Co-trimoxazole prophylaxis is associated with reduced risk of incident tuberculosis in participants in the Swiss HIV Cohort Study.

Co-trimoxazole reduces mortality in HIV-infected adults with tuberculosis (TB), and in vitro data suggest potential antimycobacterial activity of co-trimoxazole. We aimed to evaluate whether prophylaxis with co-trimoxazole is associated with a decreased risk of incident TB in Swiss HIV Cohort Study (SHCS) participants. We determined the incidence of TB per 1,000 person-years from January 1992 to December 2012. Rates were analyzed separately in participants with current or no previous antiretroviral treatment (ART) using Poisson regression adjusted for CD4 cell count, sex, region of origin, injection drug use, and age. A total of 13,431 cohort participants contributed 107,549 person-years of follow-up: 182 patients had incident TB-132 (73%) before and 50 (27%) after ART initiation. The multivariable incidence rate ratios for cumulative co-trimoxazole exposure per year for persons with no previous ART and current ART were 0.70 (95% confidence interval [CI], 0.55 to 0.89) and 0.87 (95% CI, 0.74 to 1.0), respectively. Co-trimoxazole may prevent the development of TB among HIV-positive persons, especially among those with no previous ART.

Evaluation of a modified Broström-Gould procedure for treatment of chronic lateral ankle instability: A retrospective study with critical analysis of outcome scoring.

BACKGROUND: Chronic lateral ankle instability accounts for 20% of the ankle injuries. This study evaluates functional outcome of the modified Broström-Gould technique using suture anchors, with 4 different clinical scores. METHODS: A consecutive series of 41 patients were included with a minimum follow-up of one year. The function was assessed using 4 clinical scores including: the AOFAS for hind foot; the FAAM; the CAIT and the CAIS. RESULTS: Out of 41 patients; 27 patients were very satisfied, 11 satisfied and 3 were not satisfied. Ankle mobility returned to normal in 93% of patients. At follow-up the AOFAS was 89/100 (37-100), the FAAM 85/100% (35-100%), the CAIT 20/30 (5-30), and the CAIS 74/100% (27-100%). CONCLUSION: Outcome of modified Broström-Gould procedure is good with high satisfaction rate in terms of ankle mobility. The disparity in outcome of scores, signals towards the need of a standard evaluation system.

High cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients with mild impairment of renal function.

High-dose cefepime therapy is recommended for febrile neutropenia. Safety issues have been raised in a recent meta-analysis reporting an increased risk of mortality during cefepime therapy. Cefepime-related neurological toxicity has been associated with overdosing due to severe renal dysfunction. This study aimed to investigate the association between cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients. Cefepime trough concentrations (by high-performance liquid chromatography) were retrospectively analyzed for 30 adult febrile neutropenic patients receiving the recommended high-dose regimen (6 g/day for a glomerular filtration rate [GFR] of >50 ml/min). The dose adjustment to renal function was evaluated by the ratio of the cefepime daily dose per 100 ml/min of glomerular filtration. The association between cefepime plasma concentrations and neurological toxicity was assessed on the basis of consistent neurological symptoms and/or signs (by NCI criteria). The median cefepime concentration was 8.7 mg/liter (range, 2.1 to 38 mg/liter) at a median of 4 days (range, 2 to 15 days) after the start of therapy. Neurological toxicity (altered mental status, hallucinations, or myoclonia) was attributed to cefepime in 6/30 (20%) patients (median GFR, 45 ml/min; range, 41 to 65 ml/min) receiving a median dose of 13.2 g/day per 100 ml/min GFR (range, 9.2 to 14.3 g/day per 100 ml/min GFR). Cefepime discontinuation resulted in complete neurological recovery for five patients and improvement for one patient. A multivariate logistic regression model confirmed high cefepime concentrations as an independent predictor of neurological toxicity, with a 50% probability threshold at ≥22 mg/liter (P = 0.05). High cefepime plasma concentrations are associated with neurological toxicity in febrile neutropenic patients with mild renal dysfunction. Careful adherence to normalized dosing per 100 ml/min GFR is crucial. Monitoring of plasma concentrations may contribute to preventing neurological toxicity of high-dose therapy for this life-threatening condition.

Determinants of persistence in hypertensive patients treated with irbesartan: results of a postmarketing survey.

BACKGROUND: Persistence is a key factor for long-term blood pressure control, which is of high prognostic importance for patients at increased cardiovascular risk. Here we present the results of a post-marketing survey including 4769 hypertensive patients treated with irbesartan in 886 general practices in Switzerland. The goal of this survey was to evaluate the tolerance and the blood pressure lowering effect of irbesartan as well as the factors affecting persistence in a large unselected population. METHODS: Prospective observational survey conducted in general practices in all regions of Switzerland. Previously untreated and uncontrolled pre-treated patients were started with a daily dose of 150 mg irbesartan and followed up to 6 months. RESULTS: After an observation time slightly exceeding 4 months, the average reduction in systolic and diastolic blood pressure was 20 (95% confidence interval (CI) -19.6 to -20.7 mmHg) and 12 mmHg (95% CI -11.4 to -12.1 mmHg), respectively. At this time, 26% of patients had a blood pressure < 140/90 mmHg and 60% had a diastolic blood pressure < 90 mmHg. The drug was well tolerated with an incidence of adverse events (dizziness, headaches,...) of 8.0%. In this survey more than 80% of patients were still on irbesartan at 4 month. The most important factors predictive of persistence were the tolerability profile and the ability to achieve a blood pressure target < or = 140/90 mmHg before visit 2. Patients who switched from a fixed combination treatment tended to discontinue irbesartan more often whereas those who abandoned the previous treatment because of cough (a class side effect of ACE-Inhibitors) were more persistent with irbesartan. CONCLUSION: The results of this survey confirm that irbesartan is effective, well tolerated and well accepted by patients, as indicated by the good persistence. This post-marketing survey also emphasizes the importance of the tolerability profile and of achieving an early control of blood pressure as positive predictors of persistence.

Hepatitis C virus infection after liver transplantation is associated with lower levels of activated CD4(+)CD25(+)CD45RO(+)IL-7ralpha(high) T cells.

The expression of interleukin 7 receptor alpha(high) (IL-7Ralpha(high)) discriminates between activated CD25(+)CD45RO(+)CD4(+) T cells [IL-7Ralpha(high) and forkhead box P3-negative (FoxP3(-))] and regulatory T cells (IL-7Ralpha(low) and FoxP3(+)). The IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cell population has been shown to be expanded in the blood and tissues of patients after kidney transplantation and to contain alloreactive T cells (activated T cells). In the present study, we analyzed the distribution of IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cells in the blood of 53 patients after liver transplantation. The IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cell population was significantly expanded (P &lt; 0.0001) in stable transplant recipients versus healthy donors. However, the magnitude of the expansion was significantly higher (P &lt; 0.0001) in liver transplant recipients with no hepatitis C virus (HCV) infection in comparison with those with a preexisting HCV infection. Interestingly, effective suppression of HCV viremia after antiviral therapy was associated with an increase in the IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cell population to levels comparable to those of liver transplant recipients not infected with HCV. The present results indicate that (1) the IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cell population is expanded after liver transplantation, (2) it is a valuable immunological marker for monitoring activated and potential alloreactive CD4 T cells in liver transplantation, and (3) a preexisting HCV infection negatively influences the expansion of this population in liver transplant recipients.

Genetic variation in LIN28B is associated with the timing of puberty.

The timing of puberty is highly variable. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 x 10(-8)). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08-0.16; P = 2.8 x 10(-10); combined P = 3.6 x 10(-16)). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 x 10(-7); N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing, as the first genetic determinant regulating the timing of human pubertal growth and development.

A multicenter study to validate the reproducibility of MSI testing with a panel of 5 quasimonomorphic mononucleotide repeats.

Microsatellite instability (MSI) testing in clinics is becoming increasingly widespread; therefore, there is an urgent need for methodology standardization and the availability of quality control. This study is aimed to assess the interlaboratory reproducibility of MSI testing in archive samples by using a panel of 5 recently introduced, mononucleotide repeats (MNR). The quality control involved 8 European institutions. Participants were supplied with DNA extracted from 15 archive colon carcinoma samples and from the corresponding normal tissues. Every group was asked to assess the MSI status of the samples by using the BAT25, BAT26, NR21, NR24, and NR27 mononucleotide markers. Four institutions repeated the analysis using the NCI reference panel to confirm the results obtained with the MNR markers. The overall concordance among institutions for MSI analyses at single locus level was 97.7% when using the MNR panel and 95.0% with the NCI one. The laboratories obtained a full agreement in scoring the MSI status of each patient sample, both using the mononucleotide and the NCI marker sets. With the NCI marker set, however, concordance was lowered to 85.7% when considering the MSI-Low phenotype. Concordance between the 2 panels in scoring the MSI status of each sample was complete if no discrimination was made between MSI-Stable and MSI-L, whereas it dropped to 76.7% if MSI-L was considered. In conclusion, the use of the MNR panel seems to be a robust approach that yields a very high level of reproducibility. The results obtained with the 5 MNR are diagnostically consistent with those obtained by the use of the NCI markers, except for the MSI-Low phenotype.

Characterization of myocardial deformation in patients with different etiologies of left ventricular hypertrophy by using strain distribution from Magnetic Resonance Imaging

Introducción y objetivos. Se ha señalado que, en la miocardiopatía hipertrófica (MCH), la desorganización de las fibras regionales da lugar a segmentos en los que la deformación es nula o está gravemente reducida, y que estos segmentos tienen una distribución no uniforme en el ventrículo izquierdo (VI). Esto contrasta con lo observado en otros tipos de hipertrofia como en el corazón de atleta o la hipertrofia ventricular izquierda hipertensiva (HVI-HT), en los que puede haber una deformación cardiaca anormal, pero nunca tan reducida como para que se observe ausencia de deformación. Así pues, proponemos el empleo de la distribución de los valores de strain para estudiar la deformación en la MCH. Métodos. Con el empleo de resonancia magnética marcada (tagged), reconstruimos la deformación sistólica del VI de 12 sujetos de control, 10 atletas, 12 pacientes con MCH y 10 pacientes con HVI-HT. La deformación se cuantificó con un algoritmo de registro no rígido y determinando los valores de strain sistólico máximo radial y circunferencial en 16 segmentos del VI. Resultados. Los pacientes con MCH presentaron unos valores medios de strain significativamente inferiores a los de los demás grupos. Sin embargo, aunque la deformación observada en los individuos sanos y en los pacientes con HVI-HT se concentraba alrededor del valor medio, en la MCH coexistían segmentos con contracción normal y segmentos con una deformación nula o significativamente reducida, con lo que se producía una mayor heterogeneidad de los valores de strain. Se observaron también algunos segmentos sin deformación incluso en ausencia de fibrosis o hipertrofia. Conclusiones. La distribución de strain caracteriza los patrones específicos de deformación miocárdica en pacientes con diferentes etiologías de la HVI. Los pacientes con MCH presentaron un valor medio de strain significativamente inferior, así como una mayor heterogeneidad de strain (en comparación con los controles, los atletas y los pacientes con HVI-HT), y tenían regiones sin deformación.

Double-bundle transtibial posterior cruciate ligament reconstruction with a tendon-patellar bone-semitendinosus tendon autograft: clinical results with a minimum of 2 years' follow-up.

PURPOSE: The purpose of this study was to evaluate the clinical and subjective outcomes after arthroscopic-assisted double-bundle posterior cruciate ligament (PCL) reconstruction. METHODS: A series of 15 patients with grade III isolated chronic PCL tears underwent double-bundle PCL reconstruction. Of these patients, 8 (53%) had simultaneous fractures. The mean time from accident to surgery was 10.8 months (range, 8 to 15 months). The mean age at the time of surgery was 28.2 years (range, 17 to 43 years). All of the patients reported knee insecurity during activities of daily living or light sporting activities, with associated anterior knee pain in 5 patients. Preoperatively, posterolateral or posteromedial corner injuries were ruled out through accurate clinical examination. The knees were assessed before surgery and at a mean follow-up of 3.2 years (range, 2 to 5 years) with a physical examination, 4 different rating scales, and stress radiographs obtained with a Telos device (Telos, Marburg, Germany). RESULTS: Postoperative physical examination revealed a reduction of the posterior drawer and tibial step-off in all cases, although the posterior laxity was not completely normalized. Nevertheless, the patients were subjectively better after surgery. The subjective International Knee Documentation Committee score was significantly ameliorated. With regard to the objective International Knee Documentation Committee score, 6 knees (40%) were graded as abnormal because of posterior displacement of 6 mm or greater on follow-up stress radiographs with the Telos device. On the Lysholm knee scoring scale, the score was excellent in 13% of patients and good in 87%. The mean score on the Hospital for Special Surgery knee ligament rating scale was 85.8. The Tegner activity score showed an amelioration after surgery, but no patient resumed his or her preinjury level of activities. The postoperative stress radiographs revealed an improvement in posterior instability of 50% or more in all but 3 knees (20%). CONCLUSIONS: Our technique of double-bundle PCL reconstruction produced a significant reduction in knee symptoms and allowed the patients to return to moderate or strenuous activity, although the posterior tibial translation was not completely normalized and our results appear to be no better than the results of single-bundle PCL reconstruction. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer.

The tumor microenvironment mediates induction of the immunosuppressive programmed cell death-1 (PD-1) pathway, and targeted interventions against this pathway can help restore antitumor immunity. To gain insight into these responses, we studied the interaction between PD-1 expressed on T cells and its ligands (PD-1:PD-L1, PD-1:PD-L2, and PD-L1:B7.1), expressed on other cells in the tumor microenvironment, using a syngeneic orthotopic mouse model of epithelial ovarian cancer (ID8). Exhaustion of tumor-infiltrating lymphocytes (TIL) correlated with expression of PD-1 ligands by tumor cells and tumor-derived myeloid cells, including tumor-associated macrophages (TAM), dendritic cells, and myeloid-derived suppressor cells (MDSC). When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony-stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB or TLR 9 ligand, antibody-mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8(+) T cells, inhibition of suppressive regulatory T cells (Treg) and MDSC, upregulation of effector T-cell signaling molecules, and generation of T memory precursor cells. Overall, PD-1/PD-L1 blockade enhanced the amplitude of tumor immunity by reprogramming suppressive and stimulatory signals that yielded more powerful cancer control.

State Government E-Commerce Study Encouraging the Use of Electronic Financial Transactions With the Citizens of Iowa, January 20, 2006

This report was produced in compliance the 2005 Iowa Acts, Chapter 52 passed by the Eighty-First General Assembly, Session One (2005), requiring that it be submitted to the General Assembly by January 20, 2006. The legislative language mandating the report reads as follows: “It is the intent of the general assembly to encourage the use of electronic transactions with regard to the state's dealings with the citizens of Iowa and other persons. The department of administrative services shall develop recommendations, including proposed legislation, to encourage the use of electronic commerce, including the acceptance of credit card payments, with regard to transactions involving the state. The department shall consult with the state treasurer, state entities currently accepting credit card payments, and any other state entities identified as considering the acceptance of credit card payments when developing the recommendations. The department shall deliver a report to the general assembly by January 20, 2006, including any recommendations, proposed legislation, and other related information, including cost information associated with credit card payments.”

Fluvoxamine and fluoxetine do not interact in the same way with the metabolism of the enantiomers of methadone.

Six and seven addicts treated with racemic methadone (MTD) were comedicated with fluvoxamine (FLV) and fluoxetine (FLX), respectively. The plasma concentrations of both (R)- (the active enantiomer) and (S)-MTD were increased by FLV, whereas only (R)-MTD concentrations were increased by the addition of FLX. This suggests that cytochrome P450IID6 (CYP2D6), an enzyme that is strongly inhibited by FLX, preferentially metabolizes (R)-MTD, whereas CYP1A2, which is strongly inhibited by FLV, metabolizes both enantiomers. The choice of a selective serotonin reuptake inhibitor in depressive addicted patients treated with MTD and the possible use of FLX or FLV to potentiate the effects of MTD in some cases of therapeutic failure are discussed.

Longer survival for patients with alternative lengthening of telomeres (ALT) glioblastoma multiforme is due to a less aggressive phenotype and not to improved response to adjuvant therapy

Introduction: The Alternative Lengthening of Telomeres (ALT) mechanism is a significant prognostic factor for longer survival in patients with GBM, irrespective of age. The reasons for this are unknown. We considered two possibilities; firstly that ALT identifies a subset of less aggressive GBMs, or alternatively, a group of tumours that respond more favourably to adjuvant therapy. Methods: ALT was determined by staining for ALT Associated PML Bodies (APBs) in archival tissue in a retrospective analysis of 573 GBM patients. IDH1 mutation was determined by immunohistochemistry in a subset of these. Results: We identified the presence of the telomerase-independent ALT in 15% of GBM patients and found that it correlated with survival (22% of ALT patients survive more than 2 years compared to 9% for non-ALT). This survival advantage was independent of surgery type (biopsy or full resection) and treatment (radiotherapy and chemotherapy). Interestingly ALT conferred a significant survival advantage for patients who only received surgery (13.3 months compared to 5.5 months) (19% vs 1% .2 year survival). This survival benefit was also observed in GBM patients who received surgery and radiotherapy (18.5% vs 2.4%. 2 year survival), but less so for chemotherapy (21% vs 17% . 2 year survival). For the ALT patients the fraction surviving more than 2 years did not improve significantly with adjuvant therapy. IDH1 mutation also associated with ALT. Conclusions: These data indicate ALT+ tumours are biologically distinct and associated with improved patient survival, probably due to less aggressive/invasive growth. However they respond poorly to current adjuvant treatment and therefore new therapies are urgently needed for this group.

Obesity and overweight associated with lower rates of colorectal cancer screening in Switzerland.

Screening for colorectal cancer (CRC) is associated with reduced CRC mortality, but low screening rates have been reported in several settings. The aim of the study was to assess predictors of low CRC screening in Switzerland. A retrospective cohort of a random sample of 940 patients aged 50-80 years followed for 2 years from four Swiss University primary care settings was used. Patients with illegal residency status and a history of CRC or colorectal polyps were excluded. We abstracted sociodemographic data of patients and physicians, patient health status, and indicators derived from RAND's Quality Assessment Tools from medical charts. We defined CRC screening as colonoscopy in the last 10 years, flexible sigmoidoscopy in the last 5 years, or fecal occult blood testing in the last 2 years. We used bivariate and multivariate logistic regression analyses. Of 940 patients (mean age 63.9 years, 42.7% women), 316 (33.6%) had undergone CRC screening. In multivariate analysis, birthplace in a country outside of Western Europe and North America [odds ratio (OR) 0.65, 95% confidence interval (CI) 0.45-0.97], male sex of the physician in charge (OR 0.67, 95% CI 0.50-0.91), BMI 25.0-29.9 kg/m (OR 0.66, CI 0.46-0.96) and at least 30.0 kg/m (OR 0.61, CI 0.40-0.90) were associated with lower CRC screening rates. Obesity, overweight, birthplace outside of Western Europe and North America, and male sex of the physician in charge were associated with lower CRC screening rates in Swiss University primary care settings. Physician perception of obesity and its impact on their recommendation for CRC screening might be a target for further research.

Ability for self-care and its association with sociodemographic factors of people with spinal cord injury

This study aimed to verify the association between self-care ability and sociodemographic factors of people with spinal cord injury (SCI). It was a cross-sectional study, conducted in 2012, in all 58 Basic Health Units of Natal/RN, Brazil. Seventy-three subjects completed a sociodemographic form andSelf-Care Agency Scale. Statistical analyses were performed using SPSS,including Cronbach’s Alpha, Chi-square, Fisher’s and contingency coefficient tests. The Cronbach's alpha was 0.788. The result verified that sex (p = 0.028), religion (p <0.001), education (p = 0.046), current age (p = 0.027), SCI time (p = 0.020) and the SCI type (p = 0.012) were variables associated with self-care ability of the subjects. It was concluded that sociodemographic factors may interfere with the self-care ability of persons with SCI, and nurses should consider this aspect during the execution of the nursing process.