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Background: Clinical practice guidelines (CPGs) have teaching potential for health professionals in training clinical reasoning and decision-making, although their use is limited. The objective was to evaluate the effectiveness of a game-based educational strategy e-EDUCAGUIA using simulated clinical scenarios to implement an antimicrobial therapy GPC compared to the usual dissemination strategies to improve the knowledge and skills on decision-making of family medicine residents. Additionally, adherence to e-EDUCAGUIA strategy was assessed., Methods: A multicentre pragmatic cluster-randomized clinical trial was conducted involving seven Teaching Units (TUs) of family medicine in Spain. TUs were randomly allocated to implement an antimicrobial therapy guideline with e-EDUCAGUIA strategy ( intervention) or passive dissemination of the guideline (control). The primary outcome was the differences in means between groups in the score test evaluated knowledge and skills on decision-making at 1 month post intervention. Analysis was made by intention-to-treat and per-protocol analysis. Secondary outcomes were the differences in mean change intrasubject (from the baseline to the 1-month) in the test score, and educational game adherence and usability. Factors associated were analysed using general linear models. Standard errors were constructed using robust methods., Results: Two hundred two family medicine residents participated (104 intervention group vs 98 control group). 100 medicine residents performed the post-test at 1 month (45 intervention group vs 55 control group), The between-group difference for the mean test score at 1 month was 11 ( 8.67 to 13.32) and between change intrasubject was 11,9 ( 95% CI 5,9 to 17,9). The effect sizes were 0.88 and 0.75 respectively. In multivariate analysis, for each additional evidence-based medicine training hour there was an increase of 0.28 points (95% CI 0.15-0.42) in primary outcome and in the change intrasubject each year of increase in age was associated with an improvement of 0.37 points and being a woman was associated with a 6.10-point reduction. 48 of the 104 subjects in the intervention group (46.2%, 95% CI: 36.5-55.8%) used the games during the month of the study. Only a greater number of evidence-based medicine training hours was associated with greater adherence to the educational game ( OR 1.11; CI 95% 1.02-1.21)., Conclusions: The game-based educational strategy e-EDUCAGUIA shows positive effects on the knowledge and skills on decision making about antimicrobial therapy for clinical decision-making in family medicin residents in the short term, but the dropout was high and results should be interpreted with caution. Adherence to educational games in the absence of specific incentives is moderate., Trial Registration: ClinicalTrials.gov Identifier: NCT02210442 . Registered 6 August 2014., (© 2022. The Author(s).)

Background: Tobacco addiction is the leading cause of preventable morbidity and mortality worldwide, but only 1 in 20 cessation attempts is supervised by a health professional. The potential advantages of mobile health (mHealth) can circumvent this problem and facilitate tobacco cessation interventions for public health systems. Given its easy scalability to large populations and great potential, chatbots are a potentially useful complement to usual treatment., Objective: This study aims to assess the effectiveness of an evidence-based intervention to quit smoking via a chatbot in smartphones compared with usual clinical practice in primary care., Methods: This is a pragmatic, multicenter, controlled, and randomized clinical trial involving 34 primary health care centers within the Madrid Health Service (Spain). Smokers over the age of 18 years who attended on-site consultation and accepted help to quit tobacco were recruited by their doctor or nurse and randomly allocated to receive usual care (control group [CG]) or an evidence-based chatbot intervention (intervention group [IG]). The interventions in both arms were based on the 5A's (ie, Ask, Advise, Assess, Assist, and Arrange) in the US Clinical Practice Guideline, which combines behavioral and pharmacological treatments and is structured in several follow-up appointments. The primary outcome was continuous abstinence from smoking that was biochemically validated after 6 months by the collaborators. The outcome analysis was blinded to allocation of patients, although participants were unblinded to group assignment. An intention-to-treat analysis, using the baseline-observation-carried-forward approach for missing data, and logistic regression models with robust estimators were employed for assessing the primary outcomes., Results: The trial was conducted between October 1, 2018, and March 31, 2019. The sample included 513 patients (242 in the IG and 271 in the CG), with an average age of 49.8 (SD 10.82) years and gender ratio of 59.3% (304/513) women and 40.7% (209/513) men. Of them, 232 patients (45.2%) completed the follow-up, 104/242 (42.9%) in the IG and 128/271 (47.2%) in the CG. In the intention-to-treat analysis, the biochemically validated abstinence rate at 6 months was higher in the IG (63/242, 26%) compared with that in the CG (51/271, 18.8%; odds ratio 1.52, 95% CI 1.00-2.31; P=.05). After adjusting for basal CO-oximetry and bupropion intake, no substantial changes were observed (odds ratio 1.52, 95% CI 0.99-2.33; P=.05; pseudo-R 2 =0.045). In the IG, 61.2% (148/242) of users accessed the chatbot, average chatbot-patient interaction time was 121 (95% CI 121.1-140.0) minutes, and average number of contacts was 45.56 (SD 36.32)., Conclusions: A treatment including a chatbot for helping with tobacco cessation was more effective than usual clinical practice in primary care. However, this outcome was at the limit of statistical significance, and therefore these promising results must be interpreted with caution., Trial Registration: Clinicaltrials.gov NCT03445507; https://tinyurl.com/mrnfcmtd., International Registered Report Identifier (irrid): RR2-10.1186/s12911-019-0972-z., (©Eduardo Olano-Espinosa, Jose Francisco Avila-Tomas, Cesar Minue-Lorenzo, Blanca Matilla-Pardo, María Encarnación Serrano Serrano, F Javier Martinez-Suberviola, Mario Gil-Conesa, Isabel Del Cura-González, Dejal@ Group. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 27.06.2022.)

Background: The wide scale and severity of consequences of tobacco use, benefits derived from cessation, low rates of intervention by healthcare professionals, and new opportunities stemming from novel communications technologies are the main factors motivating this project. Thus, the purpose of this study is to assess the effectiveness of an intervention that helps people cease smoking and increase their nicotine abstinence rates in the long term via a chat-bot, compared to usual practice, utilizing a chemical validation at 6 months., Methods: Design: Randomized, controlled, multicentric, pragmatic clinical trial, with a 6-month follow-up., Setting: Healthcare centers in the public healthcare system of the Community of Madrid (Madrid Regional Health Service)., Participants: Smokers > 18 years of age who attend a healthcare center and accept help to quit smoking in the following month. N = 460 smokers (230 per arm) who will be recruited prior to randomization. Intervention group: use of a chat-bot with evidence-based contents to help quit smoking., Control Group: Usual treatment (according to the protocol for tobacco cessation by the Madrid Regional Health Service Main variable: Continuous nicotine withdrawal with chemical validation (carbon monoxide in exhaled air). Intention-to-treat analysis. Difference between groups in continuous abstinence rates at 6 months with their corresponding 95% confidence interval. A logistic regression model will be built to adjust for confounding factors., Results: First expected results in January 2020., Discussion: Providing science-based evidence on the effectiveness of clinical interventions via information technologies, without the physical presence of a professional, is essential. In addition to being more efficient, the characteristics of these interventions can improve effectiveness, accessibility, and adherence to treatment. From an ethics perspective, this new type of intervention must be backed by scientific evidence to circumvent pressures from the market or particular interests, improve patient safety, and follow the standards of correct practices for clinical interventions., Trial Registration: ClinicalTrials.gov, reference number NCT03445507.

Background: Clinical practice guidelines (CPGs) have been developed with the aim of helping health professionals, patients, and caregivers make decisions about their health care, using the best available evidence. In many cases, incorporation of these recommendations into clinical practice also implies a need for changes in routine clinical practice. Using educational games as a strategy for implementing recommendations among health professionals has been demonstrated to be effective in some studies; however, evidence is still scarce. The primary objective of this study is to assess the effectiveness of a teaching strategy for the implementation of CPGs using educational games (e-learning EDUCAGUIA) to improve knowledge and skills related to clinical decision-making by residents in family medicine. The primary objective will be evaluated at 1 and 6 months after the intervention. The secondary objectives are to identify barriers and facilitators for the use of guidelines by residents of family medicine and to describe the educational strategies used by Spanish teaching units of family and community medicine to encourage implementation of CPGs., Methods/design: We propose a multicenter clinical trial with randomized allocation by clusters of family and community medicine teaching units in Spain. The sample size will be 394 residents (197 in each group), with the teaching units as the randomization unit and the residents comprising the analysis unit. For the intervention, both groups will receive an initial 1-h session on clinical practice guideline use and the usual dissemination strategy by e-mail. The intervention group (e-learning EDUCAGUIA) strategy will consist of educational games with hypothetical clinical scenarios in a virtual environment. The primary outcome will be the score obtained by the residents on evaluation questionnaires for each clinical practice guideline. Other included variables will be the sociodemographic and training variables of the residents and the teaching unit characteristics. The statistical analysis will consist of a descriptive analysis of variables and a baseline comparison of both groups. For the primary outcome analysis, an average score comparison of hypothetical scenario questionnaires between the EDUCAGUIA intervention group and the control group will be performed at 1 and 6 months post-intervention, using 95 % confidence intervals. A linear multilevel regression will be used to adjust the model., Discussion: The identification of effective teaching strategies will facilitate the incorporation of available knowledge into clinical practice that could eventually improve patient outcomes. The inclusion of information technologies as teaching tools permits greater learning autonomy and allows deeper instructor participation in the monitoring and supervision of residents. The long-term impact of this strategy is unknown; however, because it is aimed at professionals undergoing training and it addresses prevalent health problems, a small effect can be of great relevance., Trial Registration: ClinicalTrials.gov: NCT02210442 .

B-1 lymphocytes comprise a unique subset of B cells that differ phenotypically, ontogenetically and functionally from conventional B-2 cells. A frequent specificity of the antibody repertoire of peritoneal B-1 cells is phosphatidylcholine. Liposomes containing phosphatidylcholine have been studied as adjuvants and their interaction with dendritic cells and macrophages has been demonstrated. However, the role of B-1 cells in the adjuvanticity of liposomes composed of phosphatidylcholine has not been explored. In the present work, we studied the contribution of B-1 cells to the humoral response against ovalbumin (OVA) encapsulated into dipalmitoylphosphatidylcholine (DPPC) and cholesterol-containing liposomes. BALB/X-linked immunodeficient (xid) mice, which are deficient in B-1 cells, showed quantitative and qualitative differences in the anti-OVA antibody response compared with wild-type animals after immunization with these liposomes. The OVA-specific immune response was significantly increased in the BALB/xid mice when reconstituted with B-1 cells from naive BALB/c mice. Our results indicate the internalization of DPPC-containing liposomes by these cells and their migration from the peritoneal cavity to the spleen. Phosphatidylcholine significantly contributed to the immunogenicity of liposomes, as DPPC-containing liposomes more effectively stimulated the anti-OVA response compared with vesicles composed of dipalmitoylphosphatidylglycerol. In conclusion, we present evidence for a cognate interaction between B-1 cells and phosphatidylcholine liposomes, modulating the immune response to encapsulated antigens. This provides a novel targeting approach to assess the role of B-1 cells in humoral immunity., (© The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Despite major advances in the treatment of classic Hodgkin's lymphoma (cHL), approximately 30% of patients in advanced stages may eventually die as result of the disease, and current methods to predict prognosis are rather unreliable. Thus, the application of robust techniques for the identification of biomarkers associated with treatment response is essential if new predictive tools are to be developed., Experimental Design: We used gene expression data from advanced cHL patients to identify transcriptional patterns from the tumoral cells and their nonneoplastic microenvironment, associated with lack of maintained treatment response. Gene-Set Enrichment Analysis was used to identify functional pathways associated with unfavorable outcome that were significantly enriched in either the Hodgkin's and Reed-Sternberg cells (regulation of the G2-M checkpoint, chaperones, histone modification, and signaling pathways) or the reactive cell microenvironment (mainly represented by specific T-cell populations and macrophage activation markers)., Results: To explore the pathways identified previously, we used a series of 52 formalin-fixed paraffin-embedded advanced cHL samples and designed a real-time PCR-based low-density array that included the most relevant genes. A large majority of the samples (82.7%) and all selected genes were analyzed successfully with this approach., Conclusions: The results of this assay can be combined in a single risk score integrating these biological pathways associated with treatment response and eventually used in a larger series to develop a new molecular outcome predictor for advanced cHL.

We evaluated prognostic factors of melphalan/fludarabine-based dose-reduced allografts in patients with multiple myeloma. From 1998 to 2002, 120 patients with multiple myeloma were treated with melphalan/fludarabine followed by allogeneic stem cell transplantation. The cumulative risk at 1 year for treatment-related mortality (TRM) was 18% (95% confidence interval [CI], 12%-28%). In a multivariate analysis, relapse after prior high-dose chemotherapy was the most significant risk factor for TRM (hazard ratio [HR], 2.80; 95% CI, 1.16-6.74; P =.02), relapse (HR, 4.14; 95% CI, 2.04-8.38; P <.001), event-free survival (HR, 3.11; 95% CI, 1.77-5.46; P <.001), and overall survival (HR, 2.69; 95% CI, 1.35-5.35; P =.005). In addition, relapse was also significantly diminished by chronic graft-versus-host disease (GVHD) in a time-dependent Cox model (HR, 0.37; 95% CI, 0.16-0.87; P =.02). At transplantation, 8% of the patients were in complete remission, whereas 27% had progressive disease. After allografting, 49% achieved complete remission, and 38% achieved partial remission. In a subgroup of patients with chemosensitivity at transplantation and no relapse after prior high-dose chemotherapy who underwent transplantation with peripheral blood stem cells (n = 46), the cumulative risk of TRM at 1 year was only 8% (95% CI, 1%-54%). The 2-year estimated event-free and overall survival was 60% (95% CI, 42%-78%) and 75% (95% CI, 59%-91%), respectively, for related donors (n = 34) and was 81% (95% CI, 59%-100%) and 92% (95% CI, 76%-100%), respectively, for unrelated donors (n = 12).

Seven cases of disseminated infection due to Dipodascus capitatus are reported. Infections occurred in a hematological unit of a tertiary hospital during a period of 5 years. Five cases were refractory to antifungal therapy. Antifungal susceptibility testing of seven isolates was performed, and strains were typed by PCR fingerprinting with the core sequence of phage M13 and by random amplification of polymorphic DNA with two primers, Ap12h and W-80A. A very short range of MICs of each antifungal agent was observed. The MICs of amphotericin B ranged between 0.50 and 2 microg/ml. Strains were susceptible in vitro to flucytosine and susceptible (dose-dependent) to fluconazole and itraconazole. Voriconazole exhibited an activity in vitro comparable to that of itraconazole. Typing techniques allowed seven additional isolates of D. capitatus neither geographically nor temporally related to be classified into two different genomic patterns. The genomic type of the seven strains from the hematological unit was identical regardless of typing technique utilized. It would indicate that the seven cases of disseminated infection could be related epidemiologically.

Introduction: Factor V Leiden and prothrombin 20210A polymorphisms are the most common mutations related to deep vein thrombosis, however their relationship with stroke is debated. This paper studies the possible relationship between both entities., Material and Methods: A case-control study was conducted during 27 months to study their association. A total of 312 stroke cases were included, 73 were under 60 years. Control group was obtained from blood donors. Factor V Leiden and prothrombin 20210A polymorphism prevalence was studied. Results were analyzed according to the age and the type of stroke (TOAST classification, 1993)., Results: Factor V Leiden was not related to stroke in the general population (OR: 0.65; 95 % CI: 0.18-2.27). The study according to age did not show any association (younger than 60 years: OR: 1.12; 95 % CI: 0.21-5.90; older than 60 years: OR: 0.50; 95 % CI: 0.11-2.14). However, prothrombin 20210A polymorphism OR in cases under 60 was OR: 2.92; 95 % CI: 0.71-11.92 suggesting a possible association between this mutation and stroke. There was no association in the general population (OR: 2.0; 95 % CI: 0.63-6.29) or in people over 60 (OR: 1.73; 95 % CI: 0.51- 5.83). The analysis according to stroke subtype did not show any association in the distribution of any of the polymorphisms studied., Conclusion: This study suggests that prothrombin 20210A polymorphism may play a role in stroke under 60 years of age. Factor V Leiden does not seem to be related to stroke.

Background: Severe liver disease, including fulminant hepatic failure and venoocclusive disease can occur after bone marrow transplantation (BMT). The aim of our study was to assess risk factors for veno occlusive disease and severe liver disease occurring within 6 months from BMT., Methods: A total of 193 consecutive patients from 15 BMT Centers were prospectively enrolled between January and June 1995. Data on donors and recipients before and after transplant were collected and included age, gender, alanine aminotransferase (ALT), hepatitis B (HBV), and hepatitis C virus (HCV) markers, hematological disease, status and type of BMT, conditioning regimen and graft versus host disease prophylaxis. Statistical analysis included univariate descriptive and multivariate analysis based on logistic regression on major end-points., Results: Forty-three of 193 patients died during the study period, and liver disease was the main cause of death (13 of 43, 30%). Incidence of severe veno occlusive disease was 8%, fulminant hepatic failure 0.5% and 12% of cases had ALT >500 U/L (normal < or =42 U/L). A de novo HBV or HCV infection occurred in 3.2 and 7% of patients respectively. Predictive risk factors for life-threatening liver disease were: unrelated donors (relative risk=5.8, confidence interval=1.7-19.8) and abnormal BMT donor ALT (relative risk=6.3, confidence interval=1. 5- 25.5)., Conclusions: This study indicates that ongoing or previous infection with HBV or HCV in donor or recipient is not an absolute contraindication for BMT. However, abnormal ALT levels in BMT donors were a significant predictor of potentially lethal liver complications. The occurrence of de novo HBV or HCV infection did not correlate with severity of liver disease observed in the first 6 months posttransplant. These findings should be carefully evaluated before disregarding HBV or HCV positive siblings with normal transaminase levels in favor of unrelated donors.

Gelatinous degeneration of marrow is a rare histological disorder associated with chronic debilitating diseases, such as anorexia nervosa, AIDS and postchemotherapy aplasia. Solid tumours have been associated with this condition but it has been reported in only two patients with leukaemia. In these cases leukaemia and gelatinous degeneration were diagnosed simultaneously. In the case reported here, a 48 year old man, gelatinous degeneration was the only histological finding observed more than two years before the diagnosis of acute myelogenous leukaemia with monosomy 7. The significance of hyaluronic acid deposition remains uncertain. Two hypotheses have been put forward: (1) that gelatinous degeneration occurs during tissue repair; and (2) that gelatinous degeneration inhibits haemopoiesis by altering the microenvironment of the bone marrow. In the case reported here, the presence of monosomy 7 suggests that myelodysplasia was the underlying disorder which finally evolved into acute leukaemia.

To assess the prevalence, risk factors, clinical causes and outcome of acute renal failure (ARF) following bone marrow transplantation (BMT), a retrospective analysis of 275 patients was undertaken. ARF was diagnosed in 72 patients (26%) and occurred in 81.9% within the first month. The three main clinical causes were multifactorial (36%), nephrotoxic (29%), and veno-occlusive disease of the liver (VOD) 15%. The prevalence was higher in allogeneic BMT (36%) than in autologous BMT (6.5%). Risk factors related to the development of ARF wee preexisting VOD and age older than 25 years. Logistic regression in allogeneic BMT confirmed this association (VOD, odds ratio 3.8; age offer than 25, odds ratio 1.9). Underlying disease, graft-versus-host disease, sepsis, conditioning therapy, and sex were not associated with ARF. Seventeen cases of ARF required hemodialysis (24%) mainly in association with VOD (70.5%). The overall morality from ARF was 45.8%, the dialyzed group having the highest mortality (88%). Survival in the ARF group was continuously worse up to 3 months and the actuarial survival at 10 years was 29.7 versus 53.2%. We conclude that ARF is a common complication mainly in allogeneic BMT and carries a grave prognosis. VOD and age were risk factors for ARF.

Three cases of busulfan-associated convulsions in 28 bone marrow transplant recipients are reported. Convulsions occurred in spite of anticonvulsant prophylaxis in two of the three cases. Fits were generalized; no neurological deficit was found after the episodes and there were no recurrences. Although conditioning regimens including busulfan are used increasingly only rare cases have been reported and little mention of this side effect is made. We emphasize that convulsions are not infrequent side effect of conditioning regimens including high dose busulfan, and efficient anticonvulsant prophylactic regimens should be used.

At present, different congenital defects in several proteins--antithrombin III (AT III), protein C (PC), protein S (PS), and plasminogen (PLG)--are known to be causes of hereditary predisposition to thrombosis (thrombophilia). The incidence of these hereditary disorders in our 204 patients (106 males and 98 females) with venous thromboembolism were 4% (three cases deficient in PC, three in PS, two in PLG, and one patient in AT III). Their families were studied. In all cases the disorders were inherited as an autosomal dominant trait. The first thrombotic episodes occurred at a age of below 40 years. There was no relationship between protein levels and the occurrence of thrombosis, although a significant relationship was observed between a positive history of thromboembolic disease and a diagnosis of protein deficiencies. We evaluated the differences between primary thrombosis and secondary thrombosis. The most common thrombotic sites were the deep veins. There were no differences between males and females. Evaluation of PC, PS, AT III, and PLG in patients with thromboembolic disease should be considered.

A case of erythema in a 'flagellate' pattern due to administration of bleomycin in a patient with Hodgkin's disease is described. Emphasis is placed on the low dose of bleomycin administered--15 mg parenterally--and the short time interval between drug administration and beginning of symptoms: 24 h. The histopathological findings were consistent with a mechanism of inflammatory oncotaxis: the attraction of tumor cells by the skin perhaps due to the bleomycin accumulated and the trauma caused by scratching subsequent to pruritus.

The aim of the present study is to analyze the relationship between serum immunoglobulin (Ig) levels and the immunological phenotype and the clinicohaematological features of B-cell chronic lymphocytic leukaemia (B-CLL) in a series of 126 patients. Eighty-eight of the cases (70%) had a decreased concentration of at least one Ig. IgM and IgA were the most frequently decreased (60% and 49% respectively). A serum monoclonal gammapathy was found in 4 patients, Ig M/k in two cases and IgM/l and IgG/k in one case. Patients with hypogammaglobulinaemia had a similar surface phenotype as patients with normal Ig levels (MRFC+, sIg+, CD20+, HLA/DR+, FMC7-, CD5+, CD9+). On the other hand the cases with hypogammaglobulinaemia displayed the features of a more advanced disease, a higher incidence of organomegalies (p less than 0.05), anaemia and/or thrombopenia (p less than 0.05), a diffuse bone marrow pattern (p less than 0.05), advanced clinical stages (p less than 0.05) as well as higher levels of both peripherial blood (p less than 0.02) and bone marrow lymphocytosis (p less than 0.02). These findings suggest that the presence of hypogammaglobulinaemia in B-cell patients is probably more related to a higher tumor burden than to either certain stages of B-cell differentiation or a particular cellular phenotype.