Dementia and co-occurring chronic conditions: a systematic literature review to identify what is known and where are the gaps in the evidence?

OBJECTIVE: The challenges posed by people living with multiple chronic conditions are unique for people with dementia and other significant cognitive impairment. There have been recent calls to action to review the existing literature on co-occurring chronic conditions and dementia in order to better understand the effect of cognitive impairment on disease management, mobility, and mortality. METHODS: This systematic literature review searched PubMed databases through 2011 (updated in 2016) using key constructs of older adults, moderate-to-severe cognitive impairment (both diagnosed and undiagnosed dementia), and chronic conditions. Reviewers assessed papers for eligibility and extracted key data from each included manuscript. An independent expert panel rated the strength and quality of evidence and prioritized gaps for future study. RESULTS: Four thousand thirty-three articles were identified, of which 147 met criteria for review. We found that moderate-to-severe cognitive impairment increased risks of mortality, was associated with prolonged institutional stays, and decreased function in persons with multiple chronic conditions. There was no relationship between significant cognitive impairment and use of cardiovascular or hypertensive medications for persons with these comorbidities. Prioritized areas for future research include hospitalizations, disease-specific outcomes, diabetes, chronic pain, cardiovascular disease, depression, falls, stroke, and multiple chronic conditions. CONCLUSIONS: This review summarizes that living with significant cognitive impairment or dementia negatively impacts mortality, institutionalization, and functional outcomes for people living with multiple chronic conditions. Our findings suggest that chronic-disease management interventions will need to address co-occurring cognitive impairment. Copyright © 2017 John Wiley & Sons, Ltd.

Antibody depletion strategy for the treatment of suspected antibody-mediated rejection in lung transplant recipients: Does it work?

BACKGROUND: Donor-specific antibodies (DSAs) after lung transplantation correlate with poor outcomes. The ideal treatment strategy for antibody-mediated rejection AMR is not defined. Our institution implemented an aggressive multimodality protocol for the treatment of suspected AMR. METHODS: Lung transplant recipients with suspected AMR were treated with a standardized protocol of plasma exchange, steroids, bortezomib, rituximab, and intravenous immune globulin. Primary outcome was DSA clearance at 6 months in those alive. Secondary endpoints included preserved allograft function at 6 months, survival at 6 and 12 months and complications due to the protocol. RESULTS: Sixteen lung transplant recipients with documented DSA and allograft dysfunction were included in the analysis. Of the 16 patients, 11 survived to 6 months. Three of those 11 patients (27%) cleared all DSAs within 6 months of the protocol. Four of the 11 patients (36%) had preserved allograft function at 6 months. Overall 12-month patient survival was 56%. Complications included thrombocytopenia (50%) and abdominal pain or gastrointestinal discomfort (18.7%). CONCLUSIONS: This multimodality protocol resulted in clearance of DSAs and preserved lung function in a minority of lung transplant recipients with suspected AMR surviving to 6 months after therapy. There were significant side effects of the protocol.

Identification of polymorphism in ethylone hydrochloride: synthesis and characterization.

Ethylone, a synthetic cathinone with psychoactive properties, is a designer drug which has appeared on the recreational drug market in recent years. Since 2012, illicit shipments of ethylone hydrochloride have been intercepted with increasing frequency at the Canadian border. Analysis has revealed that ethylone hydrochloride exists as two distinct polymorphs. In addition, several minor impurities were detected in some seized exhibits. In this study, the two conformational polymorphs of ethylone hydrochloride have been synthesized and fully characterized by FTIR, FT-Raman, powder XRD, GC-MS, ESI-MS/MS and NMR ((13) C CPMAS, (1) H, (13) C). The two polymorphs can be distinguished by vibrational spectroscopy, solid-state nuclear magnetic resonance spectroscopy and X-ray diffraction. The FTIR data are applied to the identification of both polymorphs of ethylone hydrochloride (mixed with methylone hydrochloride) in a laboratory submission labelled as 'Ocean Snow Ultra'. The data presented in this study will assist forensic scientists in the differentiation of the two ethylone hydrochloride polymorphs. This report, alongside our recent article on the single crystal X-ray structure of a second polymorph of this synthetic cathinone, is the first to confirm polymorphism in ethylone hydrochloride. © 2015 Canada Border Services Agency. Drug Testing and Analysis published by John Wiley & Sons, Ltd. © 2015 Canada Border Services Agency. Drug Testing and Analysis published by John Wiley & Sons, Ltd.

Inversion twinning in a second polymorph of the hydrochloride salt of the recreational drug ethylone.

A second polymorph of the hydrochloride salt of the recreational drug ethylone, C12H16NO3(+)·Cl(-), is reported [systematic name: (±)-2-ethylammonio-1-(3,4-methylenedioxyphenyl)propane-1-one chloride]. This polymorph, denoted form (A), appears in crystallizations performed above 308 K. The originally reported form (B) [Wood et al. (2015). Acta Cryst. C71, 32-38] crystallizes preferentially at room temperature. The conformations of the cations in the two forms differ by a 180° rotation about the C-C bond linking the side chain to the aromatic ring. Hydrogen bonding links the cations and anions in both forms into similar extended chains in which any one chain contains only a single enantiomer of the chiral cation, but the packing of the ions is different. In form (A), the aromatic rings of adjacent chains interleave, but pack equally well if neighbouring chains contain the same or opposite enantiomorph of the cation. The consequence of this is then near perfect inversion twinning in the structure. In form (B), neighbouring chains are always inverted, leading to a centrosymmetric space group. The question as to why the polymorphs crystallize at slightly different temperatures has been examined by density functional theory (DFT) and lattice energy calculations and a consideration of packing compactness. The free energy (ΔG) of the crystal lattice for polymorph (A) lies some 52 kJ mol(-1) above that of polymorph (B).

Longitudinal Association of Dementia and Depression.

OBJECTIVES: Depression is an important precursor to dementia, but less is known about the role dementia plays in altering the course of depression. We examined whether depression prevalence, incidence, and severity are higher in those with dementia versus those with mild cognitive impairment (MCI), or normal cognition. DESIGN: Prospective cohort study using the longitudinal Uniform Data Set of the National Alzheimer's Coordinating Center (2005-2013). SETTING: 34 Alzheimer Disease research centers. PARTICIPANTS: 27,776 subjects with dementia, MCI, or normal cognition. MEASUREMENTS: Depression status was determined by a clinical diagnosis of depression within the prior 2 years and by a Geriatric Depression Scale-Short Form score >5. RESULTS: Rates of depression were significantly higher in subjects with MCI and dementia compared with those with normal cognition at index visit. Controlling for demographics and common chronic conditions, logistic regression analysis revealed elevated depression in those with MCI (OR: 2.40 [95% CI: 2.25, 2.56]) or dementia (OR: 2.64 [95% CI: 2.43, 2.86]) relative to those with normal cognition. In the subjects without depression at the index visit (N = 18,842), those with MCI and dementia had higher probabilities of depression diagnosis 2 years post index visit than those with normal cognition: MCI = 21.7%, dementia = 24.7%, normal cognition = 10.5%. CONCLUSION: MCI and dementia were associated with significantly higher rates of depression in concurrent as well as prospective analyses. These findings suggest that efforts to effectively engage and treat older adults with dementia will need also to address co-occurring depression.

Existing data sets to support studies of dementia or significant cognitive impairment and comorbid chronic conditions.

BACKGROUND: Dementia or other significant cognitive impairment (SCI) are often comorbid with other chronic diseases. To promote collaborative research on the intersection of these conditions, we compiled a systematic inventory of major data resources. METHODS: Large data sets measuring dementia and/or cognition and chronic conditions in adults were included in the inventory. Key features of the resources were abstracted including region, participant sociodemographic characteristics, study design, sample size, accessibility, and available measures of dementia and/or cognition and comorbidities. RESULTS: 117 study data sets were identified; 53% included clinical diagnoses of dementia along with valid and reliable measures of cognition. Most (79%) used longitudinal cohort designs and 41% had sample sizes greater than 5000. Approximately 47% were European-based, 40% were US-based, and 11% were based in other countries. CONCLUSIONS: Many high-quality data sets exist to support collaborative studies of the effects of dementia or SCI on chronic conditions and to inform the development of evidence-based disease management programs.

Transcriptional architecture of the primate neocortex.

Genome-wide transcriptional profiling was used to characterize the molecular underpinnings of neocortical organization in rhesus macaque, including cortical areal specialization and laminar cell-type diversity. Microarray analysis of individual cortical layers across sensorimotor and association cortices identified robust and specific molecular signatures for individual cortical layers and areas, prominently involving genes associated with specialized neuronal function. Overall, transcriptome-based relationships were related to spatial proximity, being strongest between neighboring cortical areas and between proximal layers. Primary visual cortex (V1) displayed the most distinctive gene expression compared to other cortical regions in rhesus and human, both in the specialized layer 4 as well as other layers. Laminar patterns were more similar between macaque and human compared to mouse, as was the unique V1 profile that was not observed in mouse. These data provide a unique resource detailing neocortical transcription patterns in a nonhuman primate with great similarity in gene expression to human.

Chemical analysis of two new designer drugs: buphedrone and pentedrone.

The hydrochloride salts of buphedrone and pentedrone, two new designer drugs, have recently been identified in shipments destined for Canada. To confirm their identities, we have synthesized reference materials for these methcathinone analogues and herein provide complete characterization by FTIR, FT-Raman, ¹H NMR, ¹³C NMR, GC/MS and ESI-HRMS.

Safety and immunogenicity of the live attenuated varicella vaccine following T replete or T cell-depleted related and unrelated allogeneic hematopoietic cell transplantation (alloHCT).

There are limited studies assessing the live attenuated varicella vaccine following allogeneic hematopoietic cell transplantation (alloHCT). Because of the morbidity of varicella acquired after childhood, we immunized and retrospectively analyzed the safety and immunogenicity of this vaccine in 46 varicella zoster virus (VZV) seronegative patients <20 years old at HCT who achieved a CD4 cell count ≥200/µL, were off immunosuppression, and responded to ≥1 post-HCT vaccines. Two vaccinated patients lacking follow-up titers were excluded from analysis. Stem cells were derived from an HLA-matched sibling (n = 18) or an alternative (HLA mismatched related or unrelated) donor (n = 26). Median time to vaccination was 4 years. Sixty-four percent of patients seroconverted following 1 immunization. There was no significant difference in response between recipients of a matched related or alternative donor graft (P = .2) or between those given a T cell-depleted or T-replete alternative donor graft (P = .27). Three of 44 patients developed a self-limited varicella-like rash within 2.5 weeks of immunization. With a median follow-up of 29.1 (range: 6.9-167.1) months, there were no subsequent cases of varicella-like rashes. No patient developed shingles. This study suggests that this vaccine is safe and immunogenic when given according to preset clinical and immunologic milestones, warranting larger prospective studies in patients ≥24 months following HCT as outlined in current post-HCT vaccine guidelines.