An automated flowchart for the Modified Rankin Scale assessment: A multicenter inter-rater agreement analysis.

BACKGROUND AND OBJECTIVE: The Modified Rankin Scale (mRS) is a widely adopted scale for assessing stroke recovery. Despite limitations, the mRS has been adopted as primary outcome in most recent clinical acute stroke trials. Designed to be used by multidisciplinary clinical staff, the congruency of this scale is not consistent, which may lead to mistakes in clinical or research application. We aimed to develop and validate an interactive and automated digital tool for assessing the mRS-the iRankin. METHODS: A panel of five board-certified and mRS-trained vascular neurologists developed an automated flowchart based on current mRS literature. Two international experts were consulted on content and provided feedback on the prototype platform. The platform contained five vignettes and five real video cases, representing mRS grades 0-5. For validation, we invited neurological staff from six comprehensive stroke centers to complete an online assessment. Participants were randomized into two equal groups usual practice versus iRankin. The participants were randomly allocated in pairs for the congruency analysis. Weighted kappa (kw) and proportions were used to describe agreement. RESULTS: A total of 59 professionals completed the assessment. The kw was dramatically improved among nurses, 0.76 (95% confidence interval (CI) = 0.55-0.97) × 0.30 (0.07-0.67), and among vascular neurologists, 0.87 (0.72-1) × 0.82 (0.66-0.98). In the accuracy analysis, after the standard mRS values for the vignettes and videos were determined by a panel of experts, and considering each correct answer as equivalent to 1 point on a scale of 0-15, it revealed a higher mean of 10.6 (±2.2) in the iRankin group and 8.2 (±2.3) points in the control group (p = 0.02). In an adjusted analysis, the iRankin adoption was independently associated with the score of congruencies between reported and standard scores (beta coefficient = 2.22, 95% CI = 0.64-3.81, p = 0.007). CONCLUSION: The iRankin adoption led to a substantial or near-perfect agreement in all analyzed professional categories. More trials are needed to generalize our findings. Our user-friendly and free platform is available at https://www.irankinscale.com/.

Bromelain regulates TRP channels to induce orofacial nociception relief in adult zebrafish.

Bromelain, the main protease enzyme found in the pineapple plant (Ananas comosus), has had its antinociceptive effect previously demonstrated. This investigation aimed to appraise the role of TRP (Transient Receptor Potential) channels in the nociception-relieving effects of bromelain in the orofacial region of adult zebrafish. The animals were pretreated with bromelain (3.0, 10.0 or 30.0 mg/mL; gavage) and submitted to open field and acute orofacial (capsaicin - TRPV1 agonist, cinnamaldehyde - TRPA1 agonist or menthol - TRPM8 agonist) nociception tests. The investigation also explored the contribution of central afferent C-fibers. Naive groups were included for comparison. Bromelain did not independently affect the zebrafish movement patterns. However, bromelain decreased the nociceptive responses elicited by all three TRP channel activators. Capsazepine (TRPV1 inhibitor) and AMTB (TRPM8 inhibitor), but not HC-030031 (TRPA1 inhibitor), prevented the antinociceptive effect of bromelain. Moreover, capsaicin-induced desensitization effectively nullified the antinociceptive effect of bromelain. Collectively, these findings corroborate the therapeutic relevance of bromelain as a suppressor of orofacial nociception, which seems to be intricately connected to the modulation of TRP channels.

Cognitive Control as a 5-HT1A-Based Domain That Is Disrupted in Major Depressive Disorder.

Heterogeneity within Major Depressive Disorder (MDD) has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT1A [(11C)WAY-100635], as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT1A binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT1A BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets.

Gastroprotective effect of a flavone from Lonchocarpus araripensis Benth. (Leguminosae) and the possible mechanism.

The gastroprotective effect of DDF (3,6-dimethoxy-6'', 6''-dimethyl-[2'', 3'' : 7,8]-chromeneflavone) from Lonchocarpus araripensis Benth. (Leguminosae) on gastric damage induced by absolute ethanol (96%, 0.2 mL/mouse) and indometacin (30 mg kg(-1), p.o.) in mice was investigated. Intraperitoneally administered DDF at dose levels of 50, 100 and 200 mg kg(-1) markedly reduced the gastric lesions in the ethanol model by 62, 72 and 96%, and in the indometacin model by 34, 70 and 75%, respectively, as compared with misoprostol (50 microg kg(-1), p.o.), the reference compound that caused lesion suppression by 67% in ethanol model and by 72% against indometacin-induced ulceration. The ED50 of DDF in reducing gastric lesions induced by ethanol and indometacin (dose of the DDF that reduced the gastric lesion area by 50% in relation to the control value) was 50.87 and 61.56 mg kg(-1), respectively. Mechanistic studies were carried out at 100 mg kg(-1) DDF using the ethanol model. Compared with N-acetylcysteine (750 mg kg(-1), p.o.), a donor of sulfhydryls, DDF only partially replenished the ethanol-induced depletion of gastric mucosal NP-SH. Pretreatment with TRPV1 antagonist capsazepine (5 mg kg(-1), i.p.) or the non-selective cyclooxygenase inhibitor indometacin (10 mg kg(-1), p.o.) effectively blocked the gastroprotective effect of DDF (100 mg kg(-1)) against ethanol damage. Furthermore, the effect of DDF was significantly reduced in mice pretreated with L-NAME, or glibenclamide, the respective inhibitors of nitric oxide synthase and K+ ATP channel activation. These data provide evidence to show that DDF affords gastroprotection against gastric damage induced by ethanol and indometacin by different and complementary mechanisms, which include involvement of endogenous prostaglandins, nitric oxide release, the activation of TRPV1 receptor or K+ ATP channels, besides a sparing effect on NP-SH reserve.

Sex differences in ACTH pulsatility following metyrapone blockade in patients with major depression.

Numerous studies suggest that increased central drive to the hypothalamic-pituitary adrenal (HPA) axis occurs in patients with major depression. To determine if increased central drive occurs throughout the 24 h, we evaluated ACTH secretion under metyrapone blockade of cortisol production. We collected blood every 10 min for measurement of ACTH and data were analyzed for ACTH pulsatility using the pulse detection algorithm deconvolution. We studied 28 patients with major depression and 28 age and sex-matched control subjects, of which 9 pairs were men and 19 pairs were women. We found a significant group x sex interaction with number of ACTH pulses (p=0.04); depressed men showed more ACTH pulses over 24h than matched control men (p=0.02). There was also a significant sex difference in AUC pulses with men showing a smaller AUC ACTH than women. Previous analyses of these data with RM-ANOVA showed a smaller ACTH response in depressed men compared to control men. These data suggest that pulsatility and mean ACTH levels are examining different aspects of HPA axis function, and that the types of HPA axis dysregulation in depression may differ between men and women.

Sex differences in the ACTH response to 24H metyrapone in depression.

Increased hypothalamic-pituitary-adrenal (HPA) axis activation has been observed in major depression. Increased corticotropin-releasing hormone (CRH) is hypothesized to drive corticotropin (ACTH) secretion leading to increased ACTH and cortisol secretion throughout 24H. Contradicting data exist as to whether the increased drive is present throughout the day or is restricted to the late afternoon and evening. To determine if increased HPA axis activation occurs during a specific circadian phase or is found throughout the 24H, we studied 26 healthy drug-free depressed patients and 26 healthy age- and sex-matched control subjects under metyrapone inhibition of cortisol synthesis for 24H beginning at 4 PM. Blood was drawn every 10 min for 24H and assayed for ACTH and cortisol. Gender differences in response to metyrapone were seen in both patients and controls. Depressed women demonstrated increased ACTH concentrations between 4 PM and 10 PM compared to control women. Maximal ACTH response over time was identical between depressed and control women. Depressed men demonstrated significantly decreased ACTH secretion between 4 and 10 PM as well as decreased maximal ACTH response compared to control men or depressed women. These data support an increased evening CRH drive in depressed women, but overall decreased CRH drive in depressed men.

Interface of physical and emotional stress regulation through the endogenous opioid system and mu-opioid receptors.

Unraveling the pathways and neurobiological mechanisms that underlie the regulation of physical and emotional stress responses in humans is of critical importance to understand vulnerability and resiliency factors to the development of a number of complex physical and psychopathological states. Dysregulation of central stress response circuits have been implicated in the establishment of conditions as diverse as persistent pain, mood and personality disorders and substance abuse and dependence. The present review examines the contribution of the endogenous opioid system and mu-opioid receptors to the modulation and adaptation of the organism to challenges, such as sustained pain and negative emotional states, which threaten its internal homeostasis. Data accumulated in animal models, and more recently in humans, point to this neurotransmitter system as a critical modulator of the transition from acute (warning signals) to sustained (stressor) environmental adversity. The existence of pathways and regulatory mechanisms common to the regulation of both physical and emotional states transcend classical categorical disease classifications, and point to the need to utilize dimensional, "symptom"-related approximations to their study. Possible future areas of study at the interface of "mind" (cognitive-emotional) and "body" (physical) functions are delineated in this context.

Auditoria farmacêutica: estudo de caso em uma operadora de planos de saúde de Fortaleza (Brasil) / Pharmaceutical audit: a case study in a health insurance company in Fortaleza (Brazil)

O objetivo do estudo foi descrever a implantação, estruturação e desenvolvimento da prática de auditoria farmacêutica em uma operadora de planos de saúde de Fortaleza (OPS). Trata-se de um estudo descritivo do tipo estudo de caso, em que a unidade de análise foi uma OPS localizada em Fortaleza, capital do estado do Ceará (Brasil). Foram coletados e analisados dados qualitativos e quantitativos que corresponderam ao período de 2007 a 2010. Para a implantação da área de auditoria farmacêutica foi utilizada como primeira estratégia sua formalização na Diretoria de Recursos Médicos Hospitalares e na estrutura organizacional da OPS em janeiro de 2007. Com o reconhecimento do trabalho desenvolvido pela área, a equipe chegou em 2010 com dois farmacêuticos, dois assistentes de farmácia e cinco estagiários. O desenvolvimento da prática de auditoria farmacêutica resultou na exigência de pareceres técnicos para inclusão de medicamentos em tabela definida pela OPS e de solicitação para medicamentos de alto custo e de reserva terapêutica. A intervenção do farmacêutico, em seis meses de experiência, junto a pacientes em uso de antimicrobianos mostrou uma economia de R$ 279.153,80. A gestão de quimioterápicos resultou em uma economia total de R$ 2.502.278,31 para a OPS em 2009. Embora a auditoria farmacêutica envolva uma discussão recente, é preciso desde já, que aspectos relacionados à sua implantação, estruturação e desenvolvimento sejam apoiados, uma vez que essa prática ajuda na descrição e análise de elementos assistenciais e de gestão que envolve pacientes em tratamento farmacológico.

The purpose of this study was to describe the implantation, organization and development of pharmaceutical audit in a health insurance provider (HIP) in northeast Brazil. This is a descriptive case study in which the unit of analysis was an HIP located n Fortaleza, capital of Ceará State. Qualitative and quantitative data covering the period from 2007 and 2010 were collected and analyzed. In order to create the pharmaceutical auditing team, the first strategy used was to set up a section in the Hospital Medical Resources Directorate and in the managerial structure of the HIP, in January 2007. With the recognition of the work developed by the section, the team was amplified in 2010 with the arrival of two pharmacists, two pharmacy assistants and five trainees. The development of the practical aspects of pharmaceutical auditing revealed a need for technical opinions on the inclusion of medicines in the table defined by the HIP and requests for authorization in the case of high-cost medicines and those used in reserved therapy. The pharmacist’s intervention, over a six-month period, in the treatment of patients with antibiotics, yielded savings of R$ 279,153.80. The management of chemotherapy resulted in total savings of R$ 2,502,278.31 for the HIP in 2009. Although pharmaceutical auditing has only come out in recent discussions, there is an immediate need to support actions related to its implantation, organization and development, since this practice helps in describing and analyzing the healthcare and management features that involve patients under pharmacological treatment.

Efficacy of milnacipran in patients with fibromyalgia.

OBJECTIVE: Fibromyalgia (FM) is a common musculoskeletal condition characterized by widespread pain, tenderness, and a variety of other somatic symptoms. Current treatments are modestly effective. Arguably, the best studied and most effective compounds are tricyclic antidepressants (TCA). Milnacipran, a nontricyclic compound that inhibits the reuptake of both serotonin and norepinephrine, may provide many of the beneficial effects of TCA with a superior side effect profile. METHODS: One hundred twenty-five patients with FM were randomly assigned in a 3:3:2 ratio to receive milnacipran twice daily, milnacipran once daily, or placebo for 3 months in a double-blind dose-escalation trial; 92% of twice-daily and 81% of once-daily participants achieved dose escalation to the target milnacipran dose of 200 mg. RESULTS: The primary endpoint was reduction of pain. Both the once- and twice-daily groups showed statistically significant improvements in pain, as well as improvements in global well being, fatigue, and other domains. Response rates for patients receiving milnacipran were equal in patients with and without comorbid depression, but placebo response rates were considerably higher in depressed patients, leading to significantly greater overall efficacy in the nondepressed group. CONCLUSION: In this Phase II study, milnacipran led to statistically significant improvements in pain and other symptoms of FM. The effect sizes were equal to those previously found with TCA, and the drug was generally well tolerated.