Mycosis Fungoides and Granulomatous Slack Skin: A Single Entity With Distinct Clinical Phenotypes.

ABSTRACT: Granulomatous cutaneous T-cell lymphoma includes mycosis fungoides with significant granulomatous inflammation (GMF) and granulomatous slack skin (GSS), listed in the WHO classification as a subtype of mycosis fungoides (MFs). 1 These overlapping entities have shared clinical and histopathologic features which can present a diagnostic challenge. The dominance of the granulomatous infiltrate and the often sparse lymphocytic infiltrate frequently with minimal cytological atypia are features that distract from the correct diagnosis, even when raised by the clinician. We describe the clinical and histopathologic characteristics of 3 cases of granulomatous cutaneous T-cell lymphoma, illustrate the close clinical and pathologic relationship between GMF and GSS and emphasize the diagnostic difficulties that the granulomatous infiltrate can present. Furthermore, we demonstrate, for the first time, considerable elastolysis in a significant proportion of classical (Alibert-Bazin) MF lesions and therefore postulate that the differences observed between GMF and GSS are one of degree and secondary to their anatomic location rather than reflecting meaningful separate entities.

Lymphoplasmocytic plaque in children: A report of an atypical location.

Lymphoplasmocytic plaque in children (LPC) is a rare and distinctive skin disorder primarily affecting the pediatric population. Characterized by its unique histopathological features, the condition manifests as well-defined plaques with a predominance of lymphocytes and plasma cells infiltrating the dermis. Despite its limited prevalence, recognizing this entity is crucial for accurate diagnosis and appropriate management of affected patients. We report the case of a 10-year-old male presenting with LPC in the extensor surface of the upper arm, a rarely reported location, treated with both topical and intralesional corticosteroids resulting in partial improvement.

The Influence of Genetic Polymorphisms on the Expression of Interleukin-1beta, Prostaglandin E2 and Tumor Necrosis Factor Alpha in Peri-Implant Crevicular Fluid: A Cross-Sectional Study.

The aim of this study was to evaluate the possible relationships between polymorphisms in the interleukin-1 (IL-1) A, IL-1B, and IL-1RN genes and concentrations of the inflammatory mediators IL-1ß, tumor necrosis factor-alpha (TNF-α), and prostaglandin E2 (PGE2) in peri-implant crevicular fluid (PICF). A cross-sectional analytical study was conducted on 51 patients with dental implants. Samples from the buccal mucosa were obtained, and genetic analysis was performed using the real-time polymerase chain reaction (PCR) technique for IL-1A and IL-1B and PCR and restriction fragment length polymorphism analysis for IL-1RN. For the biochemical analysis, the concentrations of IL-1ß and TNF-α were analyzed using multiplexed fluorescent sphere immunoassays, and PGE2 by enzyme-linked immunosorbent assay. In patients with detected IL-1RN polymorphism, there was an increase in the concentration of the three mediators with statistically significant differences in the mean values of TNF-α and PGE2, regardless of peri-implant health status (p = 0.002 and p = 0.049, respectively). The concentrations of all three mediators were positively and significantly correlated (IL-1ß vs. TNF-α Rho = 0.480, p < 0.001; IL-1ß vs. PGE2 Rho = 0.382, p = 0.006; and TNF-α vs. PGE2 Rho = 0.528, p < 0.001). We can conclude that the IL-1RN polymorphism exerts an influence on the PICF immune response, which may explain the influence of this genetic polymorphism on the occurrence of peri-implantitis.

State-Dependent Blockade of Dorsal Root Ganglion Voltage-Gated Na+ Channels by Anethole.

Anethole is a phenolic compound synthesized by many aromatic plants. Anethole is a substance that humans can safely consume and has been studied for years as a biologically active molecule to treat a variety of conditions, including nerve damage, gastritis, inflammation, and nociception. Anethole is thought to carry out its biological activities through direct interaction with ion channels. Anethole is beneficial for neurodegenerative Alzheimer's and Parkinson's diseases. Nevertheless, nothing has been investigated regarding the effects of anethole on voltage-gated Na+ channels (VGSCs), which are major players in neuronal function. We used cultured dorsal root ganglion neurons from neonatal rats as a source of natively expressed VGSCs for electrophysiological studies using the whole-cell patch-clamp technique. Our data show that anethole interacts directly with VGSCs. Anethole quickly blocks and unblocks (when removed) voltage-activated Na+ currents in this preparation in a fully reversible manner. Anethole's binding affinity to these channels increases when the inactive states of these channels are populated, similar to lidocaine's effect on the same channels. Our data show that anethole inhibits neuronal activity by blocking VGSCs in a state-dependent manner. These findings relate to the putative anesthetic activity attributable to anethole, in addition to its potential benefit in neurodegenerative diseases.

High sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight.

BACKGROUND/OBJECTIVE: As the obesity epidemic continues, the understanding of macronutrient influence on central nervous system function is critical for understanding diet-induced obesity and potential therapeutics, particularly in light of the increased sugar content in processed foods. Previous research showed mixed effects of sucrose feeding on body weight gain but has yet to reveal insight into the impact of sucrose on hypothalamic functioning. Here, we explore the impact of liquid sucrose feeding for 12 weeks on body weight, body composition, caloric intake, and hypothalamic AgRP neuronal function and synaptic plasticity. METHODS: Patch-clamp electrophysiology of hypothalamic AgRP neurons, metabolic phenotyping and food intake were performed on C57BL/6J mice. RESULTS: While mice given sugar-sweetened water do not gain significant weight, they do show subtle differences in body composition and caloric intake. When given sugar-sweetened water, mice show similar alterations to AgRP neuronal excitability as in high-fat diet obese models. Increased sugar consumption also primes mice for increased caloric intake and weight gain when given access to a HFD. CONCLUSIONS: Our results show that elevated sucrose consumption increased activity of AgRP neurons and altered synaptic excitability. This may contribute to obesity in mice and humans with access to more palatable (HFD) diets.

Portuguese adaptation of the Chronic Heart Failure Knowledge Questionnaire (KQCHF).

BACKGROUND: A patient's knowledge of heart failure (HF) is associated with better outcomes. The more information patients have about their illness, the less likely they are to be readmitted to the hospital. Such knowledge includes the cause, symptoms, probable duration, and expected evolution of the clinical picture. In Portugal, a tool for testing patient knowledge is an unmet need. Therefore, this study aimed to adapt and test the Chronic Heart Failure Knowledge Questionnaire (KQCHF) for the Portuguese context. METHODS: This work includes three cross-sectional studies. In Study 1, subjects were divided between before and after receiving information about HF. In Study 2, participants answered the questionnaire before and after reading the brochure. In Study 3, KQCHF was applied to patients with HF. Studies 1 and 2 were carried out in the general population. Study 3 was carried out with HF outpatients. Convenience sampling was applied to participants in the three studies. RESULTS: In Study 1 (n = 45), those who received information had better scores (9.2 ± 1.9) than those who did not (6.0 ± 2.3). In Study 2 (n = 21), the scores were higher after reading the brochure (10.4 ± 1.7 vs. 6.5 ± 2.9). In Study 3 (n = 169), women had better scores than men (9.1 ± 2.1 vs. 8.3 ± 2.2, overall: 8.5 ± 2.2), and knowledge was correlated with education (r = .340, p < .001) and age (r = -.170, p = .030). CONCLUSION: The Portuguese adaptation of KQCHF captured relevant knowledge about HF and has shown promising results for clinical and research purposes. The questionnaire can be useful in assessing HF patients' knowledge of their disease and as a basis for the implementation of general and personalised educational strategies to improve HF knowledge and, therefore, promote health literacy and self-care.

Associations of medicine use and ejection fraction with the coexistence of frailty and sarcopenia in a sample of heart failure outpatients: a cross-sectional study.

BACKGROUND: Frailty and sarcopenia have been extensively studied in heart failure (HF) patients, but their coexistence is unknown. The aim of this work is to describe the coexistence of these conditions in a sample of HF outpatients and its association with the use of medication and left-ventricular ejection fraction. METHODS: Participants in this cross-sectional study were recruited from a HF outpatients' clinic in northern Portugal. Frailty phenotype was assessed according to Fried et al. Sarcopenia was evaluated according to the revised consensus of the European Working Group on Sarcopenia in Older People. RESULTS: A total of 136 HF outpatients (33.8% women, median age 59 years) integrated this study. Frailty and sarcopenia accounted for 15.4% and 18.4% of the sample, respectively. Coexistence of frailty and sarcopenia was found in 8.1% of the participants, while 17.6% had only one of the conditions. In multivariable analysis (n = 132), increasing age (OR = 1.13;95%CI = 1.06,1.20), being a woman (OR = 65.65;95%CI = 13.50, 319.15), having heart failure with preserved ejection fraction (HFpEF) (OR = 5.61; 95%CI = 1.22, 25.76), and using antidepressants (OR = 11.05; 95%CI = 2.50, 48.82), anticoagulants (OR = 6.11; 95%CI = 1.69, 22.07), furosemide (OR = 3.95; 95%CI = 1.07, 14.55), and acetylsalicylic acid (OR = 5.01; 95%CI = 1.10, 22.90) were associated with increased likelihood of having coexistence of frailty and sarcopenia, while using statins showed the inverse effect (OR = 0.06; 95%CI = 0.01, 0.30). CONCLUSIONS: The relatively low frequency of coexistence of frailty and sarcopenia signifies that each of these two conditions still deserve individual attention from health professionals in their clinical practice and should be screened separately. Being a woman, older age, having HFpEF, using anticoagulants, antidepressants, loop diuretics and acetylsalicylic acid, and not using statins, were associated with having concomitant frailty and sarcopenia. These patients can potentially benefit from interventions that impact their quality of life such as nutritional and mental health interventions and exercise training.

Basal cell carcinomas of the scalp after radiotherapy for tinea capitis: Clinicopathological study in a case series of 96 patients with analysis of 427 tumours.

BACKGROUND/OBJECTIVES: Low-dose X-ray radiotherapy to treat tinea capitis during childhood is a well-known risk factor for scalp basal cell carcinomas (BCCs). Post-radiotherapy BCCs are often multiple, and it has been suggested that they display more aggressive features. Our main objective was to study the clinicopathological aspects of post-radiotherapy BCCs to evaluate their biological behaviour and identify features that may differ from other BCCs. METHODS: We performed an observational, retrospective study assessing multiple clinical and pathological characteristics of patients with post-radiotherapy BCCs. RESULTS: We studied 96 patients with 427 post-radiotherapy scalp BCCs. Post-radiotherapy BCCs were often multiple (median of 4 lesions/patient, ranging from 1 to 54). Significant comorbidities included a high incidence of thyroid disease and meningiomas. Recurrences were observed in 23% of patients, but there may be confounding factors, such as referral bias, heterogenous treatment modalities and occurrence of new tumours due to field effect. We found a high incidence of infundibulocystic BCCs (in 14.6% of patients and corresponding to 5.4% of the total number of tumours), trichoblastomas (5.2%) and neurofibromas of the scalp (10%). CONCLUSIONS: This study is consistent with the occurrence of multiple lesions (sometimes numerous) and a relatively high tendency for recurrence in post-radiotherapy BCCs, as suggested by previous studies. We also found a high incidence of the infundibulocystic variant and a higher risk of follicular tumours and neurofibromas, which suggests that radiotherapy may influence the type of differentiation of BCCs and contribute to induce neoplasms of different cell lines.

Global Variations in Heart Failure Etiology, Management, and Outcomes.

Importance: Most epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries. Objective: To examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development. Design, Setting, and Participants: Multinational HF registry of 23 341 participants in 40 high-income, upper-middle-income, lower-middle-income, and low-income countries, followed up for a median period of 2.0 years. Main Outcomes and Measures: HF cause, HF medication use, hospitalization, and death. Results: Mean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a ß-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper-middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower-middle-income countries (39.5%) (P < .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper-middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower-middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper-middle-income countries (ratio = 2.4), similar in lower-middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper-middle-income countries (9.7%), then lower-middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower-middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies. Conclusions and Relevance: This study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally.

Health-Related Quality of Life and Mortality in Heart Failure: The Global Congestive Heart Failure Study of 23 000 Patients From 40 Countries.

BACKGROUND: Poor health-related quality of life (HRQL) is common in heart failure (HF), but there are few data on HRQL in HF and the association between HRQL and mortality outside Western countries. METHODS: We used the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) to record HRQL in 23 291 patients with HF from 40 countries in 8 different world regions in the G-CHF study (Global Congestive Heart Failure). We compared standardized KCCQ-12 summary scores (adjusted for age, sex, and markers of HF severity) among regions (scores range from 0 to 100, with higher score indicating better HRQL). We used multivariable Cox regression with adjustment for 15 variables to assess the association between KCCQ-12 summary scores and the composite of all-cause death, HF hospitalization, and each component over a median follow-up of 1.6 years. RESULTS: The mean age of participants was 65 years; 61% were men; 40% had New York Heart Association class III or IV symptoms; and 46% had left ventricular ejection fraction ≥40%. Average HRQL differed between regions (lowest in Africa [mean± SE, 39.5±0.3], highest in Western Europe [62.5±0.4]). There were 4460 (19%) deaths, 3885 (17%) HF hospitalizations, and 6949 (30%) instances of either event. Lower KCCQ-12 summary score was associated with higher risk of all outcomes; the adjusted hazard ratio (HR) for each 10-unit KCCQ-12 summary score decrement was 1.18 (95% CI, 1.17-1.20) for death. Although this association was observed in all regions, it was less marked in South Asia, South America, and Africa (weakest association in South Asia: HR, 1.08 [95% CI, 1.03-1.14]; strongest association in Eastern Europe: HR, 1.31 [95% CI, 1.21-1.42]; interaction P<0.0001). Lower HRQL predicted death in patients with New York Heart Association class I or II and III or IV symptoms (HR, 1.17 [95% CI, 1.14-1.19] and HR, 1.14 [95% CI, 1.12-1.17]; interaction P=0.13) and was a stronger predictor for the composite outcome in New York Heart Association class I or II versus class III or IV (HR 1.15 [95% CI, 1.13-1.17] versus 1.09 [95% CI, [1.07-1.11]; interaction P<0.0001). HR for death was greater in ejection fraction ≥40 versus <40% (HR, 1.23 [95% CI, 1.20-1.26] and HR, 1.15 [95% CI, 1.13-1.17]; interaction P<0.0001). CONCLUSION: HRQL is a strong and independent predictor of all-cause death and HF hospitalization across all geographic regions, in mildly and severe symptomatic HF, and among patients with preserved and reduced ejection fraction. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03078166.

Effects of Serelaxin in Patients with Acute Heart Failure.

BACKGROUND: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. METHODS: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 µg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. RESULTS: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. CONCLUSIONS: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).

An updated systematic review on heart failure treatments for patients with renal impairment: the tide is not turning.

Advanced chronic kidney disease (CKD) frequently aggravates heart failure (HF). However, these patients have inherently been excluded from most HF trials. We aim to provide updated estimates of the representation of patients with advanced CKD and the provision of baseline renal function indices in HF trials with a focused interest on the landmark trials. Updated systematic review was performed from the inception of MEDLINE to 31 December 2019 to identify all chronic HF randomized trials published in the three major cardiology and medical journals, respectively, which included mortality endpoint. The included studies were analysed based on the representativeness of the advanced CKD population and the reporting of baseline renal function. A total of 187 eligible randomized trials with 322,374 participants were included in our analysis. One hundred and six trials (56.7%) had exclusion criteria related to renal function, which remained a continuing trend-55.1% (27/49) from inception-2000, 53.4% (39/73) from 2001-2010 and 61.5% (40/65) from 2011 (P = 0.64). The exclusion criteria, however, have become less restrictive. There was a temporal improvement in the likelihood of HF trials in providing baseline renal function indices (28.6% from inception-2000 versus 53.4% from 2001-2010 and 83.1% from 2011, P < 0.001). Concordant findings were observed in the landmark trials. Patients with advanced CKD remain underrepresented in HF trials in the contemporary era, even though the exclusion criteria have become less restrictive, and the quality of renal function monitoring has improved. The continued underrepresentation of patients with advanced CKD in HF trials merits measured broadening of eligibility in further trial studies.

Damage in InGaN/GaN bilayers upon Xe and Pb swift heavy ion irradiation.

350 nm and 550 nm thick InGaN/GaN bilayers were irradiated with different energies (from ∼82 to ∼38 MeV) of xenon (129Xe) ions and different fluences of 1.2 GeV lead (208Pb) ions, respectively. The radiation effects of the swift heavy ions' (SHIs) bombardment were investigated using Rutherford Backscattering Spectrometry in Channeling mode (RBS/C), X-Ray Diffraction (XRD), and micro-Raman spectroscopy. To assess damage profiles, the RBS/C analysis was followed by Monte Carlo simulations using the McChasy code, revealing that InGaN is more susceptible to irradiation damage than GaN. Moreover, the simulations suggest that both randomly displaced atoms (possibly due to partial amorphization) and dislocation loops are formed. The elastic response to radiation was estimated by measuring the expansion of the c-lattice parameter. XRD revealed the presence of strain even in low fluence samples where only a small fraction of the sample volume suffered direct SHI impacts. Micro-Raman suggests that for low defect concentrations, it is dominantly biaxial, while for high defect concentrations, the simultaneous increase of hydrostatic and biaxial occurs. As a driving force of the lattice expansion, we point out the Poisson effect resulting from the pressure exerted by the SHI tracks on the surrounding undamaged crystal structure.

Statins are associated with reduced likelihood of sarcopenia in a sample of heart failure outpatients: a cross-sectional study.

BACKGROUND: Sarcopenia is prevalent in heart failure (HF) patients, contributing to its poor prognosis. Statin use is postulated as a probable risk for developing sarcopenia, but little is known regarding this association in HF patients. This work aims at classifying and characterising sarcopenia and at describing the association of statin use with sarcopenia in a sample of Portuguese HF outpatients. METHODS: In this cross-sectional study, a sample of 136 HF patients (median age: 59 years, 33.8% women) was recruited from an HF outpatients' clinic of a University Hospital in Portugal. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People 2. Clinical, nutritional, and dietary data were collected. RESULTS: A total of 25 (18.4%) individuals were categorised as sarcopenic, ranging from 12.2% in younger (< 65 years) participants vs. 30.4% in older ones and from 3.3% in men vs. 47.8% in women. Severe sarcopenia accounted for 7.4% of the sample and sarcopenic obesity was identified in 5.1% of the individuals. A total of 65.4% of the participants were statin users. In multivariable analysis (n = 132, 25 sarcopenic), the use of statins was inversely associated with sarcopenia (OR = 0.03; 95% CI = 0.01, 0.30). Each additional age year was associated with a 9% increase in the likelihood of being sarcopenic (OR = 1.09; 95% CI = 1.01, 1.17), and each Kg.m-2 increment in body mass index was associated with a 21% decrease in the likelihood of sarcopenia (OR = 0.79; 95% CI = 0.65, 0.96). The daily use of five or more medicines was also directly associated with sarcopenia (OR = 26.87; 95% CI = 2.01, 359.26). On the other hand, being a man and being physically active were inversely associated with sarcopenia (OR = 0.01; 95% CI = 0.00, 0.07 and OR = 0.09; 95% CI = 0.01, 0.65, respectively). CONCLUSIONS: Contrary to what was expected, patients medicated with statins were less likely to be sarcopenic. Although this finding deserves further research, we hypothesise that this might be related to the pleiotropic effects of statins on endothelial function, contributing to better neuromuscular fitness.

Erythematous brownish plaques with an annular configuration.

Granuloma annulare (GA) and cutaneous sarcoidosis show clinicopathological overlap and they are also aetiopathogenically related. Given the similarities of sarcoidal GA and sarcoidosis, and the reports of association of sarcoidal GA with systemic sarcoidosis, this diagnosis should prompt further investigation to exclude systemic involvement. Being aware of the subtle histopathological clues is of the utmost importance for an accurate diagnosis of this rare variant, but correlation with the clinical setting and use of ancillary investigations are also warranted to confidently exclude sarcoidosis.

Diffuse dermal angiomatosis: a rare cause of painful ulceration in renal insufficiency.

Diffuse dermal angiomatosis is a rare, benign, reactive cutaneous vascular proliferation that has been reported in the context of end-stage renal failure and can rarely be associated with arteriovenous fistulas. We report a striking clinical resolution following prompt diagnosis and subsequent arteriovenous fistula reversal. This case further demonstrates that accurate diagnosis is particularly rewarding since correct therapeutic approach can be curative.

Basal Cell Carcinomas After Radiotherapy Show More Frequent Follicular Differentiation Than Tumors From Sun-Exposed Areas: Immunohistochemical Study With a Special Focus on Infundibulocystic Basal Cell Carcinoma.

ABSTRACT: Patients submitted to radiotherapy for tinea capitis in childhood have an increased incidence of scalp basal cell carcinomas (BCCs) but also of other neoplasms, namely, follicular tumors. In a cohort of such patients, we also found a high incidence of infundibulocystic BCCs, an otherwise rare variant. We thus hypothesized that postradiotherapy BCCs could be more prone to display follicular differentiation. We compared the histological and immunohistochemical features of postradiotherapy BCCs [both conventional (16 cases) and infundibulocystic (16 cases)] with those of BCCs arising in sun-exposed areas (16 cases), using markers of follicular differentiation (PHLDA-1, CK15, CD34, ß-catenin, and calretinin). Postradiotherapy BCCs showed slightly higher tendency for infundibular and/or trichilemmal differentiation than BCCs from sun-exposed areas (37.5% vs. 18.8%), but this difference was not statistically significant. Nevertheless, infundibulocystic BCCs showed more frequent expression of PHLDA-1 and stronger cytoplasmic expression of CK15 compared with the other lesions. In addition, CD34 highlighted a characteristic meshwork of stromal cells surrounding the epithelial component in all infundibulocystic BCCs, in contrast to the other postradiotherapy BCCs and UV-related BCCs, in which 78.1% were negative or only focally positive. In conclusion, our study suggests a tendency for more frequent follicular differentiation in postradiotherapy BCCs compared with BCCs from sun-exposed areas. In addition, the immunohistochemical study confirms previous data from the literature regarding infundibulocystic BCCs (higher CK15 and PHLDA-1 expression) and shows a distinctive stromal positivity for CD34 that has not been previously acknowledged in these tumors.

Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes.

AIMS: The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF). METHODS AND RESULTS: HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported. CONCLUSION: The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.

Management of RAASi-associated hyperkalemia in patients with cardiovascular disease.

Renin-angiotensin-aldosterone system inhibitors (RAASi) reduce morbidity and mortality in heart failure (HF) with reduced ejection fraction in a dose-dependent manner. They also have a positive impact in other cardiovascular diseases (CVDs). However, RAASi may induce hyperkalemia, a potentially life-threatening disorder. This risk is further increased in those with concomitant chronic kidney disease, diabetes mellitus, and/or in patients with hypertension. Current treatment guidelines recommend maximal RAASi dosing to improve clinical outcomes; however, this is often limited by the development of hyperkalemia. When this occurs, current guidelines recommend RAASi down-titration/interruption, which, while improving short-term prognosis, is associated with a negative long-term prognostic impact. At present, the European Society of Cardiology suggests the consideration of novel potassium binders (patiromer and sodium zirconium cyclosilicate) for the management of RAASi-associated hyperkalemia. Both drugs can reduce serum potassium levels and prevent recurrent hyperkalemia. Additionally, patiromer showed enabling of RAASi optimization in high-risk patients. Nevertheless, precise recommendations on the use of these drugs are lacking. Building upon current HF guideline recommendations, a multidisciplinary expert panel convened to design an algorithm providing practical guidance on the use of novel potassium binders/patiromer in patients with HF and/or other CVD. As a result of that effort, we present an evidence-based treatment algorithm for the management of hyperkalemia with novel potassium binders/patiromer in patients with HF and/or other CVD receiving RAASi, including the necessary monitoring to avoid induction of hypokalemia. This algorithm aims to maintain or up-titrate RAASi to optimized doses, while maintaining normokalemia, improved clinical outcomes, and long-term prognosis.

Basal cell carcinomas of the scalp after radiotherapy for tinea capitis in childhood: A genetic and epigenetic study with comparison with basal cell carcinomas evolving in chronically sun-exposed areas.

BACKGROUND: Basal cell carcinoma (BCC) has been mostly associated with sun exposure, but ionizing radiation is also a known risk factor. It is not clear if the pathogenesis of BCC, namely at a genomic and epigenetic level, differs according to the underlying triggering factors. OBJECTIVE: The present study aims to compare genetic and epigenetic changes in BCCs related to ionizing radiation and chronic sun exposure. METHODS: Tumor samples from BCCs of the scalp in patients submitted to radiotherapy to treat tinea capitis in childhood and BCCs from sun-exposed areas were analysed through array comparative genomic hybridization (array-CGH) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to detect copy number alterations and methylation status of specific genes. RESULTS: Genomic characterization of tumor samples revealed several copy number gains and losses in all chromosomes, with the most frequent gains observed at 2p, 6p, 12p, 14q, 15q, 18q, Xp and Yp, and the most frequent losses observed at 3q, 14q, 16p, 17q, 22q, Xp, Yp and Yq. We developed a statistical model, encompassing gains in 3p and 16p and losses in 14q and 20p, with potential to discriminate BCC samples with sporadic aetiology from BCC samples that evolve after radiotherapy in childhood for the treatment of tinea capitis, which presented statistical significance (P = 0.003). Few methylated genes were detected through MS-MLPA, most frequently RARB and CD44. CONCLUSIONS: Our study represents a step forward in the understanding of the genetic mechanisms underlying the pathogenesis of BCC and suggests potential differences according to the underlying ris k factors.