Hospital de Galdakao

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

El Cuestionario SF-36 es uno de los instrumentos de Calidad de Vida Relacionada con la Salud (CVRS) más utilizados y evaluados. Tras una década de uso este artículo revisa críticamente el contenido, propiedades métricas y nuevos desarrollos de la versión española. Revisión de los artículos indizados en Medline (Pub-Med) y en las bases de datos IBECS e IME que han utilizado la versión española del cuestionario. Se seleccionaron los artículos con información sobre modelo de medida, fiabilidad, validez y sensibilidad al cambio del instrumento. Se encontraron 79 artículos, 17 de los cuales describían características métricas del cuestionario. En el 96% las escalas superaron el estándar propuesto de fiabilidad (α de Cronbach) de 0,7. Las estimaciones agrupadas obtenidas por metaanálisis fueron superiores a 0,7 en todos los casos. El SF-36 mostró buena discriminación entre grupos de gravedad, correlación moderada con indicadores clínicos y alta con otros instrumentos de CVRS. El SF-36 predijo mortalidad y detectó mejoría tras la angioplastia coronaria, la cirugía de hipertrofia prostática benigna o la ventilación domiciliaria no invasiva. Los nuevos desarrollos descritos (puntuaciones basadas en normas, la versión 2, el SF-12 y el SF-8) mejoraron sus propiedades métricas y su interpretación. El SF-36, conjuntamente con las nuevas versiones desarrolladas, es un instrumento muy adecuado para su uso en investigación y en la práctica clínica. The Short Form-36 Health Survey (SF-36) is one of the most widely used and evaluated generic health-related quality of life (HRQL) questionnaires. After almost a decade of use in Spain, the present article critically reviews the content and metric properties of the Spanish version, as well as its new developments. A review of indexed articles that used the Spanish version of the SF-36 was performed in Medline (PubMed), the Spanish bibliographic databases IBECS and IME. Articles that provided information on the measurement model, reliability, validity, and responsiveness to change of the instrument were selected. Seventy-nine articles were found, of which 17 evaluated the metric characteristics of the questionnaire. The reliability of the SF-36 scales was higher than the suggested standard (Cronbach's alpha) of 0.7 in 96% of the evaluations. Grouped evaluations obtained by meta-analysis were higher than 0.7 in all cases. The SF-36 showed good discrimination among severity groups, moderate correlations with clinical indicators, and high correlations with other HRQL instruments. Moreover, questionnaire scores predicted mortality and were able to detect improvement due to therapeutic interventions such as coronary angioplasty, benign prostatic hyperplasia surgery, and non-invasive positive pressure home ventilation. The new developments (normbased scoring, version 2, the SF-12 and SF-8) improved both the metric properties and interpretation of the questionnaire. The Spanish version of the SF-36 and its recently developed versions is a suitable instrument for use in medical research, as well as in clinical practice.

PURPOSE: Bacillus Calmette-Guerin is the most effective therapy for nonmuscle invasive bladder cancer. Recently to calculate the risks of recurrence and progression based on data from 7 European Organisation for Research and Treatment of Cancer trials a scoring system was reported. However, in that series only 171 patients were treated with bacillus Calmette-Guerin. We developed a risk stratification model to provide accurate estimates of recurrence and progression probability after bacillus Calmette-Guerin. MATERIALS AND METHODS: Data were analyzed on 1,062 patients treated with bacillus Calmette-Guerin and included in 4 Spanish Urological Club for Oncological Treatment trials. Stepwise multivariate Cox models were used to determine the effect of prognostic factors. In each patient the weight of all factors was summed to a total score. Patients were then divided into groups, and cumulative recurrence and progression rates were calculated. RESULTS: A scoring system was calculated with a score of 0 to 16 for recurrence and 0 to 14 for progression. Patients were categorized into 4 groups by score, and recurrence and progression probabilities were calculated in each group. For recurrence the variables were gender, age, grade, tumor status, multiplicity and associated Tis. For progression the variables were age, grade, tumor status, T category, multiplicity and associated Tis. For recurrence calculated risks using Spanish Urological Club for Oncological Treatment tables were lower than those obtained with Sylvester tables. For progression probabilities were lower in our model only in patients with high risk tumors. CONCLUSIONS: We propose a scoring model to stratify the risk of recurrence and progression in patients treated with bacillus Calmette-Guerin.

Aims: The clinical value of percutaneous coronary intervention (PCI) for chronic coronary total occlusions (CTOs) is not established by randomized trials. This study should compare the benefit of PCI vs. optimal medical therapy (OMT) on the health status in patients with at least one CTO. Method and results: Three hundred and ninety-six patients were enrolled in a prospective randomized, multicentre, open-label, and controlled clinical trial to compare the treatment by PCI with OMT with a 2:1 randomization ratio. The primary endpoint was the change in health status assessed by the Seattle angina questionnaire (SAQ) between baseline and 12 months follow-up. Fifty-two percent of patients have multi-vessel disease in whom all significant non-occlusive lesions were treated before randomization. An intention-to-treat analysis was performed including 13.4% failed procedures in the PCI group and 7.3% cross-overs in the OMT group. At 12 months, a greater improvement of SAQ subscales was observed with PCI as compared with OMT for angina frequency [5.23, 95% confidence interval (CI) 1.75; 8.71; P = 0.003], and quality of life (6.62, 95% CI 1.78-11.46; P = 0.007), reaching the prespecified significance level of 0.01 for the primary endpoint. Physical limitation (P = 0.02) was also improved in the PCI group. Complete freedom from angina was more frequent with PCI 71.6% than OMT 57.8% (P = 0.008). There was no periprocedural death or myocardial infarction. At 12 months, major adverse cardiac events were comparable between the two groups. Conclusion: Percutaneous coronary intervention leads to a significant improvement of the health status in patients with stable angina and a CTO as compared with OMT alone. Trial registration: NCT01760083.

This European Respiratory Society (ERS) statement provides a comprehensive overview on physical activity in patients with chronic obstructive pulmonary disease (COPD). A multidisciplinary Task Force of experts representing the ERS Scientific Group 01.02 "Rehabilitation and Chronic Care" determined the overall scope of this statement through consensus. Focused literature reviews were conducted in key topic areas and the final content of this Statement was agreed upon by all members. The current knowledge regarding physical activity in COPD is presented, including the definition of physical activity, the consequences of physical inactivity on lung function decline and COPD incidence, physical activity assessment, prevalence of physical inactivity in COPD, clinical correlates of physical activity, effects of physical inactivity on hospitalisations and mortality, and treatment strategies to improve physical activity in patients with COPD. This Task Force identified multiple major areas of research that need to be addressed further in the coming years. These include, but are not limited to, the disease-modifying potential of increased physical activity, and to further understand how improvements in exercise capacity, dyspnoea and self-efficacy following interventions may translate into increased physical activity. The Task Force recommends that this ERS statement should be reviewed periodically (e.g. every 5-8 years).

OBJECTIVE: To assess the effectiveness of the simplified medication adherence questionnaire (SMAQ) in identifying non-adherent patients. DESIGN: Prospective observational study of adherence. The six-item SMAQ was developed. The following aspects were evaluated: (i) criterion validity, comparison with electronic adherence monitoring; (ii) construct validity, association between adherence, as defined by the SMAQ, and virological outcomes; and (iii) reliability, internal consistency and reproducibility. PATIENTS: A group of 3004 unselected HIV patients who had initiated nelfinavir therapy combined with other antiretroviral drugs [21% naive, 15% protease inhibitor (PI)-naive, 64% PI-experienced] between January 1998 and December 1999 were enrolled in 69 hospitals in Spain. The SMAQ was administered at months 3, 6 and 12. RESULTS: The SMAQ showed 72% sensitivity, 91% specificity and a likelihood ratio of 7.94 to identified non-adherent patients, compared with the medication-event monitoring system (40 patients evaluated). At month 12, 1797 patients were evaluated, of whom 32.3% were defined as non-adherent; viral load < 500 copies/ml found in 68.3% of the adherent, and 46% of the non-adherent patients. A logistic regression analysis of PI-naive patients was performed, including age, sex, baseline viral load > 5 log10/ml, CD4 cell count < 200 x 10(6)/l, and non-adherence as independent variables. Non-adherence was the only significant risk factor in failing to achieve virological suppression. Cronbach's alpha internal consistency coefficient was 0.75, and overall inter-observer agreement was 88.2%. CONCLUSION: The SMAQ appears to be an adequate instrument with which to assess adherence in HIV-infected patients, and may be applied in most clinical settings.

OBJECTIVE: To assess the psychometric properties of the Spanish version of the Hospital Anxiety and Depression Scale(HADS). METHOD: We administered HADS to 685 participants (256 controls and 429 patients with five different diagnoses). The reliability of the instrument was assessed by a test-retest study. Construct validity studies were carried out through item-subscale correlation and factor analysis for the whole group and by each of the five different diagnoses. Three instruments were used as external criteria to assess concurrent validity. RESULTS: HADS test-retest reliability presented correlation coefficients above 0.85. The internal consistency was high, with a Cronbach's alpha of 0.86 (anxiety) and 0.86 (depression). Factor analysis showed a clear two-factor structure for all groups. The results showed high concurrent validity with the Beck Depression Inventory and State-Trait Anxiety Inventory and with the mental domains of the Short-Form Health Survey. CONCLUSION: The Spanish version of the HADS demonstrated good reliability and validity when used in medical patients.

Plasmablastic lymphoma was initially described as a variant of diffuse large B-cell lymphoma (DLBCL) involving the oral cavity of HIV+ patients and characterized by immunoblastic morphology and a plasma cell phenotype. However, other lymphomas may exhibit similar morphologic and immunophenotypic features. To determine the significance of plasmablastic differentiation in DLBCL and examine the heterogeneity of lymphomas with these characteristics, we examined 50 DLBCLs with low/absent CD20/CD79a and an immunophenotype indicative of terminal B-cell differentiation (MUM1/CD38/CD138/EMA-positive). We were able to define several distinct subgroups. Twenty-three tumors were classified as plasmablastic lymphoma of the oral mucosa type and showed a monomorphic population of immunoblasts with no or minimal plasmacytic differentiation. Most patients were HIV+ and EBV was positive in 74%. Eleven (48%) cases presented in the oral mucosa, but the remaining presented in other extranodal (39%) or nodal (13%) sites. Sixteen cases were classified as plasmablastic lymphoma with plasmacytic differentiation. These were composed predominantly of immunoblasts and plasmablasts, but in addition exhibited more differentiation to mature plasma cells. Only 33% were HIV+, EBV was detected in 62%, and 44% had nodal presentation. Nine cases, morphologically indistinguishable from the previous group, were secondary extramedullary plasmablastic tumors occurring in patients with prior or synchronous plasma cell neoplasms, classified as multiple myeloma in 7 of the 9. Two additional neoplasms were an HHV-8+ extracavitary variant of primary effusion lymphoma and an ALK+ DLBCL. HHV-8 was examined in 39 additional cases, and was negative in all. In conclusion, DLBCLs with plasmablastic differentiation are a heterogeneous group of neoplasms with different clinicopathological characteristics that may correspond to different entities.

A number of studies have been conducted with the onset of secondary progressive multiple sclerosis as an inclusion criterion or an outcome of interest. However, a standardized objective definition of secondary progressive multiple sclerosis has been lacking. The aim of this work was to evaluate the accuracy and feasibility of an objective definition for secondary progressive multiple sclerosis, to enable comparability of future research studies. Using MSBase, a large, prospectively acquired, global cohort study, we analysed the accuracy of 576 data-derived onset definitions for secondary progressive multiple sclerosis and first compared these to a consensus opinion of three neurologists. All definitions were then evaluated against 5-year disease outcomes post-assignment of secondary progressive multiple sclerosis: sustained disability, subsequent sustained progression, positive disability trajectory, and accumulation of severe disability. The five best performing definitions were further investigated for their timeliness and overall disability burden. A total of 17 356 patients were analysed. The best definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step ≥4 and pyramidal score ≥2. It reached an accuracy of 87% compared to the consensus diagnosis. Seventy-eight per cent of the identified patients showed a positive disability trajectory and 70% reached significant disability after 5 years. The time until half of all patients were diagnosed was 32.6 years (95% confidence interval 32-33.6) after disease onset compared with the physicians' diagnosis at 36 (35-39) years. The identified patients experienced a greater disease burden [median annualized area under the disability-time curve 4.7 (quartiles 3.6, 6.0)] versus non-progressive patients [1.8 (1.2, 1.9)]. This objective definition of secondary progressive multiple sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis.

BACKGROUND: We used a validated inpatient satisfaction questionnaire to evaluate the health care received by patients admitted to several hospitals. This questionnaire was factored into distinct domains, creating a score for each to assist in the analysis. We evaluated possible predictors of patient satisfaction in relation to socio-demographic variables, history of admission, and survey logistics. METHODS: Cross-sectional study of patients discharged from four acute care general hospitals. Random sample of 650 discharged patients from the medical and surgical wards of each hospital during February and March 2002. A total of 1,910 patients responded to the questionnaire (73.5%). Patient satisfaction was measured by a validated questionnaire with six domains: information, human care, comfort, visiting, intimacy, and cleanliness. Each domain was scored from 0 to 100, with higher scores indicating higher levels of patient satisfaction. RESULTS: In the univariate analysis, age was related to all domains except visiting; gender to comfort, visiting, and intimacy; level of education to comfort and cleanliness; marital status to information, human care, intimacy, and cleanliness; length of hospital stay to visiting and cleanliness, and previous admissions to human care, comfort, and cleanliness. The timing of the response to the mailing and who completed the questionnaire were related to all variables except visiting and cleanliness. Multivariate analysis confirmed in most cases the previous findings and added additional correlations for level of education (visiting and intimacy) and marital status (comfort and visiting). CONCLUSION: These results confirm the varying importance of some socio-demographic variables and length of stay, previous admission, the timing of response to the questionnaire, and who completed the questionnaire on some aspects of patient satisfaction after hospitalization. All these variables should be considered when evaluating patient satisfaction.

The CURB-65 score (Confusion, Urea > 7 mmol x L(-1), Respiratory rate > or = 30 x min(-1), low Blood pressure, and age > or = 65 yrs) has been proposed as a tool for augmenting clinical judgement for stratifying patients with community-acquired pneumonia (CAP) into different management groups. The six-point CURB-65 score was retrospectively applied in a prospective, consecutive cohort of adult patients with a diagnosis of CAP seen in the emergency department of a 400-bed teaching hospital from March 1, 2000 to February 29, 2004. A total of 1,100 inpatients and 676 outpatients were included. The 30-day mortality rate in the entire cohort increased directly with increasing CURB-65 score: 0, 1.1, 7.6, 21, 41.9 and 60% for CURB-65 scores of 0, 1, 2, 3, 4, and 5, respectively. The score was also significantly associated with the need for mechanical ventilation and rate of hospital admission in the entire cohort, and with duration of hospital stay among inpatients. The CURB-65 score (Confusion, Urea > 7 mmol x L(-1), Respiratory rate > or = 30 x min(-1), low Blood pressure, and age > or = 65 yrs), and a simpler CRB-65 score that omits the blood urea measurement, helps classify patients with community-acquired pneumonia into different groups according to the mortality risk and significantly correlates with community-acquired pneumonia management key points. The new score can also be used as a severity adjustment measure.

PURPOSE: Acute mesenteric ischaemia (AMI) accounts for about 1:1000 acute hospital admissions. Untreated, AMI will cause mesenteric infarction, intestinal necrosis, an overwhelming inflammatory response and death. Early intervention can halt and reverse this process leading to a full recovery, but the diagnosis of AMI is difficult and failure to recognize AMI before intestinal necrosis has developed is responsible for the high mortality of the disease. Early diagnosis and prompt treatment are the goals of modern therapy, but there are no randomized controlled trials to guide treatment and the published literature contains a high ratio of reviews to original data. Much of that data comes from case reports and often small, retrospective series with no clearly defined treatment criteria. METHODS: A study group of the European Society for Trauma and Emergency Surgery (ESTES) was formed in 2013 with the aim of developing guidelines for the management of AMI. A comprehensive literature search was performed using the Medical Subject Heading (MeSH) thesaurus keywords "mesenteric ischaemia", "bowel ischaemia" and "bowel infarction". The bibliographies of relevant articles were screened for additional publications. After an initial systematic review of the literature by the whole group, a steering group formulated questions using a modified Delphi process. The evidence was then reviewed to answer these questions, and recommendations formulated and agreed by the whole group. RESULTS: The resultant recommendations are presented in this paper. CONCLUSIONS: The aim of these guidelines is to provide recommendations for practice that will lead to improved outcomes for patients.

Development of resistance to therapy continues to be a serious clinical problem in breast cancer management. Cancer stem/progenitor cells have been shown to play roles in resistance to chemo‐ and radiotherapy. Here, we examined their role in the development of resistance to the oestrogen receptor antagonist tamoxifen. Tamoxifen‐resistant cells were enriched for stem/progenitors and expressed high levels of the stem cell marker Sox2. Silencing of the SOX2 gene reduced the size of the stem/progenitor cell population and restored sensitivity to tamoxifen. Conversely, ectopic expression of Sox2 reduced tamoxifen sensitivity in vitro and in vivo. Gene expression profiling revealed activation of the Wnt signalling pathway in Sox2‐expressing cells, and inhibition of Wnt signalling sensitized resistant cells to tamoxifen. Examination of patient tumours indicated that Sox2 levels are higher in patients after endocrine therapy failure, and also in the primary tumours of these patients, compared to those of responders. Together, these results suggest that development of tamoxifen resistance is driven by Sox2‐dependent activation of Wnt signalling in cancer stem/progenitor cells.

RATIONALE: Objective strategies are needed to improve the diagnosis of severe community-acquired pneumonia in the emergency department setting. OBJECTIVES: To develop and validate a clinical prediction rule for identifying patients with severe community-acquired pneumonia, comparing it with other prognostic rules. METHODS: Data collected from clinical information and physical examination of 1,057 patients visiting the emergency department of a hospital were used to derive a clinical prediction rule, which was then validated in two different populations: 719 patients from the same center and 1,121 patients from four other hospitals. MEASUREMENTS AND MAIN RESULTS: In the multivariate analyses, eight independent predictive factors were correlated with severe community-acquired pneumonia: arterial pH < 7.30, systolic blood pressure < 90 mm Hg, respiratory rate > 30 breaths/min, altered mental status, blood urea nitrogen > 30 mg/dl, oxygen arterial pressure < 54 mm Hg or ratio of arterial oxygen tension to fraction of inspired oxygen < 250 mm Hg, age > or = 80 yr, and multilobar/bilateral lung affectation. From the beta parameter obtained in the multivariate model, a score was assigned to each predictive variable. The model shows an area under the curve of 0.92. This rule proved better at identifying patients evolving toward severe community-acquired pneumonia than either the modified American Thoracic Society rule, the British Thoracic Society's CURB-65, or the Pneumonia Severity Index. CONCLUSIONS: A simple score using clinical data available at the time of the emergency department visit provides a practical diagnostic decision aid, and predicts the development of severe community-acquired pneumonia.

BACKGROUND: Relatively little is known about the prevalence of knee and hip osteoarthritis in the general population. METHODS: To estimate the prevalence of knee and hip osteoarthritis and the appropriateness of joint replacement in a general population of older individuals, the validated Knee and Hip OsteoArthritis Screening Questionnaire (KHOA-SQ) was sent to a random sample of individuals aged 60 to 90 years, stratified by age and sex, living in a single province in Spain. Respondents positive for knee or hip osteoarthritis on the KHOA-SQ were invited to be examined by an orthopedic surgeon. Diagnosis of knee or hip osteoarthritis was based on clinical and radiographic data. For respondents judged as having osteoarthritis, the appropriateness of knee or hip replacement was evaluated using published explicit criteria. RESULTS: Of 11 002 individuals contacted, 7577 completed the KHOA-SQ. The derived prevalence of hip osteoarthritis was approximately 7.4%. It was slightly higher in women (8.0%) than in men (6.7%) and tended to increase with age. The estimated appropriateness rate for hip replacement was 37.7% in men and 52.7% in women with osteoarthritis. The derived prevalence of knee osteoarthritis was 12.2%; it was significantly higher in women (14.9%) than in men (8.7%) and tended to increase with age. The estimated appropriateness rate for knee replacement was 11.8% in men and 17.9% in women with osteoarthritis. CONCLUSIONS: Knee and hip osteoarthritis are highly prevalent diseases in the older population. The estimation of appropriateness for hip replacement seems to be significantly higher than that for knee replacement.

IMPORTANCE: The optimal duration of antibiotic treatment for community-acquired pneumonia (CAP) has not been well established. OBJECTIVE: To validate Infectious Diseases Society of America/American Thoracic Society guidelines for duration of antibiotic treatment in hospitalized patients with CAP. DESIGN, SETTING, AND PARTICIPANTS: This study was a multicenter, noninferiority randomized clinical trial performed at 4 teaching hospitals in Spain from January 1, 2012, through August 31, 2013. A total of 312 hospitalized patients diagnosed as having CAP were studied. Data analysis was performed from January 1, 2014, through February 28, 2015. INTERVENTIONS: Patients were randomized at day 5 to an intervention or control group. Those in the intervention group were treated with antibiotics for a minimum of 5 days, and the antibiotic treatment was stopped at this point if their body temperature was 37.8°C or less for 48 hours and they had no more than 1 CAP-associated sign of clinical instability. Duration of antibiotic treatment in the control group was determined by physicians. MAIN OUTCOMES AND MEASURES: Clinical success rate at days 10 and 30 since admission and CAP-related symptoms at days 5 and 10 measured with the 18-item CAP symptom questionnaire score range, 0-90; higher scores indicate more severe symptoms. RESULTS: Of the 312 patients included, 150 and 162 were randomized to the control and intervention groups, respectively. The mean (SD) age of the patients was 66.2 (17.9) years and 64.7 (18.7) years in the control and intervention groups, respectively. There were 95 men (63.3%) and 55 women (36.7%) in the control group and 101 men (62.3%) and 61 women (37.7%) in the intervention group. In the intent-to-treat analysis, clinical success was 48.6% (71 of 150) in the control group and 56.3% (90 of 162) in the intervention group at day 10 (P = .18) and 88.6% (132 of 150) in the control group and 91.9% (147 of 162) in the intervention group at day 30 (P = .33). The mean (SD) CAP symptom questionnaire scores were 24.7 (11.4) vs 27.2 (12.5) at day 5 (P = .10) and 18.6 (9.0) vs 17.9 (7.6) at day 10 (P = .69). In the per-protocol analysis, clinical success was 50.4% (67 of 137) in the control group and 59.7% (86 of 146) in the intervention group at day 10 (P = .12) and 92.7% (126 of 137) in the control group and 94.4% (136 of 146) in the intervention group at day 30 (P = .54). The mean (SD) CAP symptom questionnaire scores were 24.3 (11.4) vs 26.6 (12.1) at day 5 (P = .16) and 18.1 (8.5) vs 17.6 (7.4) at day 10 (P = .81). CONCLUSIONS AND RELEVANCE: The Infectious Diseases Society of America/American Thoracic Society recommendations for duration of antibiotic treatment based on clinical stability criteria can be safely implemented in hospitalized patients with CAP. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2011-001067-51.

BACKGROUND: To evaluate the safety of thiopurines in patients with inflammatory bowel disease. To identify predictive factors associated with the development of thiopurine-induced adverse events. METHODS: Long-term incidence of adverse events was estimated in patients from a prospectively maintained Spanish nationwide database using Kaplan-Meier analysis. Cox regression analysis was performed to identify potential predictive factors of adverse events. RESULTS: Three thousand nine hundred and thirty-one patients were included. Ninety-five percent of patients were on azathioprine. The median follow-up with thiopurines was 44 months (range, 0-420). Adverse events occurred at a median of 1 month after starting treatment. The cumulative incidence of adverse events was 26%, with an annual risk of 7% per patient-year of treatment. Most frequent adverse events were nausea (8%), hepatotoxicity (4%), myelotoxicity (4%), and pancreatitis (4%). Four patients had lymphoma. Female and Crohn's disease increased the risk of having nausea. The risk of hepatotoxicity was lower in females and higher in Crohn's disease. The risk of myelotoxicity was significantly higher in patients treated with mercaptopurine and in females. The risk of pancreatitis was higher in Crohn's disease. Overall, 17% of patients discontinued thiopurine treatment due to adverse events. Thirty-seven percent of these patients started thiopurines again and 40% of them had adverse events again. CONCLUSIONS: As many as 1 of 4 patients on thiopurine therapy had adverse events during follow-up. A relatively high proportion of patients (17%) had to discontinue the treatment with thiopurines due to adverse events. However, more than half of patients that restarted thiopurine treatment after its discontinuation due to adverse events tolerated it. Several predictive factors for some adverse events have been identified.

In 1955 a technique was described for percutaneous renal access with the patient prone [1]; about 20 years later the percutaneous nephrolithotomy (PCNL) procedure was developed [2], and subsequently the technique of percutaneous stone manipulation was standardized [3]. PCNL, still considered the first choice for managing large-volume renal calculi, was initially used with the patient in the supine-oblique position, but later the prone position became the norm. Currently, even more complex endourological procedures, e.g. the simultaneous or subsequent use of percutaneous renal surgery and ureteroscopy, continue to be used with the patient prone, considered the conventional position for historical reasons [3–11]. The prone position is known to provide a larger surface area for the choice of puncture site, a wider space for instrument manipulation and a possibly a lower risk of splanchnic injury. Nonetheless, it also has several disadvantages, including patient discomfort, an increased radiological hazard to the urologist (working with the hands in the field of the fluoroscope), the need for several nurses to correctly position the patient before surgery and for additional intraoperative changes of the decubitus in case of simultaneous retrograde instrumentation of the ureter, a more evident risk related to pressure points, circulatory and ventilatory difficulties (especially in the morbidly obese, kyphotic and debilitated patients), endocrine and pharmacokinetic effects [12–21]. Various safe and effective modifications of patient positioning for PCNL have been proposed, including the prone split-leg position, which Scarpa et al. used some years ago, the reverse lithotomy position, the lateral decubitus, and the supine positions [7–9,19–25]. In 1987 Valdivia-Urìa described a PCNL with the patient supine, with a 3-L serum bag below the flank. Ten years later he reported 557 consecutive percutaneous nephroscopies performed in this way [23,24]. Surgical and anaesthesiological advantages were described, but despite this the technique has not become popular and remains a complementary method. Indeed, few authors subsequently reported their results obtained with patients in this position in their daily clinical practice [4,22–24,26]. Thus the present aim was to describe in detail the Galdakao-modified Valdivia position that both groups have been using in recent years on more than 160 patients under general anaesthesia for complex endourological procedures, together with the technique of percutaneous puncture and access to the renal cavities in this decubitus position. This development of the Valdivia supine position includes a modified lithotomy position [27], allowing the use of simultaneous retrograde and percutaneous access to the urinary tract, and preserving all surgical and anaesthesiological advantages of the previous Valdivia position. Advantages for the Galdakao-modified Valdivia position include greater versatility of stone manipulation along the whole upper urinary tract, given the increasing use of combined or subsequent retrograde and percutaneous access to the urinary tract with both rigid and flexible instruments. There is no need to reposition the patient, and it provides better descending drainage and retrieval of the fragments from PCNL, dètente of the urinary tract, more space for instruments and movements of the urologist, less X-ray exposure time of both the patient and the surgeon’s hands. The aim is to resolve in a one-step procedure complex renal lithiasis (staghorn and large calculi, or renal and ureteric multiple stones) and other pathologies, such as ureteric strictures and uretero-intestinal stenoses in neobladders. It is also the obvious position for uretero-ileal stenoses and stones in patients with urinary diversions such as the Bricker or colon conduit. Clearly, a prospective randomized study is needed comparing the prone decubitus to the supine position in terms of urological outcomes (stone clearance rate, number of endourological sessions, iatrogenic complications strictly related to the procedure, such as arteriovenous or urinary fistulae, bleeding, or visceral damage). As in the original Valdivia position, in the Galdakao-modified Valdivia position the hypermobility of the kidney is enhanced, compared with the prone decubitus position. However, the kidney lies nearer to the skin. No colon injuries have been reported in either supine position. Anaesthesiological pros and cons: As the treated pathology (urolithiasis or stenosis) is mainly benign, even a low incidence of major short- or long-term complications is unacceptable, especially when a simple change in the intraoperative position might be able to avoid them. Most of the cardiovascular and pulmonary problems due to being prone, i.e. the duration, and the neuroendocrine and pharmacokinetic effects (further enhanced in morbidly obese, kyphotic or debilitated patients), and postoperative visual problems and neurological deficits (such as brachial plexus palsy and myelic lesions causing paraplegia) can be avoided with the patient turned supine [12–22]. There can be minor disadvantages, including postoperative backache, possible lesions of the knee ligaments, or of the radial or ulnar nerves if the lower and upper extremities are not correctly protected and positioned, and respiratory effects deriving from the progressive cranial location of the diaphragm under general anaesthesia. Figure 1a Galdakao-modified Valdivia position: For the resolution of complex endourological procedures we have gradually adopted this new position, allowing simultaneous percutaneous and retrograde access. The supine Valdivia position is the same, but the leg of the operated side is extended, while the contralateral one is well abducted. The patient lies supine with a 3-L saline bag under the flank, filled with air and clamped with forceps, allowing volume control by adding or subtracting air with a syringe, to find the best position. Alternatively, two distinct ‘gel’ pillows define an interposed operative space on the flank, allowing the use of instruments with lower entry of the light cable. Care is taken to prevent pressure injuries by using stirrups with padding for the upper and lower extremities. Figure 1(b) Direction of the needle in the Galdakao-modified Valdivia position: It is advisable to draw the reference lines (posterior axiliary line, iliac crest, last rib) on the skin before positioning the air bag or the gel pillows below the flank. The percutaneous puncture must be made as close as possible to the posterior auxiliary line, without passing over it ventrally. The direction of the 18 G needle is towards the desired calyx, usually the lower one, within the horizontal plane and slightly up, a feature that might disorientate those used to the prone position. The puncture should be made under combined fluoroscopic and ultrasonographic (US) guidance. The ‘freehand’ US-guided percutaneous puncture allows the needle to be directed at the most appropriate angle toward the target entry point, seeking the US beam with the needle, controlling the structures located between the skin and the kidney, and defining the third dimension not covered by fluoroscopy without rotating the C-arm. The precise entry of the needle through the tip of the renal papilla can also be controlled under direct vision, using a flexible ureteroscope previously positioned in the selected calyx. A 0.09 mm guide wire is then passed. The safest system for endourology is to have a guide exiting from both the flank skin and the urethra.

OBJECTIVE: To assess the effect of continuous positive airway pressure (CPAP) on 24 hour ambulatory blood pressure monitoring values in a large number of patients with untreated systemic hypertension of new onset and obstructive sleep apnoea. DESIGN: Multicentre, double blind, randomised, placebo controlled trial. SETTING: Eleven general hospitals in Spain between 2004 and 2007. PARTICIPANTS: 340 patients recently diagnosed as having systemic hypertension by a general practitioner (systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or both) and an apnoea-hypopnoea index per hour of sleep of >15 events/hour. INTERVENTION: Patients were assigned to CPAP (n=169) or sham CPAP (n=171) for three months. Main outcome measurements Net changes in the different 24 hour ambulatory blood pressure monitoring values from baseline to three months of optimal or sham CPAP. RESULTS: 277 (81%) of the 340 patients randomised were men; the patients had a mean age of 52.4 (SD 10.5) years, a body mass index of 31.9 (5.7), an Epworth sleepiness scale score of 10.1 (4.3), an apnoea-hypopnoea index of 43.5 (24.5). No differences between groups were seen at baseline. Compared with placebo and analysed by intention to treat, the mean 24 hour ambulatory blood pressure of the CPAP group decreased by 1.5 (95% confidence interval: 0.4 to 2.7) mm Hg (P=0.01). The mean 24 hour ambulatory blood pressure monitoring measures decreased by 2.1 mm Hg (0.4 to 3.7) mm Hg (P=0.01) for systolic pressure and 1.3 (0.2 to 2.3) mm Hg (P=0.02) for diastolic blood pressure. Mean nocturnal blood pressure decreased by 2.1 (0.5 to 3.6) mm Hg (P=0.01). CONCLUSIONS: CPAP produced a statistically significant reduction in blood pressure in patients with systemic hypertension and obstructive sleep apnoea. This reduction is small and did not achieve the 3 mm Hg drop in mean 24 hour ambulatory blood pressure that the trial was powered to detect. Consequently, these results may have uncertain clinical relevance. However, taking into account the prevalence of hypertension and the likelihood of comorbidities, the decrease in blood pressure, although minimal, may be beneficial. TRIAL REGISTRATION: Clinical trials NCT00202527.

BACKGROUND: The presence of transient lesions involving the splenium of the corpus callosum (SCC) has been described in patients with encephalitis or encephalopathy of varied etiology. We have termed it RESLES (reversible splenial lesion syndrome). PURPOSE: To describe 3 additional patients (2 encephalitis, 1 hypoglycemia) and review the literature to define this syndrome, its etiology, presentation, prognosis, and possible pathophysiological mechanisms. METHODS: Search of the MEDLINE database from 1966 through 2007. English language article titles and abstracts were screened and the appropriate articles reviewed. Additional articles cited by original references were also reviewed. RESULTS: RESLES is caused by antiepileptic drug withdrawal, infection, high-altitude cerebral edema (HACE), or metabolic disorders (hypoglycemia and hypernatremia). Complete resolution after a variable lapse is the rule. Clinical presentation is nonspecific, without evidence of callosal disconnection syndromes. Neuroimaging shows a nonenhancing, round-shaped lesion centered in the SCC that disappears after a variable lapse. Diffusion studies reveal DW hypersignal with low ADC values, suggestive of cytotoxic edema. Only HACE-related cases and 1 patient with pregabalin withdrawal showed high ADC values, consistent with vasogenic edema. CONCLUSION: RESLES is a distinct clinicoradiological syndrome of varied etiology and benign course except in those patients with an underlying severe disorder.