Dyskinesia and Pain in Advanced Parkinson's Disease: Post Hoc Analysis from the Phase 3b, Open-Label, Randomized DYSCOVER Study.

INTRODUCTION: The DYSCOVER study was a phase 3b, open-label, randomized trial (NCT02799381) that evaluated levodopa-carbidopa intestinal gel (LCIG) versus optimized medical treatment (OMT) in patients with Parkinson's disease (PD) and a high burden of dyskinesia at baseline (defined as Unified Dyskinesia Rating Scale [UDysRS] total score ≥ 30). At week 12, patients receiving LCIG versus OMT experienced significant improvements in dyskinesia, pain, and health-related outcomes. The objective of this analysis was to examine correlations between dyskinesia, pain, and health-related outcomes in PD. METHODS: This post hoc analysis assessed correlations between UDysRS, King's Parkinson's Disease Pain Scale (KPPS), 8-item Parkinson's Disease Questionnaire (PDQ-8), Unified Parkinson's Disease Rating Scale part II, Clinical Global Impression of Severity (CGI-S) or Change (CGI-C), and "On" time without troublesome dyskinesia at baseline and after 12 weeks of LCIG or OMT. Correlations were assessed by Pearson correlation coefficients (categorization: weak, r = 0.20-0.39; moderate, r = 0.40-0.59; strong, r ≥ 0.60). RESULTS: Among 61 patients, moderate-to-strong positive and significant correlations were observed between UDysRS and KPPS scores (baseline, r = 0.47; week 12 change from baseline [CFB], r = 0.63; all p < 0.001). UDysRS and KPPS scores had moderate-to-strong positive and highly significant correlations with PDQ-8 scores (baseline, r = 0.45 and 0.46, respectively; CFB, r = 0.54 and 0.64, respectively; all p < 0.001). Moderate positive and significant correlations were observed between UDysRS and CGI-S/CGI-C scores (baseline, r = 0.41; CFB, r = 0.47; all p < 0.001). CONCLUSIONS: In patients with high dyskinesia burden, positive correlations were observed between dyskinesia, pain, and health-related quality of life (HRQoL) at baseline. Improvements in dyskinesia and pain were associated with improvements in HRQoL, demonstrating the clinical burden of troublesome dyskinesia. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov identifier NCT02799381.

Continuous subcutaneous foslevodopa/foscarbidopa infusion for the treatment of motor fluctuations in Parkinson's disease: Considerations for initiation and maintenance.

Background: As Parkinson's disease (PD) advances, management is challenged by an increasingly variable and inconsistent response to oral dopaminergic therapy, requiring special considerations by the provider. Continuous 24 h/day subcutaneous infusion of foslevodopa/foscarbidopa (LDp/CDp) provides steady dopaminergic stimulation that can reduce symptom fluctuation. Objective: Our aim is to review the initiation, optimization, and maintenance of LDp/CDp therapy, identify possible challenges, and share potential mitigations. Methods: Review available LDp/CDp clinical trial data for practical considerations regarding the management of patients during LDp/CDp therapy initiation, optimization, and maintenance based on investigator clinical trial experience. Results: LDp/CDp initiation, optimization, and maintenance can be done without hospitalization in the clinic setting. Continuous 24 h/day LDp/CDp infusion can offer more precise symptom control than oral medications, showing improvements in motor fluctuations during both daytime and nighttime hours. Challenges include infusion-site adverse events for which early detection and prompt management may be required, as well as systemic adverse events (eg, hallucinations) that may require adjustment of the infusion rate or other interventions. A learning curve should be anticipated with initiation of therapy, and expectation setting with patients and care partners is key to successful initiation and maintenance of therapy. Conclusion: Continuous subcutaneous infusion of LDp/CDp represents a promising therapeutic option for individuals with PD. Individualized dose optimization during both daytime and nighttime hours, coupled with patient education, and early recognition of certain adverse events (plus their appropriate management) are required for the success of this minimally invasive and highly efficacious therapy.

Continuous Subcutaneous Foslevodopa/Foscarbidopa in Parkinson's Disease: Safety and Efficacy Results From a 12-Month, Single-Arm, Open-Label, Phase 3 Study.

INTRODUCTION: Foslevodopa/foscarbidopa, a soluble formulation of levodopa/carbidopa (LD/CD) prodrugs for the treatment of Parkinson's disease (PD), is administered as a 24-hour/day continuous subcutaneous infusion (CSCI) with a single infusion site. The efficacy and safety of foslevodopa/foscarbidopa versus oral immediate-release LD/CD was previously demonstrated in patients with PD in a 12-week, randomized, double-blind, phase 3 trial (NCT04380142). We report the results of a separate 52-week, open-label, phase 3 registrational trial (NCT03781167) that evaluated the safety/tolerability and efficacy of 24-hour/day foslevodopa/foscarbidopa CSCI in patients with advanced PD. METHODS: Male and female patients with levodopa-responsive PD and ≥ 2.5 hours of "Off" time/day received 24-hour/day foslevodopa/foscarbidopa CSCI at individually optimized therapeutic doses (approximately 700-4250 mg of LD per 24 hours) for 52 weeks. The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in normalized "Off" and "On" time, percentage of patients reporting morning akinesia, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Sleep Scale-2 (PDSS-2), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQol 5-dimension questionnaire (EQ-5D-5L). RESULTS: Of 244 enrolled patients, 107 discontinued, and 137 completed treatment. Infusion site events were the most common adverse events (AEs). AEs were mostly nonserious (25.8% of patients reported serious AEs) and mild/moderate in severity. At week 52, "On" time without troublesome dyskinesia and "Off" time were improved from baseline (mean [standard deviation (SD)] change in normalized "On" time without troublesome dyskinesia, 3.8 [3.3] hours; normalized "Off" time, -3.5 [3.1] hours). The percentage of patients experiencing morning akinesia dropped from 77.7% at baseline to 27.8% at week 52. Sleep quality (PDSS-2) and quality of life (PDQ-39 and EQ-5D-5L) also improved. CONCLUSION: Foslevodopa/foscarbidopa has the potential to provide a safe and efficacious, individualized, 24-hour/day, nonsurgical alternative for patients with PD. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03781167.

Staging Parkinson's Disease According to the MNCD (Motor/Non-motor/Cognition/Dependency) Classification Correlates with Disease Severity and Quality of Life.

BACKGROUND: Recently, a novel simple classification called MNCD, based on 4 axes (Motor; Non-motor; Cognition; Dependency) and 5 stages, has been proposed to classify Parkinson's disease (PD). OBJECTIVE: Our aim was to apply the MNCD classification in a cohort of PD patients for the first time and also to analyze the correlation with quality of life (QoL) and disease severity. METHODS: Data from the baseline visit of PD patients recruited from 35 centers in Spain from the COPPADIS cohort fromJanuary 2016 to November 2017 were used to apply the MNCD classification. Three instruments were used to assess QoL:1) the 39-item Parkinson's disease Questionnaire [PDQ-39]); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8). RESULTS: Four hundred and thirty-nine PD patients (62.05±7.84 years old; 59% males) were included. MNCD stage was:stage 1, 8.4% (N = 37); stage 2, 62% (N = 272); stage 3, 28.2% (N = 124); stage 4-5, 1.4% (N = 6). A more advancedMNCD stage was associated with a higher score on the PDQ39SI (p < 0.0001) and a lower score on the PQ-10 (p< 0.0001) and EUROHIS-QOL8 (p< 0.0001). In many other aspects of the disease, such as disease duration, levodopa equivalent daily dose, motor symptoms, non-motor symptoms, and autonomy for activities of daily living, an association between the stage and severity was observed, with data indicating a progressive worsening related to disease progression throughout the proposed stages. CONCLUSION: Staging PD according to the MNCD classification correlated with QoL and disease severity. The MNCD could be a proper tool to monitor the progression of PD.

Levodopa-Carbidopa Intestinal Gel Reduces Dyskinesia in Parkinson's Disease in a Randomized Trial.

BACKGROUND: There are limited data regarding the effectiveness of levodopa-carbidopa intestinal gel (LCIG) for dyskinesia. OBJECTIVE: Compare the effectiveness of LCIG versus oral optimized medical treatment (OMT) for dyskinesia in patients with advanced Parkinson's disease (PD) using the Unified Dyskinesia Rating Scale (UDysRS). METHODS: This phase 3b, open-label, multicenter, 12-week, interventional study (NCT02799381) randomized 63 LCIG naïve patients with advanced PD (UDysRS ≥30) to LCIG (N = 30) or OMT (N = 33) treatment. Dyskinesia impact was assessed at baseline through week 12 using the UDysRS. PD-related motor and non-motor symptoms, and quality of life (QoL) were also assessed. RESULTS: Dyskinesias measured by UDysRS were significantly reduced in the LCIG group (n = 24; -17.37 ± 2.79) compared with the OMT group (n = 26; -2.33 ± 2.56) after 12 weeks (-15.05 ± 3.20; 95% CI, -21.47 to -8.63; P < 0.0001). At week 12, LCIG versus OMT also demonstrated significant improvements in "On" time without troublesome dyskinesia (P = 0.0001), QoL (P < 0.0001), global impression of change (P < 0.0001), activities of daily living (P = 0.0006), and Unified Parkinson's Disease Rating Scale (UPDRS) Part III (P = 0.0762). Treatment-emergent adverse events were reported in 27 (44.3%) patients (LCIG, 18 [64.3%]; OMT, 9 [27.3%]). Serious adverse events occurred in 2 (7.1%) LCIG-treated patients. CONCLUSIONS: LCIG significantly reduced dyskinesia compared with OMT. LCIG showed efficacy for treatment of troublesome dyskinesia in patients with advanced PD while demonstrating benefits in both motor and non-motor symptoms and QoL. © 2021 AbbVie Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

COVID-19-associated encephalitis successfully treated with combination therapy.

BACKGROUND: Acute encephalitis can occur in different viral diseases due to infection of the brain or by an immune mechanism. Severe novel coronavirus disease 2019 (COVID-19) is associated with a major immune inflammatory response with cytokine upregulation including interleukin 6 (IL-6). We report a case presenting with acute encephalitis that was diagnosed as having severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection with hyperinflammatory systemic response and recovered after therapy with immunoglobulins and cytokine blockade. CASE REPORT: A 39-year-old-man was brought to the Emergency Department with drowsiness, mental disorientation, intermittent fever and headache. A brain magnetic resonance imaging showed extensive involvement of the brain including cortical and subcortical right frontal regions, right thalamus, bilateral temporal lobes and cerebral peduncles, with no leptomeningeal enhancement. Cerebrospinal fluid (CSF) showed a leukocyte count of 20/µL (90% lymphocytes), protein level of 198 mg/dL, and glucose of 48 mg/dL. SARS-CoV-2 was detected in nasopharyngeal swabs by reverse-transcriptase-PCR (RT-PCR) but it was negative in the CSF. Remarkable laboratory findings in blood tests included low lymphocyte count and elevated ferritin, IL-6 and D-dimer. He had a complicated clinical course requiring mechanical ventilation. Intravenous immunoglobulins and cytokine blockade with tocilizumab, an IL-6 receptor antagonist, were added considering acute demyelinating encephalomyelitis. The patient made a full recovery, suggesting that it could have been related to host inflammatory response. CONCLUSION: This case report indicates that COVID-19 may present as an encephalitis syndrome mimicking acute demyelinating encephalomyelitis that could be amenable to therapeutic modulation.

Proteomic fingerprinting of Neotropical hard tick species (Acari: Ixodidae) using a self-curated mass spectra reference library.

Matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry is an analytical method that detects macromolecules that can be used for proteomic fingerprinting and taxonomic identification in arthropods. The conventional MALDI approach uses fresh laboratory-reared arthropod specimens to build a reference mass spectra library with high-quality standards required to achieve reliable identification. However, this may not be possible to accomplish in some arthropod groups that are difficult to rear under laboratory conditions, or for which only alcohol preserved samples are available. Here, we generated MALDI mass spectra of highly abundant proteins from the legs of 18 Neotropical species of adult field-collected hard ticks, several of which had not been analyzed by mass spectrometry before. We then used their mass spectra as fingerprints to identify each tick species by applying machine learning and pattern recognition algorithms that combined unsupervised and supervised clustering approaches. Both Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA) classification algorithms were able to identify spectra from different tick species, with LDA achieving the best performance when applied to field-collected specimens that did have an existing entry in a reference library of arthropod protein spectra. These findings contribute to the growing literature that ascertains mass spectrometry as a rapid and effective method to complement other well-established techniques for taxonomic identification of disease vectors, which is the first step to predict and manage arthropod-borne pathogens.

Molecular Ecological Insights into Neotropical Bird-Tick Interactions.

In the tropics, ticks parasitize many classes of vertebrate hosts. However, because many tropical tick species are only identifiable in the adult stage, and these adults usually parasitize mammals, most attention on the ecology of tick-host interactions has focused on mammalian hosts. In contrast, immature Neotropical ticks are often found on wild birds, yet difficulties in identifying immatures hinder studies of birds' role in tropical tick ecology and tick-borne disease transmission. In Panama, we found immature ticks on 227 out of 3,498 individually-sampled birds representing 93 host species (24% of the bird species sampled, and 13% of the Panamanian land bird fauna). Tick parasitism rates did not vary with rainfall or temperature, but did vary significantly with several host ecological traits. Likewise, Neotropical-Nearctic migratory birds were significantly less likely to be infested than resident species. Using a molecular library developed from morphologically-identified adult ticks specifically for this study, we identified eleven tick species parasitizing birds, indicating that a substantial portion of the Panamanian avian species pool is parasitized by a diversity of tick species. Tick species that most commonly parasitized birds had the widest diversity of avian hosts, suggesting that immature tick species are opportunistic bird parasites. Although certain avian ecological traits are positively associated with parasitism, we found no evidence that individual tick species show specificity to particular avian host ecological traits. Finally, our data suggest that the four principal vectors of Rocky Mountain Spotted Fever in the Neotropics rarely, if ever, parasitize Panamanian birds. However, other tick species that harbor newly-discovered rickettsial parasites of unknown pathogenicity are frequently found on these birds. Given our discovery of broad interaction between Panamanian tick and avian biodiversity, future work on tick ecology and the dynamics of emerging tropical tick-borne pathogens should explicitly consider wild bird as hosts.

Fingolimod: efectividad y seguridad en la práctica clínica habitual. Estudio observacional, retrospectivo y multicéntrico en la provincia de Alicante / Fingolimod: effectiveness and safety in routine clinical practice. An observational, retrospective, multi-centre study in the province of Alicante

INTRODUCCIÓN: Los estudios postautorización son importantes para confirmar si los resultados de los ensayos clínicos se reproducen en la práctica clínica habitual. OBJETIVO: Evaluar la efectividad y seguridad del fingolimod en la práctica clínica en la provincia de Alicante. PACIENTES Y MÉTODOS: Estudio multicéntrico retrospectivo de pacientes con esclerosis múltiple remitente tratados con fingolimod. Se recogen las características demográficas, clínicas y farmacológicas. Se describe la efectividad del fármaco -tasa anualizada de brotes (TAB) y porcentaje de pacientes libres de brotes- al año y a los dos años de tratamiento en relación con el año previo y datos de efectos secundarios. RESULTADOS: Se incluyó a 89 pacientes. El tratamiento previo fue inmunomodulador (interferón beta o acetato de glatiramero) en 54 pacientes y natalizumab en 32. Cincuenta pacientes cambiaron por fracaso con el inmunomodulador y 31 por serología positiva del virus JC (VJC+). La TAB global disminuyó el 67,3% el primer año (p < 0,0001) y el 84,1% el segundo (p = 0,0078). Disminuyó en los pacientes con fracaso del inmunomodulador (el 85,6% el primer año, p < 0,0001; el 88,9% el segundo año, p = 0,0039) y aumentó de forma no significativa en los pacientes VJC+ en el primer año. El porcentaje de pacientes libres de brotes en la población global aumentó del 32,6 al 68,1% en el primer año (p < 0,0019) y al 82,6% en el segundo (p = 0,0215). Este aumento no se observó en los pacientes VJC+. Trece pacientes tuvieron efectos secundarios, que obligaron a la retirada del fármaco en dos de ellos. CONCLUSIÓN: En la práctica clínica de la provincia de Alicante, el fingolimod mostró una efectividad y una seguridad ligeramente superiores a las de los ensayos clínicos

INTRODUCTION: Post-authorisation studies are important to confirm whether the outcomes of clinical trials are reproduced in usual clinical practice. AIMS: To evaluate the effectiveness and safety of fingolimod in clinical practice in the province of Alicante. PATIENTS AND METHODS: A retrospective multi-centre study was conducted with remitting multiple sclerosis patients treated with fingolimod. Demographic, clinical and pharmacological data were collected. We report on the effectiveness of the drug -annualised relapse rate (ARR) and percentage of patients free from attacks- at one and at two years after treatment in relation to the previous year, and data concerning side effects are also provided. RESULTS: The sample consisted of 89 PATIENTS: Previous treatment was with immunomodulators (interferon beta or glatiramer acetate) in 54 patients and natalizumab in 32. Fifty patients changed due to failure with the immunomodulator and 31 owing to positive serology for JC virus (JCV+). Overall ARR decreased by 67.3% the first year (p < 0.0001) and by 84.1% the second (p = 0.0078). It diminished in patients with immunomodulator failure (85.6% the first year, p < 0.0001; 88.9% the second year, p = 0.0039) and increased in a non-significant manner in JCV+ patients in the first year. The percentage of patients free from relapses in the overall population increased from 32.6% to 68.1% in the first year (p < 0.0019) and to 82.6% in the second (p = 0.0215). This increase was not observed in JCV+ PATIENTS: Side effects were reported by 13 patients, which led to the drug being withdrawn in two of them. CONCLUSIONS: In clinical practice in the province of Alicante, levels of effectiveness and safety of fingolimod proved to be slightly higher than those found in clinical trials (AU)

Amblyomma tapirellum (Acari: Ixodidae) collected from tropical forest canopy.

Free-ranging ticks are widely known to be restricted to the ground level of vegetation. Here, we document the capture of the tick species Amblyomma tapirellum in light traps placed in the forest canopy of Barro Colorado Island, central Panama. A total of forty eight adults and three nymphs were removed from carbon dioxide-octenol baited CDC light traps suspended 20 meters above the ground during surveys for forest canopy mosquitoes. To our knowledge, this represents the first report of questing ticks from the canopy of tropical forests. Our finding suggests a novel ecological relationship between A. tapirellum and arboreal mammals, perhaps monkeys that come to the ground to drink or to feed on fallen fruits.

¿Quién controla las malformaciones arteriovenosas cerebrales no quirúrgicas en España? Réplica / No disponible

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¿Quién controla las malformaciones arteriovenosas cerebrales no quirúrgicas en España? / No disponible

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