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We aimed to develop and study the implementation of a remote system for toxicity assessment and management of acute side effects of breast radiation using electronic patient-reported outcomes (ePROs).A response-adapted Patient-Reported Outcomes Common Terminology Criteria for Adverse Events-based assessment for breast radiation toxicity was administered weekly during and for 8 weeks after radiation from June 2019 to July 2020. The care team received alerts when "severe" symptoms were reported by patients, who were then contacted. Treatment, clinic, and sociodemographic characteristics were abstracted from patient records. A subsample of patients and care team members was qualitatively interviewed at follow-up.Overall, 5787 assessments were sent to 678 patients, of whom 489 (72%) completed 2607 assessments (45%). Moderate or greater toxicity was reported by 419 responders (86%; 95% CI, 82%-89%). Clinician alerts for severe toxicity were generated for 264 assessments among 139 unique patients, of which 83% occurred posttreatment. The proportion of surveys that prompted an alert was significantly higher after treatment (219 [13%]) than during treatment (45 [5%]) (P.001). Survey completion rates in the posttreatment period were higher among patients undergoing partial breast irradiation than postmastectomy radiation (incidence rate ratio, 0.70; 95% CI, 0.60-0.81) (P.001) despite these patients experiencing less severe toxicity. Interviews (15) found that patients had a positive experience with ePROs, although many thought the primary purpose was for research rather than symptom management.With the majority of toxicity occurring after breast radiation has ended, remote symptom monitoring with ePROs appears to fill a gap in clinical practice, particularly for patients undergoing shorter courses of radiation. It is important to properly onboard patients and explain that the purpose of ePROs is to aid clinical care. Further research is needed to determine whether the costs associated with ePROs can be offset by reducing routine clinic visits and whether this approach is acceptable and appropriate.

The reconstruction and analysis of genome-scale metabolic models constitutes a powerful systems biology approach, with applications ranging from basic understanding of genotype-phenotype mapping to solving biomedical and environmental problems. However, the biological insight obtained from these models is limited by multiple heterogeneous sources of uncertainty, which are often difficult to quantify. Here we review the major sources of uncertainty and survey existing approaches developed for representing and addressing them. A unified formal characterization of these uncertainties through probabilistic approaches and ensemble modeling will facilitate convergence towards consistent reconstruction pipelines, improved data integration algorithms, and more accurate assessment of predictive capacity. Supplementary Information The online version contains supplementary material available at 10.1186/s13059-021-02289-z.

Cerebral palsy occurs more often in preterm than in term deliveries and is one of the major neurologic injuries seen in preterm infants. Magnesium sulfate has been found to reduce the risk of cerebral palsy in patients at risk of delivery before 32 weeks' gestational age. Multiple large clinical trials have shown this effect. The authors recommend magnesium sulfate bolus followed by continuous dosing of magnesium sulfate in those at risk of delivery before 32 weeks' gestation until delivery occurs or is no longer imminent. This article also discusses novel and emerging therapies for the prevention of cerebral palsy.

Background ASPirin in Reducing Events in the Elderly, a randomized, double-blind, placebo-controlled trial of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast, prior randomized controlled trials, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality. Methods 19 114 Australian and US community-dwelling participants aged 70 years and older (US minorities 65 years and older) without cardiovascular disease, dementia, or physical disability were randomly assigned and followed for a median of 4.7 years. Fatal and nonfatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records. Results 981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64). Conclusions In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and, thus, suggest caution with its use in this age group.

Cancer is a significant health care challenge in the tropics. GLOBOCAN 2018 estimates 18.1 million new cases and 9.6 million deaths from cancer in 2018. While the majority of incident cases occur in high and very high income nations, 70% of the deaths from cancer will occur in medium- and low-income nations. Although worldwide, only 15.4% of cancers are due to infection, rates as high as 40% are reported in sub-Saharan Africa. An understanding of how oncogenic infections promote cancer will aid in the development of primary and secondary prevention programs. Control of HIV will contribute to a reduction in risk for HPV and Kaposi's sarcoma herpes virus (KSHV)–infected persons. Tobacco must be addressed, with particular attention to the poorest nations where use is still low. Obesity, which currently contributes to relatively few cancers in the developing world, cannot be ignored given the global rise in the problem. Economic transition is occurring faster in today's developing world, with adoption of risky lifestyles outpacing control of infections and establishment of a health care infrastructure.

Human immunodeficiency virus (HIV) is a retrovirus which became pandemic in the early 1980s. Since its initial characterization, advancements in diagnosis and management have transformed HIV infection from a terminal diagnosis to a chronic, manageable condition. Effective antiretroviral therapy, acting at multiple steps in the viral lifecycle, durably suppresses viral replication, preserves maternal health and prevents mother to child HIV transmission. Here, we review the salient clinical and ethical considerations of managing HIV infection during pregnancy and delivery.

The pharmacologic and neuropsychiatric sequelae of long-term dextromethorphan use and acute dextromethorphan intoxication are reviewed in this case report. Dextromethorphan ingestion at the high end of toxicity, although rare, can cause violence to oneself and others, even in those previously without any history of such behaviors. In this article, the neuropsychiatric consequences of dextromethorphan toxicity are highlighted in a case report of a 37-year-old woman who had been using dextromethorphan for 5 years. She presented to a large urban emergency department in a psychotic and manic state after attempting autoenucleation. She reported to consult liaison psychiatry staff that she had taken a total of 1400 mg of dextromethorphan over the course of 3 days with intent to experience altered state of consciousness. Toxicology screens on admission did not reveal any other substances in her system. She had no formal psychiatric history and no history of mania, psychosis, or self-harm. To our knowledge, this is the first case of autoenucleation resulting from dextromethorphan-induced mania with psychotic features.

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Babesiosis is a tick-borne illness caused by B. microti and other species and transmitted by the Ixodes tick. Acute respiratory distress syndrome (ARDS) can be a manifestation of babesiosis. CASE PRESENTATION: A 69 year old female with the past medical history of HTN, HLD and hypothyroidism who presented to hospital for 1 week of intermittent fever and generalized body aches. Patient denied any tick bites. She started to have intermittent fever around 40°C, nonproductive cough and generalized body aches, associated with night sweats, nausea, diarrhea. She took 1000mg Tylenol every 4 hours for fever and body aches for 1 week without improvement.Upon admission laboratory values were significant for hemolytic anemia (Hgb 9.4 g/dL, reticulocyte count 1.2%, LDH 4896 U/L, haptoglobin < 8mg/dL, total bilirubin 2.3 mg/dL), thrombocytopenia (platelet 38× 103/mm3) and leukopenia (WBC 2.7× 103/mm3), significantly elevated acetaminophen level (22.6), transaminitis (ALT 365 IU/L, AST 579 IU/L) and elevated INR (1.4). Blood parasite smear was positive for blood parasites (Malaria/Babesia: 9.6% RBC infected). Babesia Microti DNA RT-PCR was positive, Babesia Microti Ab (IgM) ≥ 1:320, Babesia Microti Ab (IgG) was 1:512, E. Chaffeensis Ab Ig G

OBJECTIVEPatients with metastatic thyroid cancer have prolonged survival compared to those with other primary tumors. The spine is the most common site of osseous involvement in cases of metastatic thyroid cancer. As a result, obtaining durable local control (LC) in the spine is crucial. This study aimed to evaluate the efficacy of spine stereotactic radiosurgery (SSRS) in patients with metastatic thyroid cancer.METHODSInformation on patients with metastatic thyroid cancer treated with SSRS for spinal metastases was retrospectively evaluated. SSRS was delivered with a simultaneous integrated boost technique using single- or multiple-fraction treatments. LC, defined as stable or reduced disease volume, was evaluated by examining posttreatment MRI, CT, and PET studies.RESULTSA total of 133 lesions were treated in 67 patients. The median follow-up duration was 31 months. Dose regimens for SSRS included 18 Gy in 1 fraction, 27 Gy in 3 fractions, and 30 Gy in 5 fractions. The histology distribution was 36% follicular, 33% papillary, 15% medullary, 13% Hurthle cell, and 3% anaplastic. The 1-, 2-, and 5-year LC rates were 96%, 89%, and 82%, respectively. The median overall survival (OS) was 43 months, with 1-, 2-, and 5-year survival rates of 86%, 74%, and 44%, respectively. There was no correlation between the absolute biological equivalent dose (BED) and OS or LC. Patients with effective LC had a trend toward improved OS when compared to patients who had local failure: 68 versus 28 months (p = 0.07). In terms of toxicity, 5 vertebral compression fractures (2.8%) occurred, and only 1 case (0.6%) of greater than or equal to grade 3 toxicity (esophageal stenosis) was reported.CONCLUSIONSSSRS is a safe and effective treatment option with excellent LC and minimal toxicity for patients with metastatic thyroid cancer. No association with increased radiation dose or BED was found, suggesting that such patients can be effectively treated with reduced dose regimens.

Background: Single-agent pemetrexed is a treatment for recurrent non-squamous non-small cell lung cancer (NSCLC) that provides limited benefit. Preclinical studies showed promising synergistic effects when the mammalian target of rapamycin (mTOR) inhibitor sirolimus was added to pemetrexed. Methods: This was a single-institution phase I/II study of pemetrexed in combination with sirolimus. The primary endpoint for the phase I was to determine the maximum tolerated dose (MTD) and safety of the combination. The primary endpoint for the phase II portion was to determine the overall response rate at the MTD. Key eligibility criteria included recurrent, metastatic NSCLC, ECOG performance status of 0–2, and adequate organ function. Sirolimus was administered orally daily after an initial loading dose, and pemetrexed was given intravenously on day 1 of every 21-day cycle. Results: Forty-two patients with recurrent, metastatic NSCLC were enrolled, 22 in phase I and 20 in phase II. The MTD was pemetrexed 500 mg/m2 every 3 weeks, and sirolimus 10 mg on day 1, and 3 mg daily thereafter. Treatment-related adverse events (AEs) occurred in 38 (90.5%) patients. The most common grade 3–4 treatment-related AEs were lymphopenia (31%) and hypophosphatemia (19%). Two treatment-related deaths occurred due to febrile neutropenia and infection, respectively. Among 27 total patients treated at the MTD, 6 (22.2%) had a partial response (PR), 12 (44.4%) had stable disease (SD) and 5 (18.5%) had progressive disease. Median progression-free survival (PFS) was 18.4 weeks (95% CI: 7.0–29.4). Conclusions: The combination of pemetrexed and sirolimus is active in heavily-pretreated NSCLC (ClinicalTrials.gov Identifier: NCT00923273).

Hepatitis C in pregnancy is on the rise, and new direct-acting antiviral agents are available that cure the disease. Published recommendations need to be reviewed and clinically evaluated for the care of pregnant women who are at risk for or have chronic hepatitis C. Available evidence and some of the medical and ethical reasons to consider universal screening and antepartum therapy for hepatitis C during pregnancy are presented. Universal screening and proactive treatment during pregnancy is on the horizon, and these measures should be quickly evaluated for safety and implemented if appropriate.

Background & Aims Paritaprevir, ombitasvir, and dasabuvir are direct-acting antivirals for treatment of chronic hepatitis C virus (HCV) infection. The aim of this study was to characterize the effects of mild, moderate, and severe hepatic impairment on the pharmacokinetics of these drugs. Methods HCV-negative subjects with normal hepatic function (n=7) or mild (Child-Pugh A, n=6), moderate (Child-Pugh B, n=6), or severe (Child-Pugh C, n=5) hepatic impairment received a single-dose of the combination of paritaprevir plus ritonavir (paritaprevir/r, 200/100mg), ombitasvir (25mg), and dasabuvir (400mg). Plasma samples were collected through 144hours after administration for pharmacokinetic assessments. Results Paritaprevir, ombitasvir, dasabuvir, and ritonavir exposures (maximal plasma concentration, C max , and area under the concentration-time curve, AUC) were minimally affected in subjects with mild or moderate hepatic impairment. Differences in exposures between healthy controls and subjects with mild or moderate hepatic impairment were less than 35%, except for 62% higher paritaprevir AUC in subjects with moderate hepatic impairment. Paritaprevir and dasabuvir AUC were significantly higher in subjects with severe hepatic impairment (950% and 325%, respectively). However, ombitasvir AUC was 54% lower and ritonavir AUC was comparable. Adverse events included eye stye, insomnia, and pain from an infiltrated intravenous line. Conclusions The changes observed in paritaprevir, ritonavir, ombitasvir, and dasabuvir exposures in subjects with mild or moderate hepatic impairment do not necessitate dose adjustment. Subjects with severe hepatic impairment had substantially higher paritaprevir and dasabuvir exposures.

The wind power industry is highly sensitive to weather, and there is a clear impact on turbine efficiency associated with icing, which can cause significant power losses and even result in the total shutdown of wind farms. Therefore, accurate analyses and forecasts of wind- and icing-related meteorological variables are of great importance. To this end, the Local Analysis and Prediction System (LAPS)–LOWICE system has been developed to produce real-time, hourly estimates of the presence, intensity, and impacts of icing on wind power production. As part of this development, it became clear that power losses did not correlate well with measured icing loads but correlated reasonably well with the time history of icing rate in combination with ice loss due to melting, sublimation, and shedding.

ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 (150 mg coadministered with ritonavir 100 mg once daily), ombitasvir (25 mg once daily), and dasabuvir (400 mg twice daily) on the pharmacokinetics, safety, and tolerability of a single dose of cyclosporine (30 mg) or tacrolimus (2 mg) in healthy volunteers (N = 12 per study). In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C₂₄), and area under the concentration-time curve from time 0 to infinity (AUC(∞)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C₂₄ and AUC(∞) were 17-fold and 57-fold, respectively, of either agent alone. Cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.

This article is an initial attempt to compare the pre-abortion disclosure mandates that have proliferated in the two decades since the Court decided Planned Parenthood v. Casey with laws that, in the context of assisted reproduction and reproductive health, require specific disclosures beyond a state's baseline informed consent requirements. While some scholars have characterized pre-abortion disclosure laws as sui generis, they share some important common features with disclosure mandates in the context of oocyte donation and other reproductive health procedures. This article suggests that in critiquing pre-abortion disclosure mandates, scholars and advocates should be careful to differentiate the use of disclosure laws in general from uses where the government interest conveys a moral preference against a particular procedure.

Purpose To evaluate, in a gynecologic cancer setting, changes in bowel position, dose-volume parameters, and biological indices that arise between full-bladder (FB) and empty-bladder (EB) treatment situations; and to evaluate, using cone beam computed tomography (CT), the validity of FB treatment presumption. Methods and Materials Seventeen gynecologic cancer patients were retrospectively analyzed. Empty-bladder and FB CTs were obtained. Full-bladder CTs were used for planning and dose optimization. Patients were given FB instructions for treatment. For the study purpose, bowel was contoured on the EB CTs for all patients. Bowel position and volume changes between FB and EB states were determined. Full-bladder plans were applied on EB CTs for determining bowel dose-volume changes in EB state. Biological indices (generalized equivalent uniform dose and normal tissue complication probability) were calculated and compared between FB and EB. Weekly cone beam CT data were available in 6 patients to assess bladder volume at treatment. Results Average (±SD) planned bladder volume was 299.7 ± 68.5 cm 3 . Median bowel shift in the craniocaudal direction between FB and EB was 12.5 mm (range, 3-30 mm), and corresponding increase in exposed bowel volume was 151.3 cm 3 (range, 74.3-251.4 cm 3 ). Absolute bowel volumes receiving 45 Gy were higher for EB compared with FB (mean 328.0 ± 174.8 vs 176.0 ± 87.5 cm 3 ; P =.0038). Bowel normal tissue complication probability increased 1.5× to 23.5× when FB planned treatments were applied in the EB state. For the study, the mean percentage value of relative bladder volume at treatment was 32%. Conclusions Full-bladder planning does not necessarily translate into FB treatments, with a patient tendency toward EB. Given the uncertainty in daily control over bladder volume for treatment, we strongly recommend a "planning-at-risk volume bowel" (PRV_Bowel) concept to account for bowel motion between FB and EB that can be tailored for the individual patient.

Many critical factors must be considered in determining the most feasible and appropriate options for decommissioning offshore oil and gas platforms, including alternatives from complete removal to partial removal with artificial reefing. Using financial-based cost/benefit analysis to evaluate decommissioning options neglects the complexities inherent in a successful platform decommissioning process, which includes non-monetary values such as the production of greenhouse gasses and the gains and/or losses of ecological services due to partial or complete removal. Multi-attribute decision analysis provides technically defensible consideration of both market and non-market values associated with the outcomes of rig decommissioning while allowing stakeholders to clearly and transparently investigate and evaluate the nexus between financial considerations and other factors (e.g., air/water quality, biological productivity, ocean access) that drive public policy. In California, the PLATFORM decision support model was a key component in helping a diverse group of stakeholders reach consensus on the preferred policy of partial removal and artificial reefing, which ultimately resulted in the creation of a public regulatory framework for rig decommissioning—the California Marine Resources Legacy Act. We describe how to use multi-variable decision analysis to facilitate offshore oil and gas platform decommissioning. We implemented decision analysis as a software tool (PLATFORM) to clarify and evaluate decommissioning alternatives against a comprehensive set of objectives, including both market and non-market values. Decommissioning options selected for in-depth analysis were complete platform removal and partial removal to 85 feet below the water line, with the remaining structure converted to an artificial reef. PLATFORM performed key analyses of the impacts of each option (e.g., on costs, fishery production, air emissions). The analysis found a near-consensus of stakeholders in support of partial removal and a "rigs-to-reefs" program. Decision support models, such as PLATFORM, are readily adaptable to support regulatory decision-making and alternatives analysis for decommissioning worldwide, including the North Sea, Australia, and Asia.

Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin.

As the immunotherapy of cancer comes of age, adding immunotherapeutic agents to radiation therapy has the potential to improve the outcomes for patients with a wide variety of malignancies. Despite the enormous potential of such combination therapy, laboratory data has been lacking and there is little guidance for pursuing novel treatment strategies. Animal models have significant limitation in combining radiation therapy with immunotherapy and some of the limitations of preclinical models are discussed in this article. In addition to the preclinical challenges, radiation therapy and immunotherapy combinations may have overlapping toxicities, and for both types of therapy, early and late manifestations of toxicity are possible. Given these risks, special attention should be given to the design of the specific Phase I clinical trial that is chosen. In this article, we describe several Phase I design possibilities that may be employed, including the 3 + 3 design (also known as the cohort of 3 design), the continual reassessment method (CRM), and the time-to-event continual reassessment method (TITE-CRM). Efficacy end points for further development of combination therapy must be based on multiple factors, including disease type, stage of disease, the setting of therapy and the goal of therapy. While the designs for future clinical trials will vary, it is clear that these two successful modalities of therapy can and should be combined for the benefit of cancer patients.

Background Interferon-containing regimens for the treatment of hepatitis C virus (HCV) infection are associated with increased toxic effects in patients who also have cirrhosis. We evaluated the interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir (ABT-267), the nonnu- cleoside polymerase inhibitor dasabuvir (ABT-333), and ribavirin in an open-label phase 3 trial involving previously untreated and previously treated adults with HCV genotype 1 infection and compensated cirrhosis. Methods We randomly assigned 380 patients with Child-Pugh class A cirrhosis to receive either 12 or 24 weeks of treatment with ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. The rate of sustained virologic response in each group was compared with the estimated rate with a telaprevir-based regimen (47%; 95% confidence interval [CI], 41 to 54). A noninferiority margin of 10.5 percentage points established 43% as the noninferiority threshold; the superiority threshold was 54%. Results A total of 191 of 208 patients who received 12 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 91.8% (97.5% CI, 87.6 to 96.1). A total of 165 of 172 patients who received 24 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 95.9% (97.5% CI, 92.6 to 99.3). These rates were superior to the historical control rate. The three most common adverse events were fatigue (in 32.7% of patients in the 12-week group and 46.5% of patients in the 24-week group), headache (in 27.9% and 30.8%, respectively), and nausea (in 17.8% and 20.3%, respectively). The hemoglobin level was less than 10 g per deciliter in 7.2% and 11.0% of patients in the respective groups. Overall, 2.1% of patients discontinued treatment owing to adverse events. Conclusions In this phase 3 trial of an oral, interferon-free regimen evaluated exclusively in patients with HCV genotype 1 infection and cirrhosis, multitargeted therapy with the use of three new antiviral agents and ribavirin resulted in high rates of sustained virologic response. Drug discontinuations due to adverse events were infrequent. (Funded by AbbVie; TURQUOISE-II ClinicalTrials.gov number, NCT01704755.)

An interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously or who had no response to prior therapy with pegylated interferon and ribavirin.In this phase 2b, open-label study with 14 treatment subgroups, 571 patients without cirrhosis who had not received treatment previously or who had not had a response to prior therapy were randomly assigned to a regimen of ABT-450/r, combined with ABT-267 or ABT-333 or both, for 8, 12, or 24 weeks and received at least one dose of therapy. All the subgroups but 1 also received ribavirin (dose determined according to body weight). The primary end point was sustained virologic response at 24 weeks after the end of treatment. The primary efficacy analysis compared rates between previously untreated patients who received three direct-acting antiviral agents and ribavirin for 8 weeks and those who received the same therapy for 12 weeks.Among previously untreated patients who received three direct-acting antiviral agents (with the ABT-450/r dose administered as 150 mg of ABT-450 and 100 mg of ritonavir) plus ribavirin, the rate of sustained virologic response at 24 weeks after treatment was 88% among those who received the therapy for 8 weeks and 95% among those who received the therapy for 12 weeks (difference, -7 percentage points; 95% confidence interval, -19 to 5; P=0.24). The rates of sustained virologic response across all treatment subgroups ranged from 83 to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia. Eight patients (1%) discontinued treatment owing to adverse events.In this phase 2b study, all-oral regimens of antiviral agents and ribavirin were effective both in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. (Funded by AbbVie; ClinicalTrials.gov number, NCT01464827.).

Background An association between switching antiretroviral therapy (ART) to integrase strand transfer inhibitor (INSTI)-based ART and weight gain has been previously reported. However, insufficient data exists on risk factors associated with such weight gain. Methods We reviewed charts of 119 virally-suppressed HIV-positive patients switched from nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI)-based ART to INSTI-based ART and compared their weight change over 17 months to 56 virally-suppressed patients who were maintained on NNRTI-based regimens over the same period.We looked at variables associated with weight gain including age, weight, body mass index (BMI), gender, CD4 count, starting ART, and final INSTI-based ART. Results The 119 patients switched to INSTI-based ART gained an average of 6.9 lbs compared with an average 1 lbs weight gain in the 56 patients who were maintained on NNRTI-based ART (P = 0.002). There was also a statistically significant difference in the percentage % weight change between the two groups (4.2% vs. 0.7%, P < 0.001).There was an average 1.2 lbs weight loss in 92 of the 119 patients with weights recorded 17 months before switching ART, compared with an average 6.7 lbs weight gain after the switch (P < 0.001).There was no association between gender, CD4 count at the time of switch, starting ART, or final INSTI-based ART with weight gain. However, patients weighing < 150 lbs at the time of switch had a greater % weight gain than patients weighing >200 lbs (6.9% vs. 2.7%, P = 0.02) and a trend to greater % weight gain than those weighing ≥150 to ≤ 200 lbs (6.9% vs. 3.8%, P = 0.06). There was marginal statistical significance when comparing those with BMIs < 25 to those with BMIs ≥25 to ≤ 30 (8.2 vs. 6.5 lbs, P = 0.069) and those with BMIs >30 (8.2 vs. 5.0 lbs, P = 0.057). There was an inverse correlation between age and weight gain, indicating that less weight was gained when switching to INSTI-based ART as the age of the patient increased (ρ = -0.211, P = 0.021). Conclusion Our study showed a statistically significant weight gain in patients switched from NNRTI- or PI- to INSTI-based ART compared with patients maintained on NNRTI-based ART.Baseline variables associated with greater weight gain included weight Disclosures All authors: No reported disclosures.

The current standard of care for patients suffering from acute respiratory distress syndrome (ARDS) is ventilation with a tidal volume of 6 ml/kg predicted body weight (PBW), but variability remains in the tidal volumes that are actually used. This study aims to identify patient scenarios for which there is discordance between physicians in choice of tidal volume and positive end-expiratory pressure (PEEP) in ARDS patients. We developed an algorithm based on fuzzy logic for encapsulating the expertise of individual physicians regarding their use of tidal volume and PEEP in ARDS patients. The algorithm uses three input measurements: (1) peak airway pressure (PAP), (2) PEEP, and (3) arterial oxygen saturation (SaO2). It then generates two output parameters: (1) the deviation of tidal volume from 6 ml/kg PBW, and (2) the change in PEEP from its current value. We captured 6 realizations of intensivist expertise in this algorithm and assessed their degree of concordance using a Monte Carlo simulation. Variability in the tidal volume recommended by the algorithm increased for PAP > 30 cmH2O and PEEP > 5 cmH2O. Tidal volume variability decreased for SaO2 > 90 %. Variability in the recommended change in PEEP increased for PEEP > 5 cmH2O and for SaO2 near 90 %. Intensivists vary in their management of ARDS patients when peak airway pressures and PEEP are high, suggesting that the current goal of 6 ml/kg PBW may need to be revisited under these conditions.

Metastatic deposits to the spine in thyroid cancer patients represent the most common site of bone involvement and can contribute to pain, neurologic deficits, and death. This study sought to determine the efficacy and safety of spine stereotactic radiosurgery (SSRS) for thyroid cancer patients.Thyroid cancer patients with spine metastases were selected and analyzed from a cohort of patients who were prospectively enrolled in two single-institution Phase I/II studies. SSRS was delivered in single or multi-fraction schedules. Dose regimens ranged from 16-18 Gy in one fraction to 27-30 Gy in three to five fractions. Toxicity was graded according to the NCI-CTC toxicity scale. Local control was determined by serial post-treatment magnetic resonance imaging scans showing no evidence of progressive disease. Patients were followed until date of death or date of last known visit for survival analyses. Local control and overall survival rates were carried out using Kaplan-Meier estimates. The log-rank test was used to assess the equality of the survivor function across groups. A p-value of ≤0.05 was considered to be statistically significant.A total of 27 spine lesions were treated in 23 patients over a six-year period. Median follow-up was 28.9 months (range 5-93 months). Local control was 88% at two years and 79% at three years. In patients with progressive disease following conventional radiation therapy, local control for salvage SSRS remained at 88% at three years. Patients requiring upfront surgical intervention and treated with adjuvant SSRS achieved sustained control rates of 86% at three years. Overall survival rates were 85% and 67% at one and two years, respectively. In patients classified with oligoprogression and controlled extra-spinal disease, overall survival was significantly higher than those with evidence of systemic progression (81% vs. 45% at two years; p = 0.01). Univariate analysis did not show significant correlations between local control and age, systemic disease status, prior (131)I therapy, SSRS fraction regimen, spine location, histological subtype, or time from initial diagnosis to evidence of spinal metastasis. No patient experienced any grade 3-5 toxicity. Pain flare was reported in 30% of patients, with only three patients (13%) requiring narcotics or short-course steroids. There was no evidence of vertebral body fracture in any patient that achieved local control in the treated area.SSRS for thyroid metastases as a primary or adjuvant/salvage therapy is well tolerated and yields high rates of local control.

Conventional radiotherapy, in addition to its well-established tumoricidal effects, can also activate the host immune system. Radiation therapy modulates tumour phenotypes, enhances antigen presentation and tumour immunogenicity, increases production of cytokines and alters the tumour microenvironment, enabling destruction of the tumour by the immune system. Investigating the combination of radiotherapy with immunotherapeutic agents, which also promote the host antitumour immune response is, therefore, a logical progression. As the spectrum of clinical use of stereotactic radiotherapy continues to broaden, the question arose as to whether the ablative radiation doses used can also stimulate immune responses and, if so, whether we can amplify these effects by combining immunotherapy and stereotactic ablative radiotherapy (SABR). In this Perspectives article, we explore the preclinical and clinical evidence supporting activation of the immune system following SABR. We then examine studies that provide data on the effectiveness of combining these two techniques - immunotherapy and SABR - in an approach that we have termed 'ISABR'. Lastly, we provide general guiding principles for the development of future clinical trials to investigate the efficacy of ISABR in the hope of generating further interest in these exciting developments.

Tuberculosis (TB) has been a persistent public health concern for hundreds of years. Despite advances in medicine and science, eliminating this disease has been beyond our reach. Several organizations, including the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), have expressed their commitment to advancing biomedical research in TB in order to increase our understanding of the causative pathogen and the disease. This basic knowledge is a critical first step in the development and implementation of new therapeutics, vaccines and diagnostics. Collaboration between researchers is a key component to accomplishing this goal; product development can no longer be limited to separate programs. Rather, the interconnectedness and possible combination of interventions must be investigated. This review will discuss ongoing TB research including NIAID's role, as well as future research that is needed to improve TB control. Emphasizing the importance of coordination among researchers, funders and advocacy groups, we aim to illustrate the fact that biomedical research, and particularly basic research, is a vital part of a complementary approach to eliminating TB across the globe.

Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder characterized by cytokine dysregulation and uncontrolled activation of T lymphocytes and macrophages. It is categorized as primary when associated with specific genetic mutations or secondary when associated with infections, malignancies, or autoimmune disorders. Clinical features of HLH include unexplained fever, hepatosplenomegaly, pancytopenia, and severe hyperferritinemia. Treatment of primary HLH has become standardized based on the HLH-2004 protocol using cyclosporine, etoposide, and dexamethasone with or without intrathecal methotrexate followed by hematopoietic stem cell transplantation. Treatment of secondary HLH is directed at control of the underlying condition. If unsuccessful, cytotoxic agents such as those in HLH-2004, steroids, intravenous γ-globulin, or targeted immune therapy have been used. Immunotherapy targeting CD52 expressed on immune effector cells of HLH is a rational therapeutic approach in patients too ill for traditional cytotoxic chemotherapy. We describe the successful use of alemtuzumab to treat HLH due to systemic lupus erythematosus.

Thomas Jefferson and Executive Power. By Jeremy D. Bailey. (Cambridge, UK: Cambridge University Press, 2007. Pp. xvi, 280. Cloth, $87.99.)Jeremy D. Bailey, "Constitutionalism, Conflict, and Consent: Jefferson on the Impeachment Power," Review of Politics 70 (June 2008), 572-94.Reviewed by R. B. BernsteinWorks of history become valuable when they persuade us to abandon former ways of seeing a given historical problem in favor of a new, illuminating perspective. By this test, Jeremy D. Bailey, who teaches political science at the University of Houston, has written a truly valuable book. Thomas Jefferson and Executive Power persuades us to discard the stale, misleading dichotomy between strong and weak presidents for the far more enlightening approach of grasping how a particular president understood his office as a constitutional institution and sought to meet the challenges that that institution posed for him.For too long, historians have privileged strong presidents and damned the weak ones; in the process, they have shown magnificent lack of attention to what "strong" or "weak" might mean in historical context or whether there might be an array of models for a "strong" presidency. Using this test and invoking the magisterial authority of Henry Adams to back it up, historians have hailed Thomas Jefferson's successes as president while stigmatizing his vision of the presidency as limited and weak by comparison with the strong presidency advocated by his great adversary, Alexander Hamilton. Under the old view, Jefferson succeeded as president because he was a skilled politician and used his personal gifts for consensus and persuasion, though ultimately giving in to the need to wield his presidency in Hamiltonian terms.Bailey rejects this interpretation, seeking instead to determine what Jefferson understood the American presidency to be and how best to make it work. Taking seriously Jefferson's insistence that he sought to govern by reference to the views of the American people, Bailey shows that Jefferson devised an approach to the presidency conceptually distinct from the Hamiltonian vision as an office of executive command. Jefferson rooted the presidency's strength in the president's ability to connect with and give voice to the will of the people, a presidency not only consonant with but governed by public opinion. Thus, Jefferson succeeded as president when he governed in line with the public opinion that he could discern and articulate, and he failed as president when, as with his embargo policy in his second term, he increasingly found himself veering away from what public opinion was trying to tell him.As Bailey shows, Jefferson's ideas about executive power go back to his earliest involvement in constitution-making in 1776 and thus had been developing and evolving in his mind for nearly a quarter-century before he took the presidential oath in March 1801. Jefferson, as Bailey demonstrates, took his democratic ideals seriously and sought to meld them with his understanding of executive power so that he could devise a way for a chief executive to be both vigorous and legitimate, with public opinion of his words and deeds as the touchstone of legitimacy. Further, Jefferson insisted that a constitutional chief executive had to be both a vehicle for needed constitutional change, by mobilizing and mustering public opinion in its support, and a respecter of the Constitution. Previous scholars have denned these two views as forming a paradox in Jefferson's thought, whereas Bailey seeks to reconcile them and show how, in Jefferson's thinking, they were both consistent and complementary.Jefferson's method for resolving the paradox was to offer the people what he called "declarations of principle," in which he both sought to voice public opinion and to educate it. (It is no accident that this method of constitutional governance was peculiarly suited to Jefferson's literary gifts, which formed one of the foundation stones of his success as a politician throughout his career. …

Although designed to target only the HIV protease, HIV protease inhibitors induce toxicities in patients such as insulin resistance and lipodystrophy that suggest that protease inhibitors have other targets in mammalian cells. Akt controls insulin signaling and is an important target in cancer, but no Akt inhibitors are approved as cancer therapeutics. These observations have prompted the study of HIV protease inhibitors as inhibitors of Akt and possible cancer therapeutics. This review will highlight the latest advances in repositioning HIV protease inhibitors as cancer therapeutics.Although protease inhibitors can inhibit Akt activation and the proliferation of over 60 cancer cell lines, as well as improve sensitivity to radiation or chemotherapy, these effects do not always correlate with Akt inhibition. Other important processes, such as the induction of endoplasmic reticulum stress, appear critical to the biological activity of protease inhibitors. These impressive and surprising preclinical data have prompted clinical testing of nelfinavir as a lead HIV protease inhibitor in cancer patients.Although mechanisms of action for the antitumor effects of HIV protease inhibitors are complex, their broad spectrum of activity, minimal toxicity, and wide availability make protease inhibitors ideal candidates for repositioning as cancer therapeutics.

Developed in the 1980s, the Determiner Phrase (DP) analysis stimulated a lot of interest in the internal structure of nominal phrases and in the study of correspondences between nominal and clausal structure. Research across a range of languages has uncovered correspondences in areas such as agreement morphology, syntactic movement, and argument structure, some of which are reviewed here. Nominal phrases and clauses also match up in terms of their semantic function: both can serve as predicates or arguments. The issue of exactly what distinguishes a nominal argument from a nominal predicate has received a lot of attention, leading in particular to proposals about the underlying role of the definite article (and determiner elements in general). This article reviews some of these issues and proposals and suggests a reformulation that appeals to the feature ‘person’, a feature found in both the nominal and clausal domains.

Environmental monitoring typically falls into one of two broad categories. Targeted designs, utilizing fixed stations, focus on describing and quantifying impacts, tracking trends, and assessing compliance with regulatory guidelines or limits. Probabilistic designs, in contrast, draw sampling stations at random from an area or region, and the stations are used to describe conditions in the region of interest based on a subpopulation of sites. These two design approaches are usually viewed as mutually exclusive, with randomized designs used for broader regional assessments of overall ambient condition and targeted designs for demonstrating regulatory compliance and/or characterizing specific, localized impacts. Combining elements of both approaches into a single design provides benefits not available from either design alone. Embedding targeted monitoring within the framework of a probabilistic design enables data from targeted stations to be viewed in a more accurate regional context and provides a consistent background against which to identify characteristic regional patterns of contamination and impact. We use the San Gabriel River Regional Monitoring Program, recently implemented in southern California, to illustrate the structure of a hybrid design and how it enables data analyses and assessments that provide a more complete picture of conditions in the watershed. For example, the hybrid design showed that approximately 80% of the metals levels at compliance sites were below the 25th percentile of the overall watershed condition as indicated by the probabilistic sampling.

Purpose To provide the foundation for combining immunotherapy to induce tumor antigen–specific T cells with proton radiation therapy to exploit the activity of those T cells. Methods and Materials Using cell lines of tumors frequently treated with proton radiation, such as prostate, breast, lung, and chordoma, we examined the effect of proton radiation on the viability and induction of immunogenic modulation in tumor cells by flow cytometric and immunofluorescent analysis of surface phenotype and the functional immune consequences. Results These studies show for the first time that ( 1 ) proton and photon radiation induced comparable up-regulation of surface molecules involved in immune recognition (histocompatibility leukocyte antigen, intercellular adhesion molecule 1, and the tumor-associated antigens carcinoembryonic antigen and mucin 1); ( 2 ) proton radiation mediated calreticulin cell-surface expression, increasing sensitivity to cytotoxic T-lymphocyte killing of tumor cells; and ( 3 ) cancer stem cells, which are resistant to the direct cytolytic activity of proton radiation, nonetheless up-regulated calreticulin after radiation in a manner similar to non-cancer stem cells. Conclusions These findings offer a rationale for the use of proton radiation in combination with immunotherapy, including for patients who have failed radiation therapy alone or have limited treatment options.

Background: Data from the CDC's National Health Care Survey (NHCS) can assist researchers studying women's healthcare utilization. Methods: Using data from the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS), component surveys of the NHCS, this paper presents prescribing trends from 1995 to 2000 for the 10 therapeutic drug classes of medications mentioned most often during women's ambulatory care visits. Results: Antidepressants top the list as the most frequently mentioned therapeutic class in 1999-2000, followed by estrogens and progestins, antiarthritics, and drugs for acid/peptic disorders. The number of medications prescribed increased by about 13% during visits by women to physicians' offices and hospital outpatient departments between 1995-1996 and 1999-2000, from 144 to 162 mentions per 100 visits, respectively. Conclusions: Researchers can use the NHCS to track changes in use over time and to target potential issues related to acce...

A B S T R AC T BACKGROUND The interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus the nonnucleoside polymerase inhibitor dasabuvir (also known as ABT-333) and ribavirin has shown efficacy against the hepatitis C virus (HCV) in patients with HCV genotype 1 infection. In this phase 3 trial, we evaluated this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. METHODS In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned previously untreated patients with HCV genotype 1 infection, in a 3:1 ratio, to an active regimen consisting of a single-tablet coformulation of ABT-450/r–ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of om bitasvir), and dasabuvir (250 mg twice daily) with ribavirin (in doses determined according to body weight) (group A) or matching placebos (group B). The patients received the study treatment during a 12-week double-blind period. The primary end point was sustained virologic response at 12 weeks after the end of treatment. The primary analysis compared the response rate in group A with the response rate (78%) in a historical control group of previously untreated patients without cirrhosis who received telaprevir with peginterferon and ribavirin. Adverse events occurring during the double-blind period were compared between group A and group B. RESULTS A total of 631 patients received at least one dose of the study drugs. The rate of sustained virologic response in group A was 96.2% (95% confidence interval, 94.5 to 97.9), which was superior to the historical control rate. Virologic failure during treatment and relapse after treatment occurred in 0.2% and 1.5%, respectively, of the patients in group A. The response rates in group A were 95.3% among patients with HCV genotype 1a infection and 98.0% among those with HCV genotype 1b infection. The rate of discontinuation due to adverse events was 0.6% in each study group. Nausea, pruritus, insomnia, diarrhea, and asthenia occurred in significantly more patients in group A than in group B (P

BACKGROUND & AIMS: The interferon-free regimen of ABT-450 (a protease inhibitor), ritonavir, ombitasvir (an NS5A inhibitor), dasabuvir (a non-nucleoside polymerase inhibitor), and ribavirin has shown efficacy in patients with hepatitis C virus (HCV) genotype 1b infection-the most prevalent subgenotype worldwide. We evaluated whether ribavirin is necessary for ABT-450, ritonavir, ombitasvir, and dasabuvir to produce high rates of sustained virologic response (SVR) in these patients. METHODS: We performed a multicenter, open-label, phase 3 trial of 179 patients with HCV genotype 1b infection, without cirrhosis, previously treated with peginterferon and ribavirin. Patients were assigned randomly (1:1) to groups given ABT-450, ritonavir, ombitasvir, and dasabuvir, with ribavirin (group 1) or without (group 2) for 12 weeks. The primary end point was SVR 12 weeks after treatment (SVR12). We assessed the noninferiority of this regimen to the rate of response reported (64%) for a similar population treated with telaprevir, peginterferon, and ribavirin. RESULTS: Groups 1 and 2 each had high rates of SVR12, which were noninferior to the reported rate of response to the combination of telaprevir, peginterferon, and ribavirin (group 1: 96.6%; 95% confidence interval, 92.8%-100%; and group 2: 100%; 95% confidence interval, 95.9%-100%). The rate of response in group 2 was noninferior to that of group 1. No virologic failure occurred during the study. Two patients (1.1%) discontinued the study owing to adverse events, both in group 1. The most common adverse events in groups 1 and 2 were fatigue (31.9% vs 15.8%) and headache (24.2% vs 23.2%), respectively. Decreases in hemoglobin level to less than the lower limit of normal were more frequent in group 1 (42.0% vs 5.5% in group 2; P < .001), although only 2 patients had hemoglobin levels less than 10 g/dL. CONCLUSIONS: The interferon-free regimen of ABT-450, ritonavir, ombitasvir, and dasabuvir, with or without ribavirin, produces a high rate of SVR12 in treatment-experienced patients with HCV genotype 1b infection. Both regimens are well tolerated, as shown by the low rate of discontinuations and generally mild adverse events. ClinicalTrials.gov number: NCT01674725.

The National Health Care Survey (NHCS), conducted by the National Center for Health Statistics, consists of separate data collection activities that can be used to track the number and content of health care encounters in the United States. Tracking even something as simple as the number of encounters, however, is complicated by the fact that the content of these encounters changes over time. Results from the NHCS indicate that the U.S. population has been receiving more drugs, more cardiac procedures, more ambulatory surgery, more therapies in nursing homes, and more home health care over time. Policymakers and researchers who examine health care trends should be wary about judging whether the number of length of encounters is positive or negative without also examining the content of these encounters.

Objective: To evaluate the effect of growth hormone (GH) therapy on pubertal onset, pubertal pace, adult testicular function, and adrenarche in boys with non-GH-deficient short stature. Study design: Randomized, double-blind, placebo-controlled trial. GH (0.074 mg/kg, subcutaneously, 3 times per week) or placebo treatment was initiated in prepubertal or early pubertal boys and continued until near final height was reached (n = 49). Statistical significance was assessed by survival analysis, repeated-measures analysis of variance, and Student t test. Results: GH therapy did not affect the age at pubertal onset, defined either by testicular volume >4 mL or by testosterone concentration >1.0 nmol/L (30 ng/dL). GH treatment also did not affect the pace of puberty, defined either by the rate of change in testicular volume or testosterone concentration during the 4 years after pubertal onset. In boys followed up to age ≥16 years during the study, there were no significant differences in final testicular volume or in plasma testosterone, luteinizing hormone, or follicle-stimulating hormone concentrations. The pace of adrenarche, assessed by change in dehydroepiandrosterone sulfate levels over time, also did not differ significantly between the GH and placebo groups. Conclusion: Our findings suggest that GH treatment does not cause testicular damage, alter the onset or pace of puberty, or alter the pace of adrenarche in boys with non-GH-deficient short stature. (J Pediatr 2001;138:406-10)

Primary malignant schwannomas are a very rare neural sheath tumor. A case of primary epithelioid-type malignant schwannoma of the uterine cervix in a 65-year-old woman is presented. This tumor is the first epithelioid malignant schwannoma documented within gynecologic tissues. Only two other cases of primary malignant schwannoma of the uterine cervix have been reported, and these cases are reviewed.

The fact that the Medicaid program has improved access to medical services for poor and vulnerable women is not disputed.1 Increasingly, Medicaid managed care in some form or other is replacing Medicaid fee-for-service. The most recent numbers available show that as of June 30, 1996, 40% of Medicaid enrollees were in some form of managed care. Broadly, Medicaid managed care can be divided into two types of care arrangements: fee-for-service arrangements with primary care case management (PCCM) programs and programs where the Medicaid providers assume some risk—that is, take some form of capitated prepayment for the care of the Medicaid enrollees they treat.2 Medicaid managed care may, in some policymakers’ minds, offer significant advantages over past fee-for-service programs in caring for the Medicaid population. Under Medicaid fee-for-service, providers could choose whether to accept Medicaid patients at all, and in many states Medicaid enrollees faced substantial barriers to access to medical care because of a shortage of Medicaid-participating providers. State Medicaid managed care programs may help alleviate this problem by inducing providers to treat Medicaid patients in addition to their commercial patients. Risk-based managed care organizations (MCOs) may also have more flexibility because they receive some capitation to substitute among different types of services to address specific populations or health problems. Lastly, MCOs hold the promise of being able to “manage” care more effectively than fee-for-service providers by stressing continuity of care and integrating processes of care across providers.2 Therefore, states have turned to Medicaid managed care in part because they believe it will improve access to care for Medicaid enrollees, improve their quality of care, and reduce state Medicaid program costs.3 Traditional managed care models (especially Health Maintenance Organizations, or HMOs) rely heavily on the principle of providing preventive care to help eliminate the need for future more expensive acute or chronic care services. Some women on Medicaid may not be educated about the importance of preventive care, which has few immediate positive outcomes and may require transportation or child care expenses that are not easily afforded. In addition, a significant proportion of women who are on Medicaid do not stay on Medicaid for a period long enough to track preventive interventions. The majority of women on Medicaid are covered for 5 or fewer years; 28% are © 1998 by the Jacobs Institute of Women’s Health Published by Elsevier Science Inc. 1049-3867/98/$19.00 PII S1049-3867(98)00033-4

We present a planning framework that structures thelarge amount of interrelated information involved indeveloping regional monitoring programs. By ’regional‘we mean programs that recognize the importance ofprocesses that occur on larger geographic scales andthat cut across more than one ecosystem component. Theframework helps visualize functional relationshipsamong qualitative ingredients such as public concernsand more concrete details such as individual dataelements. It portrays the flow of information amongthe components of a regional program and ties eachaspect of the program to management decision-makingneeds. This makes it easier, during the planningprocess, to ensure that monitoring will actuallyproduce useful information. Further, the framework‘snovel, graphically oriented, and readily accessibleformat makes key information equally available to thewide range of participants (regulators, scientists,managers, public) whose input and support arenecessary for program success.

Purpose Controversy exists whether the prostate-specific antigen (PSA) bounce phenomenon following definitive radiation for prostate cancer has prognostic significance. Here, we perform a meta-analysis to determine the association between PSA bounce and biochemical control after brachytherapy alone. Material and methods We reviewed Medline, EMBASE, and CENTRAL citations through February 2012. Studies that recorded biochemical failure rates in bouncers and non-bouncers were included. Hazard ratios describing the impact of bounce on biochemical failure were extracted directly from the studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. A random effects model was used in cases of significant effect heterogeneity (p < 0.10 using Q test). Results The final analysis included 3011 patients over 6 studies treated with brachytherapy. Meta-analysis revealed that patients experiencing PSA bounce after brachytherapy, conferred a decreased risk of biochemical failure (random effects model HR = 0.42, 95% CI: 0.30-0.59; p < 0.001). Conclusions Our meta-analysis determined that PSA bounce predicts for improved biochemical control following brachytherapy. To our knowledge, this is the first study describing this effect.

Purpose The current ventilatory care goal for acute respiratory distress syndrome (ARDS) and the only evidence-based approach for managing ARDS is to ventilate with a tidal volume ( V T ) of 6 mL/kg predicted body weight (PBW). However, it is not uncommon for some caregivers to feel inclined to deviate from this strategy for one reason or another. To accommodate this inclination in a rationalized manner, we previously developed an algorithm that allows for V T to depart from 6 mL/kg PBW based on physiological criteria. The goal of the present study was to test the feasibility of this algorithm in a small retrospective study. Materials and Methods Current values of peak airway pressure, positive end-expiratory pressure (PEEP), and arterial oxygen saturation are used in a fuzzy logic algorithm to decide how much V T should differ from 6 mL/kg PBW and how much PEEP should change from its current setting. We retrospectively tested the predictions of the algorithm against 26 cases of decision making in 17 patients with ARDS. Results Differences between algorithm and physician V T decisions were within 2.5 mL/kg PBW, except in 1 of 26 cases, and differences between PEEP decisions were within 2.5 cm H 2 O, except in 3 of 26 cases. The algorithm was consistently more conservative than physicians in changing V T but was slightly less conservative when changing PEEP. Conclusions Within the limits imposed by a small retrospective study, we conclude that our fuzzy logic algorithm makes sensible decisions while at the same time keeping practice close to the current ventilatory care goal.

Although health maintenance organization (HMO) structures and databases are not uniform across plans, there are unique characteristics of HMO data in general that make them useful in examining health policy and delivery issues. The authors examine differences in data generated by different types of HMOs. After discussing why health services research using HMO data is needed by HMOs, other providers, practitioners, payers, and consumers of health care, the authors examine ways in which HMOs can provide sound answers to crucially important questions about the future of health care. They conclude that although the need for research on HMOs is compelling, researchers need to understand the information needs of HMOs and the incentives that are shaping the industry's approach to system delivery and clinical outcomes research. If HMOs do not take the lead in conducting health services research, they will diminish their role in shaping policies that will shape their future evolution.

ABT-450 (combined with low-dose ritonavir, ABT-450/r) is a potent HCV NS3 protease inhibitor, and ABT-072 is a non-nucleoside NS5B polymerase inhibitor. The goal of this study was to evaluate the safety, tolerability, and efficacy of the peginterferon-free combination of ABT-450/r and ABT-072 with ribavirin in treatment-naïve patients with IL28B CC genotype, infected with HCV genotype 1.This was a phase 2a, multicenter, open-label, single-arm study in 11 treatment-naïve, non-cirrhotic HCV GT1-infected patients with IL28B rs12979860 genotype CC. Patients received ABT-450/r 150/100 mg once daily and ABT-072 400 mg once daily with weight-based ribavirin 1000-1200 mg/day dosed twice daily for 12 weeks.Eight (73%) patients were male, 9 (82%) were Caucasian (including 3 who self-identified as Hispanic); mean baseline HCV RNA was 6.9 log₁₀ IU/ml (range 6.5-7.3 log₁₀ IU/ml). All 11 patients completed 12 weeks of treatment and maintained HCV RNA25 IU/ml from weeks 4 through 12 of treatment. Ten patients (91%) achieved sustained virologic response 24 weeks post-treatment, with a second patient relapsing 36 weeks post-treatment. There were no deaths, serious or severe adverse events, or premature discontinuations. Adverse events were mostly mild and the most frequent were headache, fatigue, nausea, and dry skin.A 12-week regimen of ABT-450/r and ABT-072 with ribavirin was well tolerated with 9/11 patients achieving sustained virologic response through 36 weeks of post-treatment observation. These findings suggest that peginterferon-free regimens may have the potential to cure a high proportion of HCV genotype 1-infected patients.