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This Viewpoint summarizes inefficiencies in the 340B program and provides suggestions for equitable reform that will potentially benefit patients. [ABSTRACT FROM AUTHOR]

Background: Current practice and policies maintain that it is very important to disclose to potential research subjects that their treatment will be selected by randomization. In contrast, it typically is not considered important to disclose to patients how doctors select their treatment. Unfortunately, when the available treatment options are similar to one another, this approach has the potential to inadvertently undermine both clinical research and clinical care. Hence, it is important to assess whether, in the context of similar treatment options, individuals support current practice of using very different disclosure practices in research and care.Methods: Respondents were randomly presented with either (1) a “drug” scenario involving two medications for hypertension (called CTD and TRT) whose risk–benefit profiles are very similar, or (2) a “dose timing” scenario involving morning versus nighttime dosing of the same antihypertensive. Respondents were asked whether, in the presented scenario, they agree, using a 7-point scale (1 = strongly disagree, 4 = neutral, 7 = strongly agree), that it is important to disclose to potential research subjects that whether they receive CTD or TRT/AM or PM dosing will be determined by randomization. Respondents were also asked whether they agree, using the same 7-point scale, that it is important to disclose to patients who face the same treatment options how their doctor will decide whether they receive CTD or TRT/AM or PM dosing.Results: The survey was sent to 3330 online GfK KnowledgePanel members and completed by 2130 (response rate, 64.0%). Respondents indicated that it is somewhat important to disclose to potential subjects that whether they receive CTD or TRT/AM or PM dosing will be determined by randomization (mean, 5.10 [95% CI, 5.02 to 5.17]). Respondents also indicated that it is slightly more important to disclose to patients who face the same treatment options how the doctor will decide whether they receive CTD or TRT/AM or PM dosing (mean, 5.29 [95% CI, 5.22 to 5.36];p< .001). In addition, 66.4% indicated that, in the setting of similar options, it is equally important to disclose how treatment is selected in research and care, 20.5% indicated it is more important to disclose this information in clinical care, and 13.1% indicated it is more important to disclose it in research.Conclusion: When the available options are similar to each other, individuals do not support current practice and policies that maintain that disclosure of how treatments are selected is very important in clinical research but not important in clinical care. Future research will be needed to evaluate the feasibility of developing disclosure practices and policies for this context that are consistent with individuals' views. [ABSTRACT FROM PUBLISHER]

According to prominent bioethics scholars and international guidelines, researchers and sponsors have obligations to ensure that the products of their research are reasonably available to research participants and their communities. In other words, the claim is that research is unethical unless it has local social value. In this article, we argue that the existing conception of reasonable availability should be replaced with a social value obligation that extends to the global poor (and not just research participants and host communities). To the extent the social value requirement has been understood as geographically constrained to the communities that host research and the countries that can afford the products of research, it has neglected to include the global poor as members of the relevant society. We argue that a new conception of social value obligations is needed for two reasons. First, duties of global beneficence give reason for researchers, sponsors, and institutions to take steps to make their products more widely accessible. Second, public commitments made by many institutions acknowledge and engender responsibilities to make the products of research more accessible to the global poor. Future research is needed to help researchers and sponsors discharge these obligations in ways that unlock their full potential. [ABSTRACT FROM AUTHOR]

Background: Significant debate surrounds the issue of whether written consent is necessary for pragmatic randomized, controlled trials (RCTs) with low risk.Objective: To assess the U.S. public's views on alternatives to written consent for low-risk pragmatic RCTs.Design: National experimental survey (2 × 2 factorial design) examining support for written consent versus general notification or verbal consent in 2 research scenarios.Setting: Web-based survey conducted in December 2014.Participants: 2130 U.S. adults sampled from a nationally representative, probability-based online panel (response rate, 64.0%).Measurements: Respondent's recommendation to an ethics review board and personal preference as a potential participant on how to obtain consent or notification in the 2 research scenarios.Results: Most respondents in each of the 4 groups (range, 60.3% to 71.5%) recommended written informed consent, and personal preferences were generally in accord with that advice. Most (78.9%) believed that the pragmatic RCTs did not pose additional risks, but 62.5% of these respondents would still recommend written consent. In contrast, a substantial minority in all groups (28.5% to 39.7%) recommended the alternative option (general notification or verbal consent) over written consent.Limitation: Framing effects could have affected respondents' attitudes, and nonrespondents may have differed in levels of trust toward research or health care institutions.Conclusion: Most of the public favored written informed consent over the most widely advocated alternatives for low-risk pragmatic RCTs; however, a substantial minority favored general notification or verbal consent.Primary Funding Source: Time-sharing Experiments for the Social Sciences and Intramural Research Program of the National Institutes of Health Clinical Center. [ABSTRACT FROM AUTHOR]

Background: Significant debate surrounds the issue of whether written consent is necessary for pragmatic randomized, controlled trials (RCTs) with low risk. Objective: To assess the U.S. public's views on alternatives to written consent for low-risk pragmatic RCTs. Design: National experimental survey (2 × 2 factorial design) examining support for written consent versus general notification or verbal consent in 2 research scenarios. Setting: Web-based survey conducted in December 2014. Participants: 2130 U.S. adults sampled from a nationally representative, probability-based online panel (response rate, 64.0%). Measurements: Respondent's recommendation to an ethics review board and personal preference as a potential participant on how to obtain consent or notification in the 2 research scenarios. Results: Most respondents in each of the 4 groups (range, 60.3% to 71.5%) recommended written informed consent, and personal preferences were generally in accord with that advice. Most (78.9%) believed that the pragmatic RCTs did not pose additional risks, but 62.5% of these respondents would still recommend written consent. In contrast, a substantial minority in all groups (28.5% to 39.7%) recommended the alternative option (general notification or verbal consent) over written consent. Limitation: Framing effects could have affected respondents' attitudes, and nonrespondents may have differed in levels of trust toward research or health care institutions. Conclusion: Most of the public favored written informed consent over the most widely advocated alternatives for low-risk pragmatic RCTs; however, a substantial minority favored general notification or verbal consent. [ABSTRACT FROM AUTHOR]

It is widely accepted that translational research practitioners need to acquire special skills and knowledge that will enable them to anticipate, analyze, and manage a range of ethical issues. While there is a small but growing literature that addresses the ethics of translational research, there is a dearth of scholarship regarding how this might apply to engineers. In this paper we examine engineers as key translators and argue that they are well positioned to ask transformative ethical questions. Asking engineers to both broaden and deepen their consideration of ethics in their work, however, requires a shift in the way ethics is often portrayed and perceived in science and engineering communities. Rather than interpreting ethics as a roadblock to the success of translational research, we suggest that engineers should be encouraged to ask questions about the socio-ethical dimensions of their work. This requires expanding the conceptual framework of engineering beyond its traditional focus on 'how' and 'what' questions to also include 'why' and 'who' questions to facilitate the gathering of normative, socially-situated information. Empowering engineers to ask 'why' and 'who' questions should spur the development of technologies and practices that contribute to improving health outcomes. [ABSTRACT FROM AUTHOR]

In an effort to control health costs, payers are increasingly turning to step therapy (or “fail first”) policies in pharmacy benefit design. These policies restrict coverage of expensive therapies unless patients have already failed treatment with a lower-cost alternative. More than other utilization management tools such as formulary tiering, step therapy raises important ethical concerns regarding the proper balance between cost control and the ability of patients and clinicians to tailor care to the needs of the individual patient. This article provides eight design criteria to guide the ethical development and evaluation of step therapy policies and describes six clinical scenarios in which step therapy may be appropriate. The ethical criteria and scenarios are intended to provide guidance and transparency for insurers, patients, clinicians, and policy makers in choosing and paying for the appropriate therapies. [ABSTRACT FROM AUTHOR]

Abstract: Vesicle fusion has long provided an easy and reliable method to form supported lipid bilayers (SLBs) from simple, zwitterionic vesicles on siliceous substrates. However, for complex compositions, such as vesicles with high cholesterol content and multiple lipid types, the energy barrier for the vesicle-to-bilayer transition is increased or the required vesicle–vesicle and vesicle–substrate interactions are insufficient for vesicle fusion. Thus, for vesicle compositions that more accurately mimic native membranes, vesicle fusion often fails to form SLBs. In this paper, we review three approaches to overcome these barriers to form complex, biomimetic SLBs via vesicle fusion: (i) optimization of experimental conditions (e.g., temperature, buffer ionic strength, osmotic stress, cation valency, and buffer pH), (ii) α-helical (AH) peptide-induced vesicle fusion, and (iii) bilayer edge-induced vesicle fusion. AH peptide-induced vesicle fusion can form complex SLBs on multiple substrate types without the use of additional equipment. Bilayer edge-induced vesicle fusion uses microfluidics to form SLBs from vesicles with complex composition, including vesicles derived from native cell membranes. Collectively, this review introduces vesicle fusion techniques that can be generalized for many biomimetic vesicle compositions and many substrate types, and thus will aid efforts to reliably create complex SLB platforms on a range of substrates. [Copyright &y& Elsevier]

Our study evaluated the efficacy of a combination of fluconazole and the psychoactive compound sertraline against strains of Cryptococcus neoformans and Cryptococcus gattii. Using the chequerboard microdilution method based on CLSI M27-A2 guidelines, we determined the susceptibilities of each drug alone and in combination against 40 strains of serotypes A, D and AD in C. neoformans and 13 strains of serotype B C. gattii. The MIC ranged 10.8-43 and 2-64mg/l for sertraline and fluconazole, respectively. No difference in MICSertraline was observed among the serotypes. However, within C. neoformans, a significant difference in MICFluconazole was observed among the serotypes, as follows: AD >A > D (AD being the most resistant). Strains of C. gattii had MICFluconazole not significantly different from those of serotypes A and AD but significantly higher than serotype D. Synergy (FICI ≤ 0.5) was found for 31 strains, while the remaining 22 strains showed no difference. No evidence for antagonistic interaction was observed. Our study suggests the potential utility of fluconazole-sertraline combination therapy for cryptococcal infections. [ABSTRACT FROM AUTHOR]

Introduction: The study goal was to evaluate the cost-effectiveness of drug-eluting stent (DES) placement with consideration of gastrointestinal (GI) bleeding risk. DES reduce the need for future coronary revascularization, but require prolonged dual anti-platelet (DAT) therapy, which may increase the risk for GI bleeding. While DES have been found to be cost-effective in patients at average risk for GI bleeding, they may not be the most cost-effective strategy in higher risk patients. Methods: A Markov model was created to compare DES with bare metal stents (BMS). Patients were a hypothetical cohort of 60-year-old individuals with coronary artery stenosis that required nonemergent percutaneous coronary revascularization (PCI). The primary outcomes were the threshold incremental risks of GI bleeding from DAT based on willingness to pay (WTP) of $50,000, $100,000, and $150,000 per quality adjusted life year (QALY) gained. Results: For a WTP of $100,000, the relative risk of GI bleeding from DAT could be as high as 10.8 (when compared to aspirin alone) before DES would no longer be cost-effective. In patients with two risk factors for GI bleeding, the threshold relative risk could be as low as 1.6. Conclusion: In average-risk patients, the risk of GI bleeding from DAT can be substantial without affecting the cost-effectiveness of DES. However, DES are unlikely to be cost-effective in patients with two or more risk factors for GI bleeding. (J Interven Cardiol 2010;23:179-187) [ABSTRACT FROM AUTHOR]

The unique structural and biological diversity found in plants renders them a distinctive and sustainable source for discovering new antibacterial, antifungal and antiparasitic compounds. In the present study, antimicrobial and antibiofilm properties of essential oils of citrus varieties of Northeast India were studied against selected foodborne pathogens using both in vitro and in silico approaches. These essential oils showed significant antimicrobial and antibiofilm activities against foodborne pathogens. i.e. Bacillus cereus MTCC430 and Yersinia enterocolitica MTCC859. It was observed that the treatment with essential oil disturbed the membrane integrity of the pathogens, thereby causing the release of nucleic acids. This study also postulated that active compounds of the essential oils interact with different target proteins of the pathogens and provide an explanation for the mechanisms of antimicrobial and antibiofilm action of the essential oils of citrus varieties against foodborne pathogens. [ABSTRACT FROM AUTHOR]

Simple Summary: The recent evidence shows that patients with resectable non-small cell lung cancer (NSCLC) benefit from the addition of immunotherapy to chemotherapy before surgery. This approach improves pathological response rates and overall survival in these patients. However, there are many unanswered questions, especially in the context of heterogenous stage III NSCLC. In this review we discuss the new evidence, evolving definitions of resectability, controversies, possible salvage treatments and the ongoing research in this rapidly changing space. We highlight that multimodal treatment for stage III NSCLC should be individualized based on patient and tumor variables. Neoadjuvant immunotherapy and chemotherapy should be discussed with all patients with resectable (>4 cm and/or node positive, excluding N3) NSCLC. Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space. [ABSTRACT FROM AUTHOR]

RESULTS There are 97 (7%) FQHCs that are operated by government entities, serving 1.8 million patients and accounting for 5% of federal health center grants. DISCUSSION Public FQHCs serve a higher proportion of uninsured patients while achieving comparable quality on most metrics without differences in grants received or cost compared to private FQHCs. There was no difference in federal grants received per patient ($300 vs. $283, I p i = 0.55) or average cost per patient between public and non-governmental FQHCs ($1,090 vs. $1,159, I p i = 0.37). [Extracted from the article]

Objectives: Hepatic encephalopathy (HE) is associated with hospital readmissions and mortality. We sought to determine whether cognitive testing and stool frequency at discharge predicted 30-day readmission or death in cirrhotic patients admitted with overt HE.Methods: We approached consecutive inpatients with cirrhosis and overt HE when they were within 48 hours of discharge. Patients underwent cognitive tests, including Psychometric Hepatic Encephalopathy Score (PHES), and stool frequency was documented. Chart review identified Model for End-Stage Liver Disease-sodium (MELD-Na) and the presence of non-HE extrahepatic organ failures. Cox proportional hazards models were used to evaluate predictors of time to the primary composite outcome of hospital readmission for HE or death within 30 days, censoring for liver transplantation.Results: Of 51 patients consented and enrolled, 14 patients met the primary composite outcome. In unadjusted Cox models, 4 variables predicted HE readmission or death: MELD-Na (hazard ratio [HR] 1.10 [1.01-1.20], P = 0.03), respiratory failure (HR 4.26 [1.47-12.35], P = 0.008), total number of HE extrahepatic organ failures (HR 1.79 [1.12-2.88], P = 0.02), and score on a PHES subtest, Number Connection Test A (per 30 seconds; HR 1.25 [1.06-1.47], P = 0.01). PHES and 24-hour stool frequency did not predict the primary outcome. When controlling for MELD-Na, respiratory failure predicted the primary outcome (HR 3.67 [1.24-10.86], P = 0.02).Conclusion: Cognitive testing and stool frequency at discharge did not predict poor outcomes in patients admitted with HE, while respiratory failure appeared to be a strong predictor. [ABSTRACT FROM AUTHOR]

A response from authors of the article "Cost-related motivations for conducting research: Participants should be informed," is presented.

In this article, the authors talks about the need for the health care industry in the U.S. to conduct clinical trials comparing the quality of costly medical treatments with less expensive treatment options in 2014. Topics discussed include the impact of such trials on research participants, the treatment options for age-related macular degeneration, and studies related to ranibizumab. Also mentioned is the Federal Policy for the Protection of Human Subjects.

The rare, broadly neutralizing antibodies, 4E10 and 2F5, that target the HIV-1 membrane proximal external region also associate with HIV-1 membrane lipids as part of a required first-step in HIV-1 neutralization. HIV-1 virions have high concentration of cholesterol and sphingomyelin, which are able to organize into liquid-ordered domains (i.e., lipid rafts), and could influence the interaction of neutralizing antibodies with epitopes proximal to the membrane. The objective of this research is to understand how these lipid domains contribute to 2F5/4E10 membrane interactions and to antigen presentation in liposomal form of HIV-1 vaccines. To this end we have engineered biomimetic supported lipid bilayers and are able to use atomic force microscopy to visualize membrane domains, antigen clustering, and antibody-membrane interactions. Our results demonstrate that 2F5/4E10 do not interact with highly ordered gel and liquid-ordered domains and exclusively bind to a liquid-disordered lipid phase. This suggests that vaccine liposomes that contain key viral membrane components, such as high cholesterol content, may not be advantageous for 2F5/4E10 vaccine strategies. Rather, vaccine liposomes that primarily contain a liquid-disordered phase may be more likely to elicit production of lipid reactive, 2F5- and 4E10-like antibodies. [ABSTRACT FROM AUTHOR]

• During long-term follow-up, two-thirds of patients who underwent lung SABR will meet criteria for progressive disease by RECIST. • Less than 20% of these patients who meet RECIST criteria for progressive disease will have local recurrence and, therefore, the positive predictive value of RECIST in this setting is less than 20%. • These results provide context for clinicians following patients after lung SABR and advise caution in interpreting studies that use PFS as an endpoint after lung SABR. Response Evaluation Criteria in Solid Tumors (RECIST) is commonly used to assess response to anti-cancer therapies. However, its application after lung stereotactic ablative radiotherapy (SABR) is complicated by radiation-induced lung changes. This study assesses the frequency of progressive disease (PD) by RECIST following lung SABR and correlates this with actual treatment outcomes as determined by longitudinal follow-up. We reviewed patients treated with lung SABR for primary lung tumors or oligometastases between 2010 and 2015. Patients were treated with SABR doses of 54–60 Gy in 3–8 fractions. All follow-up scans were assessed and the treated lesion was serially measured over time, with the maximum diameter on axial CT slices used for RECIST calculations. Lesions demonstrating PD by RECIST criteria were identified and subsequently followed for long-term outcomes. The final 'gold-standard' assessment of response was based on size changes after PD and, as available, positron emission tomography scan and/or biopsy. Eighty-eight lesions met inclusion criteria. Seventy-five were lung primaries and thirteen were lung metastases. Median follow-up was 52 months (interquartile range: 33–68). Two-thirds (66 %, 58/88) of treated lesions met RECIST criteria for PD; however, local recurrence was only confirmed in 16 % (9/58) of cases. Most lesions that triggered PD by RECIST (47/58, 81 %) were ultimately found not to represent recurrence, while a minority (2/58, 3 %) had an uncertain response. The positive predictive value [PPV] of a RECIST defined PD event was 0.16. If PD was triggered within 12-months post-treatment, PPV was 0.08, compared to 0.21 for lesions triggering PD after 12-months. Using RECIST criteria, two-thirds of patients treated with lung SABR met criteria for PD. However, only a minority had recurrence, leading to a poor PPV of RECIST. This highlights the limitations of RECIST in this setting and provides context for physicians when interpreting post-lung SABR imaging. [ABSTRACT FROM AUTHOR]

The leading cause of autoimmune encephalitis is N-methyl-D-aspartate receptor (NMDAR) encephalitis. Symptoms can present as prominent behavioral abnormalities prompting inaccurate psychiatric diagnoses. Psychiatric features such as bizarre behavior, agitation, anxiety, delusions, and hallucinations are well noted in the current literature, but a manifestation of foreign accent syndrome has, to our knowledge, never been reported in cases of encephalitis. Once diagnosed, initiation of therapy can result in effective treatment. Here, we present a case of a 32-year-old female with new onset seizures and marked behavioral changes, such as speaking in a foreign accent, who was empirically treated for NMDAR encephalitis due to strong clinical suspicion, showed no improvement with first line therapy with IVIG and IV steroids, and finally had rapid resolution of symptoms with the early initiation of second line therapy of rituximab. In a young female presenting with nonspecific behavioral changes, NMDAR encephalitis should be on the differential and, although CSF antibodies are definitively diagnostic, there should be a low threshold to start empiric therapy and escalate to second line treatment. [ABSTRACT FROM AUTHOR]

Background There is high variability in neurosurgical costs, and surgical supplies constitute a significant portion of cost. Anecdotally, surgeons use different supplies for various reasons, but there is little understanding of how supply choices affect outcomes. Our goal is to evaluate the effect of patient, procedural, and provider factors on supply cost and to determine if supply cost is associated with patient outcomes. Methods We obtained patient information (age, gender, payor, case mix index [CMI], body mass index, admission source), procedural data (procedure type, length, date), provider information (name, case volume), and total surgical supply cost for all inpatient neurosurgical procedures from 2013 to 2014 at our institution ( n = 4904). We created mixed-effect models to examine the effect of each factor on surgical supply cost, 30-day readmission, and 30-day mortality. Results There was significant variation in surgical supply cost between and within procedure types. Older age, female gender, higher CMI, routine/elective admission, longer procedure, and larger surgeon volume were associated with higher surgical supply costs ( P < 0.05). Routine/elective admission and higher surgeon volume were associated with lower readmission rates (odds ratio, 0.707, 0.998; P < 0.01). Only patient factors of older age, male gender, private insurance, higher CMI, and emergency admission were associated with higher mortality (odds ratio, 1.029, 1.700, 1.692, 1.080, 2.809). There was no association between surgical supply cost and readmission or mortality ( P = 0.307, 0.548). Conclusions A combination of patient, procedural, and provider factors underlie the significant variation in neurosurgical supply costs at our institution. Surgical supply costs are not correlated with 30-day readmission or mortality. [ABSTRACT FROM AUTHOR]