A systematic review of the safety of lisdexamfetamine dimesylate

BACKGROUND: Here we review the safety and tolerability profile of lisdexamfetamine dimesylate (LDX), the first long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS: A PubMed search was conducted for English-language articles published up to 16 September 2013 using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). RESULTS: In short-term, parallel-group, placebo-controlled, phase III trials, treatment-emergent adverse events (TEAEs) in children, adolescents, and adults receiving LDX were typical for those reported for stimulants in general. Decreased appetite was reported by 25-39 % of patients and insomnia by 11-19 %. The most frequently reported TEAEs in long-term studies were similar to those reported in the short-term trials. Most TEAEs were mild or moderate in severity. Literature relating to four specific safety concerns associated with stimulant medications was evaluated in detail in patients receiving LDX. Gains in weight, height, and body mass index were smaller in children and adolescents receiving LDX than in placebo controls or untreated norms. Insomnia was a frequently reported TEAE in patients with ADHD of all ages receiving LDX, although the available data indicated no overall worsening of sleep quality in adults. Post-marketing survey data suggest that the rate of non-medical use of LDX was lower than that for short-acting stimulants and lower than or equivalent to long-acting stimulant formulations. Small mean increases were seen in blood pressure and pulse rate in patients receiving LDX. CONCLUSIONS: The safety and tolerability profile of LDX in individuals with ADHD is similar to that of other stimulants

The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

Health care and societal costs of the management of children and adolescents with attention-deficit/hyperactivity disorder in Spain: a descriptive analysis.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition in childhood (5.3% to 7.1% worldwide prevalence), with substantial overall financial burden to children/adolescents, their families, and society. The aims of this study were to describe the clinical characteristics of children and adolescents with ADHD in Spain, estimate the associated direct/indirect costs of the disorder, and assess whether the characteristics and financial costs differed between children/adolescents adequately responding to currently available pharmacotherapies compared with children/adolescents for whom pharmacotherapies failed. Methods: This was a multicenter, cross-sectional, descriptive analysis conducted in 15 health units representative of the overall Spanish population. Data on demographic characteristics, socio-occupational status, social relationships, clinical variables of the disease, and pharmacological and non-pharmacological treatments received were collected in 321 children and adolescents with ADHD. Direct and indirect costs were estimated over one year from both a health care system and a societal perspective. Results: The estimated average cost of ADHD per year per child/adolescent was ¿5733 in 2012 prices; direct costs accounted for 60.2% of the total costs (¿3450). Support from a psychologist/educational psychologist represented 45.2% of direct costs and 27.2% of total costs. Pharmacotherapy accounted for 25.8% of direct costs and 15.5% of total costs. Among indirect costs (¿2283), 65.2% was due to caregiver expenses. The total annual costs were significantly higher for children/adolescents who responded poorly to pharmacological treatment (¿7654 versus ¿5517; P = 0.024), the difference being mainly due to significantly higher direct costs, particularly with larger expenses for non-pharmacological treatment (P = 0.012). Conclusions: ADHD has a significant personal, familial, and financial impact on the Spanish health system and society. Successful pharmacological intervention was associated with lower overall expenses in the management of the disorder

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Does switching from oral extended-release methylphenidate to the methylphenidate transdermal system affect health-related quality-of-life and medication satisfaction for children with attention-deficit/hyperactivity disorder?

Background: To evaluate health-related quality of life (HRQL) and medication satisfaction after switching from a stable dose of oral extended-release methylphenidate (ER-MPH) to methylphenidate transdermal system (MTS) via a dose-transition schedule in children with attention-deficit/hyperactivity disorder (ADHD). Methods: In a 4-week, multisite, open-label study, 171 children (164 in the intent-to-treat [ITT] population) aged 6-12 years diagnosed with ADHD abruptly switched from a stable dose of oral ER-MPH to MTS nominal dosages of 10, 15, 20, and 30 mg using a predefined dose-transition schedule. Subjects remained on the scheduled dose for the first week, after which the dose was then titrated to an optimal effect. The ADHD Impact Module-Children (AIM-C), a disease-specific validated HRQL survey instrument measuring child and family impact, was used to assess the impact of ADHD symptoms on the lives of children and their families at baseline and study endpoint. Satisfaction with MTS use was assessed via a Medication Satisfaction Survey (MSS) at study endpoint. Both the AIM-C and MSS were completed by a caregiver (parent/legally authorized representative). Tolerability was monitored by spontaneous adverse event (AE) reporting. Results: AIM-C child and family HRQL mean scores were above the median possible score at baseline and were further improved at endpoint across all MTS doses. Similar improvements were noted for behavior, missed doses, worry, and economic impact AIM-C item scores. Overall, 93.8% of caregivers indicated a high level of satisfaction with their child's use of the study medication. The majority of treatment-emergent AEs (> 98%) were mild to moderate in intensity, and the most commonly reported AEs included headache, decreased appetite, insomnia, and abdominal pain. Seven subjects discontinued the study due to intolerable AEs (n = 3) and application site reactions (n = 4). Conclusion: This study demonstrates that MTS, when carefully titrated to optimal dose, may further improve child and family HRQL, as well as behavioral, medication worry, and economic impact item scores, as measured by the AIM-C in subjects switching to MTS from a stable dose of routinely prescribed oral ER-MPH after a short treatment period. Furthermore, following the abrupt conversion from oral ER-MPH to MTS, the majority of caregivers reported being highly satisfied with MTS as a treatment option for their children with ADHD. Trial Registration: NCT0015198

Tubulointerstitial injury and the progression of chronic kidney disease

In chronic kidney disease (CKD), once injury from any number of disease processes reaches a threshold, there follows an apparently irreversible course toward decline in kidney function. The tubulointerstitium may play a key role in this common progression pathway. Direct injury, high metabolic demands, or stimuli from various other forms of renal dysfunction activate tubular cells. These, in turn, interact with interstitial tissue elements and inflammatory cells, causing further pathologic changes in the renal parenchyma. The tissue response to these changes thus generates a feed-forward loop of kidney injury and progressive loss of function. This article reviews the mechanisms of this negative cycle mediating CKD

Herbal supplements in the print media: communicating benefits and risks

Background The rise in use of food supplements based on botanical ingredients (herbal supplements) is depicted as part of a trend empowering consumers to manage their day-to-day health needs, which presupposes access to clear and accurate information to make effective choices. Evidence regarding herbal supplement efficacy is extremely variable so recent regulations eliminating unsubstantiated claims about potential effects leave producers able to provide very little information about their products. Medical practitioners are rarely educated about herbal supplements and most users learn about them via word-of-mouth, allowing dangerous misconceptions to thrive, chief among them the assumption that natural products are inherently safe. Print media is prolific among the information channels still able to freely discuss herbal supplements. Method This study thematically analyses how 76 newspaper/magazine articles from the UK, Romania and Italy portray the potential risks and benefits of herbal supplements. Results Most articles referenced both risks and benefits and were factually accurate but often lacked context and impartiality. More telling was how the risks and benefits were framed in service of a chosen narrative, the paucity of authoritative information allowing journalists leeway to recontextualise herbal supplements in ways that serviced the goals and values of their specific publications and readerships. Conclusion Providing sufficient information to empower consumers should not be the responsibility of print media, instead an accessible source of objective information is required.</p

Structure and function of methanogenic microbial communities in soils from flooded rice and upland soybean fields from Sanjiang plain, NE China.

About 50 years ago, most of the natural wetlands in northeast China, the Sanjiang plain, were converted to either flooded rice fields or to upland soybean fields. After the conversion, natural wetland soils were either managed as artificial wetland or as drained upland resulting in soil microbial community changes. The purpose of our study was to understand how methanogenic microbial communities and their functions had changed in the two different soils upon conversion, and whether these communities now exhibit different resistance/resilience to drying and rewetting. Therefore, we determined function, abundance and composition of the methanogenic archaeal and bacterial communities in two soils reclaimed from a Carex wetland 25 years ago. We incubated the soils under anoxic conditions and measured the rates and pathways of CH4 production by analyzing concentration and ?13C of CH4 and acetate in the presence and absence of methyl fluoride, an inhibitor of aceticlastic methanogenesis. We also analyzed the abundance of bacterial and archaeal 16S rRNA genes, and of mcrA (coding for a subunit of the methyl coenzyme M reductase) using qPCR. The composition of the archaeal and bacterial 16S rRNA genes was determined by using MiSeq illumina sequencing. Our results showed clear differences in structure and function of methanogenic archaeal communities in rice field soil versus upland soil. Furthermore, in both soils composition of bacteria and archaea changed after artificial drying and became less diverse. The archaeal and bacterial signature species in the two soils were also different. However, functional changes were similar, with rates of CH4 production and contribution of aceticlastic methanogenesis decreasing upon drying and rewetting in both soils

A limited role for unforced internal variability in 20th century warming.

The early twentieth-century warming (EW; 1910–45) and the mid-twentieth-century cooling (MC; 1950–80) have been linked to both internal variability of the climate system and changes in external radiative forcing. The degree to which either of the two factors contributed to EW and MC, or both, is still debated. Using a two-box impulse response model, we demonstrate that multidecadal ocean variability was unlikely to be the driver of observed changes in global mean surface temperature (GMST) after AD 1850. Instead, virtually all (97%–98%) of the global low-frequency variability (.30 years) can be explained by external forcing. We find similarly high percentages of explained variance for interhemispheric and land–ocean temperature evolution. Three key aspects are identified that underpin the conclusion of this new study: inhomogeneous anthropogenic aerosol forcing (AER), biases in the instrumental sea surface temperature (SST) datasets, and inadequate representation of the response to varying forcing factors. Once the spatially heterogeneous nature of AER is accounted for, the MC period is reconcilable with external drivers. SST biases and imprecise forcing responses explain the putative disagreement between models and observations during the EW period. As a consequence, Atlantic multidecadal variability (AMV) is found to be primarily controlled by external forcing too. Future attribution studies should account for these important factors when discriminating between externally forced and internally generated influences on climate. We argue that AMV must not be used as a regressor and suggest a revised AMV index instead [the North Atlantic Variability Index (NAVI)]. Our associated best estimate for the transient climate response (TCR) is 1.57 K (60.70 at the 5%–95% confidence level)

Internet of Things for Environmental Sustainability and Climate Change

Our world is vulnerable to climate change risks such as glacier retreat, rising temperatures, more variable and intense weather events (e.g., floods, droughts, and frosts), deteriorating mountain ecosystems, soil degradation, and increasing water scarcity. However, there are big gaps in our understanding of changes in regional climate and how these changes will impact human and natural systems, making it difficult to anticipate, plan, and adapt to the coming changes. The IoT paradigm in this area can enhance our understanding of regional climate by using technology solutions, while providing the dynamic climate elements based on integrated environmental sensing and communications that is necessary to support climate change impacts assessments in each of the related areas (e.g., environmental quality and monitoring, sustainable energy, agricultural systems, cultural preservation, and sustainable mining). In the IoT in Environmental Sustainability and Climate Change chapter, a framework for informed creation, interpretation and use of climate change projections and for continued innovations in climate and environmental science driven by key societal and economic stakeholders is presented. In addition, the IoT cyberinfrastructure to support the development of continued innovations in climate and environmental science is discussed