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ObjectivePrior studies identified clinical factors associated with increased risk of pancreatic ductal adenocarcinoma (PDAC). However, little is known regarding their time-varying nature, which could inform earlier diagnosis. This study assessed temporality of body mass index (BMI), blood-based markers, comorbidities and medication use with PDAC risk .DesignWe performed a population-based nested case–control study of 28 137 PDAC cases and 261 219 matched-controls in England. We described the associations of biomarkers with risk of PDAC using fractional polynomials and 5-year time trends using joinpoint regression. Associations with comorbidities and medication use were evaluated using conditional logistic regression.ResultsRisk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while following a U-shaped relationship for BMI and haemoglobin. Five-year trends showed biphasic BMI decrease and HbA1c increase prior to PDAC; early-gradual changes 2–3 years prior, followed by late-rapid changes 1–2 years prior. Liver markers and blood counts (white blood cell, platelets) showed monophasic rapid-increase approximately 1 year prior. Recent diagnosis of pancreatic cyst, pancreatitis, type 2 diabetes and initiation of certain glucose-lowering and acid-regulating therapies were associated with highest risk of PDAC.ConclusionRisk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while followed a U-shaped relationship for BMI and haemoglobin. BMI and HbA1c derange biphasically approximately 3 years prior while liver markers and blood counts (white blood cell, platelets) derange monophasically approximately 1 year prior to PDAC. Profiling these in combination with their temporality could inform earlier PDAC diagnosis.

Background: Joint Injury is a major risk factor for osteoarthritis (OA) and an opportunity to prospectively examine its early processes. We investigated whether predefined baseline factors including demographic, clinical factors and protein analytes in knee synovial fluid (sf/SF) and in plasma/serum were associated with clinically relevant outcomes at two years after knee injury. Methods: This was a longitudinal cohort study (REC10/H0805/39;NCT02667756) with 150 individuals aged 16-50 recruited within 8 weeks of a clinically significant acute knee injury (effusion and structural injury on MRI), which was typically being treated surgically. Twelve SF and four plasma/serum biomarkers were measured by immunoassay as the exposures of interest. Primary outcome was “Knee Injury and Osteoarthritis Outcome Score” (KOOS)4. X-ray/3T-MRI knees were taken at baseline and two years. Linear and logistic regression models adjusting for predefined covariates assessed associations with 2year KOOS4 and secondary endpoints including new symptomatic (regular knee symptoms), tibio-femoral radiographic OA (TFROA, Kellgren Lawrence Grade 2 or more on an X-ray) respectively. Findings: Baseline KOOS4, medium/large knee effusion and moderate/severe SF blood staining and their interaction significantly predicted 2year KOOS4 (Coeff. -20·5 [95% confidence interval -34·8, -6·18]. Of the predefined markers, only sfMCP-1 and sfIL-6 -showed independent associations with 2year KOOS4 (-0.015[0.027,-0.004] and -0.0005[-0.0009,-0.0001] per change in 1 pg/ml units respectively), jointly with the interaction of effusion and blood staining accounting for 39% of outcome variability. New TFROA at two years was associated with baseline meniscal tear (OR5·7[1·25,25·92]). 13/22(59·1%) with new TFROA had no NHANES frequent knee symptoms. Only 3month medium/large effusion was associated with new symptomatic TFROA at two years (OR14·0[1·86,105·27]). No sf/blood markers were associated with predefined structural/symptomatic outcomes. Interpretation: Effusion-haemarthrosis was strongly associated with symptomatic outcomes after acute knee injury. The SF molecular protein response to acute knee injury (best represented by MCP-1 and IL-6) was independently associated with symptomatic but not with structural outcomes, with the biomarkers overall playing a minor role relative to clinical predictors. The relationship between symptoms and structure after acute knee injury and their apparent dissociation early in this process needs to be better understood to make clinical progress.

ANTECEDENTES Y OBJETIVOS El EPI-VIH es un estudio centrado en la vigilancia centinela de la infección por VIH mediante la monitorización de la prevalencia de VIH en personas que se realizan voluntariamente la prueba en centros de diagnóstico de ITS y/o VIH. A partir del año 2003 se recoge información detallada sobre los pacientes recién diagnosticados de infección por el VIH en los centros participantes. El objetivo de este estudio es describir las características epidemiológicas y clínicas de los nuevos diagnósticos de VIH según el lugar de origen en una red de centros específicos. MÉTODOS Estudio descriptivo de los nuevos diagnósticos de VIH en 19 centros situados en 11 Comunidades Autónomas. El periodo de estudio abarca desde el 2003 al 2006. Se recogieron variables sociodemográficas y clínicas mediante un cuestionario estandarizado y anónimo. Para evaluar la asociación entre variables cualitativas se utilizó la prueba de chi-cuadrado. RESULTADOS En el periodo de estudio se diagnosticaron 1.595 nuevos casos de VIH, siendo en su mayoría hombres (80,4%), con una edad media de 32,5 años (DE: 7,9) y el 64,3% tenían estudios secundarios o superiores. 681 casos (42,7%) procedían de otros países, principalmente de Latinoamérica (422 casos, 62%) y África Sub-sahariana (122, 18%). Comparando ambos grupos, se encontró que la proporción de mujeres entre los extranjeros fue mayor (23,1% frente a 9,3%) mientras que la edad media al diagnóstico fue inferior (31 años (DE:7,3) frente a 34 (DE:8,1)). (Tabla 1). Tanto entre los casos extranjeros como en los españoles el mecanismo de transmisión más frecuente fueron las relaciones sexuales entre hombres; sin embargo, mientras que el uso de drogas intravenosas fue superior en los españoles (7,3% frente a 4,1%), las relaciones heterosexuales fueron mayores en los extranjeros (32,9% frente al 16,1%) (Figura 1). El 61% de los extranjeros tenían una prueba del VIH anterior negativa, menos que los españoles (66,2%). No se encontraron diferencias significativas en la cifra de CD4 al diagnóstico. En los casos en los que la transmisión se atribuye a relaciones sexuales, el 30,8% de los extranjeros presentaron una ITS concurrente al diagnóstico de VIH frente al 25,8% en españoles. Se detectaron diferencias en el perfil de riesgo en el grupo de pacientes cuya transmisión fue sexual: los contactos con parejas ocasionales fueron superiores entre los españoles (70,9% frente al 59,0%) y el ejercicio de prostitución en los extranjeros (3,3 % frente al 26,3%) (Figura 2). CONCLUSIONES Los nuevos diagnósticos de VIH en personas de otros países son más jóvenes y la proporción de mujeres es superior que en los españoles. El mecanismo de transmisión más común en ambos fueron las relaciones sexuales, pero hay que señalar la elevada proporción de nuevos diagnósticos debidas a relaciones heterosexuales dentro de los extranjeros. En este grupo destaca la prostitución como situación de riesgo en los casos atribuidos a transmisión sexual al comparar con los españoles.

Antecedentes / Objetivos: Caracterizar a los pacientes heterosexuales con diagnóstico de sífilis y/o gonococia atribuidos a relaciones anales (RA). Métodos: Estudio descriptivo en 15 centros de ITS e IIPP (julio 2005-diciembre 2007). Se recogieron variables sociodemográficas y situaciones de riesgo (ejercicio y contacto con prostitución, relación con contacto ocasional, con pareja estable, con pareja estable u ocasional infectada por el VIH). Se ha realizado un análisis descriptivo, bivariante y multivariado de regresión logística para evaluar, en heterosexuales, los factores asociados a tener RA frente a otras prácticas sexuales. Resultados: Se identificaron 1.891 diagnósticos, de los cuales 591 (31,3%) se habían infectado a través de relaciones heterosexuales no protegidas. De estos, 70 (11,8%) tuvieron RA, exclusivamente o en combinación con otras prácticas; el 61,4% fueron hombres, con edad media de 32,9 años (DE:10,3), 45,7% eran extranjeros y el 42,9% no tenía estudios o sólo primarios. El 62,9% (44 pacientes) tenían gonococia, 35,7% (25) sífilis y 1,4% (1) ambas. Entre los 70 casos con RA, el 18,6% refiere haberlas mantenido sólo con su pareja estable, un 71,4% con contactos esporádicos o prostitución, con o sin su pareja estable, y un 10% con contactos esporádicos y prostitución teniendo o no pareja estable; el 38,6% había tenido de 3-5 parejas en el último año. En el modelo de regresión logística, ajustado por sexo, edad, estudios, país de origen y situación de riesgo, la probabilidad tener RA fue mayor en los pacientes que tuvieron de 3 a 5 parejas (OR: 5,7; IC95%: 2,3-14,3) y en los que tuvieron de 6 a 20 (OR: 3,0; IC95%: 1,0-9,1) comparados con los referían 1 a 2 parejas en los últimos 12 meses. Conclusiones: En torno al 12% de los casos con sífilis y/o gonococia que atribuyen su infección a relaciones heterosexuales, referían tener RA. La probabilidad de tener RA en esta población aumenta con el número de parejas sexuales.

Objective Develop and internally validate risk models and a clinical risk score tool to predict incident radiographic knee osteoarthritis (RKOA) in middle-aged women. Methods We analysed 649 women in the Chingford 1000 Women study. The outcome was incident RKOA, defined as Kellgren/Lawrence grade 0-1 at baseline and ≥2 at year 5. We estimated predictors’ effects on the outcome using logistic regression models. Two models were generated. The clinical model considered patient characteristics, medication, biomarkers, and knee symptoms. The radiographic model considered the same factors, plus radiographic factors (e.g., angle between the acetabular roof and ilium’s vertical cortex (hip α-angle)). The models were internally validated. Model performance was assessed using calibration and discrimination (area under the receiver characteristic curve, AUC). Results The clinical model contained age, quadriceps circumference, and a cartilage degradation marker (CTX-II) as predictors (AUC = 0.692). The radiographic model contained older age, greater quadriceps circumference, knee pain, knee baseline Kellgren/Lawrence 1 (versus 0), greater hip α-angle, greater spinal bone mineral density, and contralateral RKOA at baseline as predictors (AUC = 0.797). Calibration tests showed good agreement between the observed and predicted incident RKOA. A clinical risk score tool was developed from the clinical model. Conclusion Two models predicting incident RKOA within 4 years were developed; including radiographic variables improved model performance. First-time predictor hip α-angle and contralateral RKOA suggest osteoarthritis origins beyond the knee. The clinical tool has the potential to help physicians identify patients at risk of RKOA in routine practice, but should be externally validated.

Background Hydroxyapatite (calcium and phosphate) spherules have been implicated in the initiation and establishment of age-related macular degeneration. Bisphosphonates could increase the dissolution of hydroxyapatite crystals and when they are used in elderly patients with osteoporosis they could reduce the risk of developing age-related macular degeneration. Objective To determine if oral bisphosphonate (BP) use is associated with the incidence of age-related macular degeneration in a large “real-world” population-based cohort of incident hip fracture patients. Design A cohort of 13,974 hip fracture patients (1999 to 2013) were used to conduct a: (a) propensity score matched cohort analysis and (b) nested case-control analysis. Setting A population-based study using electronic health records from UK primary care (Clinical Practice Research Datalink). Participants Hip fracture patients aged ≥50 years without age-related macular degeneration diagnosis prior to hip fracture date or in the first year of follow-up. Prior BP-users and those who died, transferred out or with last data collected before hip fracture were excluded. Exposures Incident BP use following hip fracture. BP use was further categorised according to medication possession ratio in quartiles. Main outcome measures Primary outcome was a diagnosis of age-related macular degeneration after the first year from index date. Propensity scores were used to match 1:1 BP-users to non-BP users. Covariates in the propensity score were index year, age, gender, body mass index, smoking, alcohol drinking, region, drug confounders and comorbidities. Subhazard ratios and their 95% confidence intervals were calculated including death as a competing risk. A nested 1:20 case-control analysis using conditional logistic regression provided risk estimates according to medication possession ratio. Results Among 6,208 matched patients and during 22,142 person-years of follow-up, 57 (1.8%) and 42 (1.4%) age-related macular degeneration cases occurred in BP-users and non-BP users, respectively. The survival analysis model did not provide significant evidence of a higher risk of AMD in BP-users (subhazard ratio: 1.60; CI: 0.95-2.72; P=0.08) although there was a significant increased risk among BP-users with high medication possession ratio (top quartile) relative to non-BP users (odds ratio: 5.08, 3.11-8.30; P Conclusions Overall, oral BP use was not associated with an increased risk of age-related macular degeneration in this cohort of hip fracture patients, although the risk increased significantly with higher medication possession ratio. More data are needed to confirm these findings.

To develop and validate a clinical prediction model of patient-reported pain and function after undergoing total knee replacement (TKR). We used data of 1,649 patients from the Knee Arthroplasty Trial who received primary TKR across 34 centres in the UK. The external validation included 595 patients from Southampton University Hospital, and Nuffield Orthopaedic Centre (Oxford). The outcome was the Oxford Knee Score (OKS) 12-month after TKR. Pre-operative predictors including patient characteristics and clinical factors were considered. Bootstrap backward linear regression analysis was used. Low pre-operative OKS, living in poor areas, high body mass index, and patient-reported anxiety or depression were associated with worse outcome. The clinical factors associated with worse outcome were worse pre-operative physical status, presence of other conditions affecting mobility and previous knee arthroscopy. Presence of fixed flexion deformity and an absent or damaged pre-operative anterior cruciate ligament (compared with intact) were associated with better outcome. Discrimination and calibration statistics were satisfactory. External validation predicted 21.1% of the variance of outcome. This is the first clinical prediction model for predicting self-reported pain and function 12 months after TKR to be externally validated. It will help to inform to patients regarding expectations of the outcome after knee replacement surgery.

To develop and validate a clinical prediction model of patient-reported pain and function after undergoing total knee replacement (TKR). We used data of 1,649 patients from the Knee Arthroplasty Trial who received primary TKR across 34 centres in the UK. The external validation included 595 patients from Southampton University Hospital, and Nuffield Orthopaedic Centre (Oxford). The outcome was the Oxford Knee Score (OKS) 12-month after TKR. Pre-operative predictors including patient characteristics and clinical factors were considered. Bootstrap backward linear regression analysis was used. Low pre-operative OKS, living in poor areas, high body mass index, and patient-reported anxiety or depression were associated with worse outcome. The clinical factors associated with worse outcome were worse pre-operative physical status, presence of other conditions affecting mobility and previous knee arthroscopy. Presence of fixed flexion deformity and an absent or damaged pre-operative anterior cruciate ligament (compared with intact) were associated with better outcome. Discrimination and calibration statistics were satisfactory. External validation predicted 21.1% of the variance of outcome. This is the first clinical prediction model for predicting self-reported pain and function 12 months after TKR to be externally validated. It will help to inform to patients regarding expectations of the outcome after knee replacement surgery.

Objective: To investigate the association between oral bisphosphonate (BP) use and the risk of developing age-related macular degeneration (AMD).

Background Thymidine analogue resistance mutations (TAMs) selected under treatment with nucleoside analogues generate two distinct genotypic profiles in the HIV-1 reverse transcriptase (RT): (i) TAM1: M41L, L210W and T215Y, and (ii) TAM2: D67N, K70R and K219E/Q, and sometimes T215F. Secondary mutations, including thumb subdomain polymorphisms (e.g. R284K) have been identified in association with TAMs. We have identified mutational clusters associated with virological failure during salvage therapy with tenofovir/emtricitabine-based regimens. In this context, we have studied the role of R284K as a secondary mutation associated with mutations of the TAM1 complex. Results The cross-sectional study carried out with >200 HIV-1 genotypes showed that virological failure to tenofovir/emtricitabine was strongly associated with the presence of M184V (P < 10-10) and TAMs (P < 10-3), while K65R was relatively uncommon in previously-treated patients failing antiretroviral therapy. Clusters of mutations were identified, and among them, the TAM1 complex showed the highest correlation coefficients. Covariation of TAM1 mutations and V118I, V179I, M184V and R284K was observed. Virological studies showed that the combination of R284K with TAM1 mutations confers a fitness advantage in the presence of zidovudine or tenofovir. Studies with recombinant HIV-1 RTs showed that when associated with TAM1 mutations, R284K had a minimal impact on zidovudine or tenofovir inhibition, and in their ability to excise the inhibitors from blocked DNA primers. However, the mutant RT M41L/L210W/T215Y/R284K showed an increased catalytic rate for nucleotide incorporation and a higher RNase H activity in comparison with WT and mutant M41L/L210W/T215Y RTs. These effects were consistent with its enhanced chain-terminated primer rescue on DNA/DNA template-primers, but not on RNA/DNA complexes, and can explain the higher fitness of HIV-1 having TAM1/R284K mutations. Conclusions Our study shows the association of R284K and TAM1 mutations in individuals failing therapy with tenofovir/emtricitabine, and unveils a novel mechanism by which secondary mutations are selected in the context of drug-resistance mutations., This study was supported in part by grants of the Spanish Ministery of Science and Innovation (BIO2010/15532), Fundación para la Investigación y Prevención del SIDA en España (FIPSE) (grant 36771/08), Fondo de Investigación Sanitaria (through the “Red Temática de Investigación Cooperativa en SIDA” RD06/006), and an institutional grant from the Fundación Ramón Areces. Work at the AIDS Research Institute IrsiCaixa was supported by the European Commission FP7 under the “Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN), through integrated project 223131 (to J.M.P), and the Spanish Ministery of Science and Innovation (grant BFU2010-15194 to M.A.M). Researchers at Hospital Carlos III were also funded through the CHAIN network.

Objetivo: Describir las características de los casos de sífilis en internos de prisiones. Material y Método: Estudio descriptivo de los casos confirmados de sífilis primaria, secundaria y latente precoz diagnosticados en prisiones españolas (2007-2008). Se recogieron variables sociodemográficas, clínicas y relacionadas con la transmisión en un cuestionario estandarizado cumplimentado por los médicos de los centros. Se obtuvieron distribuciones de frecuencia de las variables cualitativas y la media y desviación estándar para la edad. Se calculó la tasa de incidencia anual por mil internos. Para evaluar la asociación entre variables cualitativas se utilizaron las pruebas de ji-cuadrado y exacta de Fisher y la de U de Mann-Whitney para las cuantitativas. Resultados: Se identificaron 94 casos de sífilis (35,1% primaria, 20,2% secundaria y 44,7% latente precoz). La tasa de incidencia fue 0,9 y 0,7 casos/1.000 internos en 2007 y 2008, respectivamente. La mayoría de enfermos fueron hombres (90,4%), entre 31 y 40 años (30,9%) y extranjeros (52,1%). El 80,9% de los diagnósticos se realizaron por cribaje. Un 5,3% presentó coinfección con el VIH y el 16% refería haber tenido infecciones de transmisión sexual (ITS) previamente. El mecanismo de transmisión más probable fueron las relaciones heterosexuales (83,0%); la situación de riesgo más común para la adquisición de sífilis fue ser cliente de prostitución (39,4%). Conclusiones: La incidencia de sífilis en prisión es elevada. La oferta de screening de sífilis ha permitido detectar pacientes que no estaban siendo tratados y pone de manifiesto la importancia del sistema penitenciario en el control de las ITS. Objective: To describe the characteristics of cases of syphilis amongst prison inmates. Materials and Methods: Descriptive study. Confirmed cases of primary, secondary and early latent syphilis were identified in prisons in Spain during 2007-2008. Socio-demographic and clinical information, as well as variables related to transmission, was collected by the attending physicians in a standard form. Frequency distributions of each variable were performed. Annual incidence rates were calculated. To evaluate the association between qualitative variables, the χ² and Fisher's exact tests were used; the Mann-Whitney test was utilized to compare quantitative variables. Results: During the study period, 94 syphilis cases were identified (35.1% primary, 20.2% secondary and 44.7% early latent). The incidence rates were 0.9 cases/1000 prisoners in 2007 and 0.7 cases/1000 prisoners in 2008. Most cases were male (90.4%), between 31-40 years old (30.9%) and foreigners (52.1%). The majority of patients were diagnosed through screening (80.9%). Heterosexual contact was the most frequent transmission route (83.0%). Overall HIV prevalence was 5.3%, and 16.0% of the patients had a history of previous sexually transmitted infections (STI). Almost 40% of the cases reported being a client of a sex worker. Conclusions: Incidence of syphilis in prison is high. Many syphilis patients were detected through screening, highlighting the role of the Spanish prison health service in STI control.

El carcinoma renal de células claras es una neoplasia con gran capacidad de diseminación y que se presenta de formas muy variadas. Presentamos un caso clínico de un sujeto que desarrolla hematuria y retención aguda de orina secundarias ambas a metástasis en pene de un carcinoma renal de células claras. A continuación se lleva a cabo una pequeña revisión de la literatura existente sobre metástasis en esta localización. Renal cell carcinoma have a great capacity of dissemination and have a great variety of clinical presentation. We exposed a clinical note of a patient diagnosed of renal cell carcinoma who developed hematuria and acute urinary retention due to a penis metastasis. Next we review the literature about this topic.