To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure firstname.lastname@example.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Understanding place-based contributors to health requires geographically and culturally diverse study populations, but sharing location data is a significant challenge to multisite studies. Here, we describe a standardized and reproducible method to perform geospatial analyses for multisite studies. Using census tract-level information, we created software for geocoding and geospatial data linkage that was distributed to a consortium of birth cohorts located throughout the USA. Individual sites performed geospatial linkages and returned tract-level information for 8810 children to a central site for analyses. Our generalizable approach demonstrates the feasibility of geospatial analyses across study sites to promote collaborative translational research.
Evidence is limited on how to synthesize and incorporate the views of stakeholders into a multisite pragmatic trial and how much academic teams change study design and protocol in response to stakeholder input. This qualitative study describes how stakeholders contributed to the design, conduct, and dissemination of findings of a multisite pragmatic clinical trial, the COMprehensive Post-Acute Stroke Services (COMPASS) Study. We engaged stakeholders as integral research partners by embedding them in study committees and community resource networks that supported local sites. Data stemmed from formal focus groups and continuous participation in working groups. Guided by Grounded Theory, we extracted themes from focus group and meeting notes. These were discussed as a team and with other stakeholder groups for feasibility. A consensus approach was used. Stakeholder input changed many aspects of the study including: the care model that treated stroke as a chronic condition after hospital discharge, training for hospital-based providers who often lacked awareness of the barriers to recovery that patients face, support for caregivers who were essential for stroke patients’ recovery, and for community-based health and social service providers whose services can support recovery yet often go underutilized. Stakeholders brought value to both pragmatic research and health service delivery. Future studies should test the impact of elements of study implementation informed by stakeholders vs those that are not.
To advance the quality of mental healthcare in Europe by developing guidance on implementing quality assurance.
We performed a systematic literature search on quality assurance in mental healthcare and the 522 retrieved documents were evaluated by two independent reviewers (B.J. and J.Z.). Based on these evaluations, evidence tables were generated. As it was found that these did not cover all areas of mental healthcare, supplementary hand searches were performed for selected additional areas. Based on these findings, fifteen graded recommendations were developed and consented by the authors. Review by the EPA Guidance Committee and EPA Board led to two additional recommendations (on immigrant mental healthcare and parity of mental and physical healthcare funding).
Although quality assurance (measures to keep a certain degree of quality), quality control and monitoring (applying quality indicators to the current degree of quality), and quality management (coordinated measures and activities with regard to quality) are conceptually distinct, in practice they are frequently used as if identical and hardly separable. There is a dearth of controlled trials addressing ways to optimize quality assurance in mental healthcare. Altogether, seventeen recommendations were developed addressing a range of aspects of quality assurance in mental healthcare, which appear usable across Europe. These were divided into recommendations about structures, processes and outcomes. Each recommendation was assigned to a hierarchical level of analysis (macro-, meso- and micro-level).
There was a lack of evidence retrievable by a systematic literature search about quality assurance of mental healthcare. Therefore, only after further topics and search had been added it was possible to develop recommendations with mostly medium evidence levels.
Evidence-based graded recommendations for quality assurance in mental healthcare were developed which should next be implemented and evaluated for feasibility and validity in some European countries. Due to the small evidence base identified corresponding to the practical obscurity of the concept and methods, a European research initiative is called for by the stakeholders represented in this Guidance to improve the educational, methodological and empirical basis for a future broad implementation of measures for quality assurance in European mental healthcare.
Optimal management of schizophrenia in adolescents is limited by the lack of available therapies. The efficacy and tolerability of aripiprazole was investigated in this patient population.
This 6-week, randomized, double-blind, placebo controlled trial was conducted at 101 international centers, with a safety monitoring board. 13-17 year-olds with a DSM-IV diagnosis of schizophrenia were randomized to placebo, or a fixed dose of aripiprazole 10 mg or 30 mg reached after a 5 or 11 day titration, respectively. The primary endpoint was mean change from baseline on the PANSS Total score at week 6. Secondary endpoints included the PANSS Positive and Negative subscales, and CGI Improvement score. Tolerabilility assessements included frequency and severity of adverse events, as well as blood chemistries, metabolic parameters and weight gain.
Over 85% of 302 patients completed this study. Both 10 mg and 30 mg doses were superior to placebo on the primary endpoint (PANSS total), with significant differences observed as early as Week 1 (30mg). Both doses showed significant improvement on the PANSS Positive and CGI-I scales; and the 10 mg dose group was superior on PANSS Negative score. Approximately 5% of aripiprazole patients discontinued due to AEs. Weight gain and changes in prolactin were minimal.
10mg and 30mg doses of aripiprazole were superior to placebo in the treatment of adolescents with schizophrenia. Aripiprazole was well tolerated, in general, with few discontinuations due to AEs. EPS was the most common AE. Change in body weight was similar to placebo.
There is limited published data from long-term pediatric bipolar clinical trials with which to guide appropriate treatment decisions. Long-term efficacy and safety of aripiprazole was investigated in this patient population.
296 youths, ages 10-17 year-old with a DSM-IV diagnosis of bipolar I disorder were randomized to receive either placebo or aripiprazole (10mg or 30mg) in a 4-week double-blind trial. Completers continued assigned treatments for an additional 26 weeks (double-blind). Efficacy endpoints included mean change from baseline to week 4 and week 30 on the Young Mania Rating Scale; Children's Global Assessment Scale, Clinical Global Impressions-Bipolar version severity scale, General Behavior Inventory, Attention Deficit Hyperactivity Disorders Rating Scale, and time to discontinuation. Tolerability/safety assessments included incidence and severity of AEs, blood chemistries and metabolic parameters.
Over the 30-week course of double-blind treatment, aripiprazole (10 mg and 30 mg) was superior to placebo as early as week 1 (p< 0.002) and at all scheduled visits from week 2 through week 30 on mean change from baseline in the Y-MRS total score (p<.0001; all visits). Significant improvements were observed on multiple endpoints including the CGAS, GBI, CGI-BP, ADHD-RS-IV total score, time to discontinuation, and response and remission rates. The 3 most common AEs were somnolence, extrapyramidal disorder, and fatigue. Mean change in body weight z-scores over 30 weeks was not clinically significant.
Over 30-weeks of treatment, both doses of aripiprazole were superior to placebo in the long term treatment of pediatric bipolar patients. Aripiprazole was generally well tolerated.
The Health Utilities Index-Mark 2 (HUI2), a generic instrument for assessing health status, is an important effectiveness input for pharmacoeconomic modelling. It has not previously been used in patients with attention deficit/hyperactivity disorder (ADHD).
To use HUI2 to assess health utility in patients aged 6–17 years with ADHD receiving the prodrug stimulant lisdexamfetamine dimesylate (LDX).
SPD489-325 was a 7-week, randomized, double-blind, placebo-controlled trial of LDX, with osmotic-release oral system methylphenidate (OROSMPH) as a reference treatment. Patients’ parents or guardians completed HUI2 questionnaires at baseline and weeks 4 and 7. Utilities were estimated for treatment responders and non-responders, with response defined as a Clinical Global Impressions-Improvement (CGI-I) score of 1 or 2, or a ≥25% or ≥30% reduction in ADHD Rating Scale IV (ADHD-RS-IV) total score.
Of 336 patients randomized, 317 were included in the full analysis set (LDX, n=104; OROS-MPH, n=107; placebo, n=106) and 196 completed the study. At endpoint, mean HUI2 utility scores across all treatment groups were higher for responders than non-responders when response was based on CGI-I score (responders: 0.896 [SD, 0.0990]; non-responders: 0.838 [0.1421]), on a ≥25% reduction in ADHD-RS-IV score from baseline (responders, 0.899 [0.0969]; non-responders, 0.809 [0.1474]), or on a ≥30% reduction in ADHD-RS-IV score from baseline (responders, 0.902 [0.0938]; non-responders 0.814 [0.1477]).
The HUI2 instrument is sensitive to treatment response in the child and adolescent ADHD patient population. Health utilities generated using HUI2 are therefore suitable for cost effectiveness evaluations of ADHD medications.
The Weiss Functional Impairment Rating Scale–Parent Report (WFIRS-P) is an ADHD-specific instrument comprising 50 items, grouped into six domains. Parents score each item on a Likert scale (0–3 or not applicable).
To evaluate functional impairment using the WFIRS-P in two phase 3 studies (SPD489-325 and SPD489-326) of lisdexamfetamine dimesylate (LDX) in children and adolescents with ADHD.
Patients’ parents or guardians completed WFIRS-P assessments at baseline, and weeks 4 and 7 of SPD489-325, a 7-week, randomized, placebo controlled trial incorporating a reference treatment (osmotic-release oral system methylphenidate; OROS-MPH). Statistical comparison of LDX versus OROS-MPH was not pre-specified. In SPD489-326, WFIRS-P assessments were performed in the ≥26-week open-label period and the subsequent 6-week randomized-withdrawal period.
In SPD489-325, statistically significant placebo-adjusted effects of LDX were observed in WFIRS-P total score (effect size, 0.924; p<0.001) and in Family, Learning and School, Social Activities and Risky Activities; OROS-MPH effects were significant in total score (effect size 0.772; p<0.001) and in all domains. In SPD489-326, scores were improved or stable in the open-label period. In the randomized-withdrawal period, total score and all domain scores were stable in the LDX group, but worsened in the placebo group. LDX was significantly more effective than placebo in Family, Learning and School, Risky Activities and in total score (effect size, 0.908; p<0.001).
Short-term treatment with LDX or OROS-MPH led to improved functional impairment scores. These benefits were maintained during long-term LDX treatment, and scores declined following treatment withdrawal.
GXR, a selective α2A-adrenergic agonist, is a non-stimulant treatment for ADHD (approved in the USA for children and adolescents and in Canada for children).
To assess the efficacy (symptoms and function) and safety of dose-optimized GXR compared with placebo in children and adolescents with ADHD.
To evaluate the efficacy (symptom and function) and safety of GXR for the treatment of ADHD. An atomoxetine (ATX) arm was included to provide reference data against placebo (NCT01244490).
Patients (6–17 years) were randomly assigned at baseline to dose-optimized GXR (6–12 years, 1–4 mg/day; 13–17 years, 1–7 mg/day), ATX (10–100mg/day) or placebo for 4 or 7 weeks. The primary efficacy measure is change from baseline in ADHD-Rating Scale-version IV (ADHD-RS-IV). Key secondary measures were defined as Clinical Global Impressions-Improvement (CGI-I) and the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P). Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms, and vital signs.
Of 338 patients randomized, 272 (80.5%) completed the study. Placebo-adjusted differences in least squares (LS) mean in ADHD-RS-IV total score, percent improvement versus placebo for CGI-I, placebo-adjusted differences in LS mean change from baseline in WFIRS-P score (family and learning and school domains) are shown in the Table. The most common TEAEs for GXR were somnolence, headache, and fatigue; 8 (7%) TEAEs were severe.
GXR was effective and well tolerated in children and adolescents with ADHD.
Placebo-adjusted difference in LS mean change from baseline in ADHD-RS-IV total score (95% Cl, p-value; effect size)
−8.9 (−11.9, −5.8, p<0.001; 0.76)
−3.8 (−6.8, −0.7, p<0.05; 0.32)
Difference in improvement from placebo for CGI-I (95% Cl, p-value)
23.7% (11.1, 36.4; p<0.001)
12.1% (−0.9, 25.1; p<0.05)
Placebo-adjusted difference in LS mean change from baseline in WFIRS-P; learning and school domain score (95%CI, p-value; effect size)
−0.22 (−0.36, −0.08, p<0.01; 0.42)
−0.16 (−0.31, −0.02, p<0.05; 0.32)
Placebo-adjusted difference in LS mean change from baseline in WFIRS-P; family domain score (95%CI, p-value; effect size)
GXR, a selective α2A-adrenergic agonist, is a non-stimulant ADHD treatment approved in the USA for children and adolescents, and in Canada for children.
To evaluate long-term maintenance of efficacy of GXR in children and adolescents with ADHD who respond to an initial open-label, short-term trial.
To determine if there is a higher rate of treatment failure for placebo vs GXR during the double-blind randomised-withdrawal phase (RWP) (NCT01081145).
Patients (6–17 years) meeting DSM-IV-TR criteria for ADHD, baseline ADHD Rating Scale-IV (ADHD-RS-IV) ≥32 and Clinical Global Impressions-Severity (CGI-S) ratings ≥4 were enrolled. Following 7-week dose optimization and 6-week maintenance periods on open-label GXR (1–7 mg/day), eligible patients entered a 26-week, double-blind, RWP with GXR or placebo. The primary endpoint was rate of treatment failure (≥50% increase in ADHD-RS-IV total score and ≥2-point increase in CGI-S at two consecutive visits, compared to the RWP baseline). The key secondary endpoint was time-to-treatment failure. Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms and vital signs.
Of 528 patients enrolled, 316 (60.0%) entered the RWP. At study end, 49.3% (GXR) and 64.9% (placebo) (95%CI; −26.6, −4.5, p<0.01) of patients had relapsed (Figure). Time-to-treatment failure was 56 days (placebo) versus 218 days (GXR), p=0.003. During the RWP, the most common GXR TEAEs (≥5% patients) were headache, somnolence and nasopharyngitis.
GXR demonstrated long-term maintenance of efficacy versus placebo in children and adolescents with ADHD.
The promises of precision medicine are often heralded in the medical and lay literature, but routine integration of genomics in clinical practice is still limited. While the “last mile” infrastructure to bring genomics to the bedside has been demonstrated in some healthcare settings, a number of challenges remain — both in the receptivity of today's health system and in its technical and educational readiness to respond to this evolution in care. To improve the impact of genomics on health and disease management, we will need to integrate both new knowledge and new care processes into existing workflows. This change will be onerous and time-consuming, but hopefully valuable to the provision of high quality, economically feasible care worldwide.
Individuals with attention-deficit/hyperactivity disorder (ADHD) may require long-term medication.
To measure growth and sexual maturation of children and adolescents with ADHD receiving lisdexamfetamine dimesylate (LDX) in a 2-year trial (SPD489-404).
To investigate the impact of long-term LDX treatment on growth and maturation.
Participants (6–17 years) received dose-optimized, open-label LDX (30–70 mg/day) for 104 weeks. Weight, height and BMI z-scores were derived using the Centers for Disease Control and Prevention norms . Sexual maturation was assessed using the Tanner scale (participant-rated as closest to their stage of development based on standardized drawings).
Of 314 enrolled participants, 191 (60.8%) completed the study. Mean z-scores at baseline and last on-treatment assessment (LOTA) were 0.53 (standard deviation, 0.963) and 0.02 (1.032) for weight, 0.61 (1.124) and 0.37 (1.131) for height, and 0.32 (0.935) and–0.27 (1.052) for BMI. In general, z-scores shifted lower over the first 36 weeks and then stabilized. At LOTA, most participants remained at their baseline Tanner stage or shifted higher, based on development of hair (males, 95.5%; females, 92.1%) or genitalia/breasts (males, 94.7%; females, 98.4%).
Consistent with previous studies of stimulants used to treat ADHD , z-scores for weight, height and BMI decreased, mostly in the first year, then stabilized. No clinically concerning trends of LDX treatment on sexual maturation or the onset of puberty were observed.
Disclosure of interest
Study funded by Shire Development LLC.
Dr Isabel Hernández Otero (Alicia Koplowitz Foundation, Eli Lilly, Forest, Janssen-Cilag, Junta de Andalucia, Roche, Shire, Shire Pharmaceuticals Iberica S.L., and Sunovion).
The practice of medicine often requires procedures that cause pain and anxiety. With the advent of modern anaesthesia these procedures have become commonplace and tolerable. Procedures with the greatest degree of pain are frequently accomplished during a state of general anaesthesia. Many procedures, however, are performed under sedation and analgesia. In contrast to general anaesthesia, sedation and analgesia use short acting medications to alleviate pain and anxiety while leaving patients capable of maintaining their airway and basic physiological functions.
Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.
We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.
In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47–0.68%, p = 2.0 × 10−8–1.0 × 10−10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10−8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10−6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10−11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10−7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10−16).
AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
Translocation and rehabilitation programmes are critical tools for wildlife conservation. These methods achieve greater impact when integrated in a combined strategy for enhancing population or ecosystem restoration. During 2002–2016 we reared 37 orphaned southern sea otter Enhydra lutris nereis pups, using captive sea otters as surrogate mothers, then released them into a degraded coastal estuary. As a keystone species, observed increases in the local sea otter population unsurprisingly brought many ecosystem benefits. The role that surrogate-reared otters played in this success story, however, remained uncertain. To resolve this, we developed an individual-based model of the local population using surveyed individual fates (survival and reproduction) of surrogate-reared and wild-captured otters, and modelled estimates of immigration. Estimates derived from a decade of population monitoring indicated that surrogate-reared and wild sea otters had similar reproductive and survival rates. This was true for males and females, across all ages (1–13 years) and locations evaluated. The model simulations indicated that reconstructed counts of the wild population are best explained by surrogate-reared otters combined with low levels of unassisted immigration. In addition, the model shows that 55% of observed population growth over this period is attributable to surrogate-reared otters and their wild progeny. Together, our results indicate that the integration of surrogacy methods and reintroduction of juvenile sea otters helped establish a biologically successful population and restore a once-impaired ecosystem.
Laboratory-identified bloodstream infections (LAB-ID BSIs) in recently discharged patients are likely to be classified as healthcare-associated community-onset (HCA-CO) infections, even though they may represent hospital-onset (HO) infections. A review of LAB-ID BSIs among patients discharged within 14 days revealed that 109 of 756 cases (14.4%) were HO infections. The BSI risk being misclassified as HCA CO may underestimate the hospital infection risk.
The rocky shores of the north-east Atlantic have been long studied. Our focus is from Gibraltar to Norway plus the Azores and Iceland. Phylogeographic processes shape biogeographic patterns of biodiversity. Long-term and broadscale studies have shown the responses of biota to past climate fluctuations and more recent anthropogenic climate change. Inter- and intra-specific species interactions along sharp local environmental gradients shape distributions and community structure and hence ecosystem functioning. Shifts in domination by fucoids in shelter to barnacles/mussels in exposure are mediated by grazing by patellid limpets. Further south fucoids become increasingly rare, with species disappearing or restricted to estuarine refuges, caused by greater desiccation and grazing pressure. Mesoscale processes influence bottom-up nutrient forcing and larval supply, hence affecting species abundance and distribution, and can be proximate factors setting range edges (e.g., the English Channel, the Iberian Peninsula). Impacts of invasive non-native species are reviewed. Knowledge gaps such as the work on rockpools and host–parasite dynamics are also outlined.
Background: Cervical sponylotic myelopathy (CSM) may present with neck and arm pain. This study investiagtes the change in neck/arm pain post-operatively in CSM. Methods: This ambispective study llocated 402 patients through the Canadian Spine Outcomes and Research Network. Outcome measures were the visual analogue scales for neck and arm pain (VAS-NP and VAS-AP) and the neck disability index (NDI). The thresholds for minimum clinically important differences (MCIDs) for VAS-NP and VAS-AP were determined to be 2.6 and 4.1. Results: VAS-NP improved from mean of 5.6±2.9 to 3.8±2.7 at 12 months (P<0.001). VAS-AP improved from 5.8±2.9 to 3.5±3.0 at 12 months (P<0.001). The MCIDs for VAS-NP and VAS-AP were also reached at 12 months. Based on the NDI, patients were grouped into those with mild pain/no pain (33%) versus moderate/severe pain (67%). At 3 months, a significantly high proportion of patients with moderate/severe pain (45.8%) demonstrated an improvement into mild/no pain, whereas 27.2% with mild/no pain demonstrated worsening into moderate/severe pain (P <0.001). At 12 months, 17.4% with mild/no pain experienced worsening of their NDI (P<0.001). Conclusions: This study suggests that neck and arm pain responds to surgical decompression in patients with CSM and reaches the MCIDs for VAS-AP and VAS-NP at 12 months.