Intrathecal baclofen therapy for treatment of spasticity and dystonia in childhood

Spasticity is a common presentation in a wide variety of neurological disorders like cerebral palsy (CP), multiple sclerosis, and spinal cord injury. Management of spasticity involves multiple modalities such as physical and occupational therapy, oral medicines, Botulinum toxin injection, and orthopaedic and neurosurgical intervention. Intrathecal Baclofen (ITB) therapy is one neurosurgical intervention to control spasticity in CP patients. The ITB pump is implanted subcutaneously or sub-facially in the abdomen which delivers the baclofen directly to the intrathecal space via a catheter. As a result of by-passing the blood-brain-barrier, intrathecal administration of a hundredth part of the oral baclofen dose is sufficient to relieve spasticity and therefore preventing the peripheral side-effects seen with oral administration. Although the ITB delivery systems demonstrate significant effectiveness in improving spasticity, the ITB delivery system is associated with a high complication rate which could interfere with the desired effect of ITB therapy. Therefore, in a retrospective observational study we aimed to analyse the ITB complications in a large (n=222) consecutive series of patients. The complication rate in relation to the long period of follow-up (939 pump years),was found to be similar or less than those reported in literature. Dystonia, young age and presence of gastrostomy tube were significantly associated with infective complications. Catheter complications were influenced by presence of dystonia and the surgical technique, whether it was a subfascial or subcutaneous implantation. The pump is refilled by baclofen solution. The frequency of refilling is dependent on the daily dosing regime and the concentration of the aqueous solution of baclofen in the pump. Baclofen solutions are available as commercial and compounded products. An experimental controlled study was conducted to evaluate the safety of using higher concentrations of compounded baclofen in comparison to commercial baclofen. Baclofen concentration of the compounded solution was found to be less accurate than the commercial product although it was within an acceptable range from the expected value. The number of invisible particulates was significantly higher in the compounded solution than in commercial baclofen. However, no clinical complications were reported in the compounded or in the commercial baclofen groups. As patients receiving ITB therapy may have clinical benefits of reduction of the severity of spasticity, they could also have improvements in their functional status and quality of life. A survey study to evaluate changes in functional status and heath related quality of life, showed improvement in both aspects, moreover, the improvement in the health related quality of life was more significant than the change in functional status

Intrathecal baclofen therapy for treatment of spasticity and dystonia in childhood

Spasticity is a common presentation in a wide variety of neurological disorders like cerebral palsy (CP), multiple sclerosis, and spinal cord injury. Management of spasticity involves multiple modalities such as physical and occupational therapy, oral medicines, Botulinum toxin injection, and orthopaedic and neurosurgical intervention. Intrathecal Baclofen (ITB) therapy is one neurosurgical intervention to control spasticity in CP patients. The ITB pump is implanted subcutaneously or sub-facially in the abdomen which delivers the baclofen directly to the intrathecal space via a catheter. As a result of by-passing the blood-brain-barrier, intrathecal administration of a hundredth part of the oral baclofen dose is sufficient to relieve spasticity and therefore preventing the peripheral side-effects seen with oral administration. Although the ITB delivery systems demonstrate significant effectiveness in improving spasticity, the ITB delivery system is associated with a high complication rate which could interfere with the desired effect of ITB therapy. Therefore, in a retrospective observational study we aimed to analyse the ITB complications in a large (n=222) consecutive series of patients. The complication rate in relation to the long period of follow-up (939 pump years),was found to be similar or less than those reported in literature. Dystonia, young age and presence of gastrostomy tube were significantly associated with infective complications. Catheter complications were influenced by presence of dystonia and the surgical technique, whether it was a subfascial or subcutaneous implantation. The pump is refilled by baclofen solution. The frequency of refilling is dependent on the daily dosing regime and the concentration of the aqueous solution of baclofen in the pump. Baclofen solutions are available as commercial and compounded products. An experimental controlled study was conducted to evaluate the safety of using higher concentrations of compounded baclofen in comparison to commercial baclofen. Baclofen concentration of the compounded solution was found to be less accurate than the commercial product although it was within an acceptable range from the expected value. The number of invisible particulates was significantly higher in the compounded solution than in commercial baclofen. However, no clinical complications were reported in the compounded or in the commercial baclofen groups. As patients receiving ITB therapy may have clinical benefits of reduction of the severity of spasticity, they could also have improvements in their functional status and quality of life. A survey study to evaluate changes in functional status and heath related quality of life, showed improvement in both aspects, moreover, the improvement in the health related quality of life was more significant than the change in functional status

Corneal endothelium, retinal nerve fiber layer, ganglion cell complex, and perimetry measurements in normal eyes and those with primary open-angle glaucoma

Background: Corneal endothelial cell (CEC) loss in glaucoma can be attributed to the direct compressive effect of elevated intraocular pressure. Herein, we aimed to evaluate specular microscopic changes in CEC count and morphology in correlation to retinal nerve fiber layer (RNFL) changes detected by spectral-domain optical coherence tomography (SD-OCT) in early and advanced primary open-angle glaucoma (POAG). Methods: This descriptive-analytical study involved patients with medically controlled POAG versus non-glaucomatous patients of the same age group. Specular microscopy, visual field testing, and SD-OCT of the RNFL and macular ganglion cell complex (GCC) were performed. Eyes with POAG were further subcategorized into early and advanced stages. Results: The study included 130 eyes of 130 participants; 70 were eyes with POAG (40 eyes with early-stage POAG, 30 eyes with advanced-stage POAG), and 60 were healthy eyes. The groups were comparable regarding mean age and sex. No significant difference was found in corneal parameters between healthy eyes, eyes with early POAG, and eyes with advanced POAG (all P > 0.05). In eyes with early-stage POAG, a significant negative correlation was found between the coefficient of variation (CV) and superior RNFL thickness (r = - 0.5; P = 0.018), and between the percentage of hexagonal cells (hexagonality) and vertical cup-to-disc ratio (r = - 0.43; P = 0.035). A significant positive correlation was found between hexagonality and superior as well as inferior RNFL thickness (r = + 0.53; P = 0.008 and r = + 0.50; P = 0.015, respectively). However, in the advanced glaucomatous eyes, no significant correlation was found between RNFL thickness and CEC parameters. Conclusions: CEC parameters were not affected in eyes with early or advanced POAG compared with healthy eyes, despite a significant thinning of RNFL and macular GCC. In eyes with early-stage POAG, a significant correlation was found between morphological characteristics of CECs, such as CV and hexagonality, with superior and inferior RNFL thickness in the optic nerve head on SD-OCT images. Future longitudinal studies with larger sample sizes are needed to verify our results

Antisense Phenotypes Reveal a Functional Expression of OsARF1, an Auxin Response Factor, in Transgenic Rice

OsARF1 is the first full-length member of auxin response factor (ARF) gene family to be cloned from monocot plant. Using quantitative RT-PCR this study found that, the transcript abundance of OsARF1 was significantly higher in embryonic tissues than in vegetative tissues. To investigate the effect of OsARF1 on the phenotype of rice, a cDNA fragment of OsARF1 was inserted in inverse orientation to the 35S promoter in vector pBin438 to produce an antisense (AS) construction. The AS-OsARF1 construct was transferred into rice (Oryza sativa L. japonica ) calli via Agrobacterium tumefaciens -mediated transformation. Molecular analysis of transgenic plants showed that the functional expression of OsARF1 was inhibited at mRNA level efficiently. The AS-OsARF1 plants showed extremely low growth, poor vigor, short curled leaves and tillered but were sterile. Therefore, the OsARF1 was shown to be essential for growth in vegetative organs and seed development

Nutritive Value of Ajuga iva as a Pastoral Plant for Ruminants: Plant Phytochemicals and In Vitro Gas Production and Digestibility

This study aims to evaluate the nutritive value of Ajuga iva (A. iva) harvested from three distinct altitude regions in Tunisia (Dougga, Mograne, and Nabeul). The chemical composition, phenolic concentration, gas production, and in vitro dry matter (DM) digestibility were determined. The highest concentrations of neutral detergent fiber (NDF) and acid detergent fiber (ADF) were for A. iva cultivated in Nabeul. In contrast, the highest crude protein (CP) concentration was observed in that cultivated in Mograne, and the lowest (p < 0.01) CP concentration was noted in that cultivated in Dougga. Additionally, the cultivation regions affected the concentrations of free-radical scavenging activity, total flavonoids, and total polyphenols (p < 0.01). The highest free-radical scavenging activity was observed with A. iva cultivated in Dougga and Mograne. The highest (p < 0.05) gas production rate and lag time were observed in A. iva cultivated in Mograne and Nabeul regions. DM digestibility differed between regions and methods of determination. The highest (p < 0.01) DM degradability, determined by the method of Tilley and Terry and the method of Van Soest et al., was for A. iva cultivated in Mograne and Dougga, while the lowest (p < 0.01) value was recorded for that cultivated in the Nabeul region. Likewise, metabolizable energy (ME) and protein digestibility values were higher for A. iva collected from Mograne region than that collected from the other sampling areas. In conclusion, the nutritive value of A. iva differed between regions. Therefore, care should be taken when developing recommendations for using A. iva in an entire region. Season- and region-specific feeding strategies for feeding A. iva are recommended

Effect of Exogenous Fibrolytic Enzymes Supplementation or Functional Feed Additives on In Vitro Ruminal Fermentation of Chemically Pre-Treated Sunflower Heads

peer reviewedThis study aims to provide possible utilization of sunflower head byproduct (SFH) as a feedstuff by implementing chemical pretreatments (4% sodium hydroxide (SFHNaOH) or 4% urea (SFHurea) and supplementation with either exogenous fibrolytic enzymes (EFE) or functional feed additive (FFA). The experimental EFE was a complex (1:1, v/v) of two enzyme products with high activity of β-1,3-1,4-glucanase and endo-1,4-β-D-xylanase and applied at 0 (SFHout), 1, 2, 5, and 10 µL/ gdry matter, while FFA was a fermentation byproduct rich in cellulase and xylanase activities, applied at 0 (SFHout), 0.5, 1, 2, and 4 mg/g DM. SFHurea had the highest (p < 0.05) crude protein (CP) content compared to other SFH substrates. Linear enhancements (p < 0.05) in kinetics of gas production (GP), metabolizable energy (ME), organic matter digestibility (OMD) and total short-chain fatty acids (SCFAs) concentrations were observed for all SFH substrates supplemented with EFE. The SFHout had the highest (p < 0.05) potential GP, maximum rate (Rmax) of GP, ME, OMD and SCFAs. Supplementation of EFE was more pronounced than FFA in affecting the kinetic parameters of in vitro GP for all SFH substrates. SFHout supplemented with EFE seems to be the most promising substrate to enhance microbial fermentation in vitro

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017

Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2\ub75th percentile and 100 as the 97\ub75th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59\ub74 (IQR 35\ub74–67\ub73), ranging from a low of 11\ub76 (95% uncertainty interval 9\ub76–14\ub70) to a high of 84\ub79 (83\ub71–86\ub77). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030