Nonpharmacological approaches reduce symptoms of depression in dementia: A systematic review and meta-analysis.

BACKGROUND: Depression is a common psychological symptom associated with dementia. Pharmacological approaches are often used despite two large negative trials of efficacy. This meta-analysis examines nonpharmacological (i.e., psychosocial) approaches for symptoms of depression in people living with dementia and reports statistical and clinical significance. METHODS: Relevant studies published between 2012 and 2020 were sourced by searching electronic databases: MEDLINE, EMBASE, PsychINFO, Social Work Abstracts and the Cochrane Central Register of Controlled Trials. Studies were assessed for methodological quality. Random-effects meta-analysis was performed to calculate a pooled effect size (ES) and 95% confidence intervals (CI). RESULTS: Overall, 37 nonpharmacological studies were identified including 2,636 participants. The mean quality rating was high (12/14, SD=1.4). Meta-analysis revealed that nonpharmacological approaches were significantly associated with reduced symptoms of depression with a medium effect size (ES=-0.53, 95%CI [-0.72, -0.33], p < 0.0001). There was considerable heterogeneity between studies. Meta-regression revealed this was not driven by intervention type or setting (residential versus community). CONCLUSIONS: Nonpharmacological approaches such as reminiscence, cognitive stimulation/ rehabilitation, therapeutic, music-based approaches and education/ training, have the potential to reduce symptoms of depression in dementia.

Pharmacological and nonpharmacological approaches to reduce disinhibited behaviors in dementia: a systematic review.

OBJECTIVES: Disinhibited behaviors in dementia are associated with multiple negative outcomes. However, effective interventions are under-researched. This systematic review aims to provide an overview of intervention studies that report outcome measures of disinhibited behaviors in dementia. DESIGN: Systematic searches of the databases MEDLINE, EMBASE, and PsychINFO, Social Work Abstracts and Cochrane Central Register of Controlled Trial databases were conducted for publications published between 2002 and March 2020. We included hand-searched reviews, original articles, case reports, cohort studies, and randomized controlled trials (RCTs). All studies were rated for research quality. Statistical and clinical significance were considered for individual studies. Effect sizes were included where provided or calculated where possible. Mean effect sizes were calculated for RCTs only. PARTICIPANTS: The systematic review included studies involving people living with dementia. MEASUREMENTS: The Neuropsychiatric Inventory disinhibition subscale was used most often. RESULTS: Nine pharmacological and 21 nonpharmacological intervention studies utilized different theoretical/clinical approaches. These included pain management, antidepressants, models of care, education and/or training, music-based approaches, and physical activity. The quality of research in RCTs was strong with a greater effect size in nonpharmacological compared to pharmacological approaches (mean Cohen's d = 0.49 and 0.27, respectively). Disinhibition was a secondary outcome in all studies. CONCLUSION: Pharmacological (including pain management and antidepressants) and, more so, nonpharmacological (models of care, education/training, physical activity, and music) approaches were effective in reducing disinhibition.

Raising awareness of research evidence among health professionals delivering dementia care: Are knowledge translation workshops useful?

Providing information about the latest research via educational sessions to health professionals caring for people with dementia may be insufficient to drive change. This project explored self-reported impacts on practice change of adding information about knowledge translation (KT) to a national dementia education program. Six national workshop days were held. Each provided the option of participating in a Principles of KT and innovation implementation seminar in addition to a clinical topic update (sexualities and dementia, or managing behavioral and psychological symptoms of dementia). Six months postworkshop, 321 participants were invited to complete a research utilization survey. Seventy-five responded. KT seminar participants were more likely to report instrumental outcomes (e.g. changed policies, procedures) than those who did not participate in the KT seminar. Including KT information in educational sessions for health professionals may increase the likelihood of practice change in the field of dementia care and warrants further research.

A randomized, double-blind study of fenofibric acid plus rosuvastatin compared with rosuvastatin alone in stage 3 chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) often have mixed dyslipidemia and high cardiovascular disease risk. Although statins reduce LDL-C, adding a fibrate may further improve lipid parameters. OBJECTIVE: This multicenter, randomized study evaluated the short-term efficacy and safety profile of fenofibric acid (FA) + rosuvastatin (R) combination therapy for improving lipid parameters in patients with stage 3 CKD and mixed dyslipidemia. The study also assessed estimated glomerular filtration rate after study drug washout. METHODS: Patients received FA 45 mg + R (5 mg for 8 weeks, then 10 mg for 8 additional weeks) or R monotherapy (5 mg for 8 weeks, then 10 mg for 8 additional weeks), followed by an 8-week washout period. Primary and secondary end points were percent changes in triglycerides and HDL-C, respectively, from baseline to week 8. RESULTS: FA 45 mg + R 5 mg, compared with R 5 mg, resulted in significant improvements in triglycerides (median % changes: week 8, -38.0% vs -22.4%, P < 0.001; week 16, -42.6% vs -29.7%, P < 0.001) and HDL-C (mean % changes: week 8, 16.9% vs 7.8%, P < 0.001; week 16, 17.3% vs 8.9%, P < 0.001). Adverse event rates were similar between groups (70.7% with FA + R vs 68.6% with R). Mean serum creatinine level at baseline was 1.36 mg/dL in the FA + R group and 1.38 mg/dL in the R group. The final treatment serum creatinine value, defined as the last nonmissing postbaseline value collected within 30 days after the last dose of study drug, was 1.52 mg/dL with FA + R (vs 1.41 mg/dL with R; P < 0.001), which then decreased to 1.39 mg/dL after the 8-week washout (vs 1.42 mg/dL with R). CONCLUSIONS: The data suggest that, after 16 weeks of therapy, FA + R has an acceptable safety profile and improved TG and HDL-C efficacy versus R. FA + R combination therapy may thus further improve lipid parameters in patients with stage 3 CKD and mixed dyslipidemia. ClinicalTrials.gov identifier: NCT00680017.

Moving in: adjustment of people living with dementia going into a nursing home and their families.

BACKGROUND: Most people with dementia in Western societies will eventually be placed in a nursing home. This can be stressful to those with dementia and to their families. The adjustment to this new caring environment by both residents and their family caregivers and the factors that influence this are the focus of this review. METHODS: A literature search of Embase, Scopus, and Medline databases of articles published in English between 1990 and 2011 using specified search terms was performed to examine this transition. The 174 titles located were screened and reference lists hand searched resulting in the 49 relevant articles included in this review. RESULTS: This decision and the subsequent adjustment period is a difficult time for people with dementia and their family caregivers. Admission has been linked to increased behavioral symptoms and in particular depression and agitation, decreasing cognition, frailty, and falls in people with dementia. For caregivers, guilt, depression, feelings of failure, and continuing burden but also improvement in quality of life have been variously reported. Research to determine what influences the trajectory of these different outcomes and the prevalence of positive outcomes for people with dementia is lacking. Successful transitions may be assisted by ensuring that the person with dementia has input into decision making, orientation procedures for the person with dementia and family member prior to and on admission, a "buddy" system for new arrivals, and a person-centered approach. CONCLUSIONS: Adjustment to admission to residential care can be difficult for people with dementia and their family caregivers. Longitudinal research examining factors influencing the adjustment can provide a basis for intervention trials to improve this transition.

Nonpharmacological management of apathy in dementia: a systematic review.

Apathy is one of the most challenging and prevalent behavioral symptoms of dementia. It is associated with increased disability and caregiver frustration as well as reduced quality of life, rehabilitation outcomes and survival after nursing home admission. A literature search to set criteria yielded 56 nonpharmacological intervention studies with outcomes relevant to apathy in dementia. Studies were rated according to quality and categorized into 7 groups: exercise, music, multisensory, animals, special care programming, therapeutic activities and miscellaneous. Despite a lack of methodological rigor, it is apparent that nonpharmacological interventions have the potential to reduce apathy. This review indicates that therapeutic activities, particularly those provided individually, have the best available evidence for effectiveness in dementia. Recommendations are provided for quality research.

Diagnostic yield of nasal scrape biopsies in primary ciliary dyskinesia: a multicenter experience.

Examination of ciliary ultrastructure remains the cornerstone diagnostic test for primary ciliary dyskinesia (PCD), a disease of abnormal ciliary structure and/or function. Obtaining a biopsy with sufficient interpretable cilia and producing quality transmission electron micrographs (TEM) is challenging. Methods for processing tissues for optimal preservation of axonemal structures are not standardized. This study describes our experience using a standard operating procedure (SOP) for collecting nasal scrape biopsies and processing TEMs in a centralized laboratory. We enrolled patients with suspected PCD at research sites of the Genetic Disorders of Mucociliary Clearance Consortium. Biopsies were performed according to a SOP whereby curettes were used to scrape the inferior surface of the inferior turbinate, with samples placed in fixative. Specimens were shipped to a central laboratory where TEMs were prepared and blindly reviewed. Four hundred forty-eight specimens were obtained from 107 young children (0-5 years), 189 older children (5-18 years), and 152 adults (> 18 years), and 88% were adequate for formal interpretation. The proportion of adequate specimens was higher in adults than in children. Fifty percent of the adequate TEMs showed normal ciliary ultrastructure, 39% showed hallmark ultrastructural changes of PCD, and 11% had indeterminate findings. Among specimens without clearly normal ultrastructure, 72% had defects of the outer and/or inner dynein arms (IDA), while 7% had central apparatus defects with or without IDA defects. In summary, nasal scrape biopsies can be performed in the outpatient setting and yield interpretable samples, when performed by individuals with adequate training and experience according to an SOP.

Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4.

Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from gram-negative bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream event in the pathogenesis of gram-negative sepsis, making TLR4 an attractive target for novel antisepsis therapy. To validate the concept of TLR4-targeted treatment strategies in gram-negative sepsis, we first showed that TLR4(-/-) and myeloid differentiation primary response gene 88 (MyD88)(-/-) mice were fully resistant to Escherichia coli-induced septic shock, whereas TLR2(-/-) and wild-type mice rapidly died of fulminant sepsis. Neutralizing anti-TLR4 antibodies were then generated using a soluble chimeric fusion protein composed of the N-terminal domain of mouse TLR4 (amino acids 1-334) and the Fc portion of human IgG1. Anti-TLR4 antibodies inhibited intracellular signaling, markedly reduced cytokine production, and protected mice from lethal endotoxic shock and E. coli sepsis when administered in a prophylactic and therapeutic manner up to 13 h after the onset of bacterial sepsis. These experimental data provide strong support for the concept of TLR4-targeted therapy for gram-negative sepsis.

What is the best dementia screening instrument for general practitioners to use?

OBJECTIVE: The objective of this study was to review existing dementia screening tools with a view to informing and recommending suitable instruments to general practitioners (GPs) based on their performance and practicability for general practice. METHOD: A systematic search of pre-MEDLINE, MEDLINE, PsycINFO, and the Cochrane Library Database was undertaken. Only available full-text articles about dementia screening instruments written in English or with an English version were included. Articles using a translation of an English language instrument were excluded unless validated in a general practice, community, or population sample. RESULTS: The General Practitioner Assessment of Cognition (GPCOG), Mini-Cog, and Memory Impairment Screen (MIS) were chosen as most suitable for routine dementia screening in general practice. The GPCOG, Mini-Cog, and MIS were all validated in community, population, or general practice samples, are easy to administer, and have administration times of 5 minutes or less. They also have negative predictive validity and misclassification rates, which do not differ significantly from those of the Mini-Mental Status Examination. CONCLUSIONS: It is recommended that GPs consider using the GPCOG, Mini-Cog, or MIS when screening for cognitive impairment or for case detection.

Psychometric validation of a monitoring-blunting measure for social anxiety disorder: the coping styles questionnaire for social situations (CSQSS).

The purpose of this investigation was to conduct a psychometric validation of the Coping Styles Questionnaire for Social Situations (CSQSS). The CSQSS was developed to measure monitoring and blunting coping styles in social situations based on Miller's conceptualization of how individuals cope with threat-related information. Study 1 evaluated the content validity of the CSQSS monitoring and blunting items. Study 2 examined factor structure, reliability, and construct validity of the CSQSS in a sample of 443 college students. Evidence supported the content and face validity of the CSQSS. In addition, an exploratory factor analysis revealed a two-factor solution consistent with the monitoring and blunting constructs. Both monitoring and blunting scores were positively correlated with measures of social anxiety, with blunting having a stronger relationship. Moreover, individuals with high social anxiety engaged in a significantly higher degree of monitoring and blunting than did individuals with low social anxiety. Taken together, these results provide support for the reliability and validity of the CSQSS. The CSQSS may serve as a useful measure for further examination of monitoring and blunting coping styles in a social anxiety disorder sample.

RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation.

Stimulation of Toll-like receptors (TLRs) initiates potent innate immune responses through Toll-interleukin 1 receptor (TIR) domain-containing adaptors such as MyD88 and Trif. Analysis of Trif-deficient mice has shown that TLR3-dependent activation of the transcription factor NF-kappa B by the TLR3 ligand double-stranded RNA is Trif dependent. Here we investigated the 'downstream' signaling events that regulate TLR3-dependent Trif-induced NF-kappa B activation. Trif recruited the kinases receptor interacting protein (RIP)-1 and RIP3 through its RIP homotypic interaction motif. In the absence of RIP1, TLR3-mediated signals activating NF-kappa B, but not the kinase JNK or interferon-beta, were abolished, suggesting that RIP1 mediates Trif-induced NF-kappa B activation. In contrast, the presence of RIP3 negatively regulated the Trif-RIP1-induced NF-kappa B pathway. Therefore, in contrast to other TLRs, which use interleukin 1 receptor-associated kinase (IRAK) proteins to activate NF-kappa B, TLR 3-induced NF-kappa B activation is dependent on RIP kinases.

MyD88S, a splice variant of MyD88, differentially modulates NF-kappaB- and AP-1-dependent gene expression.

MyD88 is an adapter protein that is involved in Toll-like receptor (TLR)- and interleukin-1 receptor (IL-1R)-induced activation of nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK). By directly binding IL-1R-associated kinase (IRAK)-1 and IRAK-4, MyD88 serves as a bridging protein, enabling IRAK-4-induced IRAK-1 phosphorylation. We previously identified a lipopolysaccharide-inducible splice variant of MyD88, MyD88(S), which specifically prevents the recruitment of IRAK-4 into the IL-1R complex and thus inhibits IRAK-4-mediated IRAK-1 phosphorylation. MyD88(S) is not able to activate NF-kappaB, and in contrast functions as a dominant negative inhibitor of TLR/IL-1R-induced NF-kappaB activation. Unexpectedly, we here demonstrate that MyD88(S) still allows JNK phosphorylation and activator protein (AP)-1-dependent reporter gene induction upon overexpression in HEK293T cells. These observations indicate that NF-kappaB and JNK activation pathways can already diverge at the level of MyD88. Moreover, the regulated expression of a MyD88 splice variant which specifically interferes with NF-kappaB- but not AP-1-dependent gene expression implies an important role for alternative splicing in the fine-tuning of TLR/IL-1R responses.

Epithelial kinetics in mouse heterotopic tracheal allografts.

Obliterative bronchiolitis (OB) is the most important cause of graft dysfunction post-lung transplantation. It is likely that the small airway epithelium is a target of the alloimmune response, and that epithelial integrity is a crucial determinant of airway patency. Our goals are to elucidate epithelial cell kinetics in the heterotopic mouse trachea model and to determine potential mechanisms of cell death in allografts. Allografts and isografts were obtained by transplanting BALB/c tracheas into C57BL/6 and BALB/c immunosuppressed and non-immunosuppressed hosts, respectively and harvested from day 3-20. Morphometry, BrdU and TUNEL labeling, and EM studies were performed. Columnar epithelium in isografts and allografts sloughs during day 0-3, but regenerates in both sets of grafts by day 10. Subsequently, allografts become inflamed and denuded, while isografts retain an intact epithelium. Prior to airway denudation, allografts exhibited significantly increased epithelial cell density, BrdU labeling index (LI), and TUNEL positive cells. Epithelial apoptosis was confirmed by electron microscopy. Allograft percent ciliated columnar epithelium and lumenal circumference were significantly decreased. Cyclosporin delayed airway fibrosis but did not alter the progression of the allograft through the phases of early ischemic injury, airway epithelial cell regeneration, and eventual cell death. These studies quantitatively demonstrate that the allograft epithelium actively regenerates in the alloimmune environment, but succumbs to increased apoptotic cell death, underscoring the importance of the airway epithelium as a self-renewing source of alloantigen.

Regulation of interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88.

MyD88 is an adaptor protein that is involved in interleukin-1 receptor (IL-1R)- and Toll-like receptor (TLR)-induced activation of NF-kappaB. It is composed of a C-terminal Toll/IL-1R homology (TIR) domain and an N-terminal death domain (DD), which mediate the interaction of MyD88 with the IL-1R/TLR and the IL-1R-associated kinase (IRAK), respectively. The interaction of MyD88 with IRAK triggers IRAK phosphorylation, which is essential for its activation and downstream signaling ability. Both domains of MyD88 are separated by a small intermediate domain (ID) of unknown function. Here, we report the identification of a splice variant of MyD88, termed MyD88(S), which encodes for a protein lacking the ID. MyD88(S) is mainly expressed in the spleen and can be induced in monocytes upon LPS treatment. Although MyD88(S) still binds the IL-1R and IRAK, it is defective in its ability to induce IRAK phosphorylation and NF-kappaB activation. In contrast, MyD88(S) behaves as a dominant-negative inhibitor of IL-1- and LPS-, but not TNF-induced, NF-kappaB activation. These results implicate the ID of MyD88 in the phosphorylation of IRAK. Moreover, the regulated expression and antagonistic activity of MyD88(S) suggest an important role for alternative splicing of MyD88 in the regulation of the cellular response to IL-1 and LPS.