Summary
Background Null mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and predispose to atopic dermatitis (AD). Cohort studies in Europe and Japan have reported an FLG ...mutation carrier frequency of between 14% and 56%, but the prevalent European FLG mutations are rare or absent in Chinese patients with IV and AD.
Objectives To investigate further the spectrum of FLG‐null mutations in Chinese patients and to compare it with that in other populations.
Methods We conducted comprehensive FLG genetic analysis in a discovery cohort of 92 Singaporean Chinese individuals with IV and/or moderate‐to‐severe AD. All detected FLG mutations were then screened in a cohort of 425 patients with AD and 440 normal controls.
Results In total, 22 FLG‐null mutations, of which 14 are novel, were identified in this study; the combined null FLG genotype of 17 mutations detected in cases and controls showed strong association with AD Fisher’s exact test; P = 5·3 × 10−9; odds ratio (OR) 3·3, palmar hyperlinearity (Fisher’s exact test; P = 9·0 × 10−15; OR 5·8), keratosis pilaris (Fisher’s exact test; P = 0·001; OR 4·7) and with increased severity of AD (permutation test; P = 0·0063).
Conclusions This study emphasizes the wider genetic landscape of FLG‐null mutations in Asia that is slowly emerging.
Background
Cognitive impairment, a defining feature of dementia, plays an important role in the compromised functional independence that characterises the condition. Cognitive training (CT) is an ...approach that uses guided practice on structured tasks with the direct aim of improving or maintaining cognitive abilities.
Objectives
• To assess effects of CT on cognitive and non‐cognitive outcomes for people with mild to moderate dementia and their caregivers.
• To compare effects of CT with those of other non‐pharmacological interventions, including cognitive stimulation or rehabilitation, for people with mild to moderate dementia and their caregivers.
• To identify and explore factors related to intervention and trial design that may be associated with the efficacy of CT for people with mild to moderate dementia and their caregivers.
Search methods
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialised Register, on 5 July 2018. ALOIS contains records of clinical trials identified through monthly searches of several major healthcare databases and numerous trial registries and grey literature sources. In addition to this, we searched MEDLINE, Embase, PsycINFO, CINAHL, LILACS, Web of Science Core Collection, ClinicalTrials.gov, and the World Health Organization's trials portal, ICTRP, to ensure that searches were comprehensive and up‐to‐date.
Selection criteria
We included randomised controlled trials (RCTs) that described interventions for people with mild to moderate dementia and compared CT versus a control or alternative intervention.
Data collection and analysis
We extracted relevant data from published manuscripts and through contact with trial authors if required. We assessed risk of bias using the Cochrane 'Risk of bias' tool. We divided comparison conditions into active or passive control conditions and alternative treatments. We used a large number of measures and data to evaluate 19 outcomes at end of treatment, as well as 16 outcomes at follow‐up in the medium term; we pooled this information in meta‐analyses. We calculated pooled estimates of treatment effect using a random‐effects model, and we estimated statistical heterogeneity using a standard Chi² statistic. We graded the evidence using GradePro.
Main results
The 33 included trials were published between 1988 and 2018 and were conducted in 12 countries; most were unregistered, parallel‐group, single‐site RCTs, with samples ranging from 12 to 653 participants. Interventions were between two and 104 weeks long. We classified most experimental interventions as 'straight CT', but we classified some as 'augmented CT', and about two‐thirds as multi‐domain interventions. Researchers investigated 18 passive and 13 active control conditions, along with 15 alternative treatment conditions, including occupational therapy, mindfulness, reminiscence therapy, and others.
The methodological quality of studies varied, but we rated nearly all studies as having high or unclear risk of selection bias due to lack of allocation concealment, and high or unclear risk of performance bias due to lack of blinding of participants and personnel.
We used data from 32 studies in the meta‐analysis of at least one outcome. Relative to a control condition, we found moderate‐quality evidence showing a small to moderate effect of CT on our first primary outcome, composite measure of global cognition at end of treatment (standardised mean difference (SMD) 0.42, 95% confidence interval (CI) 0.23 to 0.62), and high‐quality evidence showing a moderate effect on the secondary outcome of verbal semantic fluency (SMD 0.52, 95% CI 0.23 to 0.81) at end of treatment, with these gains retained in the medium term (3 to 12 months post treatment). In relation to many other outcomes, including our second primary outcome of clinical disease severity in the medium term, the quality of evidence was very low, so we were unable to determine whether CT was associated with any meaningful gains.
When compared with an alternative treatment, we found that CT may have little to no effect on our first primary outcome of global cognition at end of treatment (SMD 0.21, 95% CI ‐0.23 to 0.64), but the quality of evidence was low. No evidence was available to assess our second primary outcome of clinical disease severity in the medium term. We found moderate‐quality evidence showing that CT was associated with improved mood of the caregiver at end of treatment, but this was based on a single trial. The quality of evidence in relation to many other outcomes at end of treatment and in the medium term was too low for us to determine whether CT was associated with any gains, but we are moderately confident that CT did not lead to any gains in mood, behavioural and psychological symptoms, or capacity to perform activities of daily living.
Authors' conclusions
Relative to a control intervention, but not to a variety of alternative treatments, CT is probably associated with small to moderate positive effects on global cognition and verbal semantic fluency at end of treatment, and these benefits appear to be maintained in the medium term. Our certainty in relation to many of these findings is low or very low. Future studies should take stronger measures to mitigate well‐established risks of bias, and should provide long‐term follow‐up to improve our understanding of the extent to which observed gains are retained. Future trials should also focus on direct comparison of CT versus alternative treatments rather than passive or active control conditions.
Chitin ranks next to cellulose as the most important bio-polysaccharide which can primarily be extracted from crustacean shells. However, the emergence of new areas of the application of chitin and ...its derivatives are on the increase and there is growing demand for new chitin sources. In this study, therefore, an attempt was made to extract chitin from the house cricket (Brachytrupes portentosus) by a chemical method. The physicochemical properties of chitin and chitosan extracted from crickets were compared with commercial chitin and chitosan extracted from shrimps, in terms of proximate analysis in particular, of their ash and moisture content. Also, infrared spectroscopy, x-ray diffraction (XRD), scanning electron microscopy and elemental analysis were conducted. The chitin and chitosan yield of the house cricket ranges over 4.3%-7.1% and 2.4%-5.8% respectively. Chitin and chitosan from crickets compares favourably with those extracted from shrimps, and were found to exhibit some similarities. The result shows that cricket and shrimp chitin and chitosan have the same degree of acetylation and degree of deacetylation of 108.1% and 80.5% respectively, following Fourier transform infrared spectroscopy. The characteristic XRD strong/sharp peaks of 9.4 and 19.4° for -chitin are common for both cricket and shrimp chitin. The percentage ash content of chitin and chitosan extracted from B. portentosus is 1%, which is lower than that obtained from shrimp products. Therefore, cricket chitin and chitosan can be said to be of better quality and of purer form than commercially produced chitin and chitosan from shrimp. Based on the quality of the product, chitin and chitosan isolated from B. portentosus can replace commercial chitin and chitosan in terms of utilization and applications. Therefore, B. portentosus is a promising alternative source of chitin and chitosan.
Purpose This multinational study evaluated the antitumor activity of nivolumab in nasopharyngeal carcinoma (NPC). Tumor and plasma-based biomarkers were investigated in an exploratory analysis. ...Patients and Methods Patients with multiply pretreated recurrent or metastatic NPC were treated with nivolumab until disease progression. The primary end point was objective response rate (ORR) and secondary end points included survival and toxicity. The expression of programmed death-ligand 1 (PD-L1) and human leukocyte antigens A and B in archived tumors and plasma clearance of Epstein-Barr virus DNA were correlated with ORR and survival. Results A total of 44 patients were evaluated and the overall ORR was 20.5% (complete response, n = 1; partial response, n = 8). Nine patients received nivolumab for > 12 months (20%). The 1-year overall survival rate was 59% (95% CI, 44.3% to 78.5%) and 1-year progression-free survival (PFS) rate was 19.3% (95% CI, 10.1% to 37.2%). There was no statistical correlation between ORR and the biomarkers; however, a descriptive analysis showed that the proportion of patients who responded was higher among those with PD-L1 positive tumors (> 1% expression) than those with PD-L1-negative tumors. The loss of expression of one or both human leukocyte antigen class 1 proteins was associated with better PFS than when both proteins were expressed (1-year PFS, 30.9% v 5.6%; log-rank P = .01). There was no association between survival and PD-L1 expression or plasma Epstein-Barr virus DNA clearance. There was no unexpected toxicity to nivolumab. Conclusion Nivolumab has promising activity in NPC and the 1-year overall survival rate compares favorably with historic data in similar populations. Additional evaluation in a randomized setting is warranted. The biomarker results were hypothesis generating and validation in larger cohorts is needed.
Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric ...asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re‐evaluate and fine‐tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype‐specific treatment choices; however, this goal has not yet been achieved.
While early diagnosis of younger-onset dementia (YOD) is crucial in terms of accessing appropriate services and future planning, diagnostic delays are common. This study aims to identify predictors ...of delay to diagnosis in a large sample of people with YOD and to investigate the impact of a specialist YOD service on this time to diagnosis.
A retrospective cross-sectional study.
The inpatient unit of a tertiary neuropsychiatry service in metropolitan Victoria, Australia.
People diagnosed with a YOD.
We investigated the following predictors using general linear modeling: demographics including sex and location, age at onset, dementia type, cognition, psychiatric diagnosis, and number of services consulted with prior to diagnosis.
A total of 242 inpatients were included. The mean time to diagnosis was 3.4 years. Significant predictors of delay included younger age at onset, dementia type other than Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD), and increased number of services consulted. These predictors individually led to an increased diagnostic delay of approximately 19 days, 5 months, and 6 months, respectively. A specialized YOD service reduced time to diagnosis by 12 months.
We found that younger age at onset, having a dementia which was not the most commonly occurring AD or bvFTD, and increasing number of services were significant predictors of diagnostic delay. A novel result was that a specialist YOD service may decrease diagnostic delay, highlighting the importance of such as service in reducing time to diagnosis as well as providing post-diagnostic support.
Niemann-Pick disease type C (NPC) is a lysosomal storage disorder that presents with a spectrum of clinical manifestations from infancy and childhood or in early or mid-adulthood. Progressive ...neurological symptoms including ataxia, dystonia and vertical gaze palsy are a hallmark of the disease, and psychiatric symptoms such as psychosis and mood disorders are common. These latter symptoms often present early in the course of NPC and thus these patients are often diagnosed with a major psychotic or affective disorder before neurological and cognitive signs present and the diagnosis is revised. The commonalities and characteristics of psychotic symptoms in both NPC and schizophrenia may share neuronal pathways and mechanisms and provide potential targets for research in both disorders. The neurobiology of NPC and its relationship to the pattern of neuropsychiatric and cognitive symptoms is described in this review. A number of neurobiological models are proposed as mechanisms by which NPC causes psychiatric and cognitive symptoms, informed from models proposed in schizophrenia and other metabolic disorders. There are a number of symptomatic and illness-modifying treatments for NPC currently available. The current evidence is discussed; focussing on two medications which have shown promise, miglustat and hydroxypropyl-β-cyclodextrin.
Summary
Background
The development of alcohol dependence is associated with significant morbidity and mortality. For the majority of affected people the most appropriate goal, in terms of drinking ...behaviour, is abstinence from alcohol. Psychosocial intervention is the mainstay of the treatment but adjuvant pharmacotherapy is also available and its use recommended.
Aim
To provide an updated analysis of current and potential pharmacotherapeutic options for the management of alcohol dependence. In addition, factors predictive of therapeutic outcome, including compliance and pharmacogenetics, and the current barriers to treatment, including doctors’ unwillingness to prescribe these agents, will be explored.
Methods
Relevant papers were selected for review following extensive, language‐ and date‐unrestricted, electronic and manual searches of the literature.
Results
Acamprosate and naltrexone have a substantial evidence base for overall efficacy, safety and cost‐effectiveness while the risks associated with the use of disulfiram are well‐known and can be minimised with appropriate patient selection and supervision. Acamprosate can be used safely in patients with liver disease and in those with comorbid mental health issues and co‐occurring drug‐related problems. A number of other agents are being investigated for potential use for this indication including: baclofen, topiramate and metadoxine.
Conclusion
Pharmacotherapy for alcohol dependence has been shown to be moderately efficacious with few safety concerns, but it is substantially underutilised. Concerted efforts must be made to remove the barriers to treatment in order to optimise the management of people with this condition.
The Seniors Exercise Park program is an evidence-based outdoor physical and social activity program designed originally for older people with no cognitive impairment. This study aimed to pilot this ...program for people living with dementia in residential aged care. We examined the feasibility of delivering the program, evaluating its structure, safety, and supervision needs. In addition, physical, social, health and cognitive benefits of participation were examined. Method This was a feasibility pilot randomised controlled design. Adults aged ≥ 60 years with symptoms of dementia and/or diagnoses of dementia were recruited from an aged care facility in Australia. Participants allocated to the intervention underwent a 12-week structured supervised physical activity program using the outdoor Seniors Exercise Park equipment followed by a 12-week maintenance phase, while the controls received usual care programs. Assessments occurred at baseline, 12 and 24-weeks. Feasibility evaluation included recruitment rate, retention, attendance, overall adherence, dropout rate, adverse events, program delivery modifications and supervision requirements. A suite of cognitive and health-related questionnaires and physical function measures were also collected. Results Sixteen participants were recruited (recruitment rate: 58.6%), eight for the intervention (83.3 ± 7.5 years, 87.5% women) and eight for the control (age 87.5 ± 3.0 years, 87.5% women). Eighty-eight percent completed the 12-week structured program, with 75% retention at 24-weeks. Across the 24-week period, 84.3% participation adherence was reported. No falls or adverse events occurred. Modifications of the program mainly related to method of communication, cueing and adjustments to suit individual personality and characteristics. A ratio of one trainer to two participants was practical and safe. There were no significant changes over time between groups in any of the secondary outcomes. High level of engagement, enjoyment and mood was reported throughout the exercise program. Conclusion The Seniors Exercise Park physical activity program was safe and feasible for people living with dementia in residential care, with high levels of enjoyment, positive attitude, and engagement reported in the intervention group. Individualised communication during program delivery was needed to facilitate motivation and participation. Further research is needed to assess the program effectiveness on physical and cognitive function on a larger scale. Trial registration This trial is registered with the Australian New Zealand Clinical Trials Registry-Registry Number ACTRN12620000733976 . Registered on the 13/07/2020.
Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but ...K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related transcription factor Runx3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. Runx3-/- mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3-/- bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. Runx3-/- epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3+/- mice ( approximately 18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3+/- mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that Runx3 is essential for lung epithelial cell differentiation, and that downregulation of Runx3 is causally linked to the preneoplastic stage of lung adenocarcinoma.
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