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Background and Aims: Cholangiocarcinoma (CCA) is characterized by high resistance to chemotherapy and poor prognosis. Several oncogenic pathways converge on activation of extracellular signal-regulated kinase 5 (ERK5), whose role in CCA has not been explored. The aim of this study was to investigate the role of ERK5 in the biology of CCA. Approach and Results: ERK5 expression was detected in two established (HuCCT-1 and CCLP-1) and two primary human intrahepatic CCA cell lines (iCCA58 and iCCA60). ERK5 phosphorylation was increased in CCA cells exposed to soluble mediators. In both HuCCT-1 and CCLP-1 cells, ERK5 was localized in the nucleus, and exposure to fetal bovine serum (FBS) further increased the amount of nuclear ERK5. In human CCA specimens, ERK5 mRNA expression was increased in tumor cells and positively correlated with portal invasion. ERK5 protein levels were significantly associated with tumor grade. Growth, migration, and invasion of CCA cells were decreased when ERK5 was silenced using specific short hairpin RNA (shRNA). The inhibitory effects on CCA cell proliferation, migration and invasion were recapitulated by treatment with small molecule inhibitors targeting ERK5. In addition, expression of the angiogenic factors VEGF and angiopoietin 1 was reduced after ERK5 silencing. Conditioned medium from ERK5-silenced cells had a lower ability to induce tube formation by human umbilical vein endothelial cells and to induce migration of myofibroblasts and monocytes/macrophages. In mice, subcutaneous injection of CCLP-1 cells silenced for ERK5 resulted in less frequent tumor development and smaller size of xenografts compared with cells transfected with nontargeting shRNA. Conclusions: ERK5 is a key mediator of growth and migration of CCA cells and supports a protumorigenic crosstalk between the tumor and the microenvironment.

Purpose EAU guidelines recommend multiparametric MRI of the prostate (mpMRI) prior to biopsy to increase accuracy and reduce biopsies. Whether biopsy can be avoided in case of negative mpMRI remains unclear. Aim of this study is to evaluate predictors of overall prostate cancer (PCa) in negative mpMRI. Methods A total of 216 patients from 2018 to 2020 with suspicion of PCa and negative mpMRI (PI-RADS ≤ 2) were interviewed by telephone about outcome and further follow-up. Clinically significant PCa (csPCa) was defined as ISUP ≥ 2. Patients with vs. without biopsy and with vs. without PCa were compared. Univariate and multivariate analyses were performed to evaluate predictors of PCa occurrence in patients with negative mpMRI. Results 15.7% and 5.1% of patients with PI-RADS ≤ 2 on mpMRI showed PCa and csPCa, respectively. PCa patients had higher PSAD (0.14 vs. 0.09 ng/ml2; p = 0.001) and lower prostate volume (50.5 vs. 74.0 ml; p = 0.003). Patients without biopsy (25%) after MRI were older (69 vs. 65.5 years; p = 0.027), showed lower PSA (5.7 vs. 6.73 ng/ml; p = 0.033) and lower PSA density (0.09 vs. 0.1 ng/ml2; p = 0.027). Multivariate analysis revealed age (OR 1.09 [1.02–1.16]; p = 0.011), prostate volume (OR 0.982 [0.065; 0.997]; p = 0.027), total PSA level (OR 1.22 [1.01–1.47], p = 0.033), free PSA (OR 0.431 [0.177; 0.927]; p = 0.049) and no PI-RADS lesion vs PI-RADS 1–2 lesion (OR 0.38 [0.15–0.91], p = 0.032.) as predictive factors for the endpoint presence of PCa. Conclusions Biopsy for selected patient groups (higher age, prostate volume and free PSA as well as lower PSA-Density) with negative mpMRI can be avoided, if sufficient follow-up care is guaranteed. Detailed counseling regarding residual risk for undetected prostate cancer should be mandatory.

As the use of risk assessments for correctional populations has grown, so has concern that these instruments exacerbate existing racial and ethnic disparities. While much of the attention arising from this concern has focused on how algorithms are designed, relatively little consideration has been given to how risk assessments are used. To this end, the present study tests whether application of the risk principle would help preserve predictive accuracy while, at the same time, mitigate disparities. Using a sample of 9,529 inmates released from Minnesota prisons who had been assessed multiple times during their confinement on a fully-automated risk assessment, this study relies on both actual and simulated data to examine the impact of program assignment decisions on changes in risk level from intake to release. The findings showed that while the risk principle was used in practice to some extent, the simulated results showed that greater adherence to the risk principle would increase reductions in risk levels and minimize the disparities observed at intake. The simulated data further revealed the most favorable outcomes would be achieved by not only applying the risk principle, but also by expanding program capacity for the higher-risk inmates in order to adequately reduce their risk.

Circles of Support and Accountability (CoSA) are comprised of approximately five trained Circle volunteers who provide support during reentry to one core member previously convicted of a sexual offense. In 2008, the Minnesota Department of Corrections implemented the Minnesota Circles of Support and Accountability (MnCoSA). In-depth interviews were conducted with 33 MnCoSA volunteers and 10 core members to gain an understanding of (a) what makes volunteers desirable to core members, as well as (b) what makes CoSA desirable to volunteers. The study finds core members express a desire for the availability and consistency of volunteers, a preference for certain types of volunteers, and consistent with volunteers’ perceptions, a belief that CoSAs offer particular benefits for volunteers. Implications for recruitment of volunteers and optimal structuring of CoSAs are discussed.

Sharing a commitment to primary care, NAPCRG is partnering with the Patient-Centered Primary Care Collaborative (PCC) on the PCORI-funded capacity building project, “Bridging the Gap in Primary Care Research.” This 2-year initiative is intended to improve access to research that is most

Research on incarcerated offenders trained to help prisoners change is rare because programs that equip inmates with practical capacities for helping others rehabilitate in prison hardly exist. An exception is the Field Ministry program in Texas, which enlists inmates who have graduated from a prison-based seminary to work as “Field Ministers” and serve other inmates in various capacities. We hypothesize that inmate exposure to Field Ministers is inversely related to antisocial factors and positively to prosocial ones. We applied manifest-variable structural equation modeling to analyze data from a survey of a random sample of male inmates at three maximum-security prisons where the Field Ministry program operated. We found that inmates exposed more frequently to the Field Ministry and for a longer time period tended to report lower levels of criminological risk factors and aggressiveness and higher levels of virtues and predictors of human agency as well as religiosity and spirituality.

Circadian clocks control immunity and virus replication, as well as pharmacokinetics and efficacy therapeutics. The aim of this study was to investigate the extent of these relationships by measuring circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after remdesivir exposure. In the current study, we analysed circadian gene expression in a cohort of participants without a neuropsychiatric diagnosis. After ex vivo exposure to remdesivir to human dermal fibroblast (HDF) cultures and dexamethasone synchronization, the rhythmicity of circadian gene expression (Clock, Bmal1, Per1-3, Cry1) was analysed via qRT-PCR. In this study, D-MEQ scores indicated that participants without a neuropsychiatric diagnosis had no evening preference. Remdesivir leads to a slight phase-shift in Clock, Per1 and Per2. Significant different expressions of Bmal1 and Per3 were detected after remdesivir exposure: Bmal1 at ZT8 (t(22) = 3.26, p = 0.004), ZT24 (t(22) = − 2.66, p = 0.015), ZT28 (t(20) = − 2.14, p = 0.045) and Per3 at ZT8 (t(22) = − 4.27, p t(22) = − 2.61, p = 0.016). A significant difference between chronotype and circadian gene expression for Bmal1, Cry1 and Per3 was observed. The present study shows that remdesivir has an impact on circadian function. It is well known that the circadian rhythm effects sleep and, moreover, sleep quality. The results suggest that remdesivir medication may alter sleep quality in participants without a neuropsychiatric diagnosis and shifts chronotype to eveningness; similar as prevalent in ADHD.

The benefit of resection of liver metastases depends on primary diseases. Neuroendocrine tumors are associated with favorable prognosis after resection of liver metastases. Gastric cancer has worse tumor biology, and resection of gastric liver metastases should be performed in selected patients. A multidisciplinary approach is well established for colorectal liver metastases (CLMs). Resection remains the only curative treatment of CLM. Chemotherapy and molecular-targeted therapy have improved survival in unresectable metastatic colorectal cancer. Understanding of the following two strategies, conversion therapy and two-stage hepatectomy, are important to make this patient group to be candidates for curative-intent surgery.

A zoonotic A/sw/H1avN1 1C.2.2 influenza virus infection was detected in a German child that presented with influenza-like illness, including high fever. There was a history of close contact with pigs 3 days before symptom onset. The child recovered within 3 days. No other transmissions were observed. Serological investigations of the virus isolate revealed cross-reactions with ferret antisera against influenza A(H1N1)pdm09 virus, indicating a closer antigenic relationship with A(H1N1)pdm09 than with the former seasonal H1N1 viruses.

Objective In this study, we analyzed the relationship between state firearm laws and the incidence and severity (i.e., number of victims) of mass public shootings in the United States during the period 1976-2018. Hypotheses We hypothesized that states requiring permits to purchase firearms would have a lower incidence of mass public shootings than states not requiring permits. We also hypothesized that states banning large-capacity ammunition magazines would experience a lower number of victims in mass public shootings that did occur than states without bans. Method We developed a panel of annual, state-specific data on firearm laws and mass public shooting events and victim counts. We used a generalized estimating equations logistic regression to examine the relationship between eight state firearm laws and the likelihood of a mass public shooting. We then used a zero-inflated negative binomial model to assess the relationship between these laws and the number of fatalities and nonfatal injuries in these incidents. Results State laws requiring a permit to purchase a firearm were associated with 60% lower odds of a mass public shooting occurring (95% confidence interval [CI: -32%, -76%]). Large-capacity magazine bans were associated with 38% fewer fatalities (95% CI [-12%, -57%]) and 77% fewer nonfatal injuries (95% CI [-43%, -91%]) when a mass shooting occurred. Conclusion Laws requiring permits to purchase a gun are associated with a lower incidence of mass public shootings, and bans on large capacity magazines are associated with fewer fatalities and nonfatal injuries when such events do occur. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Data to guide surveillance following oncologic extended resection (OER) for gallbladder cancer (GBC) are lacking. Conditional recurrence-free survival (C-RFS) can inform surveillance. We aimed to estimate C-RFS and identify factors affecting conditional RFS after OER for GBC. Patients with ≥ T1b GBC who underwent curative-intent surgery in 2000–2018 at four countries were identified. Risk factors for recurrence and RFS were evaluated at initial resection in all patients and at 12 and 24 months after resection in patients remaining recurrence-free. Of the 1071 patients who underwent OER, 484 met the inclusion criteria; 290 (60%) were recurrence-free at 12 months, and 199 (41%) were recurrence-free at 24 months. Median follow-up was 24.5 months for all patients and 47.21 months in survivors at analysis. Five-year RFS rates were 47% for the overall population, 71% for patients recurrence-free at 12 months, and 87% for the patients without recurrence at 24 months. In the entire cohort, the risk of recurrence peaked at 8 months. T3–T4 disease was independently associated with recurrence in all groups: entire cohort [hazard ratio (HR) 2.16, 95% confidence interval (CI) 1.49–3.13, P

Objective: To evaluate the quality of life and its association with disease control, severity, allergic comorbidities and adherence to treatment in children and adolescents with asthma. Methods: A cross-sectional study that included children and adolescents aged seven to 17. The Paediatric Asthma Quality of Life Questionnaire (PAQLQ) was used to assess their quality of life. Sociodemographic and clinical data were obtained from the chart and from a questionnaire. Descriptive statistics were performed and chi-square or Fisher’s exact tests were used to verify the existence of associations between quality of life and disease control, severity, comorbidities and adherence to treatment. The level of statistical significance was set at p

When sex offenders in Minnesota are assigned risk levels prior to their release from prison, correctional staff frequently exercise professional judgment by overriding the presumptive risk level per an offender's score on the Minnesota Sex Offender Screening Tool-3 (MnSOST-3), a sexual recidivism risk-assessment instrument. These overrides enabled us to evaluate whether the use of professional judgment resulted in better predictive performance than did reliance on "actuarial" judgment (MnSOST-3). Using multiple metrics, we also compared the performance of a home-grown instrument (the MnSOST-3) with a global assessment (the revised version of the Static-99 [Static-99R]) in predicting sexual recidivism for 650 sex offenders released from Minnesota prisons in 2012. The results showed that use of professional judgment led to a significant degradation in predictive performance. Likewise, the MnSOST-3 outperformed the Static-99R for both sexual recidivism measures (rearrest and reconviction) across most of the performance metrics we used. These results imply that actuarial tools and home-grown tools are preferred relative to those that include professional judgment and those developed on different populations. (PsycINFO Database Record

PURPOSE OF THE STUDY: Older adults’ self-care often depends on understanding and utilizing health information. Inadequate health literacy among older adults poses a barrier to self-care because it hampers comprehension of this information, particularly when the information is not well-designed. Our goal was to improve comprehension of online health information among older adults with hypertension who varied in health literacy abilities. DESIGN AND METHODS: We identified passages about hypertension self-care from credible websites (typical passages). We used a multi-faceted approach to redesign these passages, revising their content, language, organization and format (revised passages). Older participants read both versions of the passages at their own pace. After each passage, they summarized the passage and then answered questions about the passage. RESULTS: Participants better remembered the revised than the typical passages, summarizing the passages more accurately and uptaking information more efficiently (less reading time needed per unit of information remembered). The benefits for reading efficiency were greater for older adults with more health knowledge, suggesting knowledge facilitated comprehension of information in the revised passages. IMPLICATIONS: A systematic, multi-faceted approach to designing health documents can promote online learning among older adults with diverse health literacy abilities.

F1FO ATP synthase, also known as complex V, is a key enzyme of mitochondrial energy metabolism that can synthesize and hydrolyze ATP. It is not known whether the ATP synthase and ATPase function are correlated with a different spatio-temporal organisation of the enzyme. In order to analyze this, we tracked and localized single ATP synthase molecules in situ using live cell microscopy. Under normal conditions, complex V was mainly restricted to cristae indicated by orthogonal trajectories along the cristae membranes. In addition confined trajectories that are quasi immobile exist. By inhibiting glycolysis with 2-DG, the activity and mobility of complex V was altered. The distinct cristae-related orthogonal trajectories of complex V were obliterated. Moreover, a mobile subpopulation of complex V was found in the inner boundary membrane. The observed changes in the ratio of dimeric/monomeric complex V, respectively less mobile/more mobile complex V and its activity changes were reversible. In IF1-KO cells, in which ATP hydrolysis is not inhibited by IF1, complex V was more mobile, while inhibition of ATP hydrolysis by BMS-199264 reduced the mobility of complex V. Taken together, these data support the existence of different subpopulations of complex V, ATP synthase and ATP hydrolase, the latter with higher mobility and probably not prevailing at the cristae edges. Obviously, complex V reacts quickly and reversibly to metabolic conditions, not only by functional, but also by spatial and structural reorganization., This work was supported by the DFG (INST 190/167-2).

Cardiolipin (CL) is a multifunctional dimeric phospholipid that physically interacts with electron transport chain complexes I, III, and IV, and ATP synthase (complex V). The enzyme ALCAT1 catalyzes the conversion of cardiolipin by incorporating polyunsaturated fatty acids into cardiolipin. The resulting CL species are said to be more susceptible to oxidative damage. This is thought to negatively affect the interaction of cardiolipin and electron transport chain complexes, leading to increased ROS production and mitochondrial dysfunction. Furthermore, it is discussed that ALCAT1 itself is upregulated due to oxidative stress. Here, we investigated the effects of overexpression of ALCAT1 under different metabolic conditions. ALCAT1 is located at the ER and mitochondria, probably at contact sites. We found that respiration stimulated by galactose supply promoted supercomplex assembly but also led to increased mitochondrial ROS levels. Endogeneous ALCAT1 protein expression levels showed a fairly high variability. Artificially induced ALCAT1 overexpression reduced supercomplex formation, further promoted ROS production, and prevented upregulation of coupled respiration. Taken together, our data suggest that the amount of the CL conversion enzyme ALCAT1 is critical for coupling mitochondrial respiration and metabolic plasticity.

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Patients with severe influenza virus infection, multi-organ failure and organ replacement therapy may absorb and metabolize neuraminidase inhibitors differently. Systematic pharmacokinetic/pharmacodynamic clinical trials are currently lacking in this high-risk group. Inadequate dosing increases the risk of treatment failure and drug resistance, especially in severely ill patients with elevated virus loads. This study aims to explore the impact of organ replacement therapy on oseltamivir drug concentrations. Serial pharmacokinetic/pharmacodynamic measurements and Sieving coefficients were assessed in two patients with severe influenza B infection requiring organ replacement therapy. Patient #1, a 9-year-old female with severe influenza B virus infection, biventricular assist device, and continuous veno-venous hemodiafiltration, received 75 mg oral oseltamivir twice-daily for 2 days, then intravenous oseltamivir with one-time renoprotective dosing (40 mg), followed by regular intravenous administration of 100 mg twice-daily. Plasma oseltamivir carboxylate concentrations were stable initially, but only regular administration of 100 mg resulted in virus load decline and clinical improvement. Patient #2, a 28-year-old female with influenza B virus infection requiring extracorporeal membrane oxygenation, received 75 mg oral oseltamivir twice-daily, resulting in erratic oseltamivir blood concentrations. In both patients, drug concentrations remained well within safety margins. In severe cases with multi-organ failure, administration of 100 mg intravenous oseltamivir twice-daily provided reliable drug concentrations, as opposed to renoprotective and oral dosing, thereby minimizing the risk of treatment failure and drug resistance. Evidence-based pediatric dosing recommendations and effective intravenous antiviral treatment modalities are needed for intensive care patients with life-threatening influenza disease.

Background/aim Symptomatic hiatal hernia (HH) following resection for gastric or esophageal cancer is a potentially life-threatening event that may lead to emergent surgery. However, the incidence and risk factors of this complication remain unclear. Patients and methods Data of patients who underwent resection for gastric or esophageal cancer between 2005 and 2012 were assessed and the incidence of symptomatic HH was evaluated. Factors associated with an increased risk for HH were investigated. Results Resection of gastric or esophageal cancer was performed in 471 patients. The primary tumor was located in the stomach, cardia and esophagus in 36%, 24%, and 40% of patients, respectively. The incidence of symptomatic HH was 2.8% (n=13). All patients underwent surgical hernia repair, 8 patients (61.5%) required emergent procedure, and 3 patients (23%) underwent bowel resection. Morbidity and mortality after HH repair was 38% and 8%, respectively. Factors associated with increased risk for symptomatic HH included Body-Mass-Index (median BMI with HH 27 (23-35) vs. BMI without HH 25 (15-51), p=0.043), diabetes (HH rate: with diabetes, 6.3% vs. without diabetes, 2%, p=0.034), tumor location (HH rate: stomach, 1.2% vs. esophagus, 1.1% vs. cardia, 7.9%, p=0.001), and resection type (HH rate: total/subtotal gastrectomy, 0.7% vs. transthoracic esophagectomy, 2.7% vs. extended gastrectomy, 6.1%, p=0.038). Conclusion HH is a major adverse event after resection for gastric or esophageal cancer especially among patients undergoing extended gastrectomy for cardia cancer requiring a high rate of repeat surgery. Therefore, intensive follow-up examinations for high-risk patients and early diagnosis of asymptomatic patients are essential for selecting patients for elective surgery to avoid unpredictable emergent events with high morbidity and mortality.

Reperfusion lung injury is a postoperative complication of pulmonary thromboendarterectomy that can significantly affect morbidity and mortality. Studies in other postoperative patient populations have demonstrated a reduction in acute lung injury with the use of a low-tidal volume (Vt) ventilation strategy. Whether this approach benefits patients undergoing thromboendarterectomy is unknown.We sought to determine if low-Vt ventilation reduces reperfusion lung injury in patients with chronic thromboembolic pulmonary hypertension undergoing thromboendarterectomy.Patients undergoing thromboendarterectomy at one center were randomized to receive either low (6 ml/kg predicted body weight) or usual care Vts (10 ml/kg) from the initiation of mechanical ventilation in the operating room through Postoperative Day 3. The primary endpoint was the onset of reperfusion lung injury. Secondary outcomes included severity of hypoxemia, days on mechanical ventilation, and intensive care unit and hospital lengths of stay.A total of 128 patients were enrolled and included in the analysis; 63 were randomized to the low-Vt group and 65 were randomized to the usual care group. There was no statistically significant difference in the incidence of reperfusion lung injury between groups (32%, n=20 in the low-Vt group vs. 23%, n=15 in the usual care group; P=0.367). Although differences were noted in plateau pressures (17.9 cm H2O vs. 20.1 cm H2O, P0.001) and peak inspiratory pressures (20.4 cm H2O vs. 23.0 cm H2O, P0.001) between the low-Vt and usual care groups, respectively, mean airway pressures, PaO2/FiO2, days on mechanical ventilation, and ICU and hospital lengths of stay were all similar between groups.In patients with chronic thromboembolic pulmonary hypertension undergoing pulmonary thromboendarterectomy, intra- and postoperative ventilation using low Vts (6 mg/kg) compared with usual care Vts (10 mg/kg) does not reduce the incidence of reperfusion lung injury or improve clinical outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT00747045).

Background: There are more than 200,000 incarcerated women in U.S. prisons and jails, and it is estimated that 6% to 10% are pregnant. Pregnant incarcerated women experience complex risks that can compromise their health and the health of their offspring. Objectives: Identify lessons learned from a community–university pilot study of a prison-based pregnancy and parenting support program. Methods : A community–university–corrections partnership was formed to provide education and support to pregnant incarcerated women through a prison-based pilot program. Evaluation data assessed women’s physical and mental health concerns and satisfaction with the program. Between October 2011 and December 2012, 48 women participated. Lessons Learned: We learned that providing services for pregnant incarcerated women requires an effective partnership with the Department of Corrections, adaptations to traditional community-based participatory research (CBPR) approaches, and resources that support both direct service and ongoing evaluation. Conclusions: Effective services for pregnant incarcerated women can be provided through a successful community– university–corrections partnership.

The assembly of respiratory complexes into macromolecular supercomplexes is currently a hot topic, especially in the context of newly available structural details. However, most work to date has been done with purified detergent-solubilized material and in situ confirmation is absent. We here set out to enable the recording of respiratory supercomplex formation in living cells. Fluorescent sensor proteins were placed at specific positions at cytochrome c oxidase suspected to either be at the surface of a CI1CIII2CIV1 supercomplex or buried within this supercomplex. In contrast to other loci, sensors at subunits CoxVIIIa and CoxVIIc reported a dense protein environment, as detected by significantly shortened fluorescence lifetimes. According to 3D modelling CoxVIIIa and CoxVIIc are buried in the CI1CIII2CIV1 supercomplex. Suppression of supercomplex scaffold proteins HIGD2A and CoxVIIa2l was accompanied by an increase in the lifetime of the CoxVIIIa-sensor in line with release of CIV from supercomplexes. Strikingly, our data provide strong evidence for defined stable supercomplex configuration in situ.

Rampage shootings is a relatively new term to describe a phenomenon that has a long history. Rampage shootings are mass shootings (generally defined as involving four or more victims), taking place in a public location, with victims chosen randomly or for symbolic purposes. These shootings are isolated events, meaning they are not connected to another criminal act (such as robbery or terrorism). Research suggests that rampage shootings are not a new phenomenon, but have occurred throughout the US since the early 1900s. There is some evidence of an increase in recent years, but definitional differences across studies and data sources make interpreting trends somewhat tenuous. Theories regarding the perpetration of rampage shootings center on masculinity, mental illness, and contagion effects. Policies aimed at preventing rampage shootings remain somewhat controversial and not well-tested in the literature.

Patients with colorectal liver metastases (CLM) have remarkably benefited from the advances in medical multimodal treatment and surgical techniques over the last two decades leading to significant improvements in long-term survival. More patients are currently undergoing liver resection following neoadjuvant chemotherapy, which has been increasingly established within the framework of curative-indented treatment strategies. However, the use of several cytotoxic agents has been linked to specific liver injuries that not only impair the ability of liver tissue to regenerate but also decrease long-term survival. One of the most common agents included in modern chemotherapy regimens is oxaliplatin, which is considered to induce a parenchymal damage of the liver primarily involving the sinusoids defined as sinusoidal obstruction syndrome (SOS). Administration of bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), has been reported to improve response of CLM to chemotherapy in clinical studies, concomitantly protecting the liver from the development of SOS. In this review, we aim to summarize current data on multimodal treatment concepts for CLM, give an in-depth overview of liver damage caused by cytostatic agents focusing on oxaliplatin-induced SOS, and evaluate the role of bevacizumab to improve clinical outcomes of patients with CLM and to protect the liver from the development of SOS.

Background Infants exhibit elevated influenza virus loads and prolonged viral shedding, which may increase the risk for resistance development, especially in cases of suboptimal exposure to antiviral therapy. Methods We performed a prospective surveillance of hospitalized infants undergoing oseltamivir therapy during the 2008–2009 and 2011–2012 influenza seasons at two paediatric hospitals in Germany. A total of 37 infants less than 1 year of age with laboratory confirmed influenza A(H3N2) infection received oseltamivir as per physician's order for 5 days (2008–2009 season: 2 mg/kg twice daily; 2011–2012 season: 2.0 mg/kg; 2.5 mg/kg and 3.0 mg/kg twice daily for infants Results Overall, 73% of the infants continued to shed viral RNA detectable by reverse transcription (RT)-PCR after dose number 10 of oseltamivir; 12 infants shed viruses, 2 of them (both 9 months of age) shed resistant viruses. Resistance was characterized by ≥1,000-fold increase of 50% inhibitory concentration (IC50) for oseltamivir, up to 50-fold for zanamivir and elevated Km values when compared to susceptible A(H3N2) strains. Sanger sequencing revealed the selection of the NA-R292K substitution in both instances (after dose number 10 on day 6). Conclusions Our data suggest that it may be relevant to monitor antiviral resistance systematically in all infants, considering that the European Medicines Agency has recently extended the licensure for oseltamivir to include full-term infants.

Vaginal bleeding may be present in up to 30% of patients presenting with signs and symptoms of a rupture of the fetal membranes (ROM). The presence of blood may lead to false positive results with biochemical markers. The data presented in this study came from a multi-centric prospective observational clinical study that, for the first time, systematically evaluated the performance of placental alpha microglobulin-1 (PAMG-1) and insulin-like growth factor binding protein-1 (IGFBP-1) detecting tests in 151 women with vaginal bleedings as well as signs and symptoms indicative of ROM. Our data showed better performance for the PAMG-1 compared with the IGFBP-1 detecting tests in all quality parameters evaluated. In detail, sensitivity (SN) was 97.8% (91.0%), specificity (SP) was 91.5% (75.0%), positive predictive value (PPV) was 94.6% (83.5%) and negative predictive value (NPV) was 96.4% (85.7%) for PAMG-1 tests (and IGFBP-1 tests, respectively). A major difference between both tests was related to the number of non-evaluable test results (e.g., hidden bands due to blood smear on the test strips). While 2% of all results were not evaluable for PAMG-1 tests, this artifact appeared in 11% of the results obtained with IGFBP-1 tests. This difference and also those in Specificity and PPV were statistically significant, demonstrating superiority of PAMG-1 over IGFBP-1 detecting tests. In conclusion, the PAMG-1 detecting test was significantly less susceptible to interference by blood than the IGFBP-1 detecting test.

The Power of People (PoP) is a personal leadership development course that was originally developed in a non-correctional setting and now serves as a prison-based life skills course. This study examined PoP’s effect on four different types of recidivism: rearrest, reconviction, reincarceration, and technical violation revocation. The results of the analyses revealed that PoP does not have a significant effect on any of the four measures of recidivism. Following established principles of effective correctional treatment, we make several recommendations that could improve PoP’s effectiveness on recidivism outcomes. Overall, this study provides guidance on how to make programs not originally designed for correctional systems into effective recidivism-reducing tools.

In a climate in which stigmatic shaming is increasing for sex offenders as they leave prison, restorative justice practices have emerged as a promising approach to sex offender reentry success and have been shown to reduce recidivism. Criminologists and restorative justice advocates believe that providing ex-offenders with social support that they may not otherwise have is crucial to reducing recidivism. This case study describes the expressive and instrumental social support required and received, and its relationship to key outcomes, by sex offenders who participated in Circles of Support and Accountability (COSAs), a restorative justice, reentry program in Minnesota. In-depth interviews with re-entering sex offenders and program volunteers revealed that 75% of offenders reported weak to moderate levels of social support leaving prison, 70% reported receiving instrumental support in COSAs, and 100% reported receiving expressive support. Findings inform work on social support, structural barriers, and restorative justice programming during sex offender reentry.

Infants and small children are the most effective transmitters of influenza, while bearing a high risk of hospitalization and adverse disease outcomes. This study aims to investigate virus load kinetics and resistance development during oseltamivir therapy in infants and children infected with influenza A(H1N1) 2009 and influenza B viruses.Virus load in nasopharyngeal samples and phenotypic/genotypic neuraminidase inhibitor resistance were determined at baseline, at day 5 and in additional follow-up samples, if available. Patient-specific viral clearance indices CLν(i) were determined along with estimates of the time required to achieve nondetectable virus load.No evidence of baseline oseltamivir resistance was detected in 36 patients infected with influenza A(H1N1) 2009 (n = 27) or influenza B (Victoria, Yamagata; n = 9) before oseltamivir therapy. On average, viral loads were lower for influenza type B (median = 5.9·10/mL) than for drug-resistant (median = 2.6·10/mL) and sensitive A(H1N1) 2009 (median = 4.8·10/mL), P = 0.04 and P = 0.09, respectively. Time required to achieve nondetectable virus load was significantly longer in drug-resistant A(H1N1) 2009 (median 15.4 days) compared with drug-sensitive A(H1N1) 2009 (P = 0.003; median 7.7 days) and drug-sensitive influenza B (P = 0.001; median 5 days). No evidence of viral rebound was observed once viral clearance was achieved.Our data indicate that influenza subtyping in combination with baseline viral load measurements might help to optimize the duration of antiviral therapy in the individual child. Lower than expected virologic response rates in patients without malabsorption or compliance issues may suggest resistance development.

Summary Cell migration entails protrusion of lamellipodia, densely packed networks of actin filaments at the cell front. Filaments are generated by nucleation, likely mediated by Arp2/3 complex and its activator Scar/WAVE [1]. It is unclear whether formins contribute to lamellipodial actin filament nucleation or serve as elongators of filaments nucleated by Arp2/3 complex [2]. Here we show that the Diaphanous-related formin FMNL2, also known as FRL3 or FHOD2 [3], accumulates at lamellipodia and filopodia tips. FMNL2 is cotranslationally modified by myristoylation and regulated by interaction with the Rho-guanosine triphosphatase Cdc42. Abolition of myristoylation or Cdc42 binding interferes with proper FMNL2 activation, constituting an essential prerequisite for subcellular targeting. In vitro, C-terminal FMNL2 drives elongation rather than nucleation of actin filaments in the presence of profilin. In addition, filament ends generated by Arp2/3-mediated branching are captured and efficiently elongated by the formin. Consistent with these biochemical properties, RNAi-mediated silencing of FMNL2 expression decreases the rate of lamellipodia protrusion and, accordingly, the efficiency of cell migration. Our data establish that the FMNL subfamily member FMNL2 is a novel elongation factor of actin filaments that constitutes the first Cdc42 effector promoting cell migration and actin polymerization at the tips of lamellipodia., Highlights ► FMNL2 is a novel Cdc42 effector accumulating at lamellipodial and filopodial tips ► FMNL2 is regulated but not localized by N-terminal myristoylation and Cdc42 binding ► FMNL2 processively elongates actin filaments in the presence of profilin ► FMNL2 drives cell migration by increasing the efficiency of lamellipodia protrusion

Women who are or may become pregnant need up-to-date information about Down syndrome (DS). Asking women about their knowledge, opinions, resources, and information needs on the topic of DS is an important precursor to develop effective strategies for education. We conducted 24 focus groups (N = 111) in two US cities with women who were recently pregnant (who had a child ≤ 3 years old without DS) and women who planned to have a child in the next year. Groups were further segmented by age and race-ethnicity. Questions explored women's knowledge, attitudes, and beliefs about DS; resources used to obtain information about health and DS; and information needs on the topic of DS. All participants reported having some knowledge of DS: facial features, chromosomal condition, and maternal age as a risk factor. Many participants had misconceptions, including the life expectancy for persons with DS, other maternal and paternal risk factors, and the idea that having a child with DS would disrupt their lives. Participants requested stories to help illustrate what life is like for families with DS. Many Hispanic and African American participants said they only saw or knew of Caucasian persons with DS and requested culturally diverse educational materials about DS. Participants said they would seek information on DS from the Internet and from their health care providers. Results suggest that women need tailored materials that contain clinical information about DS as well as information about living with a child with DS. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

This study evaluated the effectiveness of the InnerChange Freedom Initiative (InnerChange), a faith-based prisoner reentry program, by examining recidivism outcomes among 732 offenders released from Minnesota prisons between 2003 and 2009. Results from the Cox regression analyses revealed that participating in InnerChange significantly reduced reoffending (rearrest, reconviction, and new offense reincarceration), although it did not have a significant impact on reincarceration for a technical violation revocation. The findings further suggest that the beneficial recidivism outcomes for InnerChange participants may have been due, in part, to the continuum of mentoring support some offenders received in the institution and the community. The results imply that faith-based correctional programs can reduce recidivism, but only if they apply evidence-based practices that focus on providing a behavioral intervention within a therapeutic community, addressing the criminogenic needs of participants and delivering a continuum of care from the institution to the community. Given that InnerChange relies heavily on volunteers and program costs are privately funded, the program exacts no additional costs to the State of Minnesota. Yet, because InnerChange lowers recidivism, which includes reduced reincarceration and victimization costs, the program may be especially advantageous from a cost-benefit perspective.

Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) occurs in many occupational settings. There is evidence in animal models that maternal exposure to PAHs during pregnancy is associated with gastroschisis in offspring; however, to our knowledge, no human studies examining this association have been conducted. Objective: Our goal was to conduct a case–control study assessing the association between estimated maternal occupational exposure to PAHs and gastroschisis in offspring. Methods: Data from gastroschisis cases and control infants were obtained from the population-based National Birth Defects Prevention Study for the period 1997–2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to determine the association between estimated occupational PAH exposure and gastroschisis among children whose mothers were employed for at least 1 month during the month before conception through the third month of pregnancy. Results: The prevalence of estimated occupational PAH exposure was 9.0% in case mothers (27 of 299) and 3.6% in control mothers (107 of 2,993). Logistic regression analyses indicated a significant association between occupational PAHs and gastroschisis among mothers ≥ 20 years of age [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.27, 5.04] after adjusting for maternal body mass index, education, gestational diabetes, and smoking. This association was not seen in mothers < 20 years (OR = 1.14; 95% CI: 0.55, 2.33), which is notable because although young maternal age is the strongest known risk factor for gastroschisis, most cases are born to mothers ≥ 20 years. Conclusion: Our findings indicate an association between occupational exposure to PAHs among mothers who are ≥ 20 years and gastroschisis. These results contribute to a body of evidence that PAHs may be teratogenic.

Selected antiepileptic drugs (AEDs) increase the risk of birth defects. To assess the impact of influencing AED prescribing practices on spina bifida and cleft palate we searched the literature for estimates of the association between valproic acid or carbamazepine use during pregnancy and these defects and summarized the associations using meta-analyses. We estimated distributions of the prevalence of valproic acid and carbamazepine use among women of childbearing age based on analyses of four data sets. We estimated the attributable fractions and the number of children born with each defect that could be prevented annually in the United States if valproic acid and carbamazepine were not used during pregnancy. The summary odds ratio estimate for the association between valproic acid and spina bifida was 11.9 (95% uncertainty interval (UI): 4.0–21.2); for valproic acid and cleft palate 5.8 (95% UI: 3.3–9.5); for carbamazepine and spina bifida 3.6 (95% UI: 1.3–7.8); and for carbamazepine and cleft palate 2.4 (95% UI: 1.1–4.5) in the United States. Approximately 40 infants (95% UI: 10–100) with spina bifida and 35 infants (95% UI: 10–70) with cleft palate could be born without these defects each year if valproic acid were not used during pregnancy; 5 infants (95% UI: 0–15) with spina bifida and 5 infants (95% UI: 0–15) with cleft palate could be born without these defects each year if carbamazepine were not used during pregnancy. This modeling approach could be extended to other medications to estimate the impact of translating pharmacoepidemiologic data to evidence-based prenatal care practice. Published 2011 Wiley-Liss, Inc. {

Summary In response to the rapid global spread of an antigenically novel A/H1N1 influenza virus in 2009, the World Heath Organization (WHO) recommended surveillance and monitoring for antiviral resistance of influenza viruses. We designed and evaluated pyrosequencing (PSQ)-based genotypic assays for high-throughput analysis of the susceptibility of pandemic A/H1N1 influenza viruses to neuraminidase (NA) inhibitors. A total of 1570 samples circulating in Germany between April 2009 and April 2010 were tested for determination of molecular markers of resistance to the NA inhibitors oseltamivir and zanamivir, and 635 of them were evaluated by phenotypic fluorescence-based assay with MUNANA substrate. Eight (0.5%) viruses were resistant to oseltamivir due to the H274Y NA substitution (N2 numbering). Six of these oseltamivir-resistant cases were treatment-related; four of them were selected in immunocompromised patients, two in patients suffered from chronic diseases. The two remaining oseltamivir-resistant viruses seem to have evolved in the absence of drug treatment and were isolated from immunocompetent healthy patients. All tested A/H1N1 pandemic viruses were sensitive to zanamivir. In addition, analysis of 1011 pandemic A/H1N1 virus samples by a PSQ-based assay according to the WHO protocol revealed the presence of mutation S31N in the M2 protein that conferred resistance to M2 ion channel inhibitors. Our data demonstrate a low incidence of oseltamivir-resistant pandemic A/H1N1 influenza variants isolated under drug selection pressure as well as community-acquired or naturally evolving viruses.

This study assessed reported use of assisted reproductive technology (ART) and other (non-ART) fertility treatments among a population-based sample and examined factors related to use.The data for this study were collected as part of the National Birth Defects Prevention Study (NBDPS), limited to women from the control group who delivered liveborn infants with no major birth defects. We described prevalence of the use of ART and clomiphene citrate (the most commonly used non-ART treatment) by demographic and lifestyle factors and examined associations among use of fertility treatments and pregnancy outcomes, timing of prenatal care initiation, and use of prenatal testing technologies.Overall, 4.2% of women reported any type of maternal fertility treatment use; 1.0% reported ART use, 1.6% reported clomiphene citrate use without ART, and 1.7% reported other fertility treatments. Women who reported any fertility treatment type were more likely than women with an unassisted conception to be non-Hispanic white,30 years of age, and more highly educated. Overall, women who reported ART use were more likely than women who reported unassisted pregnancy to have an amniocentesis; however, this association was no longer evident after adjustment for maternal age.Fertility treatment use and type of treatment vary by maternal characteristics. This information may be useful to inform a broad maternal and child health audience about the growing use of fertility treatments, including who is using the treatments and the choices they are making about prenatal care.

Using a retrospective quasi-experimental design, this study evaluates the effectiveness of prison-based treatment by examining recidivism outcomes among 2,040 sex offenders released from Minnesota prisons between 1990 and 2003 (average follow-up period of 9.3 years). To reduce observed selection bias, the authors used propensity score matching to create a comparison group of 1,020 untreated sex offenders who were not significantly different from the 1,020 treated offenders. In addition, intent-to-treat analyses and the Rosenbaum bounds method were used to test the sensitivity of the findings to treatment refuser and unobserved selection bias. Results from the Cox regression analyses revealed that participating in treatment significantly reduced the hazard ratio for rearrest by 27% for sexual recidivism, 18% for violent recidivism, and 12% for general recidivism. These findings are consistent with the growing body of research supporting the effectiveness of cognitive—behavioral treatment for sex offenders.

The neuraminidase of influenza viruses is the target of the inhibitors oseltamivir and zanamivir. Recent reports on influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAI) are a cause for concern. Several amino acid substitutions, each as a consequence of one single nucleotide mutation, are known to confer resistance to NAI. An increase of NAI-resistant viruses appears to be likely as a result of a wider application of NAI for treatment and prophylaxis of seasonal influenza infections. Monitoring the occurrence and spread of resistant viruses is an important task. Therefore, RT-PCR assays were developed with subsequent pyrosequencing analysis (PSQ-PCR). These assays allow a rapid, high-throughput and cost-effective screening of subtype A/H1N1, A/H3N2, and A/H5N1 viruses. Various specimens such as respiratory swabs, allantoic fluid, or cell-propagated viruses can be used and results are available within hours. Several A/H1N1, A/H3N2, and A/H5N1 viruses isolated from human and avian specimens were tested to evaluate the method. Positive controls encoding resistance-associated mutations were created using site-directed mutagenesis. The results obtained with these controls showed that the assay can discriminate clearly the wild-type virus from a mutant virus. The detection limit of minor virus variants within the viral quasispecies amounts to 10%.

This article offers an ethnographic account of the "self-projects" of inmate graduates of Louisiana State Penitentiary's (aka "Angola's") unique prison seminary program. Angola's Inmate Minister program deploys seminary graduates in bivocational pastoral service roles throughout America's largest maximum-security prison. Drawing upon the unique history of Angola, inmates establish their own churches and serve in lay-ministry capacities in hospice, cellblock visitation, tier ministry, officiating inmate funerals, and through tithing with "care packages" for indigent prisoners. Four themes of positive criminology prominently emerge from inmate narratives: (a) the importance of respectful treatment of inmates by correctional administrations, (b) the value of building trusting relationships for prosocial modeling and improved self-perception

Objective To evaluate whether the presence of kissing ovaries at ultrasound is a marker for endometriosis and whether it correlates with the severity of the disease. Design Prospective observational study. Setting Gynecologic departments of two university hospitals. Patient(s) A total of 722 consecutive premenopausal women who had laparoscopic surgery for an adnexal mass or suspected pelvic endometriosis. Intervention(s) Preoperative ultrasound evaluation and laparoscopic surgery. Main outcome measure(s) Diagnostic and predictive value of ultrasound identification of kissing ovaries in the detection of endometriosis. Result(s) Kissing ovaries were diagnosed at ultrasound and confirmed laparoscopically in 32 patients. Of these, 27 had moderate to severe endometriosis and five others had benign adnexal masses. Bowel (18.5% vs. 2.5%) and fallopian tube (92.6% vs. 33%) endometriosis were significantly more frequent in patients with kissing ovaries than in patients without kissing ovaries. In infertile patients (n = 145), kissing ovaries were associated with a higher proportion of women with fallopian tube obstruction (80% vs. 8.6%). Considering patients with moderate to severe endometriosis (n = 189), the median (range) revised American Fertility Society score (74 [32–148] vs. 35 [16–146]) and the operative time (115 minutes [65–245 minutes] vs. 50 [15–180 minutes]) were significantly higher in patients with than in those without kissing ovaries. Conclusion(s) The detection of kissing ovaries at ultrasound is strongly associated with the presence of endometriosis and is a marker of the most severe form of this disease.

In July 2001, the United States Joint Commission on Accreditation of Health care Organizations adopted a new leadership standard that requires department heads in health care organizations to perform at least one Failure Mode and Effects Analysis (FMEA) every year. This proactive approach to error prevention has proven to be highly effective in other industries, notably aerospace, but remains untested in acute care hospitals. For several reasons, the intensive care unit (ICU) potentially is an attractive setting for early adoption of FMEA; however, successful implementation of FMEA in ICUs is likely to require strong, effective leadership and a sustained commitment to prevent errors that may have occurred rarely or never before in the local setting. This article describes FMEA in relation to critical care medicine and reviews some of the attractive features together with several potential pitfalls that are associated with this approach to error prevention in ICUs.

Acute respiratory infections represent common pediatric emergencies. Infection control warrants immediate and accurate diagnoses. In the past, first-generation respiratory syncytial virus (RSV) rapid tests (strip tests) have shown suboptimal sensitivities. In 2013, the Food and Drug Administration licensed a second-generation RSV rapid test providing user-independent readouts (SOFIA™-RSV) using automated fluorescence assay technology known to yield superior results with influenza rapid testing. We are reporting the first point-of-care evaluation of the SOFIA™-RSV rapid test. In the Charite Influenza-Like Disease Cohort, 686 nasopharyngeal samples were tested in parallel with SOFIA™-RSV and SOFIA™-Influenza A+B. Compared to real-time PCR, SOFIA™-RSV sensitivities/specificities were 78.6%/93.9%, respectively (SOFIA™-Influenza A: 80.6%/99.3%). Performance was greatest in patients below 2 years of age with a test sensitivity of 81.8%. RSV sensitivities were highest (85%) in the first 2 days of illness and with nasopharyngeal compared to nasal swabs (P=0.055, McNemar's test). Second-generation RSV and influenza rapid testing provides highly accurate results facilitating timely patient cohortation and management.

Objective: The study should answer the question of whether identical symptom presentations of depression in male and female patients leads to similar recognition rates in primary care. Method: We performed a survey in primary care. Two written case vignettes were presented to 170 family physicians in a face-to-face interview which took place in their practices. The case vignettes described either a mildly depressed otherwise healthy old patient (case 1) or a severely depressed patient with somatic comorbidity (case 2). For each case different versions with regard to patients’ gender were used: in case 1 only the gender of the patient varied; in case 2 both the gender and the anamnesis (stroke/hypothyroidism) varied. Afterwards the interviewers asked standardised open questions. The physicians were not aware of the mental health focus and the gender focus of the study. Results: The study is representative with a response rate of 77.6%. For primary diagnosis, the female versions were given the diagnosis of depression more often. There was a non-significant trend that female physicians considered depression more often. Conclusion: The results show that gender-related experience and stereotypes on the physicians’ side influence the diagnosis of (old age) depression in primary care. Further studies should elucidate the influence of the physicians’ gender on the management of psychiatric disorders.

We investigated the estrogenic activity of various environmental pollutants (xenobiotics), in particular the xenoestrogen o,p-DDT, and compared their effects with those of endogenous estrogens, phytoestrogens, and mycoestrogens on estrogen receptor binding capacity, induction of estrogen end products, and activation of cell proliferation in estrogen-sensitive human breast cancer cells in monolayer culture. We also quantified the levels of phytoestrogens in extracts of some common foods, herbs, and spices and in human saliva following consumption of a high phytoestrogen food source (soy milk) to compare phytoestrogen abundance and bioavailability relative to the reported xenoestrogen burden in humans. Results show that natural endogenous estrogens, phytoestrogens, mycoestrogens, and xenoestrogens bind estrogen receptor (ER) in intact cells, but demonstrate marked differences in their ability to induce end products of estrogen action and to regulate cell proliferation. All of the different classes of estrogens stimulated cell proliferation at concentrations that half-saturated ER, but only some classes were able to induce estrogen-regulated end products. Genistein, a common phytoestrogen found in soy foods, differed from the xenoestrogen DDT in its effects on cell proliferation and ability to induce estrogen-regulated end products. Moreover, we found that many of the foods, herbs, and spices commonly consumed by humans contain significant amounts of phytoestrogens, and consumption of soy milk, a phytoestrogen-rich food, markedly increases the levels of phytoestrogens in saliva. In conclusion, our in vitro results predict that a diet high in phytoestrogens would significantly reduce the binding of weak xenoestrogens to ER in target tissues in vivo.

Performance improvement is a mainstay of operations management and maintenance of certification. In this study at a University Hospital inpatient rehabilitation unit, Lean management techniques were used to manage throughput of patients into and out of the inpatient rehabilitation unit. At the start of this process, the average admission time to the rehabilitation unit was 5:00 p.m., with a median time of 3:30 p.m., and no patients received therapy on the day of admission. Within 8 mos, the mean admission time was 1:22 p.m., 50% of the patients were on the rehabilitation unit by 1:00 p.m., and more than 70% of all patients received therapy on the day of admission. Negative variance from this performance was evaluated, the identification of inefficient discharges holding up admissions as a problem was identified, and a Lean workshop was initiated. Once this problem was tackled, the prime objective of 70% of patients receiving therapy on the date of admission was consistently met. Lean management tools are effective in improving throughput on an inpatient rehabilitation unit.