Knowledge regarding the pathophysiological basis of Parkinson's disease (PD) has been greatly expanded over the past two decades, with extraordinary contributions from the field of genetics. However, genetic classifications became complex, difficult to follow, and at times misleading, by placing well‐established monogenic forms of the disease along with others associated with risk loci, often ill characterized. The present paper summarizes the genetic, clinical, and neuropathological findings of the currently described monogenic forms of PD and also approaches the progress made in determining genetic risk factors for PD. Furthermore, the text incorporates the data into a recently proposed classification system that will hopefully bring a “user‐friendly” approach to this issue. This paper also highlights a number of inconsistencies regarding classification of PD as a single, unique clinicopathological entity—in fact, in order to achieve the development of truly innovative therapies, PD should probably be regarded clinically as a “Parkinson's disease cluster”, instead of a single disease. In the future, we hope that an in‐depth and groundbreaking understanding of PD will allow the development of truly disease‐modifying therapies that will target the molecular processes responsible for the cascade of pathological events underlying each form of PD.

BackgroundMigraine and temporomandibular disorders (TMDs) are reported to be associated. However, there are no reports on the association among migraines, TMDs and changes in body posture. ObjectivesTo assess changes in body posture in women suffering migraines with or without TMD compared with a control group. MethodSixty-six women with a mean age of 18 to 45 years participated in this study. The groups were composed of 22 volunteers with migraine and TMD (MTMD), 22 volunteers with migraines without TMD (MG) and 22 women in the control group (CG). Static posture was assessed by photogrammetry, and 19 angles were measured. ResultsPostural asymmetry was observed in the face for 4 angles measured on the frontal plane in the MG group and for 4 angles of the trunk in the MG and MTMD groups with respect to CG. However, for comparisons between MTMD and CG, clinical relevance was identified for two angles of the sagittal plane (Cervical and Lumbar Lordosis, Effect Size - ES - moderate: 0.53 and 0.60). For comparisons between the MG and CG, the clinical relevance/potential was verified for three angles with moderate ES (ES>0.42). The clinical relevance when comparing MTMD and CG was identified for four angles of facial symmetry head inclination (ES>0.54) and for two angles between MG and CG (ES>0.48). Conclusion The results demonstrated the presence of postural changes compared with a control group in women with migraines with or without TMD, and there were similar clinically relevant postural changes among the patients with migraines with and without TMD.

The understanding of the association between salt intake and precancerous lesions may contribute to clarify the causal relation with gastric cancer. We systematically reviewed 17 articles addressing the association between dietary salt exposure and gastric intestinal metaplasia and conducted meta-analyses for quantitative synthesis (random effects model). Salt exposure was estimated assessing salted/salty food consumption, preference for salted/salty foods, use of table salt, or sodium urinary excretion. Heterogeneity was also large regarding food items evaluated, consumption categories, and data analysis. The combined odds ratio (OR) was 1.68 (95% confidence interval (CI) = 0.98-2.90; I(2) = 55.4%) for the association between salted/salty meat and intestinal metaplasia (4 studies) and the OR was 1.53 (95% CI = 0.72-3.24; I(2) = 76.8%) for salt preference. There was a positive, nonstatistically significant association between intestinal metaplasia and urinary sodium excretion. The heterogeneity of methodological options and results preclude quantitative synthesis or its proper interpretation, even if the available evidence may suggest a positive association between salt and intestinal metaplasia.

Background: Resistance to endocrine therapy remains a major clinical challenge with aberrant PI3K/ mTOR pathway activation being one of the main drivers. Randomised clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Vistusertib (AZD2014), a dual inhibitor of mTORC1 and mTORC2, has shown a broader range of activity in preclinical ER+ breast cancer models, showing superior activity to everolimus (EVE) both in hormone-sensitive and resistant models. The MANTA trial was desgined to evaluate the safety and efficacy of vistusertib (VIS) in combination with fulvestrant (FULV) relative to FULV alone or FULV + EVE. In addition to a continuous (cont) daily schedule of VIS, the study also explored an intermittent (int) schedule to assess the potential of short-term, maximum target inhibition. Methods: MANTA is an investigator-led, randomised, open-label phase II trial. Postmenopausal women with estrogen-receptor (ER)-positive breast cancer were eligible if they had disease recurrence while on or within 12 months of end of adjuvant treatment with an aromatase inhibitor (AI), or progression while on or within one month of end of AI treatment for locally advanced or metastatic breast cancer. Patients were randomly assigned (2:3:3:2) to receive either FULV (500 mg intramuscular injection on day 1, followed by 500 mg doses on days 15 and 29, and then every 28 days); FULV + daily VIS (50mg BD), FULV + intermittent VIS (2 days on, 5 days off; 125mg BD); or FULV + EVE (10mg OD). Treatment was given until disease progression (RECIST 1.1) or intolerable toxicity. Patients were stratified by disease measurability and response to prior endocrine therapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary objectives included objective response, clinical benefit rate, duration of response and clinical benefit, overall survival and safety. Results: Between 04/2014 and 10/2016, a total of 333 patients were randomised at 88 sites in 9 countries. 66 patients were assigned to receive FULV; 101 to FULV+VIS (cont), 95 to FULV+VIS (int); and 64 to FULV+EVE. Median PFS was 4.6 months (95% CI 3.4–6.9) in patients assigned to FULV; 7.5 months (95% CI 5.6–9.4) in those assigned to FULV+VIS (cont); 7.6 months (95% CI 5.5–9.6) in those assigned to FULV+VIS (int); and 12.2 months (95% CI 7.5–14.3) in those assigned to FULV+EVE. No significant difference was recorded between the patients assigned to FULV+VIS (cont) and FULV (hazard ratio 0.87, 95% CI 0.62-1.23; log-rank p=0.42); FULV+VIS (int) and FULV (HR 0.78, 95% CI 0.55-1.12; log-rank p=0.16); and FULV+VIS (cont) and FULV+VIS (int) (HR 1.11, 95% CI 0.81-1.52; log-rank p=0.52). PFS was significantly longer in patients assigned to FULV+EVE compared to FULV+VIS (cont) (HR 0.64, 95% CI 0.45-0.91; log-rank p=0.01) and FULV+EVE compared to FULV (HR 0.64, 95% CI 0.43-0.94; log-rank p=0.02). Conclusion: The trial failed to demonstrate a benefit of adding the TORC1/2 inhibitor vistusertib (AZD2014) to FULV. The combination FULV+EVE demonstrated significantly longer PFS compared to FULV+VIS or FULV. Citation Format: Schmid P, Zaiss M, Harper-Wynne C, Ferreira M, Dubey S, Chan S, Makris A, Nemsadze G, Brunt AM, Kuemmel S, Ruiz Cabrero I, Perelló A, Kendall A, Brown J, Kristeleit H, Conibear J, Saura C, Grenier J, Máhr K, Schenker M, Sohn JH, Lee KS, Sarker S-J, Coetzee C, Mousa K, Cortes Castan J. MANTA - A randomized phase II study of fulvestrant in combination with the dual mTOR inhibitor AZD2014 or everolimus or fulvestrant alone in estrogen receptor-positive advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS2-07.

The results of this study suggest that that the FIQR-Br is a reliable and valid instrument for assessing fibromyalgia-related impact, and supports its use in clinical settings and research. The structure of the three domains of the FIQR-Br was also confirmed. Implications for Rehabilitation Fibromyalgia is a chronic musculoskeletal disorder characterized by widespread and diffuse pain, fatigue, sleep disturbances, and depression. The disease significantly impairs patients' quality of life and can be highly disabling. To be used in multicenter research efforts, the Revised Fibromyalgia Impact Questionnaire (FIQR) must be cross-culturally validated and psychometrically tested. This paper will make available a new version of the FIQR-Br since another version already exists, but there are concerns about its measurement properties. The availability of an instrument adapted to and validated for Brazilian Portuguese may make it possible to reliably verify the effects of rehabilitation programs on disability from fibromyalgia. The FIQR-Br showed results comparable with other versions of the FIQR in other languages, thereby enabling comparison of effects of rehabilitation interventions on disability from fibromyalgia conducted in Brazil with results of studies carried out in other parts of the world.

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Despite the clinical benefits of aspirin, the interindividual variation in response to this antiplatelet drug is considerable. The manifestation of aspirin resistance (AR) is frequently observed, although this complex process remains poorly understood. While AR etiology is likely to be multifactorial, genetic factors appear to be preponderant. According to several genetic association studies, both genome-wide and candidate gene studies, numerous SNPs in cyclooxygenase, thromboxane and platelet receptors-related genes have been identified as capable of negatively affecting aspirin action. Thus, it is essential to understand the clinical relevance of AR-related SNPs as potential predictive and prognostic biomarkers as they may be essential to defining the AR phenotype.

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