SARS-CoV-2 Infection in the Pediatric Oncology Population: The Definitive Comprehensive Report of the Infectious Diseases Working Group of AIEOP.

OBJECTIVE: The objective of this study was to assess the clinical impact and outcome of the SARS-CoV-2 infection on children with cancer or those who received a hematopoietic stem cell transplantation. METHODS: AIEOP (Italian Association of Pediatric Hematology and Oncology) performed a nationwide multicenter observational cohort study, including consecutive patients between April 2020 and November 2022. RESULTS: Twenty-five Italian centers participated and 455 patients were enrolled. We reported a significant increasing trend of symptomatic cases over the years, while the number of nonmild infections remained stable. Early infection after oncologic diagnosis (<60 days) and severe neutropenia were identified as independent risk factors for developing moderate, severe, or critical infections. The percentage of patients who were asymptomatic and mildly symptomatic and who stopped chemotherapy reduced over the years of the pandemic. Nine patients died, but no death was attributed to SARS-CoV-2 infection. CONCLUSIONS: SARS-CoV-2 infection presented a self-limiting benign course in the Italian pediatric oncohematology population during the pandemic, and its main consequence has been the discontinuation of cancer-directed therapies. The rate of patients who were asymptomatic and stopped chemotherapy reduced over the years, suggesting that the continuation of chemotherapy is a feasible option.

Complete urethral disruption after motor vehicle crash without pelvic fracture.

Urethral injuries are rare among the pediatric population, and the majority occur after trauma. This is the case of an eight-year-old female with complete proximal urethral disruption and ruptured bladder neck without pelvic fracture after a motor vehicle crash. After the accident, her bladder neck was reapproximated and a suprapubic tube was placed. Three months later, she underwent reconstruction for a bladder neck closure and appendicovesicostomy. In managing these patients, focus should first be directed at achieving a safe means of urinary drainage, and next to repair the lower urinary tract to maximize continence and minimize complications.

The rights of migrants to the identification of their dead: an attempt at an identification strategy from Italy.

Europe is turning a blind eye on a humanitarian disaster unfolding at its doorsteps, with thousands of migrants dying unidentified in Mediterranean waters. Since 2014, Italy has been struggling in an almost indifferent international scenario to identify its dead migrants. Despite the lack of sufficient resources, of the difficulties in collecting post mortem data from the disseminated bodies, and of the problems of contacting and collecting ante mortem information from relatives, it has been proven, with a series of pilot studies, that not only can these bodies be identified but that relatives are also looking for their loved ones and need death certificates. This article focuses on the administrative limbo and lack of regulations obliging single states to engage in appropriate procedures to maximise identification.

Use of music therapy in pediatric oncology: an Italian AIEOP multicentric survey study in the era of COVID-19.

Music therapy (MT) is a complementary therapy offered to children, young adults, and their families in pediatric oncology and palliative care. We performed a survey to collect information about MT in pediatric oncology in Italy. The outbreak of COVID-19 unavoidably changed the scenario of MT, suggesting some considerations presented in this survey. 27/32 (84.4%) centers belonging to the Infections and Supportive Therapy Working Group of Association of Pediatric Hematology and Oncology (AEIOP) completed in 2 different time points (T1 and T2) an online survey on MT, before and after COVID-19 pandemia. Different kinds of music approach were used taking care of patients in 21/27 centers, while in 14/21 (66%), a specific project of MT conducted by a music therapist was present. In 6/14 centers, MT activities were delivered for < 3 h/week, in 3 centers for > 3 and < 10 h/week, and in the remaining 5 for > 3 h/week. MT sessions were in different areas, day hospital, or ward (patient rooms, operating rooms, waiting rooms), on an individual basis or by groups. Patients were invited to MT by psychologists, caring physician, or nurse, or on equipé decision. MT was evaluated with tools self-made by music therapist in 11/14 centers. After COVID-19, MT has been withdrawn in 3 centers, sessions in the waiting rooms were reduced, individual sessions were preferred, and enrollment by multidisciplinary teams increased. CONCLUSION: This survey represents the starting platform to compare and discuss different experience of MT in AIEOP centers, to implement MT in pediatric oncology for a more qualified assistance to patients, and to improve quality of care. WHAT IS KNOWN: • Music therapy in pediatric oncology and palliative care can be used for the management and prevention of various somatic and psychological symptoms of patients and often is provided to children together with their families. • In Italy the application of Music therapy in the AIEOP pediatric oncology centers is constantly increasing, but due to the outbreak of Covid-19 Pandemic, Italian pediatric oncology departments were obliged to adopt restrictive measures. WHAT IS NEW: • Although the majority of Centres did not abrogate MT interventions, judgment about limitation should be carefully taken since MT helps children and even more adolescents in their fight against cancer. • The best practice of Music therapy in pediatric oncology requires communication and collaboration among qualified music therapists and multidisciplinary care team, using a model of family-centered care that actively involves parents/ caregivers in assessment, treatment planning, and care delivery.

The Involvement of Natural Polyphenols in Molecular Mechanisms Inducing Apoptosis in Tumor Cells: A Promising Adjuvant in Cancer Therapy.

Various literature data show how a diet rich in vegetables could reduce the incidence of several cancers due to the contribution of the natural polyphenols contained in them. Polyphenols are attributed multiple pharmacological actions such as anti-inflammatory, anti-oxidant, antibiotic, antiseptic, anti-allergic, cardioprotective and even anti-tumor properties. The multiple mechanisms involved in their anti-tumor action include signaling pathways modulation associated with cell proliferation, differentiation, migration, angiogenesis, metastasis and cell death. Since the dysregulation of death processes is involved in cancer etiopathology, the natural compounds able to kill cancer cells could be used as new anticancer agents. Apoptosis, a programmed form of cell death, is the most potent defense against cancer and the main mechanism used by both chemotherapy agents and polyphenols. The aim of this review is to provide an update of literature data on the apoptotic molecular mechanisms induced by some representative polyphenol family members in cancer cells. This aspect is particularly important because it may be useful in the design of new therapeutic strategies against cancer involving the polyphenols as adjuvants.

Cdk4 Regulates Glioblastoma Cell Invasion and Stemness and Is Target of a Notch Inhibitor Plus Resveratrol Combined Treatment.

Glioblastoma multiforme (GBM) is one of the most aggressive types of cancer characterized by poor patient outcomes. To date, it is believed that the major cause of its recurrence and chemoresistance is represented by the enrichment of GBM stem cells (GSCs) sustained by the abnormal activation of a number of signaling pathways. In this study, we found that in GBM cells, treatment with low toxicity doses of the γ-secretase inhibitor RO4929097 (GSI), blocking the Notch pathway activity, in combination with resveratrol (RSV) was able to reverse the basal mesenchymal phenotype to an epithelial-like phenotype, affecting invasion and stemness interplay. The mechanism was dependent on cyclin D1 and cyclin-dependent kinase (CDK4), leading to a reduction of paxillin (Pxn) phosphorylation. Consequently, we discovered the reduced interaction of Pxn with vinculin (Vcl), which, during cell migration, transmits the intracellular forces to the extracellular matrix. The exogenous expression of a constitutively active Cdk4 mutant prevented the RSV + GSI inhibitory effects in GBM cell motility/invasion and augmented the expression of stemness-specific markers, as well as the neurosphere sizes/forming abilities in untreated cells. In conclusion, we propose that Cdk4 is an important regulator of GBM stem-like phenotypes and invasive capacity, highlighting how the combined treatment of Notch inhibitors and RSV could be prospectively implemented in the novel therapeutic strategies to target Cdk4 for these aggressive brain tumors.

Hemorrhagic cystitis: a review of the literature and treatment options.

INTRODUCTION: Hemorrhagic cystitis (HC) is a morbid condition for patients and can be challenging for urologists to manage. There are many potential contributing etiologies and the severity of bleeding can be variable. It is important to consider each clinical scenario when formulating management strategies in order to provide the highest quality of care to patients. We provide a review of the literature including diagnosis and treatment options. MATERIALS AND METHODS: We performed a literature search on PubMed using the following keywords: hemorrhagic cystitis, cystitis, gross hematuria, intractable hematuria. We considered all available published articles with no specific inclusion or exclusion criteria for the purposes of this review. RESULTS: We reviewed a total of 41 articles and identified a broad differential diagnosis for intractable hemorrhagic cystitis including infection, chemical exposure, malignancy, nephropathy, trauma, radiation therapy, and idiopathic etiology. Depending on the severity of bleeding, many treatments have been described. These range from conservative strategies (bladder fulguration and continuous irrigation) to more extreme and morbid therapies (intravesical instillations, embolization, and urinary diversion). CONCLUSION: Hemorrhagic cystitis is a relatively common and can be a difficult condition to manage for urologists. It is important to understand the etiology and available treatments options in order to best treat our patients. We provide a comprehensive and thorough review of the literature and propose a stepwise treatment approach.

Notch Signaling in Breast Tumor Microenvironment as Mediator of Drug Resistance.

Notch signaling dysregulation encourages breast cancer progression through different mechanisms such as stem cell maintenance, cell proliferation and migration/invasion. Furthermore, Notch is a crucial driver regulating juxtracrine and paracrine communications between tumor and stroma. The complex interplay between the abnormal Notch pathway orchestrating the activation of other signals and cellular heterogeneity contribute towards remodeling of the tumor microenvironment. These changes, together with tumor evolution and treatment pressure, drive breast cancer drug resistance. Preclinical studies have shown that targeting the Notch pathway can prevent or reverse resistance, reducing or eliminating breast cancer stem cells. In the present review, we will summarize the current scientific evidence that highlights the involvement of Notch activation within the breast tumor microenvironment, angiogenesis, extracellular matrix remodeling, and tumor/stroma/immune system interplay and its involvement in mechanisms of therapy resistance.

Survival of patients with stage IIIC and IIID melanomas with nodal metastases in the light of new therapies.

Introduction: Within stage III melanoma prognosis and outcomes significantly vary. Advances in systemic therapy improved prognosis in metastatic melanoma. Adjuvant therapy in stage III significantly lowered relapses, although the effect on survival is less evident. Analysis of treatment results in stage IIIC and IIID before introduction of the modern adjuvant therapy, but after introduction of the effective systemic therapy in metastatic relapse, is needed. Aim: To analyse the clinical outcomes in patients with stage IIIC and IIID melanoma before the introduction of the novel adjuvant therapy. Material and methods: Consecutive stage IIIC and IIID melanoma patients treated in 2015-2018 in 4 reference centres in Poland were enrolled in the analysis of RFS and OS (in-transit metastases excluded). Median follow-up was 26.6 months (1.7-67.2). Results: There were 224 stage IIIC and 49 stage IIID patients. Recurrence was observed in 170 (62.2%); 102 (45.5%) deaths in stage IIIC and 28 (57.1%) in stage IIID were reported. RFS and OS were better in stage IIIC compared to stage IIID. RFS and OS in the IIIC group were 19.7 and 36.2 months, respectively, and in IIID - 8.9 and 27.8 months, respectively. Conclusions: The survival of patients with high-risk melanomas has improved in recent years, however, it is still unsatisfactory. The major changes in melanoma management related to the introduction of the adjuvant therapy require further careful observation.

Relevant domains and outcome measurement instruments in neuropsychiatric systemic lupus erythematosus: a systematic literature review.

OBJECTIVES: Although neuropsychiatric involvement in SLE (NPSLE) is one of the most complex and troubling manifestations of the disease, validated outcome instruments to be used as sensitive endpoints in controlled clinical trials are lacking. We performed a systematic literature review (SLR) to identify outcome measurement instruments and domains used to assess NPSLE. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used. Articles available in English (1967-2020), listed in PubMed, Embase, PsycINFO, Cochrane Library and the EULAR outcome measures library were screened. All domains and outcome measurement instruments were characterized according to the OMERACT Filter 2.1, considering core areas (manifestations/abnormalities, life impact, death/lifespan, societal/resource use) and contextual factors. RESULTS: Of 3392 abstracts evaluated, 83 studies were included in the SLR (15 974 patients, females 89.9%). Eligible studies included domains and instruments pertinent to all core areas defined by the OMERACT, except for 'societal/resource use'. The most common core areas were 'manifestations/abnormalities', covering 10 domains pertinent to laboratory and instrumental markers, indexes and neuropsychiatric dimension (cognitive, neurologic and psychiatric field), and 'life impact', covering 7 domains related to physical function (from both the perspective of the patient and the physician), pain and quality of life. CONCLUSION: Our study revealed great heterogeneity in the instruments derived from populations with NPSLE and none of these had high-quality evidence. This supports the need to develop and further validate a core domain set and outcome measurement instruments to promote clinical research in this field, enhancing comparability across studies.

Evaluation and management of female urinary incontinence.

INTRODUCTION Urinary incontinence (UI) is a common condition in all demographics of women and consists of stress UI (SUI), Urgency UI (UUI), and mixed UI (MUI). Treatment includes lifestyle modifications, medical treatment, and surgery depending on the type of UI and severity of symptoms. This review is an update on the evaluation and management of UI in women. MATERIALS AND METHODS: This review article covers the evaluation and management options for UI in women and includes the most recent guidelines from the American Urological Association (AUA) as well as recently published literature on the management of UI. RESULTS: Any evaluation of UI should include a thorough targeted history and physical, and counseling for treatment should consider patient goals and desired outcomes. For both SUI and UUI, behavioral therapy and lifestyle modifications are effective first line treatments. Patients with UUI can benefit from medical therapy which includes anticholinergics and ß3-agonist medications, as well as neuromodulation in treatment refractory patients. SUI patients may further benefit from mechanical inserts which prevent leaks, urethral bulking agents, and surgical treatments such as the mid urethral sling and autologous fascial pubovaginal sling. CONCLUSIONS: Treatment of UI in women requires a graded approach that considers patient goals and symptom severity, beginning with lifestyle and behavioral modifications before progressing to more aggressive interventions.

Surgical management of vaginal prolapse: current surgical concepts.

INTRODUCTION Pelvic organ prolapse (POP) is a condition defined by a loss of structural integrity within the vagina and often results in symptoms which greatly interfere with quality of life in women. POP is expected to increase in prevalence over the coming years, and the number of patients undergoing surgery for POP is expected to increase by up to 13%. Two categories of surgery for POP include obliterative and reconstructive surgery. Patient health status, goals, and desired outcomes must be carefully considered when selecting a surgical approach, as obliterative surgeries result in an inability to have sexual intercourse postoperatively. MATERIALS AND METHODS: This review article covers the role of traditional native tissue repairs, surgical options and techniques for vaginal and abdominal reconstruction for POP and the associated complications, and considerations for prevention and management of post-cystectomy vaginal prolapse. RESULTS: Studies comparing native and augmented anterior repairs demonstrate better anatomic outcomes in patients with mesh at the cost of more surgical complications, while different procedures for posterior repair result in similar improvements in symptoms and quality of life. In the management of apical prolapse, vaginal obliterative repair, namely colpocleisis, results in very low risk of recurrence at the cost of the impossibility of having sexual intercourse postoperatively. Reconstructive procedures preserve vaginal length along with the ability to have intercourse, but show higher failure rates over time. They can be divided into vaginal approaches which include sacrospinous ligament fixation (SSLF) and uterosacral vaginal vault suspension (USVS), and the abdominal approach which primarily includes abdominal sacrocolpopexy (ASC). There is evidence that ASC confers a distinct advantage over vaginal approaches with respect to symptom recurrence, sexual function, and quality of life. Patients who have had radical cystectomy for bladder cancer are at an increased risk of POP, and may benefit from preventative measures and prophylactic repair during surgery. Importantly, the success rates of POP surgery vary depending on whether anatomic or clinical definitions of success are used, with success rates improving when metrics such as the presence of symptoms are incorporated. CONCLUSIONS: The surgical management of POP should greatly take into account the postoperative goals of every patient, as different approaches result in different sexual and quality of life outcomes. It is important to consider clinical metrics in the evaluation of success for POP surgery as opposed to using exclusively anatomic criteria. Preoperative counseling is critical in managing expectations and increasing patient satisfaction postoperatively.

Impact of cuddler service-learning program in medical student education of opioid use disorder in pregnancy and neonatal opioid withdrawal syndrome.

Background: Given the increasing incidence of neonatal opioid withdrawal syndrome (NOWS), medical student training on substance use disorders (SUDs) and opioid use disorder (OUD) in pregnancy must be augmented. Through the Cuddling Assists in Lowering Maternal and Infant Stress (CALM) service-learning program, medical students attend SUD-related didactics and provide monthly cuddling services to infants with NOWS. Objective: This study examines the impact of CALM on medical students' attitudes toward individuals with SUDs and self-reported comfort with clinical skills related to caring for this population. Methods: Self-reported pre- and post-survey data was collected at the beginning and end of an academic year from the intervention group, CALM cuddlers, and the control group, non-cuddlers for 2 years. Mean total survey scores and individual survey questions using a 3-point Likert scale were compared before and after 1 year of participation for cuddlers and for non-cuddlers using paired t-tests and two sample t-tests. Results: The mean total score increased for cuddlers after participation in the intervention (MD 0.13, SD 0.26, p = 0.03). Mean scores for the comfort-related subset of questions also increased significantly for cuddlers after participation in the intervention (MD 0.22, SD 0.41, p = 0.01). Cuddlers felt more comfortable discussing substance use with appropriate language (72.0% vs 51.5%, p = 0.03), talking with patients about substance use (72.0% vs 36.0%, p = 0.01), and asking about substance use or recovery (80.0% vs 48.0%, p = 0.01). Conclusion: OUD- and NOWS-related service-learning positively impacts student attitudes and self-reported comfort with skills related to caring for individuals with SUDs, such as communicating about substance use.

One year in review 2020: novelties in the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) management is driven by evidence, and new 2019 EULAR recommendations help in refining the relevant place of different disease-modifying anti-rheumatic drugs (DMARDs) in treatment schedules. At present, new drugs are in phase of development, mainly Janus Kinase inhibitors (JAKis), however, specific treatment strategies seem to count more than individual DMARDs in terms of treatment responses, given the substantial lack of head-to-head comparisons between specific biological (b) and targeted synthetic (ts)DMARDs, and with the general perception of a similar efficacy profile across drugs. In this setting, when reliable biomarkers able to predict treatment responses are lacking, treatment decisions are mainly driven by specific clinical or individual factors, given the recognised role of comorbidities, treatment-specific side effects, patients' preferences, and costs on drug choice. In this narrative review, the authors give their specific point of view on the management of RA, based on a critical revision of the literature published in 2019, focusing on relevant novelties and future research directions.

Posaconazole delayed-release tablets in paediatric haematology-oncology patients.

BACKGROUND: To date, there are few studies that describe pharmacokinetics, safety and efficacy of posaconazole delayed-release tablet (DRT) formulation in the paediatric population. OBJECTIVES: We evaluated retrospectively posaconazole plasma concentrations and safety of posaconazole DRT in paediatric haematology-oncology patients. PATIENTS AND METHODS: Posaconazole DRT was assessed in 28 haematological paediatric patients with a median age 15 of years (range 5-18) and a median body weight of 50 kg (range 22-83 kg). Twenty-one patients received posaconazole DRT as prophylaxis and 7 patients as therapy. RESULTS: As prophylaxis, the median daily dose was 5.5 mg/kg/day (range 2.2-22.2) with posaconazole trough level ≥ 0.7 µg/mL in 80% by first week, 62.5% by second week and 87.5% by fourth week. As therapy, the median daily dose was 4 mg/kg/day (range 3.3-4.5) with trough level ≥ 1 µg/mL 100% by first week, 80% by second week and 33.4% by fourth week. CONCLUSIONS: Posaconazole DRT is feasible in paediatric patients capable to swallow tablets. Specific pharmacokinetic studies are needed.

Optimizing Intersession Reliability of Heart Rate Variability-The Effects of Artifact Correction and Breathing Type.

Gisselman, AS, D'Amico, M, and Smoliga, JM. Optimizing intersession reliability of heart rate variability-the effects of artifact correction and breathing type. J Strength Cond Res 34(11): 3199-3207, 2020-This study aimed to comprehensively investigate the reliability of multiple heart rate variability (HRV) parameters and to explore the influence of artifact removal and breathing condition on HRV reliability. Resting HRV was collected using Polar Team monitors on 41 participants (age: 19.9 ± 1.2 years; 28 females and 13 males) during 2 separate days. Within each session, participants performed 10 minutes each of spontaneous and controlled breathing (randomized order). Kubios HRV analysis software was used to analyze 180-second data epochs using "low" or "strong" artifact removal. Relative reliability was assessed using intraclass correlation coefficient (ICC2,1), and absolute reliability was quantified using mean-normalized SEM%. Time-domain and nonlinear parameters produced poor to good intersession agreement (ICC = 0.34-0.68; SEM% = 11.0-39.0) with "low" artifact removal, regardless of breathing condition. Frequency-domain parameters demonstrated fair intersession agreement during controlled breathing (ICC = 0.40-0.45; SEM% = 26.0-70.0) but poor agreement during spontaneous breathing (ICC = 0.07-0.13; SEM% = 32.0-81.0). Minimal differences in ICCs were observed between "low" and "strong" artifact removal. Thus, this study provides 3 practical applications: (a) HRV monitoring is most reliable when using time-domain and nonlinear parameters, regardless of breathing or filtering condition, but no single parameter is especially reliable. The large variation and poor intersession reliability of frequency indices during spontaneous breathing are improved by controlling breathing rate; (b) "Low" artifact removal seems superior to more aggressive artifact removal; and (c) intersession differences in HRV measurements <30% may be indicative of normal daily variation rather than true physiologic changes.

Surgical management of retained needle in a transgender woman's phallus.

Intracavernosal self-injection (ICI) is an effective treatment for erectile dysfunction. A rare but serious complication is needle breakage. We report an unusual case of a 51-year-old transgender female patient who did not desire gender-affirming surgery, and used ICI to treat her longstanding erectile dysfunction. She presented to the emergency department 2 months after needle breakage during ICI, and was subsequently successfully treated with intraoperative fluoroscopy and needle fragment extraction. It is important to recognize transgender patients may desire to preserve sexual function, and for providers to engage in discussion surrounding sexual health throughout treatment for gender dysphoria.

A comparative effectiveness trial of two faecal immunochemical tests for haemoglobin (FIT). Assessment of test performance and adherence in a single round of a population-based screening programme for colorectal cancer.

AIM: To compare acceptability and diagnostic accuracy of a recently available faecal immunochemical test (FIT) system (HM-JACKarc) with the FIT routinely used in an established screening programme (OC-Sensor). DESIGN: Randomised controlled trial (ISRCTN20086618) within a population-based colorectal cancer (CRC) screening programme. Subjects eligible for invitation in the Umbria Region (Italy) programme were randomised (ratio 1:1) to be screened using one of the FIT systems. RESULTS: Screening uptake among the 48 888 invitees was the same for both systems among subjects invited in the first round and higher with OC-Sensor than with HM-JACKarc (relative risk (RR): 1.03; 95% CI 1.02 to 1.04) among those invited in subsequent rounds. Positivity rate (PR) was similar with OC-Sensor (6.5%) as with HM-JACKarc (6.2%) among subjects performing their first FIT screening and higher with OC-Sensor (5.6%, RR: 1.25, 95% CI 1.12 to 1.40) than with HM-JACKarc (4.4%) among those screened in previous rounds. Positive predictive value (PPV) (OC-Sensor: 25.9%, HM-JACKarc: 25.6%) and detection rate (DR) (OC-Sensor: 1.40%; HM-JACKarc: 1.42%) for advanced neoplasia (AN: CRC + advanced adenoma) were similar among subjects performing their first FIT screening. The differences in the AN PPV (OC-Sensor: 20.3%, HM-JACKarc: 22.6%) and DR (OC-Sensor: 0.96%, HM-JACKarc: 0.83%) among those screened in previous rounds were not statistically significant. The number needed to scope to detect one AN was 3.9 (95% CI 5.8 to 2.9) and 3.9 (95% CI 5.5 to 2.9) at first and 4.9 (95% CI 5.8 to 4.2) and 4.4 (95% CI 5.3 to 3.7) at subsequent screening, with OC-Sensor and HM-JACKarc, respectively. CONCLUSIONS: Our results suggest that acceptability and diagnostic performance of HM-JACKarc and of OC-Sensor systems are similar in a screening setting. TRIAL REGISTRATION NUMBER: ISRCTN20086618; Results.

Prognostic Value of Lymphocyte G Protein-Coupled Receptor Kinase-2 Protein Levels in Patients With Heart Failure.

RATIONALE: Sympathetic nervous system hyperactivity is associated with poor prognosis in patients with heart failure (HF), yet routine assessment of sympathetic nervous system activation is not recommended for clinical practice. Myocardial G protein-coupled receptor kinase-2 (GRK2) is upregulated in HF patients, causing dysfunctional ß-adrenergic receptor signaling. Importantly, myocardial GRK2 levels correlate with levels found in peripheral lymphocytes of HF patients. OBJECTIVE: The independent prognostic value of blood GRK2 measurements in HF patients has never been investigated; thus, the purpose of this study was to evaluate whether lymphocyte GRK2 levels predict clinical outcome in HF patients. METHODS AND RESULTS: We prospectively studied 257 HF patients with mean left ventricular ejection fraction of 31.4±8.5%. At the time of enrollment, plasma norepinephrine, serum NT-proBNP, and lymphocyte GRK2 levels, as well as clinical and instrumental variables were measured. The prognostic value of GRK2 to predict cardiovascular (CV) death and all-cause mortality was assessed using the Cox proportional hazard model including demographic, clinical, instrumental, and laboratory data. Over a mean follow-up period of 37.5±20.2 months (range, 3-60 months), there were 102 CV deaths. Age, left ventricular ejection fraction, New York Heart Association class, chronic obstructive pulmonary disease, chronic kidney disease, N-terminal-pro brain natriuretic peptide, and lymphocyte GRK2 protein levels were independent predictors of CV mortality in HF patients. GRK2 levels showed an additional prognostic and clinical value over demographic and clinical variables. The independent prognostic value of lymphocyte GRK2 levels was also confirmed for all-cause mortality. CONCLUSIONS: Lymphocyte GRK2 protein levels can independently predict prognosis in patients with HF.

IL-6 Activates PI3K and PKCζ Signaling and Determines Cardiac Differentiation in Rat Embryonic H9c2 Cells.

INTRODUCTION: IL-6 influences several biological processes, including cardiac stem cell and cardiomyocyte physiology. Although JAK-STAT3 activation is the defining feature of IL-6 signaling, signaling molecules such as PI3K, PKCs, and ERK1/2 are also activated and elicit different responses. Moreover, most studies on the specific role of these signaling molecules focus on the adult heart, and few studies are available on the biological effects evoked by IL-6 in embryonic cardiomyocytes. AIM: The aim of this study was to clarify the biological response of embryonic heart derived cells to IL-6 by analyzing the morphological modifications and the signaling cascades evoked by the cytokine in H9c2 cells. RESULTS: IL-6 stimulation determined the terminal differentiation of H9c2 cells, as evidenced by the increased expression of cardiac transcription factors (NKX2.5 and GATA4), structural proteins (α-myosin heavy chain and cardiac Troponin T) and the gap junction protein Connexin 43. This process was mediated by the rapid modulation of PI3K, Akt, PTEN, and PKCζ phosphorylation levels. PI3K recruitment was an upstream event in the signaling cascade and when PI3K was inhibited, IL-6 failed to modify PKCζ, PTEN, and Akt phosphorylation. Blocking PKCζ activity affected only PTEN and Akt. Finally, the overexpression of a constitutively active form of PKCζ in H9c2 cells largely mimicked the morphological and molecular effects evoked by IL-6. CONCLUSIONS: This study demonstrated that IL-6 induces the cardiac differentiation of H9c2 embryonic cells though a signaling cascade that involves PI3K, PTEN, and PKCζ activities.