Characterization of the genetic determinants of context-specific DNA methylation in primary monocytes.

To better understand inter-individual variation in sensitivity of DNA methylation (DNAm) to immune activity, we characterized effects of inflammatory stimuli on primary monocyte DNAm (n = 190). We find that monocyte DNAm is site-dependently sensitive to lipopolysaccharide (LPS), with LPS-induced demethylation occurring following hydroxymethylation. We identify 7,359 high-confidence immune-modulated CpGs (imCpGs) that differ in genomic localization and transcription factor usage according to whether they represent a gain or loss in DNAm. Demethylated imCpGs are profoundly enriched for enhancers and colocalize to genes enriched for disease associations, especially cancer. DNAm is age associated, and we find that 24-h LPS exposure triggers approximately 6 months of gain in epigenetic age, directly linking epigenetic aging with innate immune activity. By integrating LPS-induced changes in DNAm with genetic variation, we identify 234 imCpGs under local genetic control. Exploring shared causal loci between LPS-induced DNAm responses and human disease traits highlights examples of disease-associated loci that modulate imCpG formation.

The many faces of H3.3 in regulating chromatin in embryonic stem cells and beyond.

H3.3 is a highly conserved nonreplicative histone variant. H3.3 is enriched in promoters and enhancers of active genes, but it is also found within suppressed heterochromatin, mostly around telomeres. Accordingly, H3.3 is associated with seemingly contradicting functions: It is involved in development, differentiation, reprogramming, and cell fate, as well as in heterochromatin formation and maintenance, and the silencing of developmental genes. The emerging view is that different cellular contexts and histone modifications can promote opposing functions for H3.3. Here, we aim to provide an update with a focus on H3.3 functions in early mammalian development, considering the context of embryonic stem cell maintenance and differentiation, to finally conclude with emerging roles in cancer development and cell fate transition and maintenance.

The aftermath of the COVID-19 pandemic on pediatric mental health: A pediatric emergency department's perspective.

BACKGROUND: Pediatric mental health visits in the United States has become a public health crisis. Pediatric emergency departments (PED) encounter these patients during mental health emergencies. The COVID-19 pandemic disrupted the social environment of pediatric patients which potentially lead to new and worsening mental health issues. This study examined the proportion of mental health visits to PED around the first wave of the COVID-19 pandemic. METHODS: This retrospective cohort study assessed the proportion of mental health visits at a urban, PED between September 2019 to February 2022. Inclusion criteria were subjects aged 6 to 18 years with a holding order assigned, and one of identified mental health International Classification of Disease, Tenth Division (ICD-10) codes: F01-F99, T14.19, R45, R46.89. Proportion of mental health visits were compared in 6-month periods with the first 6-months representing the pre-COVID-19 period. Secondary analysis compared demographic information and ICD-10 codes. RESULTS: A total of 1036 charts were studied: 126 charts from 2019 to 2020, 512 from 2020 to 2021, and 398 from 2021 to 2022. The proportion of mental health visits from September 2019 to February 2020 was 1.4%, and for the following 6-month periods, the proportion of mental health visits was 1.2%, 7.5%, 4.9%, and 5.7%. There was a statistically significant difference (p < 0.001) demonstrating a higher proportion of mental health visits after the start of the COVID-19 pandemic. Secondary analysis demonstrated statistically significant difference in both median age (p < 0.001) and median length of hospitalization (p < 0.001). CONCLUSION: This study demonstrated a significant increase in pediatric mental health visits following the start of the COVID-19 pandemic. We believe further investigation into the needs and management during acute surges will improve the care we provide to this vulnerable population.

Beating the clock: Reduced time to first antibiotic dose administration following an audit and feedback intervention.

OBJECTIVE: Quality improvement interventions and policy revisions have been shown to improve clinical practice and patient outcomes. This study evaluated an intervention to shorten the time from the first antibiotic dose ordering to its administration in patients hospitalised with bacterial infections. METHODS: An intervention consisting of a weekly email report to nurse and physician leaders in hospital departments was introduced. The report included the percentage of patients who received their first antibiotic dose within 3 hours and details of those who did not. Interrupted time series analysis was used to compare the delay between the order and administration of antibiotics in various wards (surgical and medical) and daily nursing shifts. RESULTS: The total number of orders pre-intervention and post-intervention was 58 320 and 52 127, respectively. The most protracted delays were observed during the morning shift in the surgical and medical wards (161 and 100 minutes, respectively). Comparing the pre- to post-intervention time to the first antibiotic dose (TTFAD), a reduction in the morning shift was noted both in the surgical wards (87 minutes, 55%) and medical wards (37 minutes, 37%) and with a preserved trend (P < 0.001). The slope's angle before and after the intervention was not affected. CONCLUSION: Using an audit and feedback automatic weekly report significantly reduced TTFAD in hospitalised patients. This intervention proved to be simple and sustainable over time. Raising staff awareness of current medical care practices is an effective way of improving performance.

PRC2-independent actions of H3.3K27M in embryonic stem cell differentiation.

The histone H3 variant, H3.3, is localized at specific regions in the genome, especially promoters and active enhancers, and has been shown to play important roles in development. A lysine to methionine substitution in position 27 (H3.3K27M) is a main cause of Diffuse Intrinsic Pontine Glioma (specifically Diffuse Midline Glioma, K27M-mutant), a lethal type of pediatric cancer. H3.3K27M has a dominant-negative effect by inhibiting the Polycomb Repressor Complex 2 (PRC2) activity. Here, we studied the immediate, genome-wide, consequences of the H3.3K27M mutation independent of PRC2 activity. We developed Doxycycline (Dox)-inducible mouse embryonic stem cells (ESCs) carrying a single extra copy of WT-H3.3, H3.3K27M and H3.3K27L, all fused to HA. We performed RNA-Seq and ChIP-Seq at different times following Dox induction in undifferentiated and differentiated ESCs. We find increased binding of H3.3 around transcription start sites in cells expressing both H3.3K27M and H3.3K27L compared with WT, but not in cells treated with PRC2 inhibitors. Differentiated cells carrying either H3.3K27M or H3.3K27L retain expression of ESC-active genes, in expense of expression of genes related to neuronal differentiation. Taken together, our data suggest that a modifiable H3.3K27 is required for proper histone incorporation and cellular maturation, independent of PRC2 activity.

[Impact of Home Return Assistance Service in Heart Failure (PRADO-IC) on the one year re-hospitalisation and mortality in a heart failure hospitalized population of patients]. / Impact du programme d'aide au retour à domicile-insuffisance cardiaque (PRADO-IC) sur la mortalité et la réhospitalisation à un an dans une population de patients insuffisants cardiaques.

INTRODUCTION: Congestive heart failure (CHF) is associated with prolonged and recurrent hospitalizations; the prognosis remains poor. Since 2013, the Caisse Primaire d'Assurance Maladie (CPAM) has set up a support program PRADO-IC (support program for returning home after hospitalisation for heart failure). The aim of this study was to evaluate the impact of PRADO-IC on the heart failure readmission rate and death rate at one year. METHODS: From September 2016 to September 2018, all patients hospitalized for heart failure at Saint-Joseph Hospital were included in an observational study. The inclusion in PRADO-IC program was at physician's discretion. Two groups were compared according to the inclusion in PRADO-IC or not (T). The primary endpoints were the comparison of one-year mortality and heart failure readmission rate between the two groups. RESULTS: Six hundred and thirty-three patients were included, 262 in the PRADO-IC group and 371 in the non-PRADO group. Patients in the PRADO-IC cohort more frequently present severity criteria (age, weight, BNP level, arrhythmia, anemia, renal failure). Mortality at one year (19.5% vs 16.2%, p = 0.28) are equivalent in both groups. There were no significant differences in one-year rehospitalization rate for heart failure (HF) (35.1% in PRADO cohort vs 28% in T group, p = 0.06), the time to first hospitalization (74.5 days in PRADO vs 54.5 days in T, p = 0.55) and the length of hospitalization (6.0 days in PRADO vs 7.0 days in T, p = 0.29) between the two groups. Age, hyponatremia, anemia, cancer, HF re-hospitalization were variables linked to a risk of mortality, in a multivariable analysis. CONCLUSION: Our study shows that the PRADO-IC program concerned to the most severe patients. Despite this, the one-year mortality and the HF readmission rate are similar between the two groups.

Données épidémiologiques d'une cohorte de patients hospitalisés pour insuffisance cardiaque. Étude mono-centrique sur 3 ans. Comparaison avec les données régionales.

INTRODUCTION: Congestiveheart failure (CHF) is associated with prolonged and recurrent hospitalizations, the prognosis remains poor. The aim of this study was to collect epidemiologic data at admission and at six month follow-up in a cohort of patients with CHF admitted to a single center between 2017 and 2019 (Saint Joseph Hospital, HSJ) and to compare these data with regional data (Ile-de-France, IdF). METHODS: Local and regional data were provided by National Health Service, Regional Department of Ile de France(DRSM) using national data base. CHF in-hospital stay was defined by appropriate CIM 10 code reported on the final medical form. RESULTS: From 2017 to 2019, 1967 CHF in-hospital stays were collected, mean age of the population was 81.4 (=mean) ± 11.7 yearsIC95% [80.8; 81.9], mean length of stay was 8.6 ± 6.8 days IC95% [8.3; 8.9], in-hospital mortality was 5.3 %, 9.6% at 2nd month and 15.9% at 6th month. Readmission rate was 23.7%, time to readmission was 59.5 ± 47.5 days IC95% [57.4; 61.6]. IdF data collected 60973 CHF in-hospital stays at the same period. Compared to the IdF population, our population was older (81.4 ± 11.6 versus 80.4 ± 12.6 years, p = 0.001). Length of stay was shorter (8.6 ± 6.8 versus 11.3 ± 10.1 days p<0.001), in-hospital mortality was lower (5.3% versus 7.8% p < 0.001), 2nd month and 6th month mortality was lower (respectively 9.6% versus 14.2% and 15.9% versus 21.3%, p <0.001), home discharge rate was higher (66.9% versus 60.8%, p < 0.001) in the HSJ population. The proportion of patients included in PRADO-IC program (Programme d'aide au retour à domicile-Insuffisance Cardiaque, Returning home support program) was higher in SJ population (22.6% versus 8.8% p < 0.001). CONCLUSION: CHF admission involved elderly patients, the in-hospital and 6th month mortality is high, with early and frequent readmissions. Differences between HSJ and IdF populations may be explained by the heterogeneity of health care facilities, management facilities and organization of transition of care.

Post-Bariatric Surgery Care in Israeli Adolescents: A Qualitative Study.

Undergoing bariatric surgery is a life-changing experience for adolescents. However, little is known about post-bariatric surgery management among Israeli adolescents. We aimed to identify the post-operative needs and support from a qualitative aspect. Seventeen adolescents who underwent bariatric surgery were interviewed by semi-structure telephone interview. The interview guide was validated by 10 content experts from different hospitals across the country. Data were collected in 2018. Analysis of the interviews revealed three major themes: "multi-disciplinary team management," "patient satisfaction," and "follow-up." The "multi-disciplinary team management" theme was further divided into three major categories: "pain management," "physiotherapy," and "nutrition." "Patient satisfaction" was further divided into "guidance" and "team handling" categories. The "follow-up" theme included recommendations for improvement. The analysis provides novel information about adolescents' needs after bariatric surgery. Healthcare professionals' awareness of the adolescents' perspective could contribute to providing optimal post-operative care to this population.

Phantom testing of the sensitivity and precision of a sub-epidermal moisture scanner.

The majority of pressure ulcers (PUs) including deep tissue injuries (DTIs) are preventable, and even reversible if detected in their early phase. One of the greatest barriers in PU prevention is that clinicians traditionally depended on subjective and qualitative techniques, particularly routine visual skin assessments that would only document existing, macroscopic PUs/DTIs, rather than preventing them or detecting them at their microscopic phase. At the early phase of cell damage, when a forming PU is still microscopic, there is a local increase in extracellular fluid contents within affected tissues, which is called sub-epidermal moisture (SEM). This new understanding has led to an emerging technology, a SEM Scanner (BBI LLC, Bruin Biometrics) that has been designed to effectively examine the health status of tissues, by measuring local changes in the biophysical SEM marker. In the present work, the SEM Scanner was tested under controlled laboratory conditions to experimentally determine its sensitivity and precision in identifying small (1 mL) water content changes in phantoms of the human heel and skull/face, which simulated common PU development scenarios. In both phantom configurations, the locally increased water contents resulted in consistent, statistically significant elevated SEM readings, which confirms that the SEM Scanner is able to detect fluid content changes that are as small as 1 mL. In agreement with a simplified theoretical (mathematical) SEM model, which was also developed here, changes in water contents had a consistent trend of effect on SEM delta values, which increased with each 1 mL increment in intra-tissue-substitute water contents.

Dressings cut to shape alleviate facial tissue loads while using an oxygen mask.

Non-invasive ventilation (NIV) masks are commonly used for respiratory support where intubation or a surgical procedure can be avoided. However, prolonged use of NIV masks involves risk to facial tissues, which are subjected to sustained deformations caused by tightening of the mask and microclimate conditions. The risk of developing such medical device-related pressure ulcers can be reduced by providing additional cushioning at the mask-face interface. In this work, we determined differences in facial tissue stresses while using an NIV mask with versus without using dressing cuts (Mepilex Lite; Mölnlycke Health Care, Gothenburg, Sweden). First, we developed a force measurement system that was used to experimentally determine local forces applied to skin at the bridge of the nose, cheeks, and chin in a healthy sample group while using a NIV mask. We further demonstrated facial temperature distributions after use of the mask using infrared thermography. Next, using the finite element method, we delivered the measured compressive forces per site of the face in the model and compared maximal effective stresses in facial tissues with versus without the dressing cuts. The dressings have shown substantial biomechanical effectiveness in alleviating facial tissues deformations and stresses by providing localised cushioning to the tissues at risk.

Open chromatin structure in PolyQ disease-related genes: a potential mechanism for CAG repeat expansion in the normal human population.

The human genome contains dozens of genes that encode for proteins containing long poly-glutamine repeats (polyQ, usually encoded by CAG codons) of 10Qs or more. However, only nine of these genes have been reported to expand beyond the healthy variation and cause diseases. To address whether these nine disease-associated genes are unique in any way, we compared genetic and epigenetic features relative to other types of genes, especially repeat containing genes that do not cause diseases. Our analyses show that in pluripotent cells, the nine polyQ disease-related genes are characterized by an open chromatin profile, enriched for active chromatin marks and depleted for suppressive chromatin marks. By contrast, genes that encode for polyQ-containing proteins that are not associated with diseases, and other repeat containing genes, possess a suppressive chromatin environment. We propose that the active epigenetic landscape support decreased genomic stability and higher susceptibility for expansion mutations.

Sacral Soft Tissue Deformations When Using a Prophylactic Multilayer Dressing and Positioning System: MRI Studies.

PURPOSE: The sacrum is the most common location of pressure injuries (PIs) in bedridden patients. The purpose of this study was to measure the effect of specific pressure preventive devices on sacral skeletal muscle, subcutaneous fat, and skin tissue deformations. SUBJECTS AND SETTING: The sample comprised 3 healthy adults residing in a community setting in Tel Aviv, Israel. DESIGN: Descriptive, comparative design. METHODS: Tissue thickness changes of 3 healthy adults were measured using magnetic resonance imaging (MRI) in weight-bearing sacral skin, subcutaneous fat, and muscle. Changes in tissue thickness were compared under the following conditions: (1) lying supine on a rigid surface (unpadded MRI table), (2) lying on a standard foam mattress, (3) lying on a mattress after application of a prophylactic multilayer dressing, and (4) lying on a standard foam mattress with a prophylactic multilayer dressing and a positioning system. One-way analysis of variance and post hoc Tukey-Kramer multiple pairwise comparisons were used to compare outcomes. RESULTS: The mattress, the prophylactic multilayer dressing, and the turning and positioning device when applied together resulted in significantly lower deformation levels of each of the soft tissue layers (ie, skin, subcutaneous fat, and muscle separately) as well as of the total soft tissue bulk, with respect to the rigid MRI table (P < .05). CONCLUSION: Study findings suggest that a combination of preventive interventions may reduce the risk of developing a sacral PI.

Deep tissue loads in the seated buttocks on an off-loading wheelchair cushion versus air-cell-based and foam cushions: finite element studies.

For wheelchair users, a common injury is a sitting-acquired pressure ulcer (PU) which typically onsets near the interface between the ischial tuberosity (IT) and the overlying soft tissues. The risk of developing PUs can be reduced considerably if an adequate cushion is placed on the wheelchair in order to protect tissues from PUs by minimising interface mechanical loads between the body and cushion and also, exposure to internal soft tissue loads. In this work, we studied the biomechanical performances of an off-loading (OL) cushion with limited adjustability, in comparison to a standard foam cushion and a fully adjustable air-cell-based (ACB) cushion. These different cushion design approaches were methodologically and quantitatively analysed and compared here using a finite element (FE) modelling framework. We determined the internal mechanical deformations, strains and stresses in soft tissues of the seated buttocks during symmetric sitting, in a specific anatomy of a person with a spinal cord injury that was acquired during sitting in an open, magnetic resonance imaging configuration. Our results have shown that strains and stresses in muscle, fat and skin tissues are orders of magnitude lower for the ACB cushion with respect to the standard foam and OL cushions. The OL cushion design has taken the approach of protecting at-risk sites of the buttocks by transferring local internal tissue loads away from the ITs and towards the greater trochanters, at the price of increasing exposure to internal tissue loads at sites other than the ITs. The ACB cushion design, however, has taken a different approach, that is, immersion and envelopment of the entire buttocks structure, which is useful for minimising the exposure to internal tissue loads throughout the whole buttocks. Quantifying performances of wheelchair cushions using FE modelling provides insights into deep tissue loads, which is essential for informed decision-making in developing sitting solutions for individuals at risk, as well as for patient groups.

Diabetes control in the Bedouin population in southern Israel.

BACKGROUND: The Bedouins in the Negev are a population in transition from traditional nomadic to a western sedentary lifestyle, characterized by changes in dietary habits and reduction in physical activity, with substantial changes in morbidity patterns. To describe the current state of diabetes prevalence and control among the Bedouin population in the Negev and to compare it to the non-Bedouin population. MATERIAL/METHODS: A cross-sectional study was performed utilizing the database of Clalit Health Services. In patients with a confirmed diagnosis of diabetes, the following variables were extracted from the laboratory records: hemoglobinA1c (HgA1C) level, urine microalbumin level and low density lipoprotein (LDL) level. Chi-square test was used to compare categorical parameters between the groups. RESULTS: Age-adjusted prevalence of diabetes was 5.1% in the Bedouin population as compared to 3.7% in the non-Bedouin population (p<0.001). Diabetes was more prevalent in urban as compared to rural settlements (5.5% vs. 3.9%, respectively, p<0.001). The proportion of Bedouins patients with controlled diabetes (HgA1C<7) was significantly lower in Bedouin patients (29.3%) as compare to Non-Bedouin patients (46.7%) (p<0.001). CONCLUSIONS: Age-adjusted prevalence of diabetes is increased in the Bedouin population as compared to the Non-Bedouin population in southern Israel. Despite similar performance status of laboratory tests and similar treatment regimens, the overall control of diabetes is poorer in the Bedouin population as compared to the Non-Bedouin population. These findings support previous observations that diabetes has become a major public health problem among Bedouins.

Characterization of extracellular lytic enzymes produced by the yeast biocontrol agent Candida oleophila.

The yeast Candida oleophila, the base of the commercial product Aspire, is recommended for the control of postharvest decay of citrus and pome fruit. Competition for nutrients and space is believed to be the major mode of action. Involvement of fungal cell wall-degrading enzymes is also suggested to play a role in the mechanism of action of yeast antagonists. The present study showed that the yeast C. oleophila is capable of producing and secreting various cell wall-degrading enzymes, including exo-beta-1,3-glucanase, chitinase and protease. Exo-beta-1,3-glucanase and chitinase were produced and maximized in the early stages of growth, whereas protease reached a maximum level only after 6-8 days. Production of exo-beta-1,3-glucanase, chitinase and protease was stimulated by the presence of cell wall fragments of Penicillium digitatum in the growth medium, in addition to glucose. This study also provided evidence that C. oleophila is capable of secreting exo-beta-1,3-glucanase into the wounded surface of grapefruit. The role of exo-beta-1,3-glucanase ( CoEXG1) in the biocontrol activity of C. oleophila was tested using CoEXG1-knockouts and double- CoEXG1 over-producing transformants. In vitro bioassays showed that wild-type C. oleophila and exo-beta-1,3-glucanase over-expressing transformants had similar inhibitory effects on spore germination and germ-tube elongation; and both were more inhibitory to the fungus than the knockout transformant. In experiments conducted on fruit to test the biocontrol activity against infection by P. digitatum, no significant difference in inhibition was observed between transformants and untransformed C. oleophila cells at the high concentrations of cells used, whereas at a lower concentration of yeast cells the knockout transformants appeared to be less effective.