COntrolling NUTritional Status (CONUT) as Predictive Score of Hospital Length of Stay (LOS) and Mortality: A Prospective Cohort Study in an Internal Medicine and Gastroenterology Unit in Italy.

BACKGROUND: Hospital malnutrition affects nearly 30% of patients in medical wards and correlates with worse outcomes. An early assessment is necessary to stratify the risk of short-term outcomes and mortality. The predictive role of COntrolling NUTritional status (CONUT) score in this context has not yet been elucidated in Western countries. We aimed to test CONUT at admission as a predictive score of hospital outcomes, in an Internal Medicine and Gastroenterology Department of an Italian Tertiary Care University hospital. METHODS: We prospectively enrolled patients admitted to our center, stratifying them into the four CONUT classes (normal = 0-1; mild = 2-4; moderate = 5-8; severe = 9-12 points) according to serum albumin (g/dL), total lymphocyte count (/mm3), and total cholesterol (mg/dL); the primary outcome measure was length of stay (LOS) and the secondary one was in-hospital mortality. RESULTS: Out of a total of 203 patients enrolled, 44 (21.7%) patients had a normal status (0-1), 66 (32.5%) had a mild impairment (2-4), 68 (33.5%) had a moderate impairment (5-8), and 25 (12.3%) a severe impairment (9-12). The mean LOS was 8.24 ± 5.75 days; nine patients died. A moderate-severe CONUT correlated with a higher LOS at the univariate [HR 1.86 (95% CI 13.9-3.47); p < 0.0001] and multivariate analysis [HR 1.52 (95% CI 1.10-2.09); p = 0.01]. The CONUT score was also a predictor of mortality, with an AUC of 0.831 (95% CI 0.680-0.982) and with an optimal cut-off at 8.5 points. Nutritional supplementation within 48 h from admission correlated with lower mortality [OR 0.12 (95% CI 0.02-0.56) p = 0.006]. CONCLUSIONS: CONUT is a reliable and simple predictor of LOS and in-hospital mortality in medical wards.

Incidence and Impact of Refeeding Syndrome in an Internal Medicine and Gastroenterology Ward of an Italian Tertiary Referral Center: A Prospective Cohort Study.

Background: Refeeding syndrome (RS) is a neglected, potentially fatal syndrome that occurs in malnourished patients undergoing rapid nutritional replenishment after a period of fasting. The American Society for Parenteral and Enteral Nutrition (ASPEN) recently released new criteria for RS risk and diagnosis. Real-life data on its incidence are still limited. Methods: We consecutively enrolled patients admitted to the Internal Medicine and Gastroenterology Unit of our center. The RS risk prevalence and incidence of RS were evaluated according to ASPEN. The length of stay (LOS), mortality, and re-admission rate within 30 days were assessed. Results: Among 203 admitted patients, 98 (48.3%) were at risk of RS; RS occurred in 38 patients (18.7% of the entire cohort). Patients diagnosed with RS had a higher mean LOS (12.5 days ± 7.9) than those who were not diagnosed with RS (7.1 ± 4.2) (p < 0.0001). Nine patients (4.4%) died. Body mass index (OR 0.82; 95% CI 0.69−0.97), RS diagnosis (OR 10.1; 95% CI 2.4−42.6), and medical nutritional support within 48 h (OR 0.12; 95% CI 0.02−0.56) were associated with mortality. Conclusions: RS incidence is high among clinical wards, influencing clinical outcomes. Awareness among clinicians is necessary to identify patients at risk and to support those developing this syndrome.

Current Competencies of Game Facilitators and Their Potential Optimization in Higher Education: Multimethod Study.

BACKGROUND: Serious games can be a powerful learning tool in higher education. However, the literature indicates that the learning outcome in a serious game depends on the facilitators' competencies. Although professional facilitators in commercial game-based training have undergone specific instruction, facilitators in higher education cannot rely on such formal instruction, as game facilitation is only an occasional part of their teaching activities. OBJECTIVE: This study aimed to address the actual competencies of occasional game facilitators and their perceived competency deficits. METHODS: Having many years of experience as professional and occasional facilitators, we (n=7) defined requirements for the occasional game facilitator using individual reflection and focus discussion. Based on these results, guided interviews were conducted with additional occasional game facilitators (n=4) to check and extend the requirements. Finally, a group of occasional game facilitators (n=30) answered an online questionnaire based on the results of the requirement analysis and existing competency models. RESULTS: Our review produced the following questions: Which competencies are needed by facilitators and what are their training needs? What do current training courses for occasional game facilitators in higher education look like? How do the competencies of occasional game facilitators differ from other competencies required in higher education? The key findings of our analysis are that a mix of managerial and technical competencies is required for facilitating serious games in higher educational contexts. Further, there is a limited or no general competence model for game facilitators, and casual game facilitators rarely undergo any specific, formal training. CONCLUSIONS: The results identified the competencies that game facilitators require and a demand for specific formal training. Thus, the study contributes to the further development of a competency model for game facilitators and enhances the efficiency of serious games.

Dengue Surveillance System in Brazil: A Qualitative Study in the Federal District.

Dengue's increasing trends raise concerns over global health and pose a challenge to the Brazilian health system, highlighting the necessity of a strong surveillance system to reduce morbidity, mortality, and the economic burden of this disease. Although the Brazilian surveillance system reports more dengue cases than any other country, recent studies suggest that non-reported cases are the majority. The aim of the study is to explore the strengths and weaknesses of the Brazilian surveillance system, particularly looking at the functioning of data collection and reporting. This was done through qualitative semi-structured interviews with 17 experts in dengue surveillance, supported by quantitative data from the official notification system. To select the interviewees, purposive and theoretical sampling were used. Data were analyzed through thematic analysis. The research highlighted that a lack of human and technological resources in healthcare units and surveillance departments slows down the notification process and data analysis. Due to a lack of integration in the private sector, the surveillance system fails to detect the socioeconomic profile of the patients. Investments in public healthcare, human and technological resources for surveillance and better integration in the private healthcare system, and vector surveillance may improve dengue surveillance.

The prevalence and correlates of low sexual functioning in women on hemodialysis: A multinational, cross-sectional study.

Sexual dysfunction may affect 80% of women in hemodialysis. However the specific patterns and clinical correlates of sexual functioning remain poorly described. The aim of this study was to assess prevalence and correlates of the individual domains of sexual functioning in women treated with hemodialysis. We recruited, into this multinational cross-sectional study, women treated with long-term hemodialysis (Collaborative Working Group on Depression and Sexual dysfunction in Hemodialysis study). Self-reported domains of sexual functioning were assessed by the Female Sexual Function Index, which is routinely administered within the network of dialysis patients followed by the working group. Lower scores represented lower sexual functioning. Socio-demographic and clinical correlates of each domain of sexual functioning were identified by stepwise multivariable linear regression. Sensitivity analyses were restricted to women who reported being sexually active. We found that of 1309 enrolled women, 659 (50.3%) provided complete responses to FSFI survey questions and 232 (35%) reported being sexually active. Overall, most respondents reported either no sexual activity or low sexual functioning in all measured domains (orgasm 75.1%; arousal 64.0%; lubrication 63.3%; pain 60.7%; satisfaction 60.1%; sexual desire 58.0%). Respondents who were waitlisted for a kidney transplant reported scores with higher sexual functioning, while older respondents reported scores with lower functioning. The presence of depression was associated with worse lubrication and pain scores [mean difference for depressed versus non-depressed women (95% CI) -0.42 (-0.73 to -0.11), -0.53 (-0.89 to -0.16), respectively] while women who had experienced a previous cardiovascular event reported higher pain scores [-0.77 (-1.40- to -0.13)]. In conclusion, women in hemodialysis reported scores consistent with marked low sexual functioning across a range of domains; the low functioning appeared to be associated with comorbidity.

Tp53-gene transfer induces hypersensitivity to low doses of X-rays in glioblastoma cells: a strategy to convert a radio-resistant phenotype into a radiosensitive one.

Tp53 is frequently mutated or inactivated in glioblastomas. Due to the impairment of p53 activity, glioblastomas show a high degree of radioresistance. In an attempt to convert the radioresistant phenotype to a more radiosensitive one, we evaluated the efficacy of the combination of Adp53 gene transfer and X-ray irradiation. The combination of Adp53, at low multiplicity in order to mimic the low in vivo efficiency of virus-mediated gene delivery, with X-ray irradiation resulted in a marked decrease of glioblastoms cell survival. Interestingly, Adp53 was able to induce low dose (<2Gy) hypersensitivity. The data suggest the possibility for the development of new therapeutic strategies.

[Clopidogrel- induced hepatotoxicity in hemodialyzed patient: a case report]. / Epatotossicità da clopidogrel in emodializzato: caso clinico.

Drug-induced liver injury is a frequent cause of acute liver failure. It may cause clinical manifestations ranging from simple alteration of the common liver function tests until more severe manifestations including encephalopathy, coagulopathy, and in many cases progressive multi-organ dysfunction. The condition, therefore, may be associated with higher morbidity and mortality as well as higher consumption of economic resources. In this paper, we present the case of a 71-year-old patient treated with hemodialysis, diabetic, with ischemic cardiopathy and severe peripheral vascular disease. The patient presented a progressive clinical deterioration with the development of ascites, jaundice and significant deterioration of liver function. Diagnostic studies have ruled out viral and immunological diseases and, in agreement with the score obtained from the Maria and Victorino scale, clopidogrel was identified as the major factor responsible for the damage. After the suspension of the drug, the follow-up has led to the complete and stable recovery of liver function.

MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts.

MDMX is a p53 binding protein, which shares a high degree of homology with MDM2, a negative regulator of the tumor suppressor p53. MDMX has been shown to counteract MDM2-dependent p53 degradation and to stabilize p53 in its inactive form. In this study: we identify two MDMX proteolytic pathways that control its intracellular levels, and show that MDMX post-translational processing may be regulated by p53. Mouse MDMX is cleaved in vitro and in vivo by caspase activity, between aminoacids 358 and 361, producing a p54 minor form. In addition, MDMX is subjected to proteasome-mediated degradation, which concurs to MDMX proteolysis mainly through degradation of p54. A D361A-MDMX mutant, resistant to caspase cleavage, exhibits prolonged intracellular lifetime in comparison to wild-type protein, indicating that caspase cleavage affects stability of MDMX protein probably by modulating its further degradation. Overexpression of exogenous p53 increases the intracellular levels of p54 product. Similarly, activation of endogenous p53 by adriamycin enhances MDMX cleavage and produces a marked decrease of its intracellular levels, while not affecting the D361A-MDMX mutant. In addition, the D361A-MDMX mutant lacks the ability to inhibit p53 transactivation in respect to wild-type MDMX, suggesting that MDMX caspase cleavage play an important functional role. In conclusion, our results demonstrate that, in analogy to MDM2, MDMX may be subjected to proteolytic modifications that regulate its intracellular levels. Moreover, decrease of MDMX protein levels following p53 activation suggests a p53-dependent regulatory feedback of MDMX function.

Loss of Ca2+/calmodulin kinase kinase beta affects the formation of some, but not all, types of hippocampus-dependent long-term memory.

Long-term memory (LTM) requires activation of the transcription factor cAMP-responsive element binding protein (CREB). Signaling by the Ca2+/calmodulin (CaM) kinase cascade has been implicated in CREB activation and memory consolidation processes in the hippocampus. The CaM kinase kinase beta isoforms belong to the CaM kinase cascade, and we have generated null mutant mice to investigate the role of these kinases in several forms of learning and memory. The null mutants were impaired in spatial training-induced CREB activation and spatial memory formation. Furthermore, the mutants lacked late, but not early, long-term potentiation at the hippocampal CA1 synapse, and they were impaired in LTM, but not short-term memory, for the social transmission of food preferences. We suggest that the CaM kinase kinasebeta isoforms are required for the formation of hippocampal LTM. Surprisingly, however, these kinases were not needed for contextual, trace fear, and passive avoidance LTM. Our results demonstrate that different signaling processes underlie the formation of these types of hippocampal LTM.

The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation.

Hyperphosphorylation of the microtubule-associated protein tau is a characteristic feature of neurodegenerative tauopathies including Alzheimer disease. Over-activation of proline-directed kinases, such as cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3 (GSK3), has been implicated in the aberrant phosphorylation of tau at proline-directed sites. In this study we tested the roles of Cdk5 and GSK3 in tau hyperphosphorylation in vivo using transgenic mice with p25-induced Cdk5 over-activation. We found that over-activation of Cdk5 in young transgenic animals does not induce tau hyperphosphorylation at sites recognized by the antibodies AT8, AT100, PHF-1, and TG3. In fact, we observed that Cdk5 over-activation leads to inhibition of GSK3. However, in old transgenic animals the inhibition of GSK3 is lost and results in increased GSK3 activity, which coincides with tau hyperphosphorylation at the AT8 and PHF-1 sites. Pharmacological inhibition of GSK3 in old transgenic mice by chronic treatment with lithium leads to a reduction of the age-dependent increase in tau hyperphosphorylation. Furthermore, we found that Cdk5, GSK3, and PP2A co-immunoprecipitate, suggesting a functional association of these molecules. Together, these results reveal the role of GSK3 as a key mediator of tau hyperphosphorylation, whereas Cdk5 acts as a modulator of tau hyperphosphorylation via the inhibitory regulation of GSK3. Furthermore, these findings suggest that disruption of regulation of GSK3 activity underlies tau hyperphosphorylation in neurodegenerative tauopathies. Hence, GSK3 may be a prime target for therapeutic intervention in tauopathies including Alzheimer disease.

Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory.

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase with a multitude of functions. Although Cdk5 is widely expressed, it has been studied most extensively in neurons. Since its initial characterization, the fundamental contribution of Cdk5 to an impressive range of neuronal processes has become clear. These phenomena include neural development, dopaminergic function and neurodegeneration. Data from different fields have recently converged to provide evidence for the participation of Cdk5 in synaptic plasticity, learning and memory. In this review, we consider recent data implicating Cdk5 in molecular and cellular mechanisms underlying synaptic plasticity. We relate these findings to its emerging role in learning and memory. Particular attention is paid to the activation of Cdk5 by p25, which enhances hippocampal synaptic plasticity and memory, and suggests formation of p25 as a physiological process regulating synaptic plasticity and memory.

Improved reversal learning and altered fear conditioning in transgenic mice with regionally restricted p25 expression.

Cleavage of the cyclin-dependent kinase 5 activator p35 generates the protein fragment p25, which accumulates in the forebrain of patients with Alzheimer's disease. Although p25 expression has been suggested to affect learning and memory, this hypothesis has not been tested to date. To investigate the role of p25 in hippocampus-dependent learning and memory we have generated transgenic mice expressing p25 preferentially in postnatal forebrain. p25 expression was highest in hippocampus where it averaged approximately 33% of endogenous p35 expression. This low level of p25 expression did not seem to result in hyperphosphorylation of tau, but increased the phosphorylation of neurofilament M and enhanced the expression of tau protein. These molecular changes did not correlate with neurodegeneration or motor abnormalities. In the Morris water maze the p25 mutants were normal in learning an initial platform location, but surprisingly reversal learning was improved when the platform position was changed. The p25 mutants were normal in contextual fear conditioning. However, when trained with a tone presentation the mutants showed reduced contextual conditioning and enhanced tone fear conditioning. We conclude that low p25 expression has pleiotropic effects on learning and memory. As p25 expression can improve learning and memory, p25 formation could be a compensatory mechanism for learning and memory deficits in Alzheimer's disease.

MDM4 (MDMX) overexpression enhances stabilization of stress-induced p53 and promotes apoptosis.

Rescue of embryonic lethality in MDM4(-/-) mice through concomitant loss of p53 has revealed a functional partnership between the two proteins. Biochemical studies have suggested that MDM4 may act as a negative regulator of p53 levels and activity. On the other hand, MDM4 overexpression has been reported to stabilize p53 levels and to counteract MDM2-degradative activity. We have investigated the functional role of MDM4 overexpression on cell behavior. In both established and primary cells cultured under stress conditions, overexpression of MDM4 significantly increased p53-dependent cell death, in correlation with enhanced induction of the endogenous p53 protein levels. This phenomenon was associated with induced p53 transcriptional activity and increased levels of the proapoptotic protein, Bax. Further, p53 stabilization was accompanied by decreased association of the protein to its negative regulator, MDM2. These findings reveal a novel role for MDM4 by demonstrating that in non-tumor cells under stress conditions it may act as a positive regulator of p53 activity, mainly by controlling p53 levels. They also indicate a major distinction between the biological consequences of MDM4 and MDM2 overexpression.

Estudo nåo-comparativo sobre o sevoflurano na anestesia de pacientes adultos ambulatóriais / A non-comparative study on sevoflurane in adult outapatients

Background and objectives - Sevoflurane is a new inhalational anesthetic with short induction and recovery times, which make it appropriate for outpatient surgery. The purpose of this study is to present our experience with sevoflurane in adult outpatients. Methods - Sevoflurane was used for maintenance of anesthesia in 40 adult patients, with age range of 30.9 +- 10.5 years and ASA physical status I or II, undergoing ambulatory procedures. Induction of anesthesia was obtained with midazolam 0.25 mg/Kg-1 and alfetanil 30 ug/Kg-1 and the patients were maintained with N2O/O2 (60/40 per cent), under tracheal intubation and controlled mechanical vntilation, in a rebreating system with CO2 absorption. Sevoflurane was administered via the Ohmeda Sevotec 5 vaporizer. Monitoring included SpO2, PETCO2, ETN2O, and ETSEVO, with the aid of the CapnomacOhmeda Datex. Systol;ic and diastolic blood pressure and heart rate were registered at the following moments: 1) one minute before induction; 2) one minute after tracheal intubation; 3) one minute before surgical incision; 4) five minutes after surgical incision; 5) ten minutes after discontinuation of sevoflurane. The following parameters related to recovery from anesthesia were studied: awakening time, time to verbal command, time to orientation, time to liberation from phase I, time to liberation from phase II (hospital discharge). Time of exposure to sevoflurane and untoward effects were also registered. Results - Mean time of exposure to sevoflurane was 81.1 +- 43.9 min and mean values of end tidal sevoflurane were 1.07 +- 0.40 per cent one miute after tracheal intubation, 1.75 +- 0.38 per cent one minute before surgical incision and 1.85 +- 0.61 per cent five minutes after surgical incision. Recovery times from anesthesia were as follows: awakening 19.1 +- 9.5 min; response to command 21.8 +- 11.2 min; orientation 26.8 +- 11.5 min; phase I 53.2 +- 9.7 min; phase II 144.9 +- 41.7 min. Hypotension (decrease in SBP greater than 30 per cent of pre induction values) ocurred in 17 patients (42.5 per cent) and was promptly controlled by reducing the inspired concentration of sevoflurane. Awareness did not occur and acceptance was good in all cases. Conclusions - The fast recovery and the low incidence of untoward effects indicate that sevoflurane is an appropriate anesthetic for outpatients

Estudo comparativo sobre sevoflurano e halotano na induçåo e manutençåo de anestesia pediátrica ambulatorial / A comparative study of sevoflurane versus halothane dor induction and maintance of anesthesia in pediatric outopatients

Background and objectives - Sevoflurane is a new anhalational agent with low blood solubility which provides rapid induction and recovery, desirable characteristics in outpatient anesthesia. The aim of this study was to compare sevoflurane and halothane regarding quality of induction, cardiovascular stability and characteristics of post-anesthetic recovery in pediatric outpatients. Methods - Forty-one physical status ASA I pediatric outpatients were allocated into two groups, as they received sevoflurane or halothane in N2O/O2 (50/50 per cent) for induction and maintenance of anesthesia. Orotracheal intubation was performed after a sigle dose of succinylcholine. Monitoring throughout the study included PET CO2, ET N2O, ET O2, ET SEVO, ET HALO, SBP, DBP and HR. Results - Exposure time to the anesthetics were similar in both groups. There were no significant differences in induction times between the groups. Times to eye opening, to obey command, to orientation, and to discharge from phase I recovery were significantly shorter in the sevoflurane group as compared to the halothane group. Time to discharge from phase II recovery was also shorter in the sevoflurane group, although not statistically significant. The incidence of adverse effects was similar in both groups. Cardiovascular stability was good with both agents. Conclusions - The smooth and rapid induction, the good cardiovascular stability and the relatively low incidence of adverse effects make sevoflurane a good anesthetic for pediatric outpatients. The results of thie study regarding postanesthetic recovery time indicate some advantage of sevoflurane over halothane. Nevertheless, the early arousal causes intense pain perception soon after discontinuation of the anesthetic, thus requiring an effective method of postoperative analgesia

Sufentanil em infusåo venosa contínua para cirurgias abdominais / Continuous intravenous infusion of sufentanil for abdomianal surgery

Background and Objectives - Sufentanil is 5 to 10 times more potent than fentanyl and this property parallels its greateraffinity for opioid receptors. The aims of thisnon-comparative study were to determine the dose requirements of sufentanil used as part of a balanced technique and to evaluate the cardiovascular consequences and the recovery from anesthesia following its use. Methods - Fifty adult ASA physical status I-II patients, aged 41.02 +- 11.45 years undergoing elective intra-abdominal surgeries were studied. Anesthesia was induced with midazolam 0.2 mg.Kg-1 and sufentanil 3.0 ug.Kg-1, followed by pancuronium and tracheal intubation. Patients received N2O/O2 (50/50 per cenmt) and were maintained under mechanical controlled ventilation in a rebreathing circuit with CO2 absorbant. Sufentanil infusion rate was adjusted in order to avoidsigns of light anesthesia. Both the opioid and N2O were discontinued 10 min before the presumed end surgery. Using non-invasive methods, systolic (SAP), diastolic (DAP) and mean (MAP) arterial pressure, heart rate (HR) and oxygen saturation (SpO2) were monitored throughout the procedure. Total consumption of sufentanil and infusion rate requirements were evaluated, as well as duration and quality anesthesia recovery, residual analgesia and perioperative complications. Results - The mean duration of the procedures was 162.42+-69.16 min, the mean total dose of sufentanil was 6.78+-2.29 ug.Kg-1 and the mean infusion rate was 0.024+-0.06 ug.Kg-1. The mean time for recovery to stage IV (well oriented in time and space) was 39.88+-13.95 min. Forty patients (80 per cent) required naloxone to antagonize respiratory depression 30 minafter the discontinuation of opioid infusion. Despiste the reduction in SAP, DAP and MAP following induction, tracheal intubation and surgical incision, there was good cardiovascular stability. Residual analgesia lasting more than 6 hours after discontinuation of sufentanil was observed in 66 per cent of the patients. Conclusions - The technique provides good anesthesia for intra-abdominal surgeries. In order to avoid light anesthesia, sufentanil infusion rate should be titrated for each patient. The high incidence of respiratory depression in the immediate postoperative period requires special observation of these patients in the recovery room