Inducible nitric oxide synthase: Good or bad? Lind, Maggie; Hayes, Alan; Caprnda, Martin ...
Biomedicine & pharmacotherapy,
September 2017, 2017-Sep, 2017-09-00, 20170901, Letnik:
93
Journal Article
Recenzirano
Nitric oxide synthases (NOS) are a family of isoforms responsible for the synthesis of the potent dilator nitric oxide (NO). Expression of inducible NOS (iNOS) occurs in conditions of inflammation, ...and produces large amounts of NO. In pathological conditions iNOS is regarded as a harmful enzyme and is proposed to be a major contributor to diseases of the cardiovascular system such as atherosclerosis. In this review, we address the notion that iNOS is a detrimental enzyme in disease and discuss its potentially beneficial roles. Additionally, we describe other molecules associated with iNOS in diseases such as atherosclerosis, and current research on therapeutic inhibitors tested to reduced pathology associated with cardiovascular diseases (CVD).
We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) ...extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
Patients from historically under-represented racial and ethnic groups are enrolled in cancer clinical trials at disproportionately low rates in the USA
. As these patients often have limited English ...proficiency
, we hypothesized that one barrier to their inclusion is the cost to investigators of translating consent documents. To test this hypothesis, we evaluated more than 12,000 consent events at a large cancer centre and assessed whether patients requiring translated consent documents would sign consent documents less frequently in studies lacking industry sponsorship (for which the principal investigator pays the translation costs) than for industry-sponsored studies (for which the translation costs are covered by the sponsor). Here we show that the proportion of consent events for patients with limited English proficiency in studies not sponsored by industry was approximately half of that seen in industry-sponsored studies. We also show that among those signing consent documents, the proportion of consent documents translated into the patient's primary language in studies without industry sponsorship was approximately half of that seen in industry-sponsored studies. The results suggest that the cost of consent document translation in trials not sponsored by industry could be a potentially modifiable barrier to the inclusion of patients with limited English proficiency.
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Background: Patients (pts) from historically underrepresented groups often have limited English proficiency (LEP). One challenge specific to obtaining consent from these pts to participate in ...clinical trials is the need for translated CDs. CD translation leads to enrollment delays and increases costs to study sponsors. We hypothesized that NISS, for which the principal investigator pays translation costs, would consent proportionately fewer pts with a primary language other than English and pts with LEP compared to industry sponsored studies (ISS). Methods: Pts’ primary language and English proficiency were assessed for all 12,082 consent events with appropriate available data at the Jonsson Comprehensive Cancer Center from 2013 to 2018. Pts with LEP were pts (or parent/guardian for pediatric pts) who had a primary language other than English, and the electronic health record indicated that the pt required a translator within 6 months of the consent date. CD language was documented per chart review when available, and when not, languages of available IRB-approved CDs were evaluated. The proportion of consent events for pts with a primary language other than English and with LEP were compared between NISS and ISS using generalized estimating equations, and the odds of signing CDs in the pts primary language were evaluated by multivariable analyses. Discrepant CD language data was evaluated by McNemar’s test. All analyses were performed using SAS 9 (SAS Institute, Cary, NC, USA). Results: Pts with a primary language other than English represented 8.1% of consent events in ISS vs 4.4% in NISS (p<0.001) and 5.5% vs 2.8% (p<0.001) for pts with LEP. Pts with a primary language other than English represented 4.5% vs 1.2% of consent events utilizing CDs in the pts’ primary language in ISS vs NISS (p<0.001) and 3.7% vs 0.9% (p<0.001) for pts with LEP. On multivariable analyses, the odds for pts with a primary language other than English of signing CDs to a NISS was 0.74 (CI, 0.63-0.94, p=0.005), and of signing CDs in their primary language was 0.38 (CI, 0.27-0.52, p<0.001) compared to pts whose primary language was English. The odds for pts with LEP of signing CD to a NISS was 0.74 (CI, 0.58-0.95, p=0.02), and signing CDs in their primary language was 0.35 (CI, 0.25-0.50, p<0.001) compared to pts whose primary language was English. Of 52 pts who signed CDs for both ≥1 NISS and ≥1 ISS, 18 signed in discrepant languages, with 16 of those 18 signing translated CDs for the ISS but not the NISS (p=0.002). Conclusions: Although the role of cost as an effect driver cannot be proven in a retrospective analysis, consistent with our hypothesis, the proportion of consent events utilizing appropriately translated CDs for pts with a primary language other than English and pts LEP was lower in NISS vs ISS, driven by lower odds of signing CDs and lower frequency of signing translated CDs. Approaches that reduce translation costs for investigators should be investigated.
Phase I studies of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin previously showed signs of activity coupled with 5-fold decreased anthracycline toxicity in chemotherapy-refractory ...patients. Here we report phase II studies using a similar material (FCE28068) in patients with breast (n=17), non-small cell lung (NSCLC, n=29) and colorectal (n=16) cancer. Up to 8 courses of PK1 (280 mg/m(2) doxorubicin-equivalent) were given i.v., together with 123I-labelled imaging analogue. Toxicities were tolerable, with grade 3 neutropenia more prominent in patients with breast cancer (4/17, 23.5% compared with 5/62, 8.1% overall). Of 14 evaluable patients with breast cancer 3 had partial responses (PR), all anthracycline-naïve patients. In 26 evaluable patients with NSCLC, 3 chemotherapy-naïve patients had PR. In contrast, none of the 16 evaluable patients with colorectal cancer responded. Imaging of 16 patients (5 with breast cancer, 6 NSCLC, 5 colorectal cancer) showed obvious tumour accumulation in 2 metastatic breast cancers, although unfortunately no images were obtained from patients who responded. These results show 6/62 PR with limited side effects, supporting the concept that polymer-bound therapeutics can have modified and improved anticancer activities and suggesting the approach should be explored further for breast cancer and NSCLC.
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Background: Racial/ethnic minority patients (pts) are underrepresented in cancer clinical trials. Challenges specific to LEPPs include the need for translated CDs, which can cause research ...delays and add cost. While most enrollment barriers are similar between industry sponsored studies (ISS) and NISS, costs of CD translation are typically covered by the sponsor in ISS. NISS often have limited, or no funds allocated for CD translation. Although it is required that LEPPs sign translated CDs, we hypothesized that investigators on NISS would find ways to avoid incurring the cost of CD translation. Methods: All pts who consented to studies at the UCLA Jonsson Comprehensive Cancer Center from 2013-2018 were included. Electronic health record data was reviewed. Adult LEPPs had a primary language other than English and their chart either flagged them as needing an interpreter or the pt used an interpreter in their care 6 months before or after the consent date. For pediatric patients, regardless of the pts primary language, LEPPs had a guardian who needed an interpreter within 6 months of the consent date. CD language was documented when available by chart review, but when not, we evaluated all IRB-approved CDs for the corresponding study and assumed that the pt signed appropriately translated CDs if available at the time of consent or within the following month. Chi square tests were used to compare the proportion of LEPPs who consented to NISS vs ISS and the proportion of LEPPs who consented with CDs not in their primary language. All analyses were performed using JMP, Version 16. SAS Institute Inc., Cary, NC, 19892021. Results: Although we do not have access to data on to whom consents were offered, of the 12202 consenting events during the study period, the proportion of consenting events for LEPPs was 2.7% in NISS vs 5.4% for ISS (p < 0.01). This difference did not appear to be driven by study type, as results were similar when only consenting events for interventional studies (n = 9886) were considered, with LEPPs representing 2.4% in NISS vs 5.5% in ISS (p < 0.01). Among LEPPs, 67.2% of participants who consented to NISS consented with CDs in a language other than their primary language vs 32.2% in ISS (p < 0.01). LEPPs who consented with language appropriate CDs represented 0.9% of those consenting to NISS vs 3.7% for ISS (p < 0.01). Conclusions: LEPPs consented less frequently to NISS compared to ISS, and when they did consent to NISS, the CDs were usually not translated into the pts primary language. We posit that the cost of translating CD discourages investigators from consenting LEPPs to NISS. Approaches that reduce or eliminate translation costs should increase the availability of translated CDs, potentially increasing enrollment of LEPPs to NISS while ensuring that they are fully informed about the purpose, procedures, and risks involved in these trials.
The need for patient-centered care has become a focal point of healthcare improvement initiatives. Shared decision making—in which patients and clinicians communicate about various treatment options ...and goals and patient input is considered when making treatment decisions—has been associated with improved health and quality of life. A method of treatment evaluation allowing incorporation of patient-specific goals and perspectives is of increasing interest to healthcare providers, payers, and patients. An approach that allows incorporation of shared goal setting is possible via use of an instrument called the Goal Attainment Scale (GAS). This scale provides the structure for measuring progress toward treatment goals set through patient–clinician collaboration. The goal attainment approach has been used as a primary outcomes measure in numerous studies but not in major depressive disorder (MDD). As MDD is a complex, multidimensional disorder affecting each patient differently, the use of GAS methodology is a relevant framework for setting personalized meaningful treatment goals. Initial research into the feasibility of using the GAS in MDD (GAS-D) to measure patient-centric outcomes that may be neglected when more traditional scales are used has been encouraging. The objective of this Commentary is to provide background and rationale for implementation of the GAS-D in clinical practice.
Funding
Takeda Pharmaceutical Company, Ltd., and Lundbeck LLC.
Major depressive disorder (MDD) is a highly prevalent disorder, frequently diagnosed and treated in a primary care setting; however, little information is available about the treatment ...decision-making process between MDD patients and their providers. A shared decision-making and goal attainment approach to establishing and tracking progress toward treatment goals that are meaningful to individual patients is explored in this survey study. In addition, information about patient perspectives on setting treatment goals, medication selection/switching, and engaging patients with their health care professionals was also collected and evaluated.
A 50-question online survey was administered to members of the PatientsLikeMe community who indicated an MDD diagnosis and a switch in antidepressant medications within the past 2 years. Follow-up interviews were also conducted with a small subset of these participants.
Of the 200 participants who completed the survey, 42% reported currently having goals for MDD treatment. These goals were typically in the areas of physical health (62.7%), cognitive functioning (60.2%), and social aspects of life (57.8%). A majority of survey participants (61%) believed the goal attainment approach would be helpful to set and evaluate treatment goals.
The data provide important insights into patient perspectives on the development of formal treatment plans and goals for MDD. In addition, the data also support the use of a patient-centric approach to shared decision-making by using a goal attainment scale to establish and track progress toward treatment goals that are meaningful to MDD patients in real-world clinical practice. The results of this study can be used to inform best practices in patient-clinician communication when developing an MDD treatment plan and goals.
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