Reducing Nighttime Interruptions and Improving Sleep for Hospitalized Patients by Restructuring Nighttime Clinical Workflow.

BACKGROUND: Nighttime sleep disruptions negatively impact the experience of hospitalized patients. OBJECTIVE: To determine the impact of adopting a sleep-promoting nighttime clinical workflow for hospitalized patients on nocturnal disruptions and sleep. DESIGN: Survey-based pre- and post-intervention cross-sectional study using convenience samples. PARTICIPANTS: Hospitalized veterans on a 23-bed general medical ward at a tertiary Veterans Administration Hospital. INTERVENTIONS: Baseline sleep surveys (N=149) identified two major sources of interruptions: blood pressure checks at 4 am for telemetry patients and subcutaneous (SQ) heparin injections between 4:30 and 6 am for venous thromboembolism prophylaxis. Clinical workflow was restructured to eliminate these disruptions: moving 4 am blood pressure checks to 6 am and providing daily SQ enoxaparin at 9 am as an alternative to Q 8-h SQ heparin, which had prompted an injection between 4:30 and 6 am. The impact of these changes was assessed in a second round of surveys (N=99). MAIN MEASURES: Frequency and sources for nighttime sleep disruptions; percentage of patients reporting longer time to fall asleep, more interruptions, and worse sleep quality (vs. home) before and after restructuring nighttime clinical workflow. KEY RESULTS: After restructuring nighttime clinical workflow, medication administration as a source of nighttime disruption decreased from 40% (59/149) to 4% (4/99) (p<0.001). Blood pressure checks as a source of disruption decreased from 56% (84/149) to 42% (42/99) (p=0.033). Fewer patients reported taking longer to fall asleep in the hospital vs. home (39% pre-intervention vs. 25% post-intervention, p=0.021). Similarly, fewer patients experienced waking up more frequently in the hospital vs. home (46% pre-intervention vs. 32% post-intervention, p=0.036). Fewer patients reported sleeping worse in the hospital (44% pre-intervention vs. 39% post-intervention), though this trend was not statistically significant (p=0.54). CONCLUSIONS: Nighttime disruptions in hospitalized patients frequently interfere with sleep. Restructuring of the clinical workflow significantly reduced disruptions and improved sleep.

Transcriptomic landscape of TIMP3 oncosuppressor activity in thyroid carcinoma.

BACKGROUND: Papillary thyroid cancer (PTC) is the most frequent thyroid tumor. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene encodes a matrix metalloproteinases inhibitor that exerts a tumor suppressor role in several tumor types. TIMP3 is frequently downregulated in PTC by promoter methylation. We have previously functionally demonstrated that TIMP3 exerts an oncosuppressor role in PTC: TIMP3 restoration in the PTC-derived NIM1 cell line affects in vitro migration, invasion and adhesive capability, while reduces tumor growth, angiogenesis and macrophage recruitment in vivo. To get a deeper insight on the mediators of TIMP3 oncosuppressor activity in thyroid tumors, here we focused on the TIMP3 related transcriptome. METHODS: TCGA database was used for investigating the genes differentially expressed in PTC samples with low and high TIMP3 expression. Genome wide expression analysis of clones NIM1-T23 (expressing a high level of TIMP3 protein) and NIM1-EV (control empty vector) was performed. Gene sets and functional enrichment analysis with clusterProfiler were applied to identify the modulated biological processes and pathways. CIBERSORT was used to evaluate the distribution of different immunological cell types in TCGA-PTC tumor samples with different TIMP3 expression levels. Real time PCR was performed for the validation of selected genes. RESULTS: Thyroid tumors with TIMP3-high expression showed a down-modulation of inflammation-related gene sets, along with a reduced protumoral hematopoietic cells fraction; an enrichment of cell adhesion functions was also identified. Similar results were obtained in the TIMP3-overexpessing NIM1 cells in vitro model, where a down-regulation of immune-related function gene sets, some of which also identified in tumor samples, was observed. Interestingly, through enrichment analysis, were also recognized terms related to cell adhesion, extracellular matrix organization, blood vessel maintenance and vascular process functions that have been found modulated in our previous in vitro and in vivo functional studies. CONCLUSIONS: Our results highlight the correlation of TIMP3 expression levels with the regulation of inflammatory functions and the immune infiltration composition associated with different PTC prognosis, thus providing a broader view on the oncosuppressor role of TIMP3 in PTC.

Persistent pain in intensive care survivors: a systematic review.

BACKGROUND: According to earlier studies where the main aim has been quality of life, there is growing evidence of increased levels of persistent pain in survivors of critical illness. The cause of admission and several factors during intensive care may have associated risk factors for pain persistence. This systematic review aims to determine the incidence or prevalence of persistent pain after critical illness and to identify risk factors for it. METHODS: Six databases were searched, and eventually nine studies were included in the final systematic process. The validity of observational and cross-sectional studies was analysed using the National Institute of Health 'Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies'. RESULTS: The incidence of persistent pain after intensive care varied from 28% to 77%. Risk factors for persistent pain were acute pain at discharge from ICU, higher thoracic trauma score, surgery, pre-existing pain, organ failure, longer length of ventilator or hospital stay, and sepsis. No difference in incidence between medical and surgical patients was found. CONCLUSIONS: New systematic, observational studies are warranted to identify persistent pain-related factors in intensive care to improve pain management protocols and thereby diminish the risk of persistent pain after ICU stay.

Insulin-like growth factor I, binding proteins -1 and -3, risk of type 2 diabetes and macronutrient intakes in men.

The insulin-like growth factor (IGF) axis may be involved in the development of type 2 diabetes. We examined the associations of IGF-I and IGF binding proteins (IGFBP)-1 and -3 with diabetes risk and evaluated macronutrient intakes related to the observed associations. In a nested case-control study of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish male smokers aged 50-69 years, the IGF variables were measured from baseline serum samples for a random sample of 310 men with diabetes diagnosed during a 12-year follow-up and for 310 controls matched by age, recruitment day and intervention group. Diet at baseline was assessed using a validated FFQ. The associations of IGF proteins with diabetes risk were estimated using conditional logistic regression and the associations with macronutrient intakes using linear regression. IGF-I and IGFBP-3 were not associated with the incidence of diabetes. Higher IGFBP-1 was associated with lower diabetes risk in an unadjusted crude model (OR 0·25; 95 % CI 0·15, 0·42 in the highest quartile compared with the lowest), but not after adjustment for BMI (corresponding OR 0·76; 95 % CI 0·41, 1·40). Intakes of carbohydrates, plant protein and milk protein associated positively and intake of meat protein and fat negatively with IGFBP-1 (P<0·005). IGFBP-1 was inversely associated with diabetes risk, but the association was substantially dependent on BMI. The associations between macronutrient intakes and IGFBP-1 may reflect influences of nutrients or foods on insulin concentrations.

Isotretinoin and lymecycline treatments modify the skin microbiota in acne.

Oral retinoids and tetracyclines have a major role in acne treatment. Here, we report for the first time the effect of isotretinoin and lymecycline therapy on the skin microbiota in cheek, back and armpit swab samples of acne vulgaris patients using 16S ribosomal RNA (16S rRNA) gene amplicon sequencing. Propionibacterium acnes was the most common in sebaceous areas of healthy and untreated acne skin and more abundant in back than cheek samples. Five taxa, including a Streptococcus taxon, differed significantly between the cheek samples of healthy controls and acne patients, and acne severity was positively correlated with the abundance of Propionibacterium. Both treatments reduced clinical acne grades and the abundance of Propionibacterium, while the abundance of several other taxa was significantly higher in treated cheek samples compared with untreated ones. Less variation was observed in back samples and none in armpit samples. There were no differences in alpha diversity between control and acne patients in any of the sampled skin areas, but the diversity of the microbiota on the cheek and the back was significantly increased after acne treatments. This study provides insight into the skin microbiota in acne and how it is modulated by systemic acne treatment.

Glucocorticoids: The mode of action in bullous pemphigoid.

Bullous pemphigoid (BP) is the most common of pemphigoid diseases caused by autoantibodies against the structures of dermoepidermal junction followed by complement activation, innate immune cell infiltration, neutrophil proteinase secretion and subepidermal blister formation. The first-line treatment of BP is topical and systemic glucocorticoids (GC). Regulation of the immune system and inflammatory cells is the main target of GC actions. GCs act through genomic and non-genomic mechanisms. The human glucocorticoid receptor (GR) mediates most of the biologic effects of GC: cytosolic GR binds GCs and is capable to bind to glucocorticoid response elements in DNA and either transactivate or transrepress genes depending on the tissue and cell type. In addition, GR exerts rapid, non-genomic effects possibly mediated by membrane-localized receptors or by translocation to mitochondria. GCs can also interact directly with several enzymes and cytokines. As a target treatment for BP, the production of autoantibodies should be discontinued. GCs, in spite of their wide immunosuppressive actions, are weak to stop immunoglobulin G (IgG) autoantibody formation. However, both systemic and topical GCs are able to reduce the clinical symptoms of BP. GCs are used to inhibit the secondary inflammation and symptoms, such as blistering and pruritus, and it is shown that GC treatment will gradually decrease also the autoantibody formation. Our review article analyses the mode of action of GC treatment in BP, as far it is possible due to paucity of modern immunological studies.

Clinical Efficiency of Topical Calcipotriol/Betamethasone Treatment in Psoriasis Relies on Suppression of the Inflammatory TNFα - IL-23 - IL-17 Axis.

The effects of topical calcipotriol/betamethasone combination therapy and betamethasone monotherapy on inflammatory T-cell numbers and molecular markers were compared in patients with psoriasis. Combination therapy down-regulated the expression of tumour necrosis factor (TNF)-α, interleukin (IL)-23A, IL-17A, S100A7, CCL-20 and interferon (IFN)-γ in skin and TNF-α, IL-6, IL-23A, T-bet and IFN-γ in peripheral blood mononuclear cells (PBMCs). Betamethasone monotherapy had less effect. Expression of FoxP3 in both skin and PBMCs was down-regulated by calcipotriol/betamethasone, but not by betamethasone. Immunohistochemical analysis revealed that calcipotriol/betamethasone reduced the numbers of CD4+ and CD8+ T cells and Tregs in psoriatic lesions more than betamethasone. Flow cytometric analyses demonstrated that calcipotriol/betamethasone decreased the numbers of circulating CD8+ T cells, Tregs, skin-homing Th17 memory cells and Th22 memory cells, while betamethasone had little or no effect. Glucocorticoid receptors GRα and GRß were expressed in psoriatic skin. In conclusion, calcipotriol increases the immunosuppressive power of betamethasone by suppressing the inflammatory TNF-α - IL-23 - IL-17 axis.

The genetics of extreme microgeographic adaptation: an integrated approach identifies a major gene underlying leaf trichome divergence in Yellowstone Mimulus guttatus.

Microgeographic adaptation provides a particularly interesting context for understanding the genetic basis of phenotypic divergence and may also present unique empirical challenges. In particular, plant adaptation to extreme soil mosaics may generate barriers to gene flow or shifts in mating system that confound simple genomic scans for adaptive loci. Here, we combine three approaches - quantitative trait locus (QTL) mapping of candidate intervals in controlled crosses, population resequencing (PoolSeq) and analyses of wild recombinant individuals - to investigate one trait associated with Mimulus guttatus (yellow monkeyflower) adaptation to geothermal soils in Yellowstone National Park. We mapped a major QTL causing dense leaf trichomes in thermally adapted plants to a <50-kb region of linkage Group 14 (Tr14) previously implicated in trichome divergence between independent M. guttatus populations. A PoolSeq scan of Tr14 region revealed a cluster of six genes, coincident with the inferred QTL peak, with high allele frequency differences sufficient to explain observed phenotypic differentiation. One of these, the R2R3 MYB transcription factor Migut.N02661, is a plausible functional candidate and was also strongly associated (r2  = 0.27) with trichome phenotype in analyses of wild-collected admixed individuals. Although functional analyses will be necessary to definitively link molecular variants in Tr14 with trichome divergence, our analyses are a major step in that direction. They point to a simple, and parallel, genetic basis for one axis of Mimulus guttatus adaptation to an extreme habitat, suggest a broadly conserved genetic basis for trichome variation across flowering plants and pave the way for further investigations of this challenging case of microgeographic incipient speciation.

Expression of Glucocorticoid Receptors GRα and GRß in Bullous Pemphigoid.

First-line treatments of bullous pemphigoid (BP) are topical and systemic glucocorticoids (GC). The actions of GC are mediated by glucocorticoid receptors (GR), which exist in several isoforms, of which GRα and GRß are the most important. In many inflammatory diseases, up-regulation of GRß is associated with GC insensitivity. The aims of this study were to determine the expression of GRα and GRß in patients with BP and to investigate the effect of prednisolone treatment on the expression of GR isoforms in BP. Quantitative real-time PCR (qPCR) analysis demonstrated that GR isoform mRNAs are expressed in peripheral blood mononuclear cells (PBMC) from patients with BP. Expression of GRα and GRß protein was confirmed by immunohistochemical staining of BP skin biopsies and by Western blot analysis and flow cytometric analysis of PBMCs. During prednisolone treatment, GRα and GRß expression varied markedly, but changes were not suitable as a clinical marker of GC sensitivity in patients with BP.

Glycaemic index, carbohydrate substitution for fat and risk of CHD in men.

We have examined the associations between dietary glycaemic index (GI), substitutions of total, low-, medium- and high-GI carbohydrates for fat and the risk of CHD. The study consisted of 21 955 male smokers, aged 50-69 years, within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The diet was assessed at baseline using a validated FFQ. During a 19-year follow-up, 4379 CHD cases (2377 non-fatal myocardial infarctions and 2002 CHD deaths) were identified from national registers. Relative risks (RR) and CI for CHD were analysed using Cox proportional hazards modelling, and multivariate nutrient density models were applied to examine the associations between the substitutions of macronutrients and the risk of CHD. Dietary GI was inversely associated with CHD risk: multivariate RR in the highest v. lowest quintile was 0·89 (95 % CI 0·81, 0·99). Replacement of higher-GI carbohydrates with lower-GI carbohydrates did not associate with the risk. Replacing saturated and trans-fatty acids with carbohydrates was associated with decreased CHD risk: RR for substitution of 2 % of energy intake was 0·97 (95 % CI 0·94, 0·99). On the contrary, replacing MUFA with carbohydrates was associated with an increased risk: RR for substitution of 2 % of energy intake was 1·08 (95 % CI 1·01, 1·16). We conclude that in the present study population, contrary to the hypothesis, a lower GI does not associate with a decreased risk of CHD. The associations of carbohydrates with CHD risk depend on the fatty acid composition of the diet.

Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer.

BACKGROUND: In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC. RESULTS: Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside. CONCLUSION: Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC.

Relative validity of a FFQ in measuring carbohydrate fractions, dietary glycaemic index and load: exploring the effects of subject characteristics.

FFQ require validation as part of epidemiological research of diet-disease relationships. Studies exploring associations between carbohydrate type and chronic diseases are rapidly increasing, but information on the validity of carbohydrate fractions, dietary glycaemic index (GI) and the glycaemic load (GL) estimated by FFQ is scarce. Likewise, the effects of subject characteristics on FFQ validity have been poorly documented. The present study evaluates the relative validity of an 131-item FFQ in relation to two 3 d food records (FR) performed 6 months apart focusing on the intake of carbohydrate fractions, dietary GI and the GL. Furthermore, we assessed the extent to which subjects' age, education and BMI explain differences between these methods. The study sample comprised 218 men and 292 women aged 25-74 years participating in a large population-based survey in Finland. Energy-adjusted Spearman's rank correlations ranged from 0.27 (sugars) to 0.70 (lactose) for men and from 0.37 (sugars) to 0.69 (lactose) for women. On average, 73 % of the subjects were categorised into the same or adjacent distribution quintile based on the two methods. In general, the FFQ overestimated the intakes compared with FR. Especially in women, FFQ validity for some nutrients was associated with the level of intake, subjects' age and, to a lesser extent, education but not BMI. In conclusion, the FFQ appears to be reasonably valid in the assessment of carbohydrate exposure variables, but the findings show a need for adjustment of diet-disease relationships for subjects' age and education.

Low-, medium- and high-glycaemic index carbohydrates and risk of type 2 diabetes in men.

Findings on dietary glycaemic index (GI) and glycaemic load (GL) as risk factors for type 2 diabetes have been controversial. We examined the associations of dietary GI and GL and the associations of substitution of lower-GI carbohydrates for higher-GI carbohydrates with diabetes risk in a cohort of Finnish men. The cohort consisted of 25 943 male smokers aged 50-69 years. Diet was assessed, at baseline, using a validated diet history questionnaire. During a 12-year follow-up, 1098 incident diabetes cases were identified from a national register. Cox proportional hazard modelling was used to estimate the risk of diabetes, and multivariate nutrient density models were used to examine the effects of substitution of different carbohydrates. Dietary GI and GL were not associated with diabetes risk; multivariate relative risk (RR) for highest v. lowest quintile for GI was 0·87 (95 % CI 0·71, 1·07) and for GL 0·88 (95 % CI 0·65, 1·17). Substitution of medium-GI carbohydrates for high-GI carbohydrates was inversely associated with diabetes risk (multivariate RR for highest v. lowest quintile 0·75, 95 % CI 0·59, 0·96), but substitution of low-GI carbohydrates for medium- or high-GI carbohydrates was not associated with the risk. In conclusion, dietary GI and GL were not associated with diabetes risk, and substitutions of lower-GI carbohydrates for higher-GI carbohydrates were not consistently associated with a lower diabetes risk. The associations of dietary GI and GL with diabetes risk should be interpreted by considering nutritional correlates, as foods may have different properties that affect risk.

Several specific high-resolution computed tomography patterns correlate with survival in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Evidence of honeycombing in high-resolution computed tomography (HRCT) is a recognized risk factor for shortened survival in patients with idiopathic pulmonary fibrosis (IPF), but few studies have evaluated the feasibility of exploiting other specific patterns for predicting survival. The aim of this study was to examine the extent of specific HRCT patterns in IPF and determine whether they correlate with clinical features, pulmonary function tests (PFT), and survival. METHODS: Both the presence and extent of specific HRCT patterns, such as traction bronchiectasis, honeycombing, architectural distortion, reticulation, emphysema, and ground glass opacity, in 129 HRCT examinations were scored semi-quantitatively in three zones of each lung. HRCT examinations were also re-classified according to the 2011 and 2018 international statements. Correlations were calculated between the scores of specific HRCT patterns, clinical features, PFT, and patient survival. RESULTS: The extent of traction bronchiectasis was found to be an independent risk factor of shortened survival (HR 1.227, P=0.001). Patients with a possible usual interstitial pneumonia (UIP) pattern had a better median survival than the patients with a definite UIP pattern (61 vs. 37 months, P=0.026). The extents of traction bronchiectasis, honeycombing, and architectural distortion displayed an inverse correlation with all PFT values at the time of diagnosis. There were few differences between the radiological classifications of the 2011 and 2018 international statements. CONCLUSIONS: We conclude that several specific HRCT patterns displayed a correlation with shortened survival in IPF; these may help in evaluating the risk of death in IPF patients.

The change in child self-assessed and parent proxy-assessed Health Related Quality of Life (HRQL) in early adolescence (age 10-12).

AIMS: To examine the development of self-assessed and parent proxy-assessed health related quality of life (HRQL) in pre-adolescent schoolchildren. METHODS: The population (n = 1,346) consisted of the total cohort of children starting 4th grade (age 10) in 2004 in primary schools in a Finnish city of 175,000 inhabitants. HRQL was assessed using the Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0). The baseline study was conducted in 2004 (child age 10) and follow-up in a panel setting in 2006 (child age 12). The response rate for the children was 80% (n = 1,094) in 2004 and 85% (n = 1,139) in 2006. The response rate for children having responded both in 2004 and 2006 was 73% (n = 986). For parents of the children, one parent participated in the parents' survey (n = 999 in 2004, n = 888 in 2006). RESULTS: HRQL scores increased significantly in the two-year follow up (child t = 10.16-5.95, p < 0.0001, parent-proxy t = 6.35-2.76, p < 0.0001-0.006). Correlation between baseline and follow-up assessments was significant (child r = 0.4-0.5, p < 0.0001, parent r = 0.47-0.57, p < 0.0001). The correlation between baseline HRQL and change was negative (child r =-0.67 to -0.56, p < 0.0001, parent r =-0.62 to -0.46, p < 0.0001). Correlation between child and parent assessments increased from baseline (r = 0.20-0.39, p < 0.0001) to follow up (r = 0.3-0.42, p < 0.0001). CONCLUSIONS: Child-assessed and parent proxy-assessed HRQL scores increase, suggesting HRQL improves, when children grow from age 10 to age 12. Baseline HRQL may not strongly predict future HRQL in early adolescence. The correlation between child self-assessment and parent proxy-assessment is fragile.

Beneficial Effects of Ketogenic Diet on Phosphofructokinase Deficiency (Glycogen Storage Disease Type VII).

Background: A deficiency of muscle phosphofructokinase (PFKM) causes a rare metabolic muscle disease, the Tarui disease (Glycogen storage disease type VII, GSD VII) characterized by exercise intolerance with myalgia due to an inability to use glucose as an energy resource. No medical treatment for GSD VII currently exists. The aim of this study was to determine whether a dietary intervention with excessive fat intake would benefit GSD VII. Patient and Methods: A ketogenic diet (KD) intervention implemented as a modified Atkins diet was established for one patient with PFKM deficiency, with a low late lactate response and very high ammonia levels associated with exercise. We recorded the KD intervention for a total of 5 years with clinical and physiotherapeutic evaluations and regular laboratory parameters. Cardiopulmonary exercise testing, including breath gas analysis and venous lactate and ammonia measurements, was performed before KD and at 3, 8 months and 5 years after initiation of KD. Results: During the 5 years on KD, the patient's muscle symptoms had alleviated and exercise tolerance had improved. In exercise testing, venous ammonia had normalized, the lactate profile remained similar, but oxygen uptake and mechanical efficiency had increased and parameters showing ventilation had improved. Conclusions: This study is the first to show a long-term effect of KD in GSD VII with an alleviation of muscle symptoms, beneficial effects on breathing, and improvement in exercise performance and oxygen uptake. Based on these findings, KD can be recommended under medical and nutritional supervision for selected patients with GSD VII, although further research of this rare disease is warranted.