Current views on the potentials of convalescent plasma therapy (CPT) as Coronavirus disease 2019 (COVID-19) treatment: A systematic review and meta-analysis based on recent studies and previous respiratory pandemics.

Convalescent plasma therapy (CPT) has been investigated as a treatment for COVID-19. This review evaluates CPT in COVID-19 and other viral respiratory diseases, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and influenza. PubMed and Google scholar databases were used to collect eligible publications until 8 December 2020. Meta-analysis used Mantel-Haenszel risk ratio (RR) with 95% confidence interval (CI) and pooled analysis for individual patient data with inverse variance weighted average. The study is registered at PROSPERO with the number of CRD4200270579. Forty-four studies with 36,716 participants were included in the pooled analysis and 20 studies in the meta-analysis. Meta-analysis showed reduction of mortality (RR 0.57, 95% CI [0.43, 0.76], z = 3.86 [p < 0.001], I2  = 44% [p = 0.03]) and higher number of discharged patients (RR 2.53, 95% CI [1.72, 3.72], z = 4.70 [p < 0.001], I2  = 3% [p = 0.39]) in patients receiving CPT compared to standard care alone. A possible mechanism of action is prompt reduction in viral titre. Serious transfusion-related adverse events were reported to be less than 1% of cases, suggesting the overall safety of CPT; nevertheless, the number of patients participating in the studies was still limited. It is also important to notice that in all the studies, the majority of patients were also given other medications, such as antivirals, antibiotics and corticosteroid; furthermore, randomized controlled studies involving more patients and in combination with other treatment modalities are urgently needed.

Periventricular hypodensity is associated with the incidence of pre-shunt seizure in hydrocephalic children.

BACKGROUND: The seizure incidence in hydrocephalic children has been acknowledged in a lot of studies previously; nonetheless, seizure pathogenesis in these children remains unclear. Its high proportion of hydrocephalic children who underwent shunt surgery suggests that the seizure might be associated with the protocol of shunt placement and/or the shunt existence intracranially; however, this hypothesis could not explain the pre-shunt seizure incidence in hydrocephalic children. OBJECTIVE: This study aims to evaluate the patients' characteristics and CT findings in pre-shunt hydrocephalic children to identify the possible seizure etiology in these patients. METHODS: Three hundred and thirty-four children with hydrocephalus were included in this study, including 147 hydrocephalic children with the pre-shunt seizure history and 187 hydrocephalic children presented without the pre-shunt seizure history. The following information was retrieved from the patients' medical records: gender, age, pediatric Glasgow Coma Scale (pGCS) upon admission, and hydrocephalus diagnoses. CT findings were re-evaluated to assess the compression association of sulci and gyri, Sylvian fissures, cisterns, FH/ID ratio, Evan's ratio, and periventricular hypodensity with pre-shunt seizure. RESULTS: The results show that the pre-shunt seizure incidence is significantly higher in hydrocephalic children aged 1 to 5 years old (63/113 (55%), p = 0.0001), diagnosed with communicating hydrocephalus (97/163 (59%), p = 0.0001) or infectious hydrocephalus (80/109 (73%), p = 0.0001). The presence of periventricular hypodensity is significantly associated with the pre-shunt seizure incidence (132/205 (64.3%), p = 0.0001). Results from univariate analyses suggest significant association between periventricular hypodensity in every location and pre-shunt seizure (p < 0.0001). Multivariate analyses identify that temporal horn in the right lateral ventricle as the location of periventricular hypodensity has the strongest association with the pre-shunt seizure. CONCLUSION: The presence of periventricular hypodensity in head CT scan is significantly associated with the pre-shunt seizure incidence. Further investigation to confirm this finding and evaluate the possible roles of inflammation in the pre-shunt seizure in hydrocephalic children is important to seek its possible implication on the treatment of pre-shunt seizure in these children.

Neurodevelopmental outcomes after ventriculoperitoneal shunt placement in children with non-infectious hydrocephalus: a meta-analysis.

BACKGROUND: Hydrocephalus is diagnosed when an accumulating amount of cerebrospinal fluid (CSF) fails to circulate and/or absorbed in the ventricular system. Based on its etiology, hydrocephalus can be classified into infectious and non-infectious hydrocephalus. In children, non-infectious hydrocephalus includes congenital hydrocephalus, posthemorrhagic hydrocephalus, neural tube defect-related hydrocephalus, and tumor-related hydrocephalus. Regardless of the cause, a CSF diversion device is placed to divert the excess fluid from the ventricles into peritoneal cavity. Among all, ventriculoperitoneal (VP) shunt is arguably the most commonly used CSF diversion device to date. Until now, the long-term neurodevelopmental impact of VP shunt placement in non-infectious hydrocephalus patients remained unclear. OBJECTIVE: This study aims to evaluate the neurodevelopmental outcomes in children with non-infectious hydrocephalus who had VP shunt placement. MATERIALS AND METHODS: Systematic searches were performed using PubMed, Google Scholar, Scopus databases, and reference lists. Publications that fulfilled the inclusion criteria were included in the meta-analysis. Calculation of Mantel-Haezel risk ratio (RR) was applied, and heterogeneity index (I2) test was used to evaluate the existence of heterogeneity in all studies. Risk of bias was assessed based on the criteria from the Newcastle-Ottawa Scale (NOS). RESULTS: Of the 1929 studies identified, 12 publications were concluded to have fulfilled the inclusion criteria. Results from the meta-analysis showed that the risks of cerebral palsy, visual and hearing impairment, epilepsy, or seizures are significantly higher in children with non-infectious hydrocephalus who already had VP shunt placement (shunted non-infectious hydrocephalus, S-NIH) compared to that of the healthy control. The meta-analysis on intelligent quotient (IQ) and mental development index (MDI) showed that S-NIH children tend to score lower IQ and acquire risk of having mental development delay. On motoric development, S-NIH children scored lower motoric score and have significantly higher risk of motor development delay compared to control. Although normal children tend to have more internalizing behavior compared to S-NIH children, overall assessment on the risk of behavioral abnormalities showed that the differences between these two groups are insignificant. CONCLUSION: S-NIH children have significantly higher risks of disabilities and mental and motoric development delays; thus, planning on continuous rehabilitation for children with non-infectious hydrocephalus who already had placement of VP shunt is important to acquire their optimum potentials and quality of life.

Clinical Parameters, Routine Inflammatory Markers, and LTA4H Genotype as Predictors of Mortality Among 608 Patients With Tuberculous Meningitis in Indonesia.

Background: Damaging inflammation is thought to contribute to the high morbidity and mortality of tuberculous meningitis (TBM), but the link between inflammation and outcome remains unclear. Methods: We performed prospective clinical and routine laboratory analyses of a cohort of adult patients with TBM in Indonesia. We also examined the LTA4H promoter polymorphism, which predicted cerebrospinal fluid (CSF) leukocyte count and survival of Vietnamese patients with TBM. Patients were followed for >1 year. Results: We included 608 patients with TBM, of whom 67.1% had bacteriological confirmation of disease and 88.2% had severe (ie, grade II or III) disease. One-year mortality was 43.7% and strongly associated with decreased consciousness, fever, and focal neurological signs. Human immunodeficiency virus (HIV) infection, present in 15.3% of patients, was associated with higher mortality and different CSF characteristics, compared with absence of HIV infection. Among HIV-uninfected patients, mortality was associated with higher CSF neutrophil counts (hazard ratio [HR], 1.10 per 10% increase; 95% confidence interval [CI], 1.04-1.16), low CSF to blood glucose ratio (HR, 1.16 per 0.10 decrease; 95% CI, 1.04-1.30), CSF culture positivity (HR, 1.37; 95% CI, 1.02-1.84), and blood neutrophilia (HR, 1.06 per 109 neutrophils/L increase; 95% CI, 1.03-1.10). The LTA4H promoter polymorphism correlated with CSF mononuclear cell count but not with mortality (P = .915). Conclusions: A strong neutrophil response and fever may contribute to or be a result of (immuno)pathology in TBM. Aggressive fever control might improve outcome, and more-precise characterization of CSF leukocytes could guide possible host-directed therapeutic strategies in TBM.

Strong Association of Metabolic Parameters with ADMA and VCAM-1 in Normo-Weight Subjects with Metabolic Syndrome.

Background: Metabolic syndrome (MetS) is a risk factor for cardiovascular disease and is linked to obesity. Subjects with MetS who have normo-weight potentially show higher mortality and morbidity. Purpose: This study aims to reveal the critical essential metabolic parameters associated with endothelial dysfunction in MetS subjects with normo-weight compared to obese. Patients and Methods: The study was designed using a case-control approach. Ninety-nine MetS subjects (34 Normo-weight and 65 obese) from the urban population were enrolled in this study. The components of MetS are based on NCEP/ATP III criteria. Asymmetric dimethylarginine (ADMA) and vascular cell adhesion molecule 1 (VCAM-1) as markers for endothelial dysfunction were measured in both groups. Results: Fasting blood glucose (FBG) levels were higher in the normo-weight group (143.38 ± 79.8 mg/dL) compared to the obese group (120.89 ± 46.5 mg/dL). High-density lipoprotein cholesterol (HDL-c) levels in the normo-weight group were lower (42.82 ± 10.1 mg/dL) compared to obesity (45.74 ± 9.3 mg/dL), while triacylglycerol (TAG) levels were higher in the obese (197.25 ± 110.5 mg/dL) compared to the normo-weight group (167.03 ± 98.4 mg/dL), although the differences were statistically not significant (all p > 0.05). The difference between ADMA and VCAM-1 levels was statistically not significant in both groups. Correlation between MetS components with endothelial dysfunction parameters shows that metabolic parameters correlate strongly. Interestingly, a stronger correlation between FBG and ADMA was observed in normo-weight (r = 0.519) compared to obese groups (r = 0.445). In addition, TAG consistently shows a significant correlation with ADMA and VCAM-1 in normo-weight groups. Conclusion: Metabolic parameters, especially FBG and TAG, correlate strongly with endothelial dysfunction parameters in normo-weight subjects with metabolic syndrome.

Intelligence, motoric and psychological outcomes in children from different ART treatments: a systematic review and meta-analysis.

BACKGROUND: Subtle abnormalities in children's intelligence, motor skills, and psychology from various assisted reproductive treatments (ARTs) might be underdiagnosed. Understanding the prognosis of intelligence, motor skills, and psychology in children from ART would provide parents with reasonable expectations and enable them to plan relevant support to achieve the optimum potential in ART children. METHODS: We searched PubMed, EMBASE, Ovid, Google Scholar, and Scopus databases until April 13, 2021, to identify relevant studies. Thirty-four studies met the inclusion and exclusion criteria. The meta-analysis employed a standardized mean difference model. The outcome of this study is to compare intelligence quotient (IQ), motoric ability, and behavioral problems between all ARTs, in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) to naturally conceived (NC) children. Subdomains of intelligence based on the Cattell, Horn, and Carroll Model (CHC Model) of cognitive architecture, including fluid reasoning, short-term and working memory, processing speed, visual-spatial ability, long-term memory retrieval, and crystalized intelligence (knowledge), were evaluated and summarized in details. Motor skill was stratified into two domains: gross motoric and fine motoric. Behavioral problem was categorized as externalizing and internalizing behavior. RESULTS: Meta-analysis showed that verbal intelligence score in IVF toddlers is significantly lower than NC toddlers (p = 0.02); conversely, ICSI toddlers scored significantly higher verbal intelligence score compared to NC toddlers (p = 0.005). Toddlers born after ART had significantly lower non-verbal intelligence score (p = 0.047). IVF toddlers scored significantly lower fine motor score (p = 0.01) compared to naturally conceived toddlers. Based on parent's CBCL, NC toddlers had higher total (p = 0.01) and externalizing behavior (p = 0.001) scores  compared to ART toddlers. Evaluation of full scale IQ and all domains of intelligence in preschool and primary school children revealed that no significant differences exist between ART and NC children. Based on preschool and primary school parents' CBCL, IVF children had significantly lower externalizing behavior score compared to NC children (p = 0.04). Meta-analyses of studies on young adolescents revealed that ART young adolescents scored higher academically than their NC counterparts, including on mathematics (p < 0.00001) and reading or language (p < 0.00001). CONCLUSIONS: Despite differences in certain aspects, this finding suggests that ART is unlikely to cause negative impacts on children's neurodevelopment.

Method development, validation, and impurity measurement of ß-estradiol from radiolabeled [131I]ß-estradiol using radio-high-performance liquid chromatography for radioligand of saturation binding assay.

ß-estradiol is an estrogen steroid hormone and acts as an estrogen receptor agonist. Radiolabeled ß-estradiol is widely used as a radioligand for binding assays. In this present study, the synthesis of [131I]ß-estradiol has been successfully carried out. Accordingly, the measurement of the radiochemical purity (RCP) value and the presence of chemical impurities are needed. To validate the method for identifying the RCP and chemical impurities from [131I]ß-estradiol using high-performance liquid chromatography (HPLC). The synthesis of [131I]ß-estradiol was accomplished by a radioiodination reaction, and the RCP was determined by radio-HPLC. The method for ß-estradiol measurement was validated by reversed-phase HPLC radio-analytical employing ultraviolet-visible (UV-Vis) and radioactive detector. The method for radio-HPLC analysis was validated and established using a C-18 column and MeCN: H2O (55:45 v/v) as the mobile phase. The following conditions were applied: a flow rate of 1.2 mL/min, isocratic, and a UV-Vis detector at 280 nm. The RCP of [131I]ß-estradiol measured by thin-layer chromatography and radio-HPLC was 99.27% ± 1.25% and 95.75% ± 2.41%, respectively. The validation parameters were appropriate and met the requirements for acceptance. HPLC analysis was able to identify the presence of unlabeled estradiol (24.51%-27.29%) in the mixture of [131I]ß-estradiol. As a result, purification using preparative HPLC or other methods will be required in future studies.

Hydrocephalus is an independent factor affecting morbidity and mortality of ICH patients: Systematic review and meta-analysis.

Background: Despite advances in our knowledge of the causes, preventions, and treatments of stroke, it continues to be a leading cause of death and disability. The most common type of stroke-related morbidity and mortality is intracerebral haemorrhage (ICH). Many prognostication scores include an intraventricular extension (IVH) after ICH because it affects mortality independently. Although it is a direct result of IVH and results in significant damage, hydrocephalus (HC) has never been taken into account when calculating prognostication scores. This study aimed to evaluate the significance of hydrocephalus on the outcomes of ICH patients by meta-analysis. Methods: Studies that compared the rates of mortality and/or morbidity in patients with ICH, ICH with IVH (ICH â€‹+ â€‹IVH), and ICH with IVH and HC (ICH â€‹+ â€‹IVH â€‹+ â€‹HC) were identified. A meta-analysis was performed by using Mantel-Haezel Risk Ratio at 95% significance. Results: This meta-analysis included thirteen studies. The findings indicate that ICH â€‹+ â€‹IVH â€‹+ â€‹HC has higher long-term (90-day) and short-term (30-day) mortality risks than ICH (4.26 and 2.30 higher risks, respectively) and ICH â€‹+ â€‹IVH (1.96 and 1.54 higher risks). Patients with ICH â€‹+ â€‹IVH â€‹+ â€‹HC have lower rates of short-term (3 months) and long-term (6 months) good functional outcomes than those with ICH (0.66 and 0.38 times) or ICH â€‹+ â€‹IVH (0.76 and 0.54 times). Confounding variables included vascular comorbidities, haemorrhage volume, midline shift, and an initial GCS score below 8. Conclusion: Hydrocephalus causes a poorer prognosis in ICH patients. Thus, it is reasonable to suggest the inclusion of hydrocephalus in ICH prognostication scoring systems.

The Role of Amino Acids in Tuberculosis Infection: A Literature Review.

Recently, there was an abundance of studies being conducted on the metabolomic profiling of tuberculosis patients. Amino acids are critical metabolites for the immune system, as they might contribute to providing nutrients for the host intracellular pathway. In tuberculosis, several amino acids play important roles in both the mycobacteria infection mechanism and the host. Individual studies showed how the dynamics of metabolite products that result from interactions between Mycobacterium tuberculosis (Mtb) and the host play important roles in different stages of infection. In this review, we focus on the dynamics of amino-acid metabolism and identify the prominent roles of amino acids in the diagnostics and treatment of tuberculosis infection. Online resources, including PubMed, ScienceDirect, Scopus, and Clinical Key, were used to search for articles with combination keywords of amino acids and TB. The inclusion criteria were full-text articles in English published in the last 10 years. Most amino acids were decreased in patients with active TB compared with those with latent TB and healthy controls. However, some amino acids, including leucine, isoleucine, valine, phenylalanine, aspartate, and glutamate, were found to be at higher levels in TB patients. Additionally, the biomarkers of Mtb infection included the ratios of kynurenine to tryptophan, phenylalanine to histidine, and citrulline to arginine. Most amino acids were present at different levels in different stages of infection and disease progression. The search for additional roles played by those metabolomic biomarkers in each stage of infection might facilitate diagnostic tools for staging TB infection.

Cardiometabolic risk factors in adults with normal weight obesity: A systematic review and meta-analysis.

Normal weight obesity (NWO) is a new emerging phenotype of obesity, defined as a normal body mass index with a high body fat percentage. While several studies have described the impact of NWO on cardiometabolic risk factors, the association between them remains uncertain. This meta-analysis systematically evaluated cardiometabolic risk factors in adults with NWO compared to adults with normal weight lean (NWL). A systematic literature search was performed from the inception until September 21, 2021 in order to comprehensively search for all observational studies that had three important variables, including adults (age ≥18 years old), NWO and cardiometabolic risk factors including metabolic syndrome, hypertension, diabetes mellitus, dyslipidaemia or all laboratory findings related to cardiometabolic risk factors. Twenty-four cross-sectional studies with a total of 75 201 subjects are included in the qualitative and quantitative analysis. Overall, older age and female sex are more likely in NWO population. Compared to NWL, NWO is significantly associated with cardiometabolic risk factors, including metabolic syndrome (OR = 2.24 [1.74, 2.89]; p < .001; I2  = 76%, Pheterogeneity < 0.001), hypertension (OR = 1.60[1.36, 1.89]; p < .001; I2  = 76%, Pheterogeneity < 0.001), diabetes mellitus (OR = 1.72[1.54, 1.92]; p < .001; I2  = 47%, Pheterogeneity < 0.001), dyslipidaemia (OR = 1.50 [1.03, 2.18]; p = .03; I2  = 94%, Pheterogeneity < 0.001) and other laboratory findings, except for C-reactive protein in both sexes group; and adiponectin levels in female group. Our meta-analysis showed that NWO was associated with cardiometabolic risk factors. Thus, the traditional definition of obesity using the BMI criteria should be challenged, as those with NWO might still be exposed to a heightened risk of cardiometabolic disorders. Nonetheless, further prospective cohort studies are needed better to understand this syndrome.

Brain MRI Volumetry Analysis in an Indonesian Family of SCA 3 Patients: A Case-Based Study.

Introduction: Spinocerebellar ataxia type-3 (SCA3) is an adult-onset autosomal dominant neurodegenerative disease. It is caused by expanding of CAG repeat in ATXN3 gene that later on would affect brain structures. This brain changes could be evaluated using brain MRI volumetric. However, findings across published brain volumetric studies have been inconsistent. Here, we report MRI brain volumetric analysis in a family of SCA 3 patients, which included pre-symptomatic and symptomatic patients. Methodology: The study included affected and unaffected members from a large six-generation family of SCA 3, genetically confirmed using PolyQ/CAG repeat expansion analysis, Sanger sequencing, and PCR. Clinical evaluation was performed using Scale for the Assessment and Rating of Ataxia (SARA). Subjects' brains were scanned using 3.0-T MRI with a 3D T1 BRAVO sequence. Evaluations were performed by 2 independent neuroradiologists. An automated volumetric analysis was performed using FreeSurfer and CERES (for the cerebellum). Result: We evaluated 7 subjects from this SCA3 family, including 3 subjects with SCA3 and 4 unaffected subjects. The volumetric evaluation revealed smaller brain volumes (p < 0.05) in the corpus callosum, cerebellar volume of lobules I-II, lobule IV, lobule VIIB and lobule IX; and in cerebellar gray matter volume of lobule IV, and VIIIA; in the pathologic/expanded CAG repeat group (SCA3). Conclusion: Brain MRI volumetry of SCA3 subjects showed smaller brain volumes in multiple brain regions including the corpus callosum and gray matter volumes of several cerebellar lobules.

Synthesis, stability, and cellular uptake of 131I-estradiol against MCF7 and T-47D human cell lines as a radioligand for binding assay.

Estradiol is a steroid hormone that works as an agonist estrogen receptor (ER). This compound is widely used as a ligand and bind specifically to the ERα. Radioligand binding assay is an in vitro method for drug development from natural products by synthesizing estradiol through radiolabeling using the radioiodination method. Synthesis of 131I-estradiol was perfomed by direct method using chloramine T as an oxidizer and by indirect labeling using 131I-histamine. The purity of chemical was determined by thin-layer chromatography and paper electrophoresis, as well as its stability for 30 days of storage in refrigerator, freezer and room temperature. The cellular uptake test of the radioligands from both methods was carried out with MCF7 and T-47D cell lines at 60 min. The results exhibited that 131I-estradiol was succesfully obtained with radiochemical purity greater than 95% and more stable in the refrigerator until 21 days than freezer and room temperature. 131I-estradiol and 131I-his-estradiol were internalized higher in T-47D cells than MCF7 cells (44.34 ± 5.93% vs. 17.27 ± 1.71% and 45.34 ± 6.42% vs. 4.92 ± 1.59%, respectively). Furthermore, the radioligands can be used to binding assay in determining the agonist or antagonist to ER of new drugs development.

Clinical and genetic profile in index patients with spinocerebellar ataxia type 3 in Indonesia: case report.

Spinocerebellar ataxia (SCA) is an autosomal dominant hereditary disease with progressive course, and no causal therapy. Diagnostics are still challenging, due to facility and protocols, and so as in Indonesia. As a national referral center, Dr. Hasan Sadikin Central General Hospital has received a lot of patients from all over Indonesia, particularly from Western Java. Study related to SCA (including clinical and genetic profile) is still limited in Indonesia. We identified index patients from three families with ataxia, hence intend to determine their clinical and genetic pattern. The hereditary pattern is autosomal dominant. Scale for the assessment and rating of ataxia (SARA) shows mild and moderate ataxia. Inventory of non-ataxia signs (INAS) scores of the patients were 3, 5 and 6. Montreal cognitive assessment-Indonesian version (MOCA-INA) shows only one patient has mild cognitive impairment, despite young age. Barthel index shows 1 subject has moderate dependency. Mutation in Ataxin3 polyQ repeats shows pathologically long CAG repeats, 72,10; 72,10; and 72,23 respectively in mutant and wild type allele. We diagnosed the index patients with spinocerebellar ataxia type 3. This study is the first case series study in Indonesia. The hereditary pattern is clearly shown as an autosomal dominant ataxia. The clinical and genetic profile was varied, and the symptom is progressive and deteriorates overtime, including wide based gait, speech problem, motor and sensor complaint, and cognitive decline complaint. Despite the same polyQ stretch length, the onset and clinical characteristics of patients are diverse.

Risk of neurodevelopmental disorders in children born from different ART treatments: a systematic review and meta-analysis.

BACKGROUND: Various techniques in assisted reproductive technology (ART) have been developed as solutions for specific infertility problems. It is important to gain consensual conclusions on the actual risks of neurodevelopmental disorders among children who are born from ART. This study aimed to quantify the relative risks of cerebral palsy, intellectual disability, autism spectrum disorder (ASD), and behavioral problems in children from different ART methods by using systematic review and meta-analysis. Healthcare providers could use the results of this study to suggest the suitable ART technique and plan optimum postnatal care. METHODS: Pubmed, Google Scholar, and Scopus databases were used to search for studies up to January 2020. Of the 181 screened full manuscripts, 17 studies (9.39%) fulfilled the selection criteria. Based on the Newcastle-Ottawa scale ratings, 7 studies were excluded, resulting in 10 studies that were eventually included in the meta-analyses. Mantel-Haenszel risk ratio model was used in the meta-analysis, and the results are described using forest plot with 95% confidence interval. Heterogeneity was assessed using the I2 value. RESULTS: Pooled evaluation of 10 studies showed that the risk of cerebral palsy in children from assisted reproductive technology (ART) is higher than children from natural conceptions (risk ratio [RR] 1.82, [1.41, 2.34]; P = 0.00001). Risk of intellectual disability (RR 1.46, [1.03, 2.08]; P = 0.03) and ASD (RR 1.49 [1.05, 2.11]; P = 0.03) are higher in intracytoplasmic sperm injection (ICSI) children compared to conventional in vitro fertilization (IVF) children. The differences in the risk of neurodevelopmental disorders in children born after frozen and fresh embryo transfers are not significant. Analysis on potential cofounder effects, including multiple birth, preterm birth, and low birth body weight highlight possibilities of significant correlation to the risks of neurodevelopmental disorders. CONCLUSIONS: Pooled estimates suggest that children born after ART are at higher risk of acquiring cerebral palsy. ICSI treatment causes higher risk of intellectual disability and ASD. These findings suggest the importance of the availability of intensive care unit at the time of delivery and long-term developmental evaluation particularly in children from ICSI.

Brain MRI findings in relation to clinical characteristics and outcome of tuberculous meningitis.

Neuroradiological abnormalities in tuberculous meningitis (TBM) are common, but the exact relationship with clinical and inflammatory markers has not been well established. We performed magnetic resonance imaging (MRI) at baseline and after two months treatment to characterise neuroradiological patterns in a prospective cohort of adult TBM patients in Indonesia. We included 48 TBM patients (median age 30, 52% female, 8% HIV-infected), most of whom had grade II (90%), bacteriologically confirmed (71%) disease, without antituberculotic resistance. Most patients had more than one brain lesion (83%); baseline MRIs showed meningeal enhancement (89%), tuberculomas (77%), brain infarction (60%) and hydrocephalus (56%). We also performed an exploratory analysis associating MRI findings to clinical parameters, response to treatment, paradoxical reactions and survival. The presence of multiple brain lesion was associated with a lower Glasgow Coma Scale and more pronounced motor, lung, and CSF abnormalities (p-value <0.05). After two months, 33/37 patients (89%) showed worsening of MRI findings, mostly consisting of new or enlarged tuberculomas. Baseline and follow-up MRI findings and paradoxical responses showed no association with six-month mortality. Severe TBM is characterized by extensive MRI abnormalities at baseline, and frequent radiological worsening during treatment.

Epidermal Growth Factor and Adenosine Triphosphate Induce Natrium Iodide Symporter Expression in Breast Cancer Cell Lines.

AIM: This study aims to investigate the effect of ATP, EGF and combination of those two to the Natrium Iodide Symporter (NIS) expression in MCF7, SKBR3 and HaCaT cell lines. METHODS: MCF7, SKBR3 and HaCaT cell lines were treated with ATP, EGF and combination of those two for 6, 12 and 24 hours. The expression of NIS mRNA was measured through quantitative-reverse transcription-polymerase chain reaction (qRT-PCR). The NIS protein expression was confirmed by immunocytofluorescence. RESULTS: NIS mRNA was expressed in SKBR3 and HaCaT cell lines but not in MCF7. The levels of NIS mRNA expression, after treatment by epidermal growth factor (EGF), adenosine Tri-Phosphate (ATP) or the combination of both for 6 and 12 hours were not significantly different from those of untreated cells. However, the treatment by a combination of ATP and EGF for 24 hours increases the level of NIS mRNA expression by 1.6 fold higher than that of the untreated cells (1.6241 ± 0.3, p < 0.05) and protein NIS expression increase significantly by the treatment than untreated cells (P < 0.05). CONCLUSION: The level of NIS expression varies among the different subtypes of breast cancer cell lines. MCF7 cell line is representing the luminal A subtype of breast cancer does not express NIS. Only SKBR3 cell line express NIS and this subtype might be suitable to receive radioiodine therapy as those cells expressing NIS. A combination treatment of EGF and ATP increases the expression of NIS mRNA and protein at the membrane in SKBR3 cells.

Immune cell characteristics and cytokine responses in adult HIV-negative tuberculous meningitis: an observational cohort study.

Immunopathology contributes to high mortality in tuberculous meningitis (TBM) but little is known about the blood and cerebrospinal fluid (CSF) immune response. We prospectively characterised the immune response of 160 TBM suspects in an Indonesian cohort, including 67 HIV-negative probable or definite TBM cases. TBM patients presented with severe disease and 38% died in 6 months. Blood from TBM patients analysed by flow cytometry showed lower αßT and γδT cells, NK cells and MAIT cells compared to 26 pulmonary tuberculosis patients (2.4-4-fold, all p < 0.05) and 27 healthy controls (2.7-7.6-fold, p < 0.001), but higher neutrophils and classical monocytes (2.3-3.0-fold, p < 0.001). CSF leukocyte activation was higher than in blood (1.8-9-fold). CSF of TBM patients showed a predominance of αßT and NK cells, associated with better survival. Cytokine production after ex-vivo stimulation of whole blood showed a much broader range in TBM compared to both control groups (p < 0.001). Among TBM patients, high ex-vivo production of TNF-α, IL-6 and IL-10 correlated with fever, lymphocyte count and monocyte HLA-DR expression (all p < 0.05). TBM patients show a strong myeloid blood response, with a broad variation in immune function. This may influence the response to adjuvant treatment and should be considered in future trials of host-directed therapy.

Association between VEGF-634G>C Gene Polymorphism with Gastric Premalignant Lesions and Serum VEGF Levels in Helicobacter pylori Gastritis Patients.

AIM: To evaluate the association between VEGF-634G>C gene polymorphism with premalignant gastric lesions as well as the level of VEGF. METHODS: This cross-sectional study included patients with H. pylori gastritis at Haji Adam Malik General Hospital, Permata Bunda General Hospital, and Universitas Sumatera Utara Hospital, Medan, Indonesia. Detection of H. pylori infection was made using positive results of 14C-UBT, rapid urease test, and/or immunohistochemistry. Gastric premalignant lesion diagnosis was made when one or more of the following were present: chronic atrophic gastritis, intestinal metaplasia, or dysplasia. Real-time polymerase chain reaction (RT-PCR) was used to examine VEGF-634G>C gene polymorphism. Additionally, serum samples of patients with H. pylori gastritis were obtained to determine the level of circulating VEGF. Data were analysed using SPSS version 22. RESULTS: A total number of 87 patients with H. pylori gastritis were included in this study. Of all participants, 26 patients (29.9%) showed gastric premalignancy. There was a significant association between GG+GC genotype of VEGF-634G>C and gastric premalignant lesions (P = 0.003; OR (CI 95%) = 6.07 (1.88-41.71)). VEGF-634 G>C polymorphism also showed an association with VEGF serum levels (P = 0.005). Patients with the GG+GC genotype would be at risk of 3.16 times to have high VEGF levels compared to CC genotypes. CONCLUSION: VEGF-634G>C polymorphism, in particular, GG+GC genotype was associated with an increased risk of gastric premalignant transformation as well as having high VEGF levels in patients with H.pylori gastritis.

Cerebral tryptophan metabolism and outcome of tuberculous meningitis: an observational cohort study.

BACKGROUND: Immunopathology contributes to the high mortality of tuberculous meningitis, but the biological pathways involved are mostly unknown. We aimed to compare cerebrospinal fluid (CSF) and serum metabolomes of patients with tuberculous meningitis with that of controls without tuberculous meningitis, and assess the link between metabolite concentrations and mortality. METHODS: In this observational cohort study at the Hasan Sadikin Hospital (Bandung, Indonesia) we measured 425 metabolites using liquid chromatography-mass spectrometry in CSF and serum from 33 HIV-negative Indonesian patients with confirmed or probable tuberculous meningitis and 22 control participants with complete clinical data between March 12, 2009, and Oct 27, 2013. Associations of metabolite concentrations with survival were validated in a second cohort of 101 patients from the same centre. Genome-wide single nucleotide polymorphism typing was used to identify tryptophan quantitative trait loci, which were used for survival analysis in a third cohort of 285 patients. FINDINGS: Concentrations of 250 (70%) of 351 metabolites detected in CSF were higher in patients with tuberculous meningitis than in controls, especially in those who died during follow-up. Only five (1%) of the 390 metobolites detected in serum differed between patients with tuberculous meningitis and controls. CSF tryptophan concentrations showed a pattern different from most other CSF metabolites; concentrations were lower in patients who survived compared with patients who died (9-times) and to controls (31-times). The association of low CSF tryptophan with patient survival was confirmed in the validation cohort (hazard ratio 0·73; 95% CI 0·64-0·83; p<0·0001; per each halving). 11 genetic loci predictive for CSF tryptophan concentrations in tuberculous meningitis were identified (p<0·00001). These quantitative trait loci predicted survival in a third cohort of 285 HIV-negative patients in a prognostic index including age and sex, also after correction for possible confounders (p=0·0083). INTERPRETATION: Cerebral tryptophan metabolism, which is known to affect Mycobacterium tuberculosis growth and CNS inflammation, is important for the outcome of tuberculous meningitis. CSF tryptophan concentrations in tuberculous meningitis are under strong genetic influence, probably contributing to the variable outcomes of tuberculous meningitis. Interventions targeting tryptophan metabolism could improve outcomes of tuberculous meningitis. FUNDING: Royal Dutch Academy of Arts and Sciences; Netherlands Foundation for Scientific Research; Radboud University; National Academy of Sciences; Ministry of Research, Technology, and Higher Education, Indonesia; European Research Council; and PEER-Health.

Predominance of modern Mycobacterium tuberculosis strains and active transmission of Beijing sublineage in Jayapura, Indonesia Papua.

Mycobacterium tuberculosis genotype distribution is different between West and Central Indonesia, but there are no data on the most Eastern part, Papua. We aimed to identify the predominant genotypes of M. tuberculosis responsible for tuberculosis in coastal Papua, their transmission, and the association with patient characteristics. A total of 199 M. tuberculosis isolates were collected. Spoligotyping was applied to describe the population structure of M. tuberculosis, lineage identification was performed using a combination of lineage-specific markers, and genotypic clusters were identified using a combination of 24-locus-MIRU-VNTR and spoligotyping. A high degree of genetic diversity was observed among isolates based on their spoligopatterns. Strains from modern lineage 4 made up almost half of strains (46.9%), being more abundant than the ancient lineage 1 (33.7%), and modern lineage 2 (19.4%). Thirty-five percent of strains belonged to genotypic clusters, especially strains in the Beijing genotype. Previous TB treatment and mutations associated with drug resistance were more common in patients infected with strains of the Beijing genotype. Papua shows a different distribution of M. tuberculosis genotypes compared to other parts of Indonesia. Clustering and drug resistance of modern strains recently introduced to Papua may contribute to the high tuberculosis burden in this region.