with higher rates of self-reported depression and subjective memory impairment. SUDEP rates require careful monitoring in patients undergoing responsive ictal onset zone stimulation. There is insufficient evidence to make firm conclusive statements on the efficacy and safety of hippocampal DBS, centromedian thalamic DBS and cerebellar stimulation. There is a need for more, large and well-designed RCTs to validate and optimize the efficacy and safety of invasive intracranial neurostimulation treatments

A further critique of the analytic strategy of adjusting for covariates to identify biologic mediation

BACKGROUND: Epidemiologic research is often devoted to etiologic investigation, and so techniques that may facilitate mechanistic inferences are attractive. Some of these techniques rely on rigid and/or unrealistic assumptions, making the biologic inferences tenuous. The methodology investigated here is effect decomposition: the contrast between effect measures estimated with and without adjustment for one or more variables hypothesized to lie on the pathway through which the exposure exerts its effect. This contrast is typically used to distinguish the exposure's indirect effect, through the specified intermediate variables, from its direct effect, transmitted via pathways that do not involve the specified intermediates. METHODS: We apply a causal framework based on latent potential response types to describe the limitations inherent in effect decomposition analysis. For simplicity, we assume three measured binary variables with monotonic effects and randomized exposure, and use difference contrasts as measures of causal effect. Previous authors showed that confounding between intermediate and the outcome threatens the validity of the decomposition strategy, even if exposure is randomized. We define exchangeability conditions for absence of confounding of causal effects of exposure and intermediate, and generate two example populations in which the no-confounding conditions are satisfied. In one population we impose an additional prohibition against unit-level interaction (synergism). We evaluate the performance of the decomposition strategy against true values of the causal effects, as defined by the proportions of latent potential response types in the two populations. RESULTS: We demonstrate that even when there is no confounding, partition of the total effect into direct and indirect effects is not reliably valid. Decomposition is valid only with the additional restriction that the population contain no units in which exposure and intermediate interact to cause the outcome. This restriction implies homogeneity of causal effects across strata of the intermediate. CONCLUSIONS: Reliable effect decomposition requires not only absence of confounding, but also absence of unit-level interaction and use of linear contrasts as measures of causal effect. Epidemiologists should be wary of etiologic inference based on adjusting for intermediates, especially when using ratio effect measures or when absence of interacting potential response types cannot be confidently asserted

Matern Child Health J

BackgroundDespite the well-known role of parents as caregivers, few studies have addressed their health outcomes related to the Zika virus epidemic.MethodsA cross-sectional study was carried out with 146 primary caregivers of children 15\u201326 months of age, with laboratory and/or clinical evidence of Zika infection between August and October 2017 in three Brazilian municipalities: Jo\ue3o Pessoa and Campina Grande in the state of Para\uedba and Fortaleza in the state of Cear\ue1. Caregivers reported on their child\u2019s life and health, family circumstances and underwent screening for stress using the Parenting Stress Index-Short Form. Children were evaluated for developmental delays and clinical outcomes. Differences in the prevalence of risk factors between caregivers with high or clinically relevant stress and those with normal stress were evaluated.ResultsOf the 146 participants, 13% (n=19) were classified as having high or clinically relevant stress, all of them mothers. The two risk factors significantly and independently associated with high levels of stress, compared with individuals with normal stress levels, were \u201creporting difficulty in covering basic expenses\u201d (adjusted OR 3.6 (95% CI 1.1\u201311.8; p = 0.034)) and \u201chaving a child with sleep problems\u201d (adjusted OR 10.4 (95% CI 1.3\u201381.7; p = 0.026)).ConclusionsSome factors seem to contribute significantly more than others to the level of stress experienced by caregivers of children with evidence of Zika virus congenital infection. Interventions and preventive strategies should also target caregivers, who in turn will be able to respond to the unique characteristics of their child.20212022-03-01T00:00:00ZCC999999/ImCDC/Intramural CDC HHSUnited States/U2G GH001152/GH/CGH CDC HHSUnited States/NU2G GH001152/United States Agency for International Development/33245528PMC82975491101

Helicobacter pylori and its Association with Gastric and Oesophageal Carcinomas

Helicobacter pylori is one of the most common infections in man. The infection is often acquired during childhood and usually results in a chronic life-long inflammation in the gastric mucosa. The aim of our studies was to investigate the association between H. pylori seropositivity and the development of gastric and oesophageal carcinomas. Nested case-control studies were performed in the Malmö Preventive Medicine cohort consisting of 32,906 subjects. Tumour cases were identified by the Swedish National Cancer Registry. H. pylori infection was identified serologically by an in-house ELISA and a commercial Western blot method, Helicoblot 2.1. The more virulent H. pylori cagA-positive strain was identified by the CagA band in Helicoblot 2.1. We found that H. pylori seropositivity was associated with a higher risk of non-cardia gastric adenocarcinoma. H. pylori seropositivity was a risk factor for non-cardia gastric adenocarcinoma among both smoking and non-smoking subjects. CagA seropositivity was a risk factor for non-cardia gastric adenocarcinoma in the H. pylori seropositive subgroup. The size of our material did not allow the estimation of the association between H. pylori seropositivity and oesophageal adenocarcinoma or oesophageal squamous cell carcinoma, however, there was an inverse tendency associated with oesophageal squamous cell carcinoma. The Helicoblot 2.1 CagA band was evaluated in subjects with no known gastric or oesophageal malignancy. The CagA band had a bimodal peak intensity distribution. The changes in seroprevalence with year of birth suggested that CagA seropositivity was false-positive in a major proportion of H. pylori seronegative subjects when identified by Helicoblot 2.1

HERA - Environmental Risk Assessment of a contaminated estuarine environment: a case study

Sado River estuary is located in the west coast of Portugal. Previous environmental studies identified industrial contamination, non-point anthropogenic sources and contamination coming from the river, all promoting accumulation of polluted sediments with known impacts on the ecological system. Surrounding human populations have intense economic fishery activities. Together with agriculture, estuary fishing products are available to local residents. Food usage previously characterized through ethnographic studies suggests exposure to estuarine products, farming products, and water in daily activities, as potential routes of contamination. It is well established that long term exposure to heavy metals are associated with renal and neurological diseases, most heavy metals are classified as carcinogenic and teratogenic.Instituição Financiadora: FCT; Instituições participantes: IMAR -Instituto do Mar (coord.)e PRÓ-INSA, Associação para a Promoção da Investigação em Saúde, Instituto Nacional de Saúde Doutor Ricardo Jorg

국내 자살위험의 지리적 분포와 지역적 불균등에 관한 연구, 2008-2012

학위논문 (석사)-- 서울대학교 대학원 : 지리학과, 2015. 2. 박기호.The suicide problem has been grave national public health issue. This study aims to explore geographical distribution of suicide risks in regional scale and to measure the regional disparity. The study object is complete suicide, so the national mortality data, cause of death statistics, was used for this study. From the explorative analysis, significant differences of suicide rates among different sex and age strata were found. The associations between categorical socio-demographic variables and violent suicide means selection, holiday effect, and copycat effect were identified with log-linear model. Spatio-temporally comparable suicide risks and statistically robust relative risks were estimated by direct standardization and Bayesian estimation, respectively. Various visualizing techniques, such as building legend scheme, statistical significance mapping, and cartogram, were applied for mapping the risks and the results were produced with interactive maps, utilizing the interface of Google Maps and Google Earth. In metropolitan areas, bulls eye pattern was found. On the national scale, low suicide risks in southern areas were clearly distinguished with high risks in northern parts. Taking into account statistical significance, the regions with high relative risks were mainly distributed in Gangwon, Chungnam, and Chungbuk. The regional disparity of suicide risks was measured with spatial dissimilarity index, which integrates two divergent dimensions: aspatial unevenness and spatial clustering. First, the characteristics of the distribution of suicide risks were measured in each dimension. Regional unevenness was measured with aspatial inequality indices and global/local spatial autocorrelation was explored with spatial cluster analysis. The regional inequality decreased from 2008 to 2010, and increased consistently after 2010. Moreover, strong spatial autocorrelation was observed throughout the study period. Based on these observations, the global spatial dissimilarity index was computed with Gaussian kernel. It did not make any change in the pattern of temporal variation derived with aspatial measures due to the stable spatio-temporal distribution of suicide risks. However, when the administrative units are ignored with kernel smoothing, temporal pattern changed, which implies the possibility of MAUP. Lastly, cumulative frequency legend and 3D mapping was applied to suicide atlas to reflect the information on the computed regional disparity of suicide risks.Ⅰ. Introduction 1 1.1. Background 1 1.2. Objectives 2 1.3. Organization of Chapters 3 Ⅱ. Literature Review 4 2.1. Medical Geography and Disease Mapping 4 2.2. Geographical Pattern of Suicide 6 2.3. Measurement of Regional Inequality 7 2.3.1. Inequality Measures in Health Studies 7 2.3.2. Spatial Measures for Regional Inequality 8 Ⅲ. Research Methodology 10 3.1. Categorical Data Analysis 10 3.1.1. Contingency Table Analysis 10 3.1.1.1. Test of independence 10 3.1.1.2. Measures of association 11 3.1.2. Log-linear Model for Multi-way Contingency Table 12 3.2. Disease Mapping for Representing Ecological Risk 14 3.2.1. Age-sex Standardization of Rates 14 3.2.2. Bayesian Smoothing Technique 16 3.2.3. Cartogram 19 3.3. Measurement of Regional Inequality 20 3.3.1. A-spatial Measurement of Regional Disparity 20 3.3.1.1. Extended Gini index 20 3.3.1.2. Generalized Entropy Index 20 3.3.1.3. Dissimilarity Index 20 3.3.2. Spatial Cluster Analysis 22 3.3.2.1. Global Detection of Cluster 22 3.3.2.2. Local Detection of Cluster 23 3.3.3. Spatial Dissimilarity Indices 24 Ⅳ. Analysis and Results 27 4.1. Explorative Analysis on Suicide Mortality Data 27 4.1.1. Data Description 27 4.1.2. Descriptive Statistics 30 4.1.3. Contingency Table Analysis on Suicide Data 35 4.1.3.1. Violent suicide means 36 4.1.3.2. Holiday effect 41 4.1.3.3. Copycat effect 44 4.2. Geographical Distribution of Suicide Risks 46 4.2.1. Standardization of Suicide Rates 46 4.2.1.1. Directly Standardized Suicide Rates 46 4.2.1.2. SMR of Suicide 50 4.2.2. Bayesian Smoothed Relative Risks 52 4.2.3. Cartogram and Web-publishing 58 4.2.3.1. Cartogram of Suicide 58 4.2.3.2. Interactive Atlas of Suicide 60 4.3. Regional Disparity of Suicide Risks 62 4.3.1. Aspatial Regional Unevenness of Suicide 62 4.3.2. Spatial Clustering of Suicide 67 4.3.3. Spatial Dissimilarity of Suicide 72 Ⅴ. Conclusion 78 References 81 Appendix 87 국문 초록 97Maste

Brain–specific proteins in Multiple Sclerosis

Brain–specific proteins (BSP) are each relatively specific for particular cell–types within the nervous system. The BSP studied were glial fibrillary acidic protein (GFAP) and S100B for the astrocyte, ferritin for microglia and neurofilaments (Nf) for the axon. BSP are released into the extracellular fluid (ECF) following cellular destruction and during phases of high cellular activity such as astrocytic or microglial activation. ECF BSP equilibrate with those in the cerebrospinal fluid (CSF). This allows us to quantify BSP from the CSF and estimate the overall average of axonal damage (CSF Nf), astrocytic and microglia activation (respectively CSF S100B, CSF ferritin) and astrogliosis (CSF GFAP). New enzyme linked immunoabsorbant assays (ELISA) have been developed for measuring Nf and GFAP in the CSF. Previously established ELISAs have been used to measure S100B and ferritin. It has been shown that spinal cord atrophy in a mouse model of autoimmune encephalomyelitis (EAE) was paralleled by a decrease of Nf indicating loss of axons, and an increase in GFAP indicating astrogliosis. These findings have been confirmed and extended in a human post–mortem study where BSP levels were quantified in multiple sclerosis (MS) lesions of different age and activity. S100B and Nf were associated with acute lesions, ferritin was elevated in all lesion types, while GFAP was increased in both acute and chronic lesions. CSF BSP levels were then quantified in a cross–sectional study of MS patients with the aim of distinguishing clinical subgroups, such as relapsing remitting (RR), primary progressive (PP) and secondary progressive (SP) disease. In addition an attempt was made to relate CSF BSP levels to grades of disability using clinical scales including Kurtzke’s EDSS, an ambulation index (AI) and the 9–hole PEG test (9HPT). It was shown that CSF S100B was higher in RR MS while CSF ferritin was elevated in PP MS patients. The S100B:ferritin ratio emphasised the distinction between the MS subtypes. CSF GFAP was higher in poorly ambulating (AI) and severely disabled (EDSS) patients. CSF GFAP correlated with the EDSS in SP MS patients. This suggests that gliosis is an important feature in SP MS. CSF Nf levels were quantified in a longitudinal study at baseline and at 3–year follow–up. It was shown that more SP/PP than RR MS patients experienced an increase in CSF Nf levels over this time, suggesting cumulative axonal damage in this subgroup. RR MS patients who had elevated CSF Nf levels at baseline had a worse clinical course, suggesting that initial high CSF Nf levels in RR MS patients are a poor prognostic sign. CSF Nf levels at follow–up correlated with the EDSS, AI and 9HPT suggesting that axonal pathology in MS is a dynamic process possibly balancing features of de- and regenerative activities

Identification of hepatocyte nuclear factor 1β-associated disease

Heterozygous mutations and deletions of the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) are the commonest known monogenic cause of developmental kidney disease. However, diagnosis remains challenging due to phenotypic variability and frequent absence of a family history. There is also no consensus as to when HNF1B genetic testing should be performed. This thesis includes work looking at the identification of HNF1B-associated disease. An HNF1B score was developed in 2014 to help select appropriate patients for genetic testing. The aim in chapter 2 was to test the clinical utility of this score in a large number of referrals for HNF1B genetic testing to the UK diagnostic testing service for the HNF1B gene. An HNF1B score was assigned for 686 referrals using clinical information available at the time of testing; performance of the score was evaluated by receiver-operating characteristic curve analysis. Although the HNF1B score discriminated between patients with and without a mutation/deletion reasonably well, the negative predictive value of 85% reduces its clinical utility. HNF1B-associated disease is due to an approximate 1.3 Mb deletion of chromosome 17q12 in about 50% of individuals. This deletion includes HNF1B plus 14 additional genes and has been linked to an increased risk of neurodevelopmental disorders, such as autism. The aim in chapter 3 was to compare the neurodevelopmental phenotype of patients with either an HNF1B intragenic mutation or 17q12 deletion to determine whether haploinsufficiency of the HNF1B gene is responsible for this aspect of the phenotype. Brief behavioural screening showed high levels of psychopathology and impact in children with a deletion. 8/20 (40%) patients with a deletion had a clinical diagnosis of a neurodevelopmental disorder compared to 0/18 with a mutation, P=0.004. 17q12 deletions were also associated with more autistic traits. Two independent clinical geneticists were able to predict the presence of a deletion with a sensitivity of 83% and specificity of 79% when assessing facial dysmorphic features as a whole. These results demonstrate that the 17q12 deletion but not HNF1B intragenic mutations are associated with neurodevelopmental disorders; we conclude that the HNF1B gene is not involved in the neurodevelopmental phenotype of these patients. Extra-renal phenotypes frequently occur in HNF1B-associated disease, including diabetes mellitus and pancreatic hypoplasia. Faecal elastase-1 levels have only been reported in a small number of individuals, the majority of which have diabetes. In chapter 4 we measured faecal elastase-1 in patients with an HNF1B mutation or deletion regardless of diabetes status and assessed the degree of symptoms associated with pancreatic exocrine deficiency. We found that faecal elastase-1 deficiency is a common feature of HNF1B-associated renal disease even when diabetes is not present and pancreatic exocrine deficiency may be more symptomatic than previously suggested. Faecal elastase-1 should be measured in all patients with a known HNF1B molecular abnormality complaining of chronic abdominal pain, loose stools or unintentional weight loss. Hypomagnesaemia is a common feature of HNF1B-associated disease and is due to renal magnesium wasting. The aim in chapter 5 was to measure both serum and urine magnesium and calcium levels in individuals with an HNF1B molecular defect and compare to a cohort of patients followed up in a general nephrology clinic in order to assess their potential as biomarkers for HNF1B-associated disease. The results of this pilot study show that using a cut-off for serum magnesium of ≤0.75 mmol/L was 100% sensitive and 87.5% specific for the presence of an HNF1B mutation/deletion. All individuals in the HNF1B cohort had hypermagnesuria with fractional excretion of magnesium >4%; a cut-off of ≥4.1% was 100% sensitive and 71% specific. This suggests serum magnesium levels and fractional excretion of magnesium are highly sensitive biomarkers for HNF1B-associated renal disease; if these results are confirmed in a larger study of patients with congenital anomalies of the kidneys or urinary tract they could be implemented as cheap screening tests for HNF1B genetic testing in routine clinical care.Medical Research Counci

Deep brain and cortical stimulation for epilepsy

Background : Despite optimal medical treatment, including epilepsy surgery, many epilepsy patients have uncontrolled seizures. Since the 1970s interest has grown in invasive intracranial neurostimulation as a treatment for these patients. Intracranial stimulation includes both deep brain stimulation (DBS) (stimulation through depth electrodes) and cortical stimulation (subdural electrodes). This is an updated version of a previous Cochrane review published in 2014. Objectives : To assess the efficacy, safety and tolerability of DBS and cortical stimulation for refractory epilepsy based on randomized controlled trials (RCTs). Search methods : We searched the Cochrane Epilepsy Group Specialized Register on 29 September 2015, but it was not necessary to update this search, because records in the Specialized Register are included in CENTRAL. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 11, 5 November 2016), PubMed (5 November 2016), ClinicalTrials. gov (5 November 2016), the WHO International Clinical Trials Registry Platform ICTRP (5 November 2016) and reference lists of retrieved articles. We also contacted device manufacturers and other researchers in the field. No language restrictions were imposed. Selection criteria : RCTs comparing deep brain or cortical stimulation versus sham stimulation, resective surgery, further treatment with antiepileptic drugs or other neurostimulation treatments (including vagus nerve stimulation). Data collection and analysis : Four review authors independently selected trials for inclusion. Two review authors independently extracted the relevant data and assessed trial quality and overall quality of evidence. The outcomes investigated were seizure freedom, responder rate, percentage seizure frequency reduction, adverse events, neuropsychological outcome and quality of life. If additional data were needed, the study investigators were contacted. Results were analysed and reported separately for different intracranial targets for reasons of clinical heterogeneity. Main results : Twelve RCTs were identified, eleven of these compared one to three months of intracranial neurostimulation with sham stimulation. One trial was on anterior thalamic DBS (n = 109; 109 treatment periods); two trials on centromedian thalamic DBS (n = 20; 40 treatment periods), but only one of the trials (n = 7; 14 treatment periods) reported sufficient information for inclusion in the quantitative meta-analysis; three trials on cerebellar stimulation (n = 22; 39 treatment periods); three trials on hippocampal DBS (n = 15; 21 treatment periods); one trial on nucleus accumbens DBS (n = 4; 8 treatment periods); and one trial on responsive ictal onset zone stimulation (n = 191; 191 treatment periods). In addition, one small RCT (n = 6) compared six months of hippocampal DBS versus sham stimulation. Evidence of selective reporting was present in four trials and the possibility of a carryover effect complicating interpretation of the results could not be excluded in five cross-over trials without any or a sufficient washout period. Moderate-quality evidence could not demonstrate statistically or clinically significant changes in the proportion of patients who were seizure-free or experienced a 50% or greater reduction in seizure frequency (primary outcome measures) after one to three months of anterior thalamic DBS in (multi) focal epilepsy, responsive ictal onset zone stimulation in (multi) focal epilepsy patients and hippocampal DBS in (medial) temporal lobe epilepsy. However, a statistically significant reduction in seizure frequency was found for anterior thalamic DBS (mean difference (MD), -17.4% compared to sham stimulation; 95% confidence interval (CI) -31.2 to -1.0; high-quality evidence), responsive ictal onset zone stimulation (MD -24.9%; 95% CI -40.1 to -6.0; high-quality evidence) and hippocampal DBS (MD -28.1%; 95% CI -34.1 to -22.2; moderate-quality evidence). Both anterior thalamic DBS and responsive ictal onset zone stimulation do not have a clinically meaningful impact on quality life after three months of stimulation (high-quality evidence). Electrode implantation resulted in postoperative asymptomatic intracranial haemorrhage in 1.6% to 3.7% of the patients included in the two largest trials and 2.0% to 4.5% had postoperative soft tissue infections (9.4% to 12.7% after five years); no patient reported permanent symptomatic sequelae. Anterior thalamic DBS was associated with fewer epilepsy-associated injuries (7.4 versus 25.5%; P = 0.01) but higher rates of self-reported depression (14.8 versus 1.8%; P = 0.02) and subjective memory impairment (13.8 versus 1.8%; P = 0.03); there were no significant differences in formal neuropsychological testing results between the groups. Responsive ictal-onset zone stimulation seemed to be well-tolerated with few side effects. The limited number of patients preclude firm statements on safety and tolerability of hippocampal DBS. With regards to centromedian thalamic DBS, nucleus accumbens DBS and cerebellar stimulation, no statistically significant effects could be demonstrated but evidence is of only low to very low quality. Authors' conclusions : Except for one very small RCT, only short-term RCTs on intracranial neurostimulation for epilepsy are available. Compared to sham stimulation, one to three months of anterior thalamic DBS ((multi) focal epilepsy), responsive ictal onset zone stimulation ((multi) focal epilepsy) and hippocampal DBS (temporal lobe epilepsy) moderately reduce seizure frequency in refractory epilepsy patients. Anterior thalamic DBS is associated with higher rates of self-reported depression and subjective memory impairment. There is insufficient evidence to make firm conclusive statements on the efficacy and safety of hippocampal DBS, centromedian thalamic DBS, nucleus accumbens DBS and cerebellar stimulation. There is a need for more, large and well-designed RCTs to validate and optimize the efficacy and safety of invasive intracranial neurostimulation treatments