"Delirium Day": A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 ± 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Rare Amyloid Precursor Protein Point Mutations Recapitulate Worldwide Migration and Admixture in Healthy Individuals: Implications for the Study of Neurodegeneration

Genetic discoveries related to Alzheimer&rsquo;s disease and other dementias have been performed using either large cohorts of affected subjects or multiple individuals from the same pedigree, therefore disregarding mutations in the context of healthy groups. Moreover, a large portion of studies so far have been performed on individuals of European ancestry, with a remarkable lack of epidemiological and genomic data from underrepresented populations. In the present study, 70 single-point mutations on the APP gene in a publicly available genetic dataset that included 2504 healthy individuals from 26 populations were scanned, and their distribution was analyzed. Furthermore, after gametic phase reconstruction, a pairwise comparison of the segments surrounding the mutations was performed to reveal patterns of haplotype sharing that could point to specific cross-population and cross-ancestry admixture events. Eight mutations were detected in the worldwide dataset, with several of them being specific for a single individual, population, or macroarea. Patterns of segment sharing reflected recent historical events of migration and admixture possibly linked to colonization campaigns. These observations reveal the population dynamics of the considered APP mutations in worldwide human groups and support the development of ancestry-informed screening practices for the improvement of precision and personalized approaches to neurodegeneration and dementia

Antimicrobial Peptides (AMPs) in the Pathogenesis of Alzheimer’s Disease: Implications for Diagnosis and Treatment

Alzheimer’s disease (AD) represents the most frequent type of dementia in elderly people. There are two major forms of the disease: sporadic (SAD)—whose causes are not completely understood—and familial (FAD)—with clear autosomal dominant inheritance. The two main hallmarks of AD are extracellular deposits of amyloid-beta (Aβ) peptide and intracellular deposits of the hyperphosphorylated form of the tau protein (P-tau). An ever-growing body of research supports the infectious hypothesis of sporadic forms of AD. Indeed, it has been documented that some pathogens, such as herpesviruses and certain bacterial species, are commonly present in AD patients, prompting recent clinical research to focus on the characterization of antimicrobial peptides (AMPs) in this pathology. The literature also demonstrates that Aβ can be considered itself as an AMP; thus, representing a type of innate immune defense peptide that protects the host against a variety of pathogens. Beyond Aβ, other proteins with antimicrobial activity, such as lactoferrin, defensins, cystatins, thymosin β4, LL37, histatin 1, and statherin have been shown to be involved in AD. Here, we summarized and discussed these findings and explored the diagnostic and therapeutic potential of AMPs in AD

Molecular effect on pre-mRNA tau alternative splicing of two novel intronic MAPT gene mutations associated to a sporadic case of frontotemporal dementia

Dottorato di Ricerca in Molecular Bio-Pathology, XXI Cycle, 2008Frontotemporal lobar degeneration (FTLD) is a heterogeneous syndrome encompassing different nosological entities characterized by behavioural and personality change, accompanied by deterioration of executive function, language and movement. Clinically FTLD results in at least three distinct syndromes: Frontotemporal dementia (FTD), Semantic dementia (SD) and Primary progressive aphasia (PPA), while the pathological classification is based on histopathological presence or absence of neuronal inclusions of tau and/or ubiquitin proteins accumulating in the neuronal/glial inclusions, being forms of FTLD differentiated in tau-positive, ubiquitin-positive and tau-negative. The most common clinical manifestation of FTLD is FTD, characterized by atrophy of the frontal and temporal lobes, with neuronal loss, gliosis and spongiosis of the superficial layers. FTD is mostly a presenile disorder showing changes in personality, impaired social conduct, emotional blunting, loss of insight, disinhibition, perseverative behaviour and hyperorality; cognitive deterioration, especially in language and in executive functions, appear later. Despite most cases of FTD are sporadic, approximately 10%-50% of FTD patients have a positive family history for dementia. Familial FTDL was associated to mutations in four genes: Microtubules associated protein tau (MAPT) and Progranulin (PGRN) genes that are responsible for the most genetic forms of FTD; instead, Valosin containing protein (VCP) gene is involved in rare forms of FTD with inclusion body myopathy and Paget’s disease of the bone and Charged multivescicolar body protein 2B (CHMP2B) is mutated in some families with a combination of FTD and Amyotrophic lateral sclerosis (ALS). Mutations in MAPT gene are responsible for 10%-20% of familial FTD. Alternative splicing of exons 2, 3 and 10 in MAPT pre m-RNA results in the expression of six isoforms. Exclusion or inclusion of Exon 10 gives rise to tau isoforms with three (tau3R, E10-) o four (tau4R, E10+) microtubule-binding repeats. In normal adult human brain the overall ratio of 3R to 4R tau is generally 1, whereas in fetal brain only the shortest tau isoform with 3R is expressed, indicating that tau expression is developmentally regulated.To date, 44 different potential pathogenic MAPT mutations have been reported, divided into two groups depending on the primary molecular mechanism involved: missense or deletion mutations that commonly modify tau interaction with microtubules and splicing mutations that affect the alternative splicing of exon 10, leading to changes of the ratio of 3R-tau/4R-tau. However, a third group of mutations exists that might have effects at protein and RNA levels. In the present study we report the molecular effect of two novel heterozygous MAPT gene mutations, a T to C transition at position -15 of intron 9 [T(-15)C] and an A to C transversion at position +4 of intron 10 (E10+4), identified in a patient with sporadic FTD, clinically and neuropathologically ascertained. Considering that both mutations are located in the splicing regulatory regions surrounding Exon 10, we analyzed their molecular effect on the alternative splicing of MAPT pre-mRNA in a minigene model system and in brain tissue. Semi-quantitative RT-PCR analyses, in minigene costructs and in brain tissue, have shown that the two novel mutations cause a novel Exon 10 splicing effect giving rise to a higher increase of mRNAs transcripts lacking Exon 10 (E10- or Tau3R) when compared with FTD-Ub+ control. Immunohistochemical and biochemical analyses on brain tissue evidenced neuronal and oligodendroglial tau deposits mostly made of Tau3R isoforms and an increased increased availability of shorter Tau3R isoform respectively. Data obtained with minigenes derived by the phenotipically healthy patient’s parents demonstrate that when the mutations are inherited in a non compound heterozygous condition the ratio of E10 including/E10 excluding transcripts is quite normal. Although the molecular mechanism underlying exon 10 splicing regulation remain to be completely elucidated, the exon 10 splice donor site is predicted to give rise to a RNA stem loop structure considered crucial for the quantitative regulation of exon 10 alternative splicing. Most of previously characterized mutations identified in the upper part of the stem loop strongly alter mRNA splicing by destabilizing the secondary structure, with a corresponding increase of E10 inclusion and 4RTau expression. Considering that the E10+4 mutation is located into the exon 10 splice donor site, we also investigated the effect of the E10+4 mutation on the thermodynamic stability of the RNA stem loop structure. Our data, based on bioinformatic prediction of the stem loop sequence thermostability and Ultraviolet Melting experiments demonstrated a strong increasing of stability in the stem-loop structure carrying the E10+4 mutation. This higher stability could be important for the skipping of exon 10, even though the E10+4 mutation alone is not able to give rise to a pathologic phenotype. We cannot exclude that the T to C transition, localized in a regulatory region upstream of exon 10, could also alter the binding of specific trans-splicing factors increasing the effect of the E10+4 mutation, giving rise when both mutation are present in the compound heterozygous condition (namely the FTD patient) to the E10 exclusion and the altered 4R/3R tau ratio observed. Thus, we can hypothesize a trans-acting regulatory effect of both mutations with known, or unknown splicing factors, which might have contributed to the very atypical clinical and pathological FTD phenotype of the patient.Università della Calabri