Clinical Infections by Herpesviruses in Patients Treated with Valproic Acid: A Nested Case-Control Study in the Spanish Primary Care Database, BIFAP.

The objective of this study is to evaluate the risk of clinical infections by herpesviruses in patients exposed to valproic acid (VPA). We performed a case-control study nested in a primary cohort selected from the Spanish primary care population-based research database BIFAP (Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria) over the period 2001-2015. The events of interest were those diseases caused by any herpesviruses known to infect humans. For each case, up to 10 controls per case matched by age, gender, and calendar date were randomly selected. A conditional logistic regression was used to compute adjusted odds ratios (OR) and their 95% confidence intervals (95% CI). Current use of VPA was associated with a trend towards a reduced risk of clinical infections by herpesviruses as compared with non-users (OR 0.84; CI 95% 0.7-1.0; p = 0.057). Among current users, a trend to a decreased risk with treatment durations longer than 90 days was also observed. The results show a trend to a reduced risk of clinical infection by herpesviruses in patients exposed to VPA. These results are consistent with those in vitro studies showing that, in cultured cells, VPA can inhibit the production of the infectious progeny of herpesviruses. This study also shows the efficient use of electronic healthcare records for clinical exploratory research studies.

Validation study of colorectal cancer diagnosis in the Spanish primary care database, BIFAP.

PURPOSE: To define and validate a case-finding algorithm to identify incident colorectal cancer (CRC) in the Spanish primary care database BIFAP. METHODS: All potential incident CRC cases recorded during the study period 2001 to 2014 among patients 20 to 89 years old were identified using a defined case-finding algorithm tailored to BIFAP database characteristics and based on codes plus text mining strategies. Potential CRC cases identified by the algorithm were classified into eight homogeneous groups according to recording characteristics. Random samples of 100 cases per group were obtained, and electronic medical records were manually reviewed by two independent researchers. Positive predictive values (PPVs) were estimated per each group and for the whole sample taking into account the stratified sampling. Standardized incidence rate (SIR) of CRC was estimated and compared with that reported by the National Cancer Registry. Negative predictive value (NPV) was also estimated in a random sample of 100 non-CRC patients by the algorithm. RESULTS: A total of 17 008 potential CRC cases were identified. Most of them (14793; 87%) were recorded as incident diagnosis with linked clinical notes as free text, having this group a PPV of 92.1% (95%CI: 87.1%-95.3%). The overall PPV including all groups was 87.3% (95%CI: 83.3%-90.4%). SIR of CRC was 55.5 per 100.000 person-years. SIR increased with age and was higher in men as compared with women (77.7 vs 38.1 per 100.000 py, respectively) which were in line with those reported by the Network of Cancer Registries in Spain. NPV was of 100% (96.3%-100%). CONCLUSIONS: This study shows a high validity of the CRC cases identified by the algorithm and a high level of CRC recording in BIFAP database and supports its appropriateness to validly identify incident CRC cases in BIFAP.

Do case-only designs yield consistent results across design and different databases? A case study of hip fractures and benzodiazepines.

BACKGROUND: The case-crossover (CXO) and self-controlled case series (SCCS) designs are increasingly used in pharmacoepidemiology. In both, relative risk estimates are obtained within persons, implicitly controlling for time-fixed confounding variables. OBJECTIVES: To examine the consistency of relative risk estimates of hip/femur fractures (HFF) associated with the use of benzodiazepines (BZD) across case-only designs in two databases (DBs), when a common protocol was applied. METHODS: CXO and SCCS studies were conducted in BIFAP (Spain) and CPRD (UK). Exposure to BZD was divided into non-use, current, recent and past use. For CXO, odds ratios (OR; 95%CI) of current use versus non-use/past were estimated using conditional logistic regression adjusted for co-medications (AOR). For the SCCS, conditional Poisson regression was used to estimate incidence rate ratios (IRR; 95%CI) of current use versus non/past-use, adjusted for age. To investigate possible event-exposure dependence the relative risk in the 30 days prior to first BZD exposure was also evaluated. RESULTS: In the CXO current use of BZD was associated with an increased risk of HFF in both DBs, AORBIFAP = 1.47 (1.29-1.67) and AORCPRD = 1.55 (1.41-1.70). In the SCCS, IRRs for current exposure was 0.79 (0.72-0.86) in BIFAP and 1.21 (1.13-1.30) in CPRD. However, when we considered separately the 30-day pre-exposure period, the IRR for current period was 1.43 (1.31-1.57) in BIFAP and 1.37 (1.27-1.47) in CPRD. CONCLUSIONS: CXO designs yielded consistent results across DBs, while initial SCCS analyses did not. Accounting for event-exposure dependence, estimates derived from SCCS were more consistent across DBs and designs.

Hip/femur fractures associated with the use of benzodiazepines (anxiolytics, hypnotics and related drugs): a methodological approach to assess consistencies across databases from the PROTECT-EU project.

BACKGROUND: Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed. OBJECTIVES: The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies. METHODS: To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated. RESULTS: Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs. CONCLUSIONS: Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs.

Effect of immigration background and country-of-origin contextual factors on adolescent substance use in Spain.

PURPOSE: The effects of adolescent- and parental-birthplace and country-of-origin contextual factors on substance use among adolescents with recent immigrant background (ARIBs) are poorly understood. We aimed to assess these effects and identify the main mediating factors in Spain. METHODS: Participants were 12,432 ARIBs (≥1 foreign-born parent) and 75,511 autochthonous adolescents from pooled 2006-2010 school surveys. Outcomes were prevalence of use of alcohol, tobacco, cannabis, stimulants and sedative-hypnotics. ARIBs were classified by adolescent birthplace (Spain/abroad), whether they had mixed-parents (one Spanish-born and one foreign-born), and country-of-origin characteristics. Adjusted prevalence ratios (aPRs) and percent change expressing disparities in risk were estimated using Poisson regression with robust variance. RESULTS: Compared to autochthonous adolescents, foreign-born ARIBs without mixed-parents showed significant aPRs <1 for all substances, which generally approached 1 in Spanish-born ARIBs with mixed-parents. The main factors mediating ARIBs' lower risk were less frequent socialization in leisure environments and less association with peers who use such substances. ARIBs' lower risk depended more on country-of-origin characteristics and not having mixed-parents than being foreign-born. Tobacco, cannabis and stimulant use in ARIBs increased with increasing population use of these substances in the country-of-origin. ARIBs from the non-Muslim-regions had a lower risk of using alcohol and higher risk of using sedative-hypnotics than those from the Muslim-region. CONCLUSIONS: Among ARIBs in Spain, parental transmission of norms and values could influence substance use as much as or more than exposure to the Spanish context. Future research should better assess effects of adolescent- and parental-birthplace and country-of-origin contextual factors on substance use.

Bisphosphonate-related osteonecrosis of the jaw: an Italian post-marketing surveillance analysis.

OBJECTIVE: Although bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) is well recognized, little is known about it in terms of pathophysiology, epidemiology or management. We analyzed all suspected BRONJ reports sent to the Italian Pharmacovigilance Adverse Event Spontaneous Reporting System (Rete Nazionale Farmacovigilanza [RNF]) to determine their pattern and add new information about this relevant issue. RESEARCH DESIGN AND METHODS: All suspected BRONJ sent to the RNF between 2003 and 2011 were retrieved. After a case-by-case assessment procedure, we analyzed BP type, BP exposure time and time since last use. RESULTS: Between 2003 and 2011, 555 reports of osteonecrosis of the jaw (ONJ) after BP administration were recorded in the RNF. These events occurred mostly in patients affected by cancer (77.84%) in which zoledronate was the most frequently suspected BP. Most patients experienced ONJ after long-term use of the drug (median time of BP exposure being between 1.3 and 8.8 years). Interestingly, 139 (25.05%) cases of ONJ occurred between 2 and 121 months after BP withdrawal. CONCLUSION: This study shows that BRONJ can occur much earlier than hitherto reported, adds new data on BRONJ onset following ibandronate treatment and reveals that patients who cease BP-based therapy develop ONJ, raising the question of post-treatment monitoring strategies.

Oral versus intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency: a pragmatic, randomised, multicentre, non-inferiority clinical trial undertaken in the primary healthcare setting (Project OB12).

BACKGROUND: The oral administration of vitamin B12 offers a potentially simpler and cheaper alternative to parenteral administration, but its effectiveness has not been definitively demonstrated. The following protocol was designed to compare the effectiveness of orally and intramuscularly administered vitamin B12 in the treatment of patients ≥65 years of age with vitamin B12 deficiency. METHODS/DESIGN: The proposed study involves a controlled, randomised, multicentre, parallel, non-inferiority clinical trial lasting one year, involving 23 primary healthcare centres in the Madrid region (Spain), and patients ≥65 years of age. The minimum number of patients required for the study was calculated as 320 (160 in each arm). Bearing in mind an estimated 8-10% prevalence of vitamin B12 deficiency among the population of this age group, an initial sample of 3556 patients will need to be recruited. Eligible patients will be randomly assigned to one of the two treatment arms. In the intramuscular treatment arm, vitamin B12 will be administered as follows: 1 mg on alternate days in weeks 1 and 2, 1 mg/week in weeks 3-8,and 1 mg/month in weeks 9-52. In the oral arm, the vitamin will be administered as: 1 mg/day in weeks 1-8 and 1 mg/week in weeks 9-52. The main outcome variable to be monitored in both treatment arms is the normalisation of the serum vitamin B12 concentration at weeks 8, 26 and 52; the secondary outcome variables include the serum concentration of vitamin B12 (in pg/ml), adherence to treatment, quality of life (EuroQoL-5D questionnaire), patient 3satisfaction and patient preferences. All statistical tests will be performed with intention to treat and per protocol. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors or factors that might alter the effect recorded will be taken into account in analyses. DISCUSSION: The results of this study should help establish, taking quality of life into account, whether the oral administration of vitamin B12 is an effective alternative to its intramuscular administration. If this administration route is effective, it should provide a cheaper means of treating vitamin B12 deficiency while inducing fewer adverse effects. Having such an alternative would also allow patient preferences to be taken into consideration at the time of prescribing treatment. TRIAL REGISTRATION: This trial has been registered with ClinicalTrials.gov, number NCT 01476007, and under EUDRACT number 2010-024129-20.

Análisis comparativo de los pacientes con y sin trastorno mental diagnosticable / A comparative study of individuals with or without mental disorder diagnosable

Objetivo: Analizar las diferencias entre las variables sociodemográficas, asistenciales y clínicas de estas dos poblaciones. Metodología: Diseño: descriptivo comparativo. Ámbito: área sanitaria urbana. Población: todos los pacientes derivados al Centro de Salud Mental durante un año (n =1187). Variables: sociodemográficas, clínicas y asistenciales que se recogieron mediante una entrevista clínica y los tests GHQ-28, SCL-90-R y una escala de expectativas. Resultados: Entre los trastornos mentales hay más solteros, menor nivel educativo, son diagnosticados con mayor frecuencia por profesionales mujeres y derivados como preferentes. Además presentan más antecedentes psiquiátricos, acuden al centro con un tratamiento psicofarmacológico pautado en mayor medida y tras la evaluación son dados de alta en menos ocasiones que los códigos Z. Los trastornos mentales puntúan más alto en todos los índices estudiados del SCL-90-R. Además señalaban que los acontecimientos vitales estaban fuera de control en más ocasiones que los códigos Z en el momento de la consulta. Conclusiones: Las diferencias sociodemográficas entre ambas poblaciones son muy discretas al igual que en los estudios previos. En nuestro trabajo ambos grupos de pacientes tienen menos contactos ambulatorios previos que en estudios internacionales, pero más medicación pautada en el momento de la consulta, sobre todo en el caso de los códigos Z. Parece que los trastornos mentales tienen menos capacidades o habilidades de afrontamiento de las circunstancias adversas y son por tanto más vulnerables que los pacientes diagnosticados de código Z (AU)

Objective: To analyze the differences between socio-demographic variables, inpatients and outpatients of individuals assessed in a community mental health center (CMHC) with or with no diagnosable mental disorders according to ICD-10 (mental disorder or Z code). Method: Design: comparative description. Scope: urban area. Population: all patients referred to the Salamanca Mental Health Service (n =1187). Variables: sociodemographics, clinical and health service utilization gathered through clinical interview, GHQ-28, SCL-90-R and an expectations scale. Results: Among the mental patients there are more singles, a lower level of education, they are diagnosed by female professionals more frequently, and they have priority referals. Moreover they have mental health history more frequently, they arrive at the mental health service with psychopharmacological treatment administered often and after the evaluation they are discharged less frequently than Z code. Mental disorders are given more weight in all the SCL-90-R indexes studied. Vital occurrences were out of control more often in mental disorders than Z codes at the time of evaluation. Conclusions: The socio-demographic differences between both populations are finite like in previous studies. In our research both patient groups have fewer clinical visits than in international studies, but more prescribed medication at the time of the evaluation, especially in Z codes. It appears that mental patients lack social skills or the ability to stressful life events and, therefore, are more vulnerable than Z codes (AU)

Characterization of a new experimental model of osteoporosis in rabbits.

To characterize an experimental model of osteoporosis in rabbits induced either by ovariectomy (OVX), glucocorticoids, or by a combination of both. Thirty-five rabbits were randomly allocated into five groups: bilateral OVX, daily methylprednisolone hemisuccinate (MPH) injections at a 1.5 mg/kg/day dose for 4 consecutive weeks (MPH group), or variable dose of MPH between 0.5 and 2 mg/kg/day in combination with OVX (OVX + MPH at low, medium, and high dose). Twenty-two animals were killed 6 weeks after OVX, and 13 were killed 16 weeks later. Dual-energy X-ray absorptiometry was obtained at baseline and 6 and 16 weeks after OVX. High-resolution magnetic resonance imaging (MRI) was carried out at 0 and 6 weeks after OVX. Glucose, total cholesterol, triglyceride, and oestradiol blood levels before and 16 weeks after OVX were determined. Bone mineral density (BMD) decreased significantly at lumbar spine in MPH and OVX + MPH medium-dose groups, and at global knee and subchondral bone of the knee in MPH, OVX + MPH low- and medium-dosage groups (P < 0.05). BMD variations in OVX rabbits were not significant in any of the three anatomical locations analyzed. BMD variation 16 weeks after OVX was significant at lumbar spine and global knee in the OVX + MPH medium-dose group and only at global knee in the OVX + MPH low-dose group (P < 0.05). MRI did not show bone or cartilage changes. Osteoporosis can be induced experimentally in rabbits through isolated MPH or by a combination of OVX and medium dose corticosteroid for 4 weeks. OVX alone was not sufficient to induce osteoporosis.

Impact of antiretroviral therapy on viral tropism in HIV-infected patients followed longitudinally for over 5 years.

BACKGROUND: Viral tropism plays a major role in HIV pathogenesis and may influence the activity of entry inhibitors. The impact of antiretroviral therapy use on the dynamics of viral tropism over time is still poorly understood. PATIENTS AND METHODS: HIV co-receptor usage was determined longitudinally for over 5 years in 237 plasma specimens collected from 73 distinct HIV-1-infected drug-naive individuals, 42 of whom initiated antiretroviral therapy thereafter and 31 who remained untreated. Viral tropism was estimated genotypically using the phenotype predictor software webPSSM, considering as X4 virus populations those with pure X4 and dual/mixed X4/R5 variants. RESULTS: At baseline, the prevalence of X4 viruses was 3.2% and 14.6% in patients who remained untreated and in those who initiated antiretroviral therapy, respectively (P = 0.112). Mean plasma HIV-RNA was lower in the former compared with the latter (3.8 +/- 0.9 versus 4.5 +/- 0.9 log; P < 0.004), while conversely the mean CD4 count was greater in untreated than in those who had begun therapy (536 +/- 191 versus 278 +/- 192 cells/mm3; P < 0.001). During follow-up, switch in co-receptor use occurred overall in 26% of the study population, with no significant differences between the groups. Emergence of X4 viruses was significantly associated with lower CD4 counts regardless of antiretroviral treatment exposure. CONCLUSIONS: The use of antiretroviral therapy does not seem to influence the selection of X4 viruses, which mainly occur in patients with low CD4 counts.

Intratumoral lymphatic vessels and VEGF-C expression are predictive factors of lymph node relapse in T1-T4 N0 laryngopharyngeal squamous cell carcinoma.

BACKGROUND: The presence of intratumoral lymphatic vessels (ILVs) and the expression of vascular endothelial growth factor-C (VEGF-C) in tumour cells have been studied as markers of lymphangiogenesis in order to evaluate their role in metastatic dissemination in laryngopharyngeal squamous cell carcinoma. METHODS: A retrospective study was performed in 76 patients of N0 laryngopharyngeal carcinoma. with variable tumour size (T1-T4), histological grade, and location (supraglottic, glottic and hypopharyngeal). The presence of ILVs, as revealed by the expression of PA2.26 antigen and VEGF-C expression, were determined by immunohistochemistry (IHC). Low-grade and high-grade lymphangiogenesis were defined by qualitative and quantitative criteria. RESULTS: Multivariate analysis revealed low-grade ILV and VEGF-C expression to be associated respectively with 30.3- and 16.2-fold higher probabilities of cervical lymph node relapse (P = 0.005 and P = 0.032) and with 16.2- and 8.44-fold shorter disease-free survival (P = 0.009 and P = 0.045). CONCLUSIONS: Low-grade ILV and VEGF-C expression are independent predictive factors of cervical lymph node relapse and shortening of time to relapse in N0 laryngopharyngeal carcinoma.

La derivación a salud mental de pacientes sin un trastorno psíquico diagnosticable / Mental health referrals of patients without diagnosable psychiatric pathology

Objetivo. Analizar las características de la derivación desde atención primaria a un centro de salud mental de los pacientes sin trastorno mental diagnosticable. Metodología. Se evaluó clínicamente a todos los pacientes nuevos (n = 1.004) que acudieron de manera consecutiva, sin excluir a ninguno, durante un año, a un centro de salud mental para determinar cuántos no pudieron ser diagnosticados de un trastorno mental según la CIE-10 (códigos Z). Se recabó la información sobre quién tuvo la idea de consultar, quién los derivó, cómo y con qué tratamiento. Además, se obtuvo información sobre sus características sociodemográficas, clínicas y asistenciales. Resultados. De un total de 1.004 pacientes evaluados en el año, 244 (el 24,4%) (intervalo de confianza [IC] del 95%, 21,6-27) no reunieron criterios para ser diagnosticados de trastorno mental según la CIE-10. Los pacientes con un diagnóstico de un código Z tienden a solicitar, ellos mismos o su familia (54,5%) (IC del 95%, 48,3-60,8), la remisión a un servicio de salud mental, que se hace casi en su totalidad (95,5%) (IC del 95%, 92,1-97,7) a través del médico de atención primaria. Más de la mitad recibe psicofármacos pautados principalmente por el médico de cabecera y un 20,9% (IC del 95%, 15,8-26) es remitido con carácter preferente. Conclusiones. En nuestro estudio se observa que hay una cantidad excesiva de pacientes que no presentan un trastorno mental diagnosticable y que son remitidos al centro de salud mental, muchos con tratamiento psicofarmacológico pautado, lo que pone en cuestión la función de filtro asistencial de la atención primaria con estas personas. Probablemente, la indiscriminada demanda asistencial de la población junto con una tendencia excesiva en la utilización de psicofármacos en la salud mental explican parte de este fenómeno

Objective. To analyze the characteristics of referral from primary health care to mental health of patients with no diagnosable mental disorder. Methods. Consecutively and without exemptions, all persons attending for first-time consultation a mental health centre in the course of a year were clinically examined. We measured the incidence of conditions not attributable to a mental disorder using ICD-10 (Z codes). Information was collected on whose idea it was that they attended, and who, how and with what treatment they were referred. In addition, data about their social, demographic and clinical characteristics were collected. Results. Of the 1004 persons examined, 244 (24.4%) (95% CI, 21.6-27) did not meet the ICD-10 diagnosis criteria for mental disorders. They themselves or their family tended to request the Z codes (54.5%) (95% CI, 48.3-60.8]. Mental health referral was almost always through the PC doctor (95.5%) (95% CI, 92.1-97.7). Half the patients were already receiving drug therapy under their general practitioner before their visit and 20.9% (95% CI, 15.8-26) were referred as priority patients. Conclusions. Our study found that a large number of patients with no diagnosable mental disorder at the mental health centre, many of them with drug treatment prescribed, were referred. This places a question-mark over the function of primary care as a filter for these patients. The population´s indiscriminate health care demand and the steady increase in treating mental health with drugs partially explain this phenomenon

[Mental health referrals of patients without diagnosable psychiatric pathology]. / La derivación a salud mental de pacientes sin un trastorno psíquico diagnosticable.

OBJECTIVE: To analyze the characteristics of referral from primary health care to mental health of patients with no diagnosable mental disorder. METHODS: Consecutively and without exemptions, all persons attending for first-time consultation a mental health centre in the course of a year were clinically examined. We measured the incidence of conditions not attributable to a mental disorder using ICD-10 (Z codes). Information was collected on whose idea it was that they attended, and who, how and with what treatment they were referred. In addition, data about their social, demographic and clinical characteristics were collected. RESULTS: Of the 1004 persons examined, 244 (24.4%) (95% CI, 21.6-27) did not meet the ICD-10 diagnosis criteria for mental disorders. They themselves or their family tended to request the Z codes (54.5%) (95% CI, 48.3-60.8]. Mental health referral was almost always through the PC doctor (95.5%) (95% CI, 92.1-97.7). Half the patients were already receiving drug therapy under their general practitioner before their visit and 20.9% (95% CI, 15.8-26) were referred as priority patients. CONCLUSIONS: Our study found that a large number of patients with no diagnosable mental disorder at the mental health centre, many of them with drug treatment prescribed, were referred. This places a question-mark over the function of primary care as a filter for these patients. The population s indiscriminate health care demand and the steady increase in treating mental health with drugs partially explain this phenomenon.