The triglycerides and glucose index is more strongly associated with metabolically healthy obesity phenotype than the lipid and obesity indices.

PURPOSE: The triglycerides and glucose (TyG) index is a reliable biomarker for estimating insulin resistance; however, evidence regarding the use of the TyG index in individuals with metabolically healthy obesity (MHO) is scarce. Thus, we examined the association between the TyG index and the MHO phenotype. METHODS: Apparently healthy men and women aged 18 years or more with obesity (body mass index [BMI] ≥ 30 kg/m2) were allocated into the following groups: MHO and metabolically unhealthy obesity (MUO). The MHO phenotype was defined by obesity and the absence of the following metabolic disorders: elevated triglyceride concentrations, elevated glucose levels, elevated blood pressure, and low HDL-C. The MUO was defined by individuals with obesity and at least one of the aforementioned cardiovascular risk factors. RESULTS: A total 827 individuals, 605 (73.1%) women and 222 (26.9%) men were enrolled and allocated into the MHO (n = 104) and MUO (n = 723) groups. The adjusted regression analysis by age, sex, BMI, and waist circumference showed that fasting glucose (OR = 0.90; 95% CI: 0.88-0.93), and triglycerides (OR = 0.97; 95% CI: 0.96-0.98), as well as the triglycerides/HDL-C (OR = 0.18; 95% CI: 0.13-0.26), lipid accumulation product (OR = 0.95; 95% CI: 0.93-0.96), visceral adipose index (OR = 0.38; 95% CI: 0.31-0.46), and TyG index (OR = 0.001; 95% CI: 0.000-0.004) are inversely associated with the MHO, while the HDL-C (OR = 1.10; 95% CI: 1.07-1.12) had a direct association. CONCLUSIONS: Our results show that the TyG index is more strongly associated with the MHO phenotype than the lipid and obesity indices.

Four-year Epidemiological Surveillance of the Spanish Registry of Research in Contact Dermatitis and Cutaneous Allergy: Current Situation and Trends. / Vigilancia epidemiológica en los últimos 4 años del Registro Español de Investigación en Dermatitis de Contacto y Alergia Cutánea: situación actual y tendencias.

BACKGROUND: The epidemiological surveillance of contact dermatitis is one of the objectives of the Spanish Registry of Research in Contact Dermatitis and Cutaneous Allergy. Knowing whether the prevalence of positive tests to the different allergens changes over time is important for this monitoring process. OBJECTIVES: To describe the various temporary trends in allergen positivity in the GEIDAC standard series from 2018 through December 31, 2022. METHODS: This was a multicenter, observational trial of consecutive patients analyzed via patch tests as part of the study of possible allergic contact dermatitises collected prospectively within the Spanish Registry of Research in Contact Dermatitis and Cutaneous Allergy. The data was analyzed using 2 statistical tests: one homogeneity test (to describe the changes seen over time) and one trend test (to see whether the changes described followed a linear trend). RESULTS: A total of 11327 patients were included in the study. Overall, the allergens associated with a highest sensitization were nickel sulfate, methylisothiazolinone, cobalt chloride, methylchloroisothiazolinone/methylisothiazolinone, and fragrance mix i. A statistically significant decrease was found in the percentage of methylisothiazolinone positive tests across the study years with an orderly trend. CONCLUSIONS: Although various changes were seen in the sensitizations trends to several allergens of the standard testing, it became obvious that a high sensitization to nickel, methylchloroisothiazolinone/methylisothiazolinone and fragrances mix i remained. Only a significant downward trend was seen for methylisothiazolinone.

Epidemiological, Clinical, and Allergic Profile of Psoriatic Patients. Evaluation of the Spanish Registry of Contact Dermatitis and Cutaneous Allergy (REIDAC). / Perfil epidemiológico, clínico y alérgico en pacientes con psoriasis. Evaluación del Registro Español de Dermatitis de Contacto (REIDAC).

BACKGROUND: Psoriasis is a chronic inflammatory dermatosis whose clinical and topographic distribution requires differential diagnosis, or the possible association with allergic contact dermatitis (ACD), requiring patch testing (PT) as part of the diagnostic procedure. OBJECTIVES: To describe the epidemiological, clinical, and allergic profile of patients with a primary or secondary diagnosis of psoriasis undergoing PT and compare them with patients with a diagnosis of ACD at the end of the diagnostic process. METHODS: Cross-sectional study with data from REIDAC from 2018 through 2023 of selected patients with a diagnosis of psoriasis and/or ACD. RESULTS: A total of 11 502 patients were included, 513 of whom had been diagnosed with primary or secondary psoriasis, 3640 with ACD, and 108 with both diseases. Men were more predominant in the groups of patients with psoriasis, psoriasis+ACD, and lesions were more predominantly seen in the hands with little association with atopic factors vs the ACD group. The rate of positivity in PT to the 2022 Spanish battery of allergens was lower in the group with psoriasis only in 27% of the patients. The most common allergens found in the psoriasis group were also the most common ones found in the overall ACD population. CONCLUSIONS: Overall, 36.2% of psoriatic patients tested positive in PT to the 2022 Spanish battery of allergens, which proved that this association is not uncommon. Overall, psoriatic patients had a higher mean age, were more predominantly men, and showed more hand involvement.

Spanish Version of the RECAP Questionnaire to Assess Control of Atopic Eczema: Translation, Cultural Adaptation, Validation, and Correlations with Other Patient-Reported Outcome Measures. / Traducción, adaptación transcultural, correlación con otros PRO y validación del cuestionario RECAP sobre el grado de control de la dermatitis atópica.

BACKGROUND: The 7-item RECAP (Recap of Atopic Eczema) questionnaire is used to assess the control of different degrees of eczema severity in patients of all ages. Long-term control of eczema is one of the 4 core outcome domains to be assessed in clinical trials of eczema therapies. After the RECAP was developed in the United Kingdom, it was translated into Chinese, German, Dutch, and French. OBJECTIVES: To produce a validated Spanish version of the RECAP questionnaire and, secondarily, to test its content validity in a group of Spanish patients with atopic eczema. MATERIAL AND METHODS: In a 7-step process we produced 2forward translations and 1back translation of the RECAP questionnaire. Experts then held two meetings to reach consensus and draft a Spanish version of the questionnaire. Fifteen adult patients with atopic eczema were interviewed to evaluate the comprehensibility, comprehensiveness, and relevance of the drafted items. These patients also completed the Atopic Dermatitis Control Tool (ADCT), the Dermatology Life Quality Index (DLQI), and the Patient-Oriented Eczema Measure (POEM). Stata software (version 16) was then used to explore the correlations between the patients' scores on these tools and the RECAP. RESULTS: The patients found the Spanish version of the RECAP to be comprehensible and easy to answer. We observed a strong correlation between results on the Spanish RECAP and the ADCT, and highly significant correlations between the RECAP and the DLQI and POEM tools. CONCLUSIONS: The culturally adapted Spanish version of the RECAP is linguistically equivalent to the original version of the questionnaire. RECAP scores correlate highly with other patient-reported outcome measures.

Effects of convective drying assisted by ultrasound and osmotic solution on polyphenol, antioxidant and microstructure of murtilla (Ugni molinae Turcz) fruit.

The effects of pretreatment with ultrasound and an osmotic solution combined with hot air convection drying on the total polyphenol content (TPC), antioxidant activity and microstructural of murtilla skin fruit were evaluated. The effects of ultrasound frequency (0 and 130 kHz), osmotic solution concentration (0 and 70 °Brix) and time (60 or 120 min) on the TPC and the antioxidant activities as measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays were evaluated. The TPC and DPPH antioxidant activity decreased significantly (p < 0.05) when ultrasound was applied at 0 °Brix for 60 min. Higher FRAP activity was obtained upon treatment with ultrasound and an osmotic solution for 60 min. The ORAC values did not significantly differ based on the pretreatment methods but decreased when an osmotic solution was applied for 120 min without ultrasound. When ultrasound and the osmotic solution were applied, the skin cells of the dried murtilla fruit became more distorted, resulting in larger spaces between them and causing loss of shape. Although the application of pretreatment procedures before murtilla fruit drying did not positively affect the TPC, DPPH or ORAC individually, the application of a Global Standardized Response based on the followed by a mathematical model adjustment indicated that a 70 °Brix osmotic solution applied for 60 min was the best treatment for preparing murtilla fruit aiming a high antioxidant activity in dried product.

Fragment-based lead discovery of a novel class of small molecule antagonists of neuropeptide B/W receptor subtype 1 (GPR7).

Here, we report the discovery of a new class of NPBWR1 antagonists identified from a fragment-based screen. Compound 1 (cAMP IC50 = 250 µM; LE = 0.29) emerged as an initial hit. Further optimization of 1 by SAR-by-catalogue and chemical modification produced 21a (cAMP IC50 = 30 nM; LE = 0.39) with a 6700-fold increase in potency from fragment 1. Somewhat surprisingly, Schild analysis of compound 21a suggested that in vitro inhibition of NPW-mediated effects on upon cAMP accumulation were saturable, and that compound 21a dose-dependently increased [125I]-hNPW23 dissociation rate constants from NPBWR1 in kinetic binding studies. Collectively, these data are inconsistent with a classic surmountable, orthosteric mechanism of inhibition. The benzimidazole inhibitors reported herein may therefore represent a mechanistically differentiated class of compounds with which to form a better appreciation of the pharmacology and physiological roles of this central neuropeptide system.

Preclinical Safety Assessment of a Highly Selective and Potent Dual Small-Molecule Inhibitor of CBP/P300 in Rats and Dogs.

Cyclic adenosine monophosphate-response element (CREB)-binding protein (CBP) and EP300E1A-binding protein (p300) are members of the bromodomain and extraterminal motif (BET) family. These highly homologous proteins have a key role in modulating transcription, including altering the status of chromatin or through interactions with or posttranslational modifications of transcription factors. As CBP and p300 have known roles for stimulating c-Myc oncogenic activity, a small-molecule inhibitor, GNE-781, was developed to selectively and potently inhibit the CBP/p300 bromodomains (BRDs). Genetic models have been challenging to develop due to embryonic lethality arising from germline homozygous mutations in either CBP or P300. Hence, the purpose of this study was to characterize the role of dual inhibition of these proteins in adult rats and dogs. Repeat dose toxicity studies were conducted, and toxicologic and pathologic end points were assessed. GNE-781 was generally tolerated; however, marked effects on thrombopoiesis occurred in both species. Evidence of inhibition of erythroid, granulocytic, and lymphoid cell differentiation was also present, as well as deleterious changes in gastrointestinal and reproductive tissues. These findings are consistent with many preclinical (and clinical) effects reported with BET inhibitors targeting BRD proteins; thus, the current study findings indicate a likely important role for CBP/p300 in stem cell differentiation.

The triglycerides and glucose index is associated with cardiovascular risk factors in metabolically obese normal-weight subjects.

PURPOSE: The aim of this study was to determine whether the triglycerides and glucose (TyG) index is associated with the presence of metabolically obese normal-weight (MONW) phenotype and related cardiovascular risk factors. METHODS: Apparently healthy men and non-pregnant women aged 20-65 years were enrolled in a population-based cross-sectional study. Overweight, obesity, smoking, alcohol consumption, pregnancy, diagnosis of hypertension, diabetes, cardiovascular disease, liver disease, renal disease, malignancy, and medical treatment were exclusion criteria. Subjects were allocated into the MONW or normal-weight groups. MONW phenotype was defined by normal weight and the presence of at least one of the following cardiovascular risk factors: elevated blood pressure, hyperglycemia, hypertriglyceridemia, and low HDL cholesterol. RESULTS: A total of 542 subjects were enrolled and allocated into the MONW (n = 354) and normal-weight (n = 188) groups. The adjusted logistic regression analysis showed that the elevated TyG index is significantly associated with the presence of MONW phenotype (OR = 11.14; 95% CI 6.04-20.57), hyperglycemia (OR = 3.18; 95% CI 1.95-5.21), hypertriglyceridemia (OR = 399.19; 95% CI 94.01-1694.98), and low HDL-C (OR = 2.60; 95% CI 1.74-3.87), but not with elevated blood pressure (OR = 1.55; 95% CI 0.93-2.60). CONCLUSION: Results of this study support that the TyG index may be a useful indicator to detect MONW phenotype and associated cardiovascular risk factors.

Comorbidity and prognostic factors on admission in a COVID-19 cohort of a general hospital. / Comorbilidad y factores pronósticos al ingreso en una cohorte COVID-19 de un hospital general.

ANTECEDENTS AND OBJECTIVE: To describe clinical features, comorbidity, and prognostic factors associated with in-hospital mortality in a cohort of COVID-19 admitted to a general hospital. MATERIAL AND METHODS: Retrospective cohort study of patients with COVID-19 admitted from 26th February, who had been discharged or died, up to 29th April, 2020. A descriptive study and an analysis of factors associated with intrahospital mortality were performed. RESULTS: Out of the 101 patients, 96 were analysed. Of these, 79 (82%) recovered and were discharged, and 17 (18%) died in the hospital. Diagnosis of COVID-19 was confirmed by polymerase chain reaction to SARS-CoV-2 in 92 (92.5%). The mean age was 63 years, and 66% were male. The most frequent comorbidities were hypertension (40%), diabetes mellitus (16%) and cardiopathy (14%). Patients who died were older (mean 77 vs 60 years), had higher prevalence of hypertension (71% vs 33%), and cardiopathy (47% vs 6%), and higher levels of lactate dehydrogenase (LDH) and reactive C protein (mean 662 vs 335UI/L, and 193 vs 121mg/L respectively) on admission. In a multivariant analysis the variables significantly associated to mortality were the presence of cardiopathy (CI 95% OR 2,58-67,07), levels of LDH≥345IU/L (CI 95% OR 1,52-46,00), and age≥65 years (CI 95% OR 1,23-44,62). CONCLUSIONS: The presence of cardiopathy, levels of LDH≥345IU/L and age ≥65 years are associated with a higher risk of death during hospital stay for COVID-19. This model should be validated in prospective cohorts.

[Diagnosis and management of Imperforated Hymen in an infant]. / Diagnóstico y manejo de Himen Imperforado en una lactante menor.

INTRODUCTION: Imperforated hymen is the most frequent congenital malformation of the female genital tract. Most cases are not investigated in childhood, due to an insufficient genital examination. Its diagnosis and resolution must be early and definitive to avoid subsequent complications. OBJECTIVE: A clinical case of an infant with imperforated himen is presented. To update on genital examination technique necessary to detect this pathology in the newborn and infants, and the proper treatment. CLINICAL CASE: 3-months-old infant that consulted due to an increase in bulging volume in the introitus area. In the physical examination, the Valsalva's maneuver was performed allowed the ex pulsion of a homogeneous pearly mass with a smooth surface, between the labia majora, suggesting imperforate hymen. The study was complemented with gynecological ultrasound, which demons trated the presence of hydrocolpos, ruling out other anomalies. A hymenotomy was performed, which allowed for the evacuation of abundant serous material, with no bad smell, and then the hymenectomy was completed by resection of the hymenal membrane. In follow-up monitoring 4 months after the intervention, a widely permeable hymen was found. CONCLUSION: Neonatal care teams require training on the correct technique of external genital examination of the newborn and infant. Hymenectomy is the technique that allows definitely resolving the condition, avoiding complications.

Which are the best parameters to obtain proteins and malondialdehyde from a tear sample?

Predictive, preventive and personalized medicine (PPPM) is a current concept in healthcare based on the analysis of biomarkers through non-invasive methods. Biomarkers for inflammation and oxidative stress are especially used for screening. Quantification of tear total protein content is important to identify potential, specific biomarkers, such as malondialdehyde concerning oxidative stress. The Schirmer strip test is an accessible and simple method for tear analysis. However, it is limited by the low concentration of biomarkers in the human tear. In this preliminary study, different procedures were compared for the extraction of tear proteins and malondialdehyde. Schirmer strips were used to obtain tears from healthy subjects. Ionic strength and surfactant agents were assessed, as well as different centrifugation parameters. Finally, several volumes of n-butanol on the process of malondialdehyde extraction were evaluated. The results showed that ionic strength strongly influences the extraction process, although most studies have suggested that surfactant agents are the most relevant factor; the most efficient results were obtained using a 2 M solution of NaCl in phosphate buffered saline. Regarding centrifugation, leaving the Schirmer strip tip left hanging outside the tube cap and using 1000 rpm was the best option, which is a lower centrifugation speed than the usually reported on literature. Moreover, 250 µL was the optimal n-butanol volume for malondialdehyde extraction. The importance of this study relies on the increasing relevance of the biomarkers in the field of PPPM and the need of a standardized method to extract biomarkers from the tears, to optimise its use.

Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling.

Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).

Cytokine Release Syndrome Grade as a Predictive Marker for Infections in Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia Treated With Chimeric Antigen Receptor T Cells.

Background: Chimeric antigen receptor (CAR)-modified T cells that target the CD19 antigen present a novel promising therapy for the treatment of relapsed B-cell acute lymphoblastic leukemia (B-ALL). Although cytokine release syndrome (CRS) and neurotoxicity have emerged as predominant noninfectious complications of CD19 CAR T-cell therapy, infections associated with this treatment modality have not been well documented. Methods: We analyzed infectious complications that followed CD19 CAR T-cell therapy in 53 adult patients with relapsed B-ALL enrolled in a phase I clinical trial at Memorial Sloan Kettering Cancer Center (NCT01044069). Results: Overall, 22 patients (42%) experienced 26 infections (17 bacterial, 4 fungal, and 5 viral) within the first 30 days of CAR T-cell infusion. In 10 of 32 (31%) patients in whom complete remission was achieved, 15 infections developed between days 31 and 180; the majority of these late infections were due to respiratory viruses. In general, bacterial, fungal, and viral infections were detected at a median of 18, 23, and 48 days, respectively, after CAR T-cell infusion. CRS grade 3 or higher was independently associated with increased risk of subsequent infection (adjusted hazard ratio [HR], 2.67; P = .05) and in particular with bloodstream infection (adjusted HR, 19.97; P < .001). Three of 53 patients (6%) died of an infection-related cause. Conclusions: Infections in adult patients with relapsed B-ALL are common after CD19 CAR T-cell therapy. Understanding the infectious complications that are temporally coincident with CD19 CAR T-cell therapy is critical for developing effective prophylactic and other supportive care measures to improve clinical outcomes. Clinical Trials Registration: NCT01044069.

Linear immunoglobulin A dermatosis mimicking toxic epidermal necrolysis: a case report of etanercept treatment.

A 65-year-old pluripathological woman attended our hospital with a cutaneous eruption of sudden appearance after vancomycin treatment. She presented targetoid lesions affecting approximately 25-30% of her body surface, large erosions with mucosal lesions and positive Nikolsky sign. Under the initial clinical suspicion of toxic epidermal necrolysis (TEN), and considering the recent literature of successful use of etanercept in these cases, she was treated with a single dose of this antitumour necrosis factor (anti-TNF) agent. Subsequently, the exanthema progression stopped and resolution of the lesions happened in a few days. Later on, histopathology revealed a subepidermal blister with dense neutrophilic infiltrate and linear deposits of immunoglobulin A (IgA) on the dermoepidermal junction, allowing us to establish the diagnosis of drug-induced linear IgA dermatosis mimicking TEN. Linear IgA dermatosis can have severe clinical manifestations, even mimicking TEN, and can have high mortality, especially in drug-induced cases. We have not found any other report of linear IgA dermatosis treated with etanercept in the English literature. Anti-TNF medications could represent useful therapeutic alternatives in this dermatosis.

Design and synthesis of a biaryl series as inhibitors for the bromodomains of CBP/P300.

A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellent CBP potency (CBP IC50 = 1 nM, MYC EC50 = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile.

The updated Charlson comorbidity index is a useful predictor of mortality in patients with Staphylococcus aureus bacteraemia.

The objective was to compare the performance of the updated Charlson comorbidity index (uCCI) and classical CCI (cCCI) in predicting 30-day mortality in patients with Staphylococcus aureus bacteraemia (SAB). All cases of SAB in patients aged ⩾14 years identified at the Microbiology Unit were included prospectively and followed. Comorbidity was evaluated using the cCCI and uCCI. Relevant variables associated with SAB-related mortality, along with cCCI or uCCI scores, were entered into multivariate logistic regression models. Global model fit, model calibration and predictive validity of each model were evaluated and compared. In total, 257 episodes of SAB in 239 patients were included (mean age 74 years; 65% were male). The mean cCCI and uCCI scores were 3.6 (standard deviation, 2.4) and 2.9 (2.3), respectively; 161 (63%) cases had cCCI score ⩾3 and 89 (35%) cases had uCCI score ⩾4. Sixty-five (25%) patients died within 30 days. The cCCI score was not related to mortality in any model, but uCCI score ⩾4 was an independent factor of 30-day mortality (odds ratio, 1.98; 95% confidence interval, 1.05-3.74). The uCCI is a more up-to-date, refined and parsimonious prognostic mortality score than the cCCI; it may thus serve better than the latter in the identification of patients with SAB with worse prognoses.

Appropriateness of magnetic resonance imaging requested by primary care physicians for patients with knee pain.

OBJECTIVE: To evaluate the appropriateness of magnetic resonance imaging (MRI) of the knee requested by primary care physicians. DESIGN: Retrospective observational study. SETTING: Six primary care centres in the Elche Department of Health of the Valencian Community, Spain. PARTICIPANTS: Three hundred patients with knee pain who were prescribed MRI. MAIN OUTCOME MEASURES: Data were collected from the electronic clinical history, which allowed us to assess the appropriateness and inappropriateness of the MRI requests for the knee based on the American College of Radiology (ACR) criteria. A multivariate logistic regression model was used to identify factors associated with an inappropriate request. RESULTS: About 45% (41-49%) of knee MRI prescriptions were assessed as inappropriate. The frequency was higher in female patients (odds ratio, OR = 1.96; P = 0.03). A history of knee trauma and urgent use of MRI were associated with a lower frequency of inappropriate requests (OR = 0.14, P < 0.001 and OR = 0.32, P = 0.03, respectively). In 82% of cases, the request for MRI was deemed inappropriate because it was used as the initial imaging test. The availability of a previous radiograph of the knee significantly reduced the rate of inappropriate requests (OR = 0.05, P < 0.001); only 47% of the patients had a previous radiograph. CONCLUSIONS: The percentage of inappropriate knee MRI prescriptions is high. Protocols should be put in place to improve the appropriateness of MRI requests by promoting understanding of the appropriate use of MRI among primary care physicians.

Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition.

Covalent modification of histones is a fundamental mechanism of regulated gene expression in eukaryotes, and interpretation of histone modifications is an essential feature of epigenetic control. Bromodomains are specialized binding modules that interact with acetylated histones, linking chromatin recognition to gene transcription. Because of their ability to function in a domain-specific fashion, selective disruption of bromodomain:acetylated histone interactions with chemical probes serves as a powerful means for understanding biological processes regulated by these chromatin adaptors. Here we describe the discovery and characterization of potent and selective small molecule inhibitors for the bromodomains of CREBBP/EP300 that engage their target in cellular assays. We use these tools to demonstrate a critical role for CREBBP/EP300 bromodomains in regulatory T cell biology. Because regulatory T cell recruitment to tumors is a major mechanism of immune evasion by cancer cells, our data highlight the importance of CREBBP/EP300 bromodomain inhibition as a novel, small molecule-based approach for cancer immunotherapy.

Incidence, recurrence and cost of hyperglycaemic crises requiring emergency treatment in Andalusia, Spain.

AIMS: Hyperglycaemic crises (diabetic ketoacidosis and hyperosmolar hyperglycaemic state) are medical emergencies in people with diabetes. We aimed to determine their incidence, recurrence and economic impact. METHODS: An observational study of hyperglycaemic crises cases using the database maintained by the out-of-hospital emergency service, the Healthcare Emergency Public Service (EPES) during 2012. The EPES provides emergency medical services to the total population of Andalusia, Spain (8.5 million inhabitants) and records data on the incidence, resource utilization and cost of out-of-hospital medical care. Direct costs were estimated using public prices for health services updated to 2012. RESULTS: Among 1 137 738 emergency calls requesting medical assistance, 3157 were diagnosed with hyperglycaemic crises by an emergency coordinator, representing 2.9 cases per 1000 persons with diabetes [95% confidence intervals (CI) 2.8 to 3.0]. The incidence of diabetic ketoacidosis was 2.5 cases per 1000 persons with diabetes (95% CI 2.4 to 2.6) and the incidence of hyperosmolar hyperglycaemic state was 0.4 cases per 1000 persons with diabetes (95% CI 0.4 to 0.5). In total, 17.7% (n = 440) of people had one or more hyperglycaemic crisis. The estimated total direct cost was €4 662 151, with a mean direct cost per episode of €1476.8 ± 217.8. CONCLUSIONS: Hyperglycaemic crises require high resource utilization of emergency medical services and have a significant economic impact on the health system.

Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance.

Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors. Such tolerance has been linked to an altered epigenetic state, and 11 decreased BRD9 binding to chromatin, and this was associated with decreased expression of ALDH1A1, a gene previously shown to be important in drug tolerance. BRD9 inhibitors may therefore show utility in preventing epigenetically-defined drug resistance.