Centro Hospitalar do Porto
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NPC1 silent variant induces skipping of exon 11 (p.V562V) and unfolded protein response was found in a specific Niemann‐Pick type C patient
Get PDFBackground: Niemann-Pick type C (NPC, MIM #257220) is a neuro-visceral disease, caused predominantly by pathogenic variants in the NPC1 gene. Here we studied patients with clinical diagnosis of NPC but inconclusive results regarding the molecular analysis.
Methods: We used a Next-Generation Sequencing (NGS)-panel followed by cDNA analysis. Latter, we used massively parallel single-cell RNA-seq (MARS-Seq) to address gene profiling changes and finally the effect of different variants on the protein and cellular levels.
Results: We identified novel variants and cDNA analysis allowed us to establish the functional effect of a silent variant, previously reported as a polymorphism. We demonstrated that this variant induces the skipping of exon 11 leading to a premature stop codon and identified it in NPC patients from two unrelated families. MARS-Seq analysis showed that a number of upregulated genes were related to the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in one specific patient. Also, for all analyzed variants, the NPC1 protein was partially retained in the ER.
Conclusion: We showed that the NPC1 silent polymorphism (p.V562V) is a disease-causing variant in NPC and that the UPR is upregulated in an NPC patient.info:eu-repo/semantics/publishedVersio
Readmissions and Mortality During the First Year After Stroke-Data From a Population-Based Incidence Study
Get PDFBackground: After a first-ever-in-a-lifetime stroke (FELS), hospital readmissions are common and associated with increased mortality and morbidity of stroke survivors, thus, raising the overall health burden of stroke. Population-based stroke studies on hospital readmissions are scarce despite it being an important healthcare service quality indicator. We evaluated unplanned readmissions or death during the first year after a FELS and their potential factors, based on a Portuguese community register. Methods: Data were retrieved from a population-based prospective register undertaken in Northern Portugal (ACIN2) in 2009-2011. Retrospective information about unplanned hospital readmissions and case fatality within 1 year after FELS index hospitalization (FELS-IH) was evaluated. Readmission/death-free survival 1 year after discharge was estimated using the Kaplan-Meyer method. Independent risk factors for readmission/death were identified using Cox proportional hazard models. Results: Unplanned readmission/death within 1 year occurred in 120 (31.6%) of the 389 hospitalized FELS survivors. In 31.2% and 33.5% of the cases, it occurred after ischemic stroke or intracerebral hemorrhage, respectively. Infections and cerebrovascular and cardiovascular diseases were the main causes of readmission. Of the readmissions, 65.3% and 52.5% were potentially avoidable or stroke related, respectively. The main cause of potentially avoidable readmissions was the continuation/recurrence of the event responsible for the initial admission or a closely related condition (71.2%). Male sex, age, previous and post-stroke functional status, and FELS-IH length of stay were independent factors of readmission/death within 1 year. Conclusions: Almost one-third of FELS survivors were readmitted/dead 1 year after their FELS-IH. This outcome persisted after the first months after stroke hospitalization in all stroke subtypes. More than half of readmissions were considered potentially avoidable or stroke related.info:eu-repo/semantics/publishedVersio
Predictors of In-Hospital Mortality after Recovered Out-of-Hospital Cardiac Arrest in Patients with Proven Significant Coronary Artery Disease: A Retrospective Study
Get PDFIntroduction: Recovered Out-of-Hospital Cardiac Arrest (rOHCA) population is heterogenous. Few studies focused on outcomes in the rOHCA subgroup with proven significant coronary artery disease (SigCAD). We aimed to characterize this subgroup and study the determinants of in-hospital mortality.
Methods: Retrospective study of consecutive rOHCA patients submitted to coronary angiography. Only patients with SigCAD were included.
Results: 60 patients were studied, 85% were male, mean age was 62.6 ± 12.1 years. In-hospital mortality rate was 43.3%. Patients with diabetes and history of stroke were less likely to survive. Significant univariate predictors of in-hospital mortality were further analysed separately, according to whether they were present at hospital admission or developed during hospital evolution. At hospital admission, initial non-shockable rhythm, low-flow time>12min, pH4.75mmol/L were the most relevant predictors and therefore included in a score tested by Kaplan-Meyer. Patients who had 0/4 criteria had 100% chance of survival till hospital discharge, 1/4 had 77%, 2/4 had 50%, 3/4 had 25%. Patients with all 4 criteria had 0% survival. During in-hospital evolution, a pH2mmol/L at 24h, anoxic brain injury and persistent hemodynamic instability proved significant. Patients who had 0/4 of these in-hospital criteria had 100% chance of survival till hospital discharge, 1/4 had 94%, 2/4 had 47%, 3/4 had 25%. Patients with all 4 criteria had 0% survival. Contrarily, CAD severity and ventricular dysfunction didn't significantly correlate to the outcome.
Conclusion: Classic prehospital variables retain their value in predicting mortality in the specific group of OHCA with SigCAD. In-hospital evolution variables proved to add value in mortality prediction. Combining these simple variables in risk scores might help refining prognostic prediction in these patients's subset.info:eu-repo/semantics/publishedVersio
Clinical 3-D Gait Assessment of Patients with Polyneuropathy Associated with Hereditary Transthyretin Amyloidosis
Get PDFHereditary amyloidosis associated with transthyretin V30M (ATTRv V30M) is a rare and inherited multisystemic disease, with a variable presentation and a challenging diagnosis, follow-up and treatment. This condition entails a definitive and progressive motor impairment that compromises walking ability from near onset. The detection of the latter is key for the disease's diagnosis. The aim of this work is to perform quantitative 3-D gait analysis in ATTRv V30M patients, at different disease stages, and explore the potential of the obtained gait information for supporting early diagnosis and/or stage distinction during follow-up. Sixty-six subjects (25 healthy controls, 14 asymptomatic ATTRv V30M carriers, and 27 symptomatic patients) were included in this case-control study. All subjects were asked to walk back and forth for 2 min, in front of a Kinect v2 camera prepared for body motion tracking. We then used our own software to extract gait-related parameters from the camera's 3-D body data. For each parameter, the main subject groups and symptomatic patient subgroups were statistically compared. Most of the explored gait parameters can potentially be used to distinguish between the considered group pairs. Despite of statistically significant differences being found, most of them were undetected to the naked eye. Our Kinect camera-based system is easy to use in clinical settings and provides quantitative gait information that can be useful for supporting clinical assessment during ATTRv V30M onset detection and follow-up, as well as developing more objective and fine-grained rating scales to further support the clinical decisions.This work was supported by the National funding agency, FCT—Fundação para a Ciência e a Tecnologia, in the context of the projects (UIDB/50014/2020; UIDB/00127/2020) and scholarship (SFRH/DB/110438/2015). This work was also supported by the Porto University Hospital Center (CHUP) in the context of the scholarship (BI.02/2018/UCA/CHP) as part of the research project [2014/167(119-DEFI/149-CES)]info:eu-repo/semantics/publishedVersio
Cecum perforation in intestinal malrotation setting in a patient with chromosome 12p deletion syndrome: A case report
No full textIntroduction: Intestinal malrotation results from failure of the normal gut rotation during embryological development. It is usually diagnosed in early childhood when it becomes symptomatic. Aetiology of intestinal malrotation has been scarcely addressed although relevant roles have been attributed to a few genes involved in gastrointestinal formation and association with certain syndromes has been suggested.
Presentation of case: We describe the case of a 23-year-old woman with 12p deletion syndrome who presented with clinical symptoms of occlusion to the emergency department. Analytically, an elevation of inflammatory parameters was confirmed and imaging revealed pneumoperitoneum originated on cecum perforation. The patient was submitted to surgery with favorable evolution.
Discussion: Clinical manifestation of intestinal malrotation is uncommon in the adult population but can have severe consequences if not diagnosed early. The abnormal positioning of the duodenojejunal loop compressed by Ladd's bands, can lead to obstruction and ischemia. Surgery via Ladd's procedure commonly applies and elective treatment may prevent added morbidity. Intestinal malrotation has been associated to certain syndromes but no prior association to chromosome 12p deletion has been described. Occlusion in a patient with 12p chromosome deletion should raise prompt suspicion for intestinal malrotation. Moreover, diagnosis of 12p chromosome deletion should increase attention towards gastrointestinal changes since elective surgery may diminish morbidity.
Conclusion: Intestinal malrotation results from abnormal embryological rotation of the midgut and is associated with certain syndromes. This paper firstly associates intestinal malrotation to chromosome 12p deletion. The possibility to address it electively may prevent morbidity in patients with this syndrome.info:eu-repo/semantics/publishedVersio
Cross-cutting view of current challenges in paediatric solid organ and haematopoietic stem cell transplantation in Europe: the European Reference Network TransplantChild
Get PDFThe low prevalence of European paediatric transplanted patients and scarcity of resources and expertise led to the need for a multidisciplinary network able to improve the quality of life of paediatric patients and families requiring a solid organ or haematopoietic stem cell transplantation. The European Reference Network (ERN) TransplantChild is one of the 24 ERNs established in a European legal framework to improve the care of patients with rare diseases. ERN TransplantChild is the only ERN focused on both solid organ and haematopoietic stem cell paediatric transplantation, based on the understanding of paediatric transplantation as a complex and highly specialised process where specific complications appear regardless the organ involved, thus linking the skills and knowledge of different organ disciplines. Gathering European centres of expertise in paediatric transplantation will give access to a correct and timely diagnosis, share expertise and knowledge and collect a critical mass of patients and data that increases the speed and value of clinical research outcomes. Therefore, the ERN TransplantChild aims for a paediatric Pan-European, Pan-transplant approach.The authors would like to thanks to the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency (CHAFEA). This work was supported by The European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency (CHAFEA) (SGA 770411 and SGA 811558).info:eu-repo/semantics/publishedVersio
Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC)
No full textObjective: The main aim of the study was to evaluate the efficacy and safety profile of Nivolumab, an immune-checkpoint-inhibitor antibody, in advanced, previously treated, Non-Small Cell Lung Cancer (NSCLC) patients, in a real world setting.
Methods: We performed a retrospective, multicentre data analysis of patients who were included in the Portuguese Nivolumab Expanded Access Program (EAP). Eligibility criteria included histologically or citologically confirmed NSCLC, stage IIIB and IV, evaluable disease, sufficient organ function and at least one prior line of chemotherapy. The endpoints included Overall Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Safety analysis was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and immune-related Adverse Events (irAEs) were treated according to protocol treatment guidelines. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Data was analysed using SPSS, version 21.0 (IBM Statistics).
Results: From June 2015 to December 2016, a total of 229 patients with advanced NSCLC were enrolled at 30 Portuguese centres. Clinical data were collected up to the end of July 2018. The baseline median age was 64 years (range 37-83) and the majority of patients were males (70.3%) and former/current smokers (69.4%). Patients with non-squamous histology predominated (88.1%), and 67.6% of the patients had received 2 or more prior lines of chemotherapy. Out of 229 patients, data was available for 219 patients (3 patients did not start treatment, while data was unavailable in 7 patients); of the 219 patients, 15.5% were not evaluated for radiological tumour assessment, 1.4% had complete response (CR), 21% partial response (PR), 31% stable disease (SD) and 31.1% progressive disease (PD). Thus, the ORR was 22.4% and DCR was 53.4% in this population. At the time of survival analysis the median PFS was 4.91 months (95% CI, 3.89-6.11) and median OS was 13.21 months (95% CI, 9.89-16.53). The safety profile was in line with clinical trial data.
Conclusions: Efficacy and safety results observed in this retrospective analysis were consistent with observations reported in clinical trials and from other centres.info:eu-repo/semantics/publishedVersio
Endobronchial ultrasound-transvascular needle aspiration (EBUS-TVNA) in the diagnosis of a hilar metastasis of an extrapulmonary neoplasm
No full textinfo:eu-repo/semantics/publishedVersio
Comparison of questionnaire and accelerometer-based assessments of physical activity in patients with heart failure with preserved ejection fraction: clinical and prognostic implications
Get PDFObjective. (i) To compare daily physical activity (PA) levels evaluated by the International Physical Activity Questionnaire (IPAQ) and by triaxial accelerometry in heart failure with preserved ejection fraction (HFpEF) patients; (ii) to describe daily PA patterns based in objective measurements; and (iii) to observe the association between prognostic indicators and PA measurements. Design. This is a cross-sectional study with 24 stable HFpEF patients. PA was assessed through the IPAQ short version and triaxial accelerometer. Time spent in moderate-to-vigorous PA (MVPA) from IPAQ was computed as self-reported walking and MVPA. Prognostic indicators were: distance on the 6-minute-walking test (6MWT), oxygen consumption (VO2) during the test, quality of life (QoL), BNP plasma level, and E/e' ratio. Results. Compared to accelerometry, IPAQ underestimated sedentary time (253 ± 156 vs. 392 ± 104 min/day, p = .001) and overestimated MVPA (44 ± 56 vs. 19.3 ± 26 min/day, p < .001). Accelerometer-derived data showed that HFpEF patients spent 50% of their waking time in sedentary behaviours and 2.5% in MVPA. Of measured surrogate prognostic markers, functional capacity (6MWT, r = 0.652, p = .04; VO2, r = 0.512, p = .02) and QoL (r=-0.490, p = .04) were correlated with MVPA. Conclusions. The IPAQ underestimated sedentary time and over-estimated MVPA in HFpEF patients. Using accelerometer-derived data, HFpEF patients spent only a minority of their time involved in MVPA, which was the only PA pattern positively associated with prognostic indicators.info:eu-repo/semantics/publishedVersio
Crescer nas sombras do suicídio
Get PDFIntroduction: Children/adolescents mourning the death of a primary caregiver face several challenges, including bond breaking and family restructuring due to loss. The negative connotation associated with suicide loss is enhanced by stigma, increasing acceptance difficulties and feelings of isolation, abandonment, shame, and guilt in face of what happened.
Objective: The aim of this study was to retrieve data on childhood bereavement due to primary caregiver suicide and explore psychopathological and psycho-affective developmental consequences of this type of grief.
Methods: Literature review of articles published on PubMed database about the subject.
Results and Discussion: Bereavement of a suicidal parent is associated with multiple psychopathological conditions: mood disorders, post-traumatic stress disorder, substance abuse, self-injurious behavior, suicidal behavior. Suicide and depressive disorder risk is higher when parental death occurred early in life course, with maternal suicide having greater impact. Antidepressants are more commonly used in cases of early parental death from suicide and are associated with increased hospitalizations for Major Depression and Bipolar Affective Disorder in adulthood. Consequences of parental death by suicide may be explained by several factors, as genetics, biological reactions, psychological factors originated from loss of an attachment figure, or social and environmental changes.
Conclusions: Parental suicide can be impactful for children’s developmental trajectory and later functioning level. The authors alert to the need for prevention and early intervention strategies associated with this process.info:eu-repo/semantics/publishedVersio