Neuronal ageing is promoted by the decay of the microtubule cytoskeleton.

Natural ageing is accompanied by a decline in motor, sensory, and cognitive functions, all impacting quality of life. Ageing is also the predominant risk factor for many neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. We need to therefore gain a better understanding of the cellular and physiological processes underlying age-related neuronal decay. However, gaining this understanding is a slow process due to the large amount of time required to age mammalian or vertebrate animal models. Here, we introduce a new cellular model within the Drosophila brain, in which we report classical ageing hallmarks previously observed in the primate brain. These hallmarks include axonal swellings, cytoskeletal decay, a reduction in axonal calibre, and morphological changes arising at synaptic terminals. In the fly brain, these changes begin to occur within a few weeks, ideal to study the underlying mechanisms of ageing. We discovered that the decay of the neuronal microtubule (MT) cytoskeleton precedes the onset of other ageing hallmarks. We showed that the MT-binding factors Tau, EB1, and Shot/MACF1, are necessary for MT maintenance in axons and synapses, and that their functional loss during ageing triggers MT bundle decay, followed by a decline in axons and synaptic terminals. Furthermore, genetic manipulations that improve MT networks slowed down the onset of neuronal ageing hallmarks and confer aged specimens the ability to outperform age-matched controls. Our work suggests that MT networks are a key lesion site in ageing neurons and therefore the MT cytoskeleton offers a promising target to improve neuronal decay in advanced age.

Enhancing patient outcomes: Integrating electronic cardiology consultation in primary care for cancer patients.

BACKGROUND: The prevalence of cancer patients with concomitant cardiovascular (CV) disease is on the rise due to improved cancer prognoses. The aim of this study is to evaluate the long-term outcomes of cancer patients referred to a cardiology department (CD) via primary care using e-consultation. METHODS: We analysed data from cancer patients with prior referrals to a CD between 2010 and 2021 (n = 6889) and compared two care models: traditional in-person consultations and e-consultations. In e-consultation model, cardiologists reviewed electronic health records (e-consultation) to determine whether the demand could be addressed remotely or necessitated an in-person consultation. We used an interrupted time series regression model to assess outcomes during the two periods: (1) time to cardiology consultation, (2) rates of all-cause and CV related hospital admissions and (3) rates of all-cause and CV-related mortality within the first year after the initial consultation or e-consultation at the CD. RESULTS: Introduction of e-consultation for cancer patients referred to cardiology care led to a 51.8% reduction (95%CI: 51.7%-51.9%) in waiting times. Furthermore, we observed decreased 1-year incidence rates, with incidence rate ratios (iRRs) [IC95%] of .75 [.73-.77] for CV-related hospitalizations, .43 [.42-.44] for all-cause hospitalizations, and .87 [.86-.88] for all-cause mortality. CONCLUSIONS: Compared to traditional in-person consultations, an outpatient care program incorporating e-consultation for cancer patients significantly reduced waiting times for cardiology care and demonstrated safety, associated with lower rates of hospital admissions.

The impact of inter-clinician electronic consultation in patients diagnosed with atrial fibrillation in primary care.

BACKGROUND: An early diagnosis and early initiation of oral anticoagulants (OAC) are main determinants for outcomes in patients with atrial fibrillation (AF). Inter-clinician electronic consultations (e-consultations) program for the general practitioner referrals to cardiologist may improve health care access by reducing the elapsed time for cardiology care. OBJECTIVE: To evaluate the effect of a reduced elapsed time to care after a inter-clinician e-consultations program implementation (2013-2019) in comparison with previous in-person consultation (2010-2012) in the outpatient health care management in a Cardiology Department. METHODOLOGY: We included 10,488 patients with AF from 1 January 2010, to 31 December 2019. Until 2012, all patients attended an in-person consultation (2010-2012). In 2013, we instituted an e-consult program (2013-2019) for all primary care referrals to cardiologists that preceded patient's in-person consultation when considered. The shared electronic patient dossier (EPD) was available between GP and cardiologist, and any change in therapy advice from cardiologist was directly implemented in this EPD. RESULTS: During the e-consultation period (2013-2019) were referred 6627 patients by GPs to cardiology versus 3861 during the in-person consultation (2010-2012). The e-consultation implementation was associated with a reduction in the elapsed time to anticoagulation prescription (177.6 ± 8.9 vs. 22.5 ± 8.1 days, p < .001), and an increase of OAC use (61% [95% IC: 19.6%-102.4%], p < .001). The e-consult program implementation was associated with a reduction in the 1-year CV mortality (.48 [95% CI: .30-.75]) and all-cause mortality (.42 [95% CI: .29-.62]). The OAC reduces the stroke mortality (.15 [95% CI: .06-.39]) and CV mortality (.43 [95% CI: .29-.62]) and all-cause mortality (.23 [95% CI: .17-.31]). CONCLUSION: A shared EPD-based inter-clinician e-consultation program significantly reduced the elapsed time for cardiology consultation and initiation of OAC. The implementation of this program was associated with a lower risk of stroke and cardiovascular/all-cause mortality.

Gender differences on healthcare accessibility and outcomes of a electronic inter-clinician consultation program at the cardiology department in a Galician Health Area.

AIMS: To assess the longer-term results (hospital admissions and mortality) in women versus men referred to a cardiology department from primary care using an e-consultation in our outpatient care programme. METHODS: We selected 61,306 patients (30,312 women and 30,994 men) who visited the cardiology service at least once between 2010 and 2021: 69.1% (19,997 women and 20,462 men) were attended in e-consultation (from 2013 to 2021) and 30.9% (8920 women and 9136 men) in in-person consultations (from 2010 to 2012) without gender differences in the proportion of patients attended in each period. Using an interrupted time series regression model, we analysed the impact of incorporating e-consultation into the healthcare model and evaluated the elapsed time to cardiology care, heart failure (HF), cardiovascular (CV), and all-cause hospital admissions and mortality during the one-year after cardiology consultation. RESULTS: The introduction of e-consultation substantially decreased waiting times to cardiology care; during the in-person consultation period, the mean delay for cardiology care was 57.9 (24.8) days in men and 55.8 (22.8) days in women. During the e-consultation period, the waiting time to cardiology care was markedly reduced to 9.41 (4.02) days in men and 9.46 (4.18) in women. After e-consultation implantation, there was a significant reduction in the 1-year rate of hospital admissions and mortality, both in women and men iRR [IC 95%]: 0.95 [0.93-0.96] for HF, 0.90 [0.89-0.91] for CV and 0.70 [0.69-0.71] for all-cause hospitalization; and 0.93 [0.92-0.95] for HF, 0.86 [0.86-0.87] for CV and 0.88 [0.87-0.89] for all-cause mortality in women; and 0.91 [0.89-0.92] for HF, 0.90 [0.89-0.91] for CV and 0.72 [0.71-0.73] for all-cause hospitalization; and 0.96 [0.93-0.97] for HF, 0.87 [95% CI: 0.86-0.87] for CV and 0.87 [0.86-0.87] for all-cause mortality, in men. CONCLUSION: Compared with the in-person consultation period, an outpatient care programme that includes an e-consultation significantly reduced waiting time to cardiology care and was safe, with a lower rate of hospital admissions and mortality in the first year, without significative gender differences.

Molecular portraits of clear cell ovarian and endometrial carcinoma with comparison to clear cell renal cell carcinoma.

OBJECTIVE: Advanced clear cell gynecologic malignancies remain among the most challenging diseases to manage. We evaluated ovarian and endometrial clear cell carcinoma (OCCC and ECCC) specimens using comprehensive sequencing technology to identify mutational targets and compared their molecular profiles to histologically similar clear cell renal cell carcinoma (ccRCC). METHODS: Using next-generation sequencing (NGS), fragment analysis (FA), and in situ hybridization (ISH), 164 OCCC, 75 ECCC and 234 ccRCC specimens from 2015 to 2018 were evaluated and compared. RESULTS: The highest mutation rates in ECCC and OCCC were noted in: ARID1A (75.0%, 87.5%), TP53 (34.8%, 11.1%), PIK3CA (25.0%, 46.8%), PPP2R1A (8.7%, 16.7%), MSI-high (8.8%, 6.4%) and PTEN (8.3%, 7.1%). Among these mutations, there was no significant difference between OCCC and ECCC mutation prevalence except in TP53, with higher mutation rates in ECCC versus OCCC (34.8 vs. 11.1%, respectively, p < 0.05). ccRCC demonstrated different mutation profiles with higher mutation rates in VHL (80.3%), PBRM1 (43.9%), SETD2 (31.1%), and KDM5C (29.2%). By contrast, VHL, PBRM1, and SETD2 mutations were not found in ECCC and OCCC (0.0%). Compared to ccRCC and ECCC, OCCC was found to have a significantly higher tumor mutation burden (TMB) (19.1%). CONCLUSION: Gynecologic and renal CCC demonstrate separate and disparate somatic profiles. However, OCCC and ECCC are diseases with similar profiles. TMB and MSI analyses indicate that a subset of OCCC may benefit from immunotherapy. Prospective clinical trials are needed and are underway to examine targeted therapies in these gynecologic disease subtypes.

Determinants of oxygen uptake and prognostic factors in cardiopulmonary exercise test in patients with Fontan surgery.

INTRODUCTION: Cardiopulmonary exercise test (CPET) allows quantification of functional capacity of patients with Fontan. The objective of this study was to determine the role of CPET parameters in predicting a higher maximum oxygen consumption (VO2 max) and to analyse the role of CPET parameters in predicting an unfavourable outcome. METHODS: A retrospective, cross-sectional, descriptive study was carried out on 57 patients with Fontan, who had undergone incremental CPET with cycloergometer between 2010 and 2020. Determinants of VO2 max and determinants of clinical deterioration were analysed. RESULTS: In the univariate analysis, the variables significantly related to VO2 max were: age, sex, body mass index (BMI), years of Fontan evolution, intracardiac Fontan, oxygen consumption at anaerobic threshold (VO2AT), CO2 equivalents at anaerobic threshold (VE/VCO2) and chronotropic insufficiency. The multiple linear regression model that best fitted the relationship between VO2 max and independent variables (correlation coefficient 0.73) included sex (correlation index 3.35; p = 0.02), BMI (-0.27; p = 0.02), chronotropic failure (-2.79; p = 0.01) and VO2AT (0.92; p < 0.0001). In the univariate analysis of the prognostic CPET variables related to an unfavourable clinical situation, significance was only obtained with chronotropic insufficiency (p = 0.003). In multivariate analysis, chronotropic insufficiency maintains its association [p= 0.017, OR = 4.65 (1.3-16.5)]. CONCLUSIONS: In conclusion, together with the anthropometric parameters universally related to VO2 max, chronotropic insufficiency and VO2AT are the main determinants of functional capacity in patients with Fontan. Moreover, chronotropic insufficiency is closely related to unfavourable clinical evolution. Our data would support the intensive treatment of chronotropic insufficiency in order to improve the quality of life and the clinical situation of patients with Fontan.

"It's impossible for them to understand me 'cause I haven't said a word": how women baby boomers shape social participation spaces in old age.

The baby boom generation's retirement will change the conceptualization of participation in old age due to their particularities from having experienced a specific socio-historical context. Likewise, the feminization of old age underscores the importance of developing research from the perspectives of gender and critical feminist gerontology. The objective of the present study is to identify and analyze women baby-boomers' conceptualizations about social participation regarding the configuration of social participation spaces. Five discussion groups and five individual interviews were conducted with 56 baby boomers residing in Andalusia (Spain). Here we focus on a separate analysis of the 27 women participating in these settings. The results were organized around four factors: desirability of social participation spaces, adaptation of spaces to preferences, facilitators and barriers in the adaptation of spaces, and the importance of agency in the social participation spaces. Through the analyzed discourse it was observed that participants in this study gave special importance to promoting spaces that involve social contribution, self-management, and self-determination of the spaces, adaptation of access, as well as exercising agency.

Re-assigning the histologic identities of COV434 and TOV-112D ovarian cancer cell lines.

OBJECTIVE: The development of effective cancer treatments depends on the availability of cell lines that faithfully recapitulate the cancer in question. This study definitively re-assigns the histologic identities of two ovarian cancer cell lines, COV434 (originally described as a granulosa cell tumour) and TOV-112D (originally described as grade 3 endometrioid carcinoma), both of which were recently suggested to represent small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), based on their shared gene expression profiles and sensitivity to EZH2 inhibitors. METHODS: For COV434 and TOV-112D, we re-reviewed the original pathology slides and obtained clinical follow-up on the patients, when available, and performed immunohistochemistry for SMARCA4, SMARCA2 and additional diagnostic markers on the original formalin-fixed, paraffin-embedded (FFPE) clinical material, when available. For COV434, we further performed whole exome sequencing and validated SMARCA4 mutations by Sanger sequencing. We studied the growth of the cell lines at baseline and upon re-expression of SMARCA4 in vitro for both cell lines and evaluated the serum calcium levels in vivo upon injection into immunodeficient mice for COV434 cells. RESULTS: The available morphological, immunohistochemical, genetic, and clinical features indicate COV434 is derived from SCCOHT, and TOV-112D is a dedifferentiated carcinoma. Transplantation of COV434 into mice leads to increased serum calcium level. Re-expression of SMARCA4 in either COV434 and TOV-112D cells suppressed their growth dramatically. CONCLUSIONS: COV434 represents a bona fide SCCOHT cell line. TOV-112D is a dedifferentiated ovarian carcinoma cell line.

Different epidemiological profiles in patients with Zika and dengue infection in Tapachula, Chiapas in Mexico (2016-2018): an observational, prospective cohort study.

BACKGROUND: The introduction of Zika and chikungunya to dengue hyperendemic regions increased interest in better understanding characteristics of these infections. We conducted a cohort study in Mexico to evaluate the natural history of Zika infection. We describe here the frequency of Zika, chikungunya and dengue virus infections immediately after Zika introduction in Mexico, and baseline characteristics of participants for each type of infection. METHODS: Prospective, observational cohort evaluating the natural history of Zika virus infection in the Mexico-Guatemala border area. Patients with fever, rash or both, meeting the modified criteria of PAHO for probable Zika cases were enrolled (June 2016-July 2018) and followed-up for 6 months. We collected data on sociodemographic, environmental exposure, clinical and laboratory characteristics. Diagnosis was established based on viral RNA identification in serum and urine samples using RT-PCR for Zika, chikungunya, and dengue. We describe the baseline sociodemographic and environmental exposure characteristics of participants according to diagnosis, and the frequency of these infections over a two-year period immediately after Zika introduction in Mexico. RESULTS: We enrolled 427 participants. Most patients (n = 307, 65.7%) had an acute illness episode with no identified pathogen (UIE), 37 (8%) Zika, 82 (17.6%) dengue, and 1 (0.2%) chikungunya. In 2016 Zika predominated, declined in 2017 and disappeared in 2018; while dengue increased after 2017. Patients with dengue were more likely to be men, younger, and with lower education than those with Zika and UIE. They also reported closer contact with water sources, and with other people diagnosed with dengue. Participants with Zika reported sexual exposure more frequently than people with dengue and UIE. Zika was more likely to be identified in urine while dengue was more likely found in blood in the first seven days of symptoms; but PCR results for both were similar at day 7-14 after symptom onset. CONCLUSIONS: During the first 2 years of Zika introduction to this dengue hyper-endemic region, frequency of Zika peaked and fell over a two-year period; while dengue progressively increased with a predominance in 2018. Different epidemiologic patterns between Zika, dengue and UIE were observed. Trial registration Clinical.Trials.gov (NCT02831699).

Design and Synthesis of Water-Soluble and Potent MMP-13 Inhibitors with Activity in Human Osteosarcoma Cells.

Osteoarthritis is a degenerative disease, often resulting in chronic joint pain and commonly affecting elderly people. Current treatments with anti-inflammatory drugs are palliative, making the discovery of new treatments necessary. The inhibition of matrix metalloproteinase MMP-13 is a validated strategy to prevent the progression of this common joint disorder. We recently described polybrominated benzotriazole derivatives with nanomolar inhibitory activity and a promising selectivity profile against this collagenase. In this work, we have extended the study in order to explore the influence of bromine atoms and the nature of the S1' heterocyclic interacting moiety on the solubility/selectivity balance of this type of compound. Drug target interactions have been assessed through a combination of molecular modeling studies and NMR experiments. Compound 9a has been identified as a water-soluble and highly potent inhibitor with activity in MG-63 human osteosarcoma cells.

Smart Bioimpedance Spectroscopy Device for Body Composition Estimation.

The purpose of this work is to describe a first approach to a smart bioimpedance spectroscopy device for its application to the estimation of body composition. The proposed device is capable of carrying out bioimpedance measurements in multiple configurable frequencies, processing the data to obtain the modulus and the bioimpedance phase in each of the frequencies, and transmitting the processed information wirelessly. Another novelty of this work is a new algorithm for the identification of Cole model parameters, which is the basis of body composition estimation through bioimpedance spectroscopy analysis. Against other proposals, the main advantages of the proposed method are its robustness against parasitic effects by employing an extended version of Cole model with phase delay and three dispersions, its simplicity and low computational load. The results obtained in a validation study with respiratory patients show the accuracy and feasibility of the proposed technology for bioimpedance measurements. The precision and validity of the algorithm was also proven in a validation study with peritoneal dialysis patients. The proposed method was the most accurate compared with other existing algorithms. Moreover, in those cases affected by parasitic effects the proposed algorithm provided better approximations to the bioimpedance values than a reference device.

The importance of symptoms in the longitudinal variability of clusters in COPD patients: A validation study.

BACKGROUND AND OBJECTIVE: Cluster analysis has been utilized to explore phenotypic heterogeneity in chronic obstructive pulmonary disease (COPD). To date, little is known about the longitudinal variability of clusters in COPD patients. We aimed to evaluate the 2-year cluster variability in stable COPD patients. METHODS: We evaluated the following variables in COPD patients at baseline and 2 years later: age, gender, pack-year history, body mass index (BMI), modified Medical Research Council (MMRC) scale, 6-min walking distance (6MWD), spirometry and COPD Assessment Test (CAT). Patient classification was performed using cluster analysis at baseline and 2 years later. Each patient's cluster variability after 2 years and its parameters associated with cluster change were explored. RESULTS: A total of 521 smokers with COPD were evaluated at baseline and 2 years later. Three different clusters were consistently identified at both evaluation times: cluster A (of younger age, mild airway limitation, few symptoms), cluster B (intermediate) and cluster C (of older age, severe airway limitation and highly symptomatic). Two years later, 70% of patients were unchanged, whereas 30% changed from one cluster to another: 20% from A to B; 15% from B to A; 15% from B to C; 42% from C to B and 8% from C to A. 6MWD, forced expiratory volume in 1 s (FEV1 ) % and CAT were the principal parameters responsible for this change. CONCLUSION: After 2 years of follow-up, most of the COPD patients maintained their cluster assignment. Exercise tolerance, lung function and quality of life were the main driving parameters in those who change their cluster assignment.

Smart Vest for Respiratory Rate Monitoring of COPD Patients Based on Non-Contact Capacitive Sensing.

In this paper, a first approach to the design of a portable device for non-contact monitoring of respiratory rate by capacitive sensing is presented. The sensing system is integrated into a smart vest for an untethered, low-cost and comfortable breathing monitoring of Chronic Obstructive Pulmonary Disease (COPD) patients during the rest period between respiratory rehabilitation exercises at home. To provide an extensible solution to the remote monitoring using this sensor and other devices, the design and preliminary development of an e-Health platform based on the Internet of Medical Things (IoMT) paradigm is also presented. In order to validate the proposed solution, two quasi-experimental studies have been developed, comparing the estimations with respect to the golden standard. In a first study with healthy subjects, the mean value of the respiratory rate error, the standard deviation of the error and the correlation coefficient were 0.01 breaths per minute (bpm), 0.97 bpm and 0.995 (p < 0.00001), respectively. In a second study with COPD patients, the values were −0.14 bpm, 0.28 bpm and 0.9988 (p < 0.0000001), respectively. The results for the rest period show the technical and functional feasibility of the prototype and serve as a preliminary validation of the device for respiratory rate monitoring of patients with COPD.

Fascin links Btl/FGFR signalling to the actin cytoskeleton during Drosophila tracheal morphogenesis.

A key challenge in normal development and in disease is to elucidate the mechanisms of cell migration. Here we approach this question using the tracheal system of Drosophila as a model. Tracheal cell migration requires the Breathless/FGFR pathway; however, how the pathway induces migration remains poorly understood. We find that the Breathless pathway upregulates singed at the tip of tracheal branches, and that this regulation is functionally relevant. singed encodes Drosophila Fascin, which belongs to a conserved family of actin-bundling proteins involved in cancer progression and metastasis upon misregulation. We show that singed is required for filopodia stiffness and proper morphology of tracheal tip cells, defects that correlate with an abnormal actin organisation. We propose that singed-regulated filopodia and cell fronts are required for timely and guided branch migration and for terminal branching and branch fusion. We find that singed requirements rely on its actin-bundling activity controlled by phosphorylation, and that active Singed can promote tip cell features. Furthermore, we find that singed acts in concert with forked, another actin cross-linker. The absence of both cross-linkers further stresses the relevance of tip cell morphology and filopodia for tracheal development. In summary, our results on the one hand reveal a previously undescribed role for forked in the organisation of transient actin structures such as filopodia, and on the other hand identify singed as a new target of Breathless signal, establishing a link between guidance cues, the actin cytoskeleton and tracheal morphogenesis.

Prevalence of persistent blood eosinophilia: relation to outcomes in patients with COPD.

The impact of blood eosinophilia in chronic obstructive pulmonary disease (COPD) remains controversial.To evaluate the prevalence and stability of a high level of blood eosinophils (≥300 cells·µL-1) and its relationship to outcomes, we determined blood eosinophils at baseline and over 2 years in 424 COPD patients (forced expiratory volume in 1 s (FEV1) 60% predicted) and 67 smokers without COPD from the CHAIN cohort, and in 308 COPD patients (FEV1 60% predicted) in the BODE cohort. We related eosinophil levels to exacerbations and survival using Cox hazard analysis.In COPD patients, 15.8% in the CHAIN cohort and 12.3% in the BODE cohort had persistently elevated blood eosinophils at all three visits. A significant proportion (43.8%) of patients had counts that oscillated above and below the cut-off points, while the rest had persistent eosinophil levels <300 cells·µL-1 A similar eosinophil blood pattern was observed in controls. Exacerbation rates did not differ in patients with and without eosinophilia. All-cause mortality was lower in patients with high eosinophils compared with those with values <300 cells·µL-1 (15.8% versus 33.7%; p=0.026).In patients with COPD, blood eosinophils ≥300 cells·µL-1 persisting over 2 years was not a risk factor for COPD exacerbations. High eosinophil count was associated with better survival.

Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type.

Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually exclusive ATPases of the SWI/SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re-expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines.

The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type.

OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome. METHODS: In 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data. RESULTS: The strongest prognostic factors were stage at diagnosis (p=2.72e-15) and treatment modality (p=3.87e-13). For FIGO stages II-IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p=0.002). Patients aged ≥40 had a worse outcome than younger patients (p=0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed <15years; carriers presented at a younger age than non-carriers (p=0.02). CONCLUSIONS: Stage at diagnosis is the most significant prognostic factor in SCCOHT and consolidation with HDC-aSCR may provide the best opportunity for long-term survival. The large fraction of SMARCA4 germline mutations carriers warrants genetic counseling for all patients.

Prevalence of and Attitudes towards Smoking among Spanish Health Professionals.

BACKGROUND: The MPOWER strategy encourages suitable monitoring of the tobacco epidemic among health professionals in all countries. OBJECTIVE: To analyse the prevalence of and attitudes towards tobacco use among Spanish health professionals. METHODS: A study was conducted based on an online survey. The study population consisted of health professionals (primary care physicians, specialist physicians and nurses). The questionnaire used included questions about tobacco consumption, knowledge of and attitudes towards smoking. The sample size was calculated according to a database with 9,500 e-mail addresses and listings of health centres and hospitals all over Spain. Statistical analysis was done using the SPSS software programme. RESULTS: The study group comprised a total of 612 health professionals: 322 were women (52.6%), 196 were nurses and 416 were physicians. 11.7% of health professionals were smokers (9.6% regular smokers and 2.1% occasional smokers) and 41.3% were ex-smokers. Within the group of daily smokers, differences were observed between the nurses and the physicians: 11.2 versus 8.9% (p = 0.009). Smoking was recognized as a chronic disorder by 58.2% of health professionals, and 54.6% knew that the most effective intervention to help quit is a combination of psychological and pharmacological treatment. 56% of health professionals always asked their patients about their tobacco consumption. CONCLUSIONS: 11.7% of Spanish health professionals are smokers. We found that they have low knowledge about strategies to quit smoking and that there is a low level of therapeutic intervention on smokers.

α-Synuclein accumulates in huntingtin inclusions but forms independent filaments and its deficiency attenuates early phenotype in a mouse model of Huntington's disease.

Huntington's disease (HD) is the most common of nine inherited neurological disorders caused by expanded polyglutamine (polyQ) sequences which confer propensity to self-aggregate and toxicity to their corresponding mutant proteins. It has been postulated that polyQ expression compromises the folding capacity of the cell which might affect other misfolding-prone proteins. α-Synuclein (α-syn) is a small neural-specific protein with propensity to self-aggregate that forms Parkinson's disease (PD) Lewy bodies. Point mutations in α-syn that favor self-aggregation or α-syn gene duplications lead to familial PD, thus indicating that increased α-syn aggregation or levels are sufficient to induce neurodegeneration. Since polyQ inclusions in HD and other polyQ disorders are immunopositive for α-syn, we speculated that α-syn might be recruited as an additional mediator of polyQ toxicity. Here, we confirm in HD postmortem brains and in the R6/1 mouse model of HD the accumulation of α-syn in polyQ inclusions. By isolating the characteristic filaments formed by aggregation-prone proteins, we found that N-terminal mutant huntingtin (N-mutHtt) and α-syn form independent filamentous microaggregates in R6/1 mouse brain as well as in the inducible HD94 mouse model and that N-mutHtt expression increases the load of α-syn filaments. Accordingly, α-syn knockout results in a diminished number of N-mutHtt inclusions in transfected neurons and also in vivo in the brain of HD mice. Finally, α-syn knockout attenuates body weight loss and early motor phenotype of HD mice. This study therefore demonstrates that α-syn is a modifier of polyQ toxicity in vivo and raises the possibility that potential PD-related therapies aimed to counteract α-syn toxicity might help to slow HD.

New GOLD classification: longitudinal data on group assignment.

RATIONALE: Little is known about the longitudinal changes associated with using the 2013 update of the multidimensional GOLD strategy for chronic obstructive pulmonary disease (COPD). OBJECTIVE: To determine the COPD patient distribution of the new GOLD proposal and evaluate how this classification changes over one year compared with the previous GOLD staging based on spirometry only. METHODS: We analyzed data from the CHAIN study, a multicenter observational Spanish cohort of COPD patients who are monitored annually. Categories were defined according to the proposed GOLD: FEV1%, mMRC dyspnea, COPD Assessment Test (CAT), Clinical COPD Questionnaire (CCQ), and exacerbations-hospitalizations. One-year follow-up information was available for all variables except CCQ data. RESULTS: At baseline, 828 stable COPD patients were evaluated. On the basis of mMRC dyspnea versus CAT, the patients were distributed as follows: 38.2% vs. 27.2% in group A, 17.6% vs. 28.3% in group B, 15.8% vs. 12.9% in group C, and 28.4% vs. 31.6% in group D. Information was available for 526 patients at one year: 64.2% of patients remained in the same group but groups C and D show different degrees of variability. The annual progression by group was mainly associated with one-year changes in CAT scores (RR, 1.138; 95%CI: 1.074-1.206) and BODE index values (RR, 2.012; 95%CI: 1.487-2.722). CONCLUSIONS: In the new GOLD grading classification, the type of tool used to determine the level of symptoms can substantially alter the group assignment. A change in category after one year was associated with longitudinal changes in the CAT and BODE index.