Tryptase in Acute Appendicitis: Unveiling Allergic Connections through Compelling Evidence.

The aetiology of acute appendicitis (AA), the most frequent abdominal surgical emergency, is still unclarified. Recent epidemiologic, clinical and laboratorial data point to an allergic component in the pathophysiology of AA. Mastocytes participate in the Th2 immune response, releasing inflammatory mediators from their granules upon stimulation by IgE-specific antigens. Among the well-known mediators are histamine, serotonin and tryptase, which are responsible for the clinical manifestations of allergies. We conducted a prospective single-centre study to measure histamine and serotonin (commercial ELISA kit) and tryptase (ImmunoCAP System) concentrations in appendicular lavage fluid (ALF) and serum. Consecutive patients presenting to the emergency department with a clinical diagnosis of AA were enrolled: 22 patients with phlegmonous AA and 24 with gangrenous AA The control group was composed of 14 patients referred for colectomy for colon malignancy. Appendectomy was performed during colectomy. Tryptase levels were strikingly different between histological groups, both in ALF and serum (p < 0.001); ALF levels were higher than serum levels. Tryptase concentrations in ALF were 109 times higher in phlegmonous AA (APA) (796.8 (194.1-980.5) pg/mL) and 114 times higher in gangrenous AA (AGA) (837.4 (272.6-1075.1) pg/mL) than in the control group (7.3 (4.5-10.3) pg/mL. For the diagnosis of AA, the discriminative power of serum tryptase concentration was good (AUC = 0.825), but discriminative power was weak (AUC = 0.559) for the differential diagnosis between APA and AGA. Mastocytes are involved in AA during clinical presentations of both phlegmonous and gangrenous appendicitis, and no significant differences in concentration were found. No differences were found in serum and ALF concentrations of histamine and serotonin between histological groups. Due to their short half-lives, these might have elapsed by the time the samples were collected. In future research, these determinations should be made immediately after appendectomy. Our findings confirm the hypersensitivity type I reaction as an event occurring in the pathogenesis of AA: tryptase levels in ALF and serum were higher among patients with AA when compared to the control group, which is in line with a Th2 immune response and supports the concept of the presence of an allergic reaction in the pathogenesis of acute appendicitis. Our results, if confirmed, may have clinical implications for the treatment of AA.

Predictors of Glaucoma After Pediatric Cataract Surgery.

PRCIS: Glaucoma after pediatric cataract surgery is common and challenging. Age at surgery and the presence of microcornea or other anterior segment (AS) abnormalities can be used to identify those at greatest risk. OBJECTIVE: To establish risk factors for developing glaucoma after pediatric cataract surgery [glaucoma following cataract surgery (GFCS)]. METHODS: Single-center, retrospective, longitudinal study of patients who underwent lensectomy for pediatric cataracts from 2008 to 2020. Included eyes presented with congenital or acquired pediatric cataracts or an anterior form of persistent fetal vasculature, and a follow-up of at least 1 year. Exclusion criteria were the presence of preexisting intraocular pressure elevation, congenital glaucoma, syndromic cataracts, and a history of trauma or uveitis. Demographic and clinical data were collected. Our primary outcome was the development of GFCS. Multivariable logistic regression with generalized estimating equations was used to model the association between potential predictors and the risk of GFCS. RESULTS: A total of 110 eyes from 74 patients were included, 38 with unilateral and 36 with bilateral pediatric cataract surgery. The average surgery age was 24.71 ± 37.26 months, with 74 eyes (67.3%) undergoing surgery ≤12 weeks of age. Patients were followed for 9.96 ± 3.64 years after surgery. Twenty-eight eyes (25.45%) developed GFCS, all requiring glaucoma surgery. In multivariable analysis, surgery before 12 weeks of age [odds ratio (OR): 34.74; P < 0.001], presence of microcornea (OR: 12.90; P = 0.002), and presence of other AS abnormalities (OR: 52.71; P < 0.001) were significantly associated with the development of GFCS. CONCLUSIONS: The development of GFCS is a common and relevant adverse event after pediatric cataract surgery whose management is challenging. Age at surgery, the presence of microcornea, and the presence of other AS abnormalities can be used to identify those at greatest risk.

Deep Learning Networks for Breast Lesion Classification in Ultrasound Images: A Comparative Study.

Accurate lesion classification as benign or malignant in breast ultrasound (BUS) images is a critical task that requires experienced radiologists and has many challenges, such as poor image quality, artifacts, and high lesion variability. Thus, automatic lesion classification may aid professionals in breast cancer diagnosis. In this scope, computer-aided diagnosis systems have been proposed to assist in medical image interpretation, outperforming the intra and inter-observer variability. Recently, such systems using convolutional neural networks have demonstrated impressive results in medical image classification tasks. However, the lack of public benchmarks and a standardized evaluation method hampers the performance comparison of networks. This work is a benchmark for lesion classification in BUS images comparing six state-of-the-art networks: GoogLeNet, InceptionV3, ResNet, DenseNet, MobileNetV2, and EfficientNet. For each network, five input data variations that include segmentation information were tested to compare their impact on the final performance. The methods were trained on a multi-center BUS dataset (BUSI and UDIAT) and evaluated using the following metrics: precision, sensitivity, F1-score, accuracy, and area under the curve (AUC). Overall, the lesion with a thin border of background provides the best performance. For this input data, EfficientNet obtained the best results: an accuracy of 97.65% and an AUC of 96.30%.Clinical Relevance- This study showed the potential of deep neural networks to be used in clinical practice for breast lesion classification, also suggesting the best model choices.

Immune checkpoint inhibitor-induced endocrinopathies: a possible indicator of improved survival.

Objective: To evaluate the association between the patients' characteristics and the development of endocrine toxicity and to assess the association between endocrine-related adverse effects (ERAE) development and mortality. Subjects and methods: A retrospective observational study was conducted in 98 patients submitted to immunotherapy in our centre since its introduction in 2015 until March 2021. We excluded patients for which data regarding the corticotroph axis evaluation was missing. We used linear and logistic regression models to address our aims. Results: We observed a significant negative association between ERAE development and death (OR 0.32; p = 0.028). We detected no associations between ERAE and the following characteristics: age at immune checkpoint inhibitors (ICI) initiation, sex, diabetes mellitus, medical history, immunotherapy duration and ICI type. Conclusion: The development of an ERAE may be associated with a better overall survival rate in advanced oncologic disease, supporting the role of an unleashed immune system response to malignant cells.

Immune checkpoint inhibitor-induced endocrinopathies: a possible indicator of improved survival

ABSTRACT Objective: To evaluate the association between the patients' characteristics and the development of endocrine toxicity and to assess the association between endocrine-related adverse effects (ERAE) development and mortality. Subjects and methods: A retrospective observational study was conducted in 98 patients submitted to immunotherapy in our centre since its introduction in 2015 until March 2021. We excluded patients for which data regarding the corticotroph axis evaluation was missing. We used linear and logistic regression models to address our aims. Results: We observed a significant negative association between ERAE development and death (OR 0.32; p = 0.028). We detected no associations between ERAE and the following characteristics: age at immune checkpoint inhibitors (ICI) initiation, sex, diabetes mellitus, medical history, immunotherapy duration and ICI type. Conclusion: The development of an ERAE may be associated with a better overall survival rate in advanced oncologic disease, supporting the role of an unleashed immune system response to malignant cells.

Comparative Analysis of Current Deep Learning Networks for Breast Lesion Segmentation in Ultrasound Images.

Automatic lesion segmentation in breast ultrasound (BUS) images aids in the diagnosis of breast cancer, the most common type of cancer in women. Accurate lesion segmentation in ultrasound images is a challenging task due to speckle noise, artifacts, shadows, and lesion variability in size and shape. Recently, convolutional neural networks have demonstrated impressive results in medical image segmentation tasks. However, the lack of public benchmarks and a standardized evaluation method hampers the networks' performance comparison. This work presents a benchmark of seven state-of-the-art methods for the automatic breast lesion segmentation task. The methods were evaluated on a multi-center BUS dataset composed of three public datasets. Specifically, the U-Net, Dynamic U-Net, Semantic Segmentation Deep Residual Network with Variational Autoencoder (SegResNetVAE), U-Net Transformers, Residual Feedback Network, Multiscale Dual Attention-Based Network, and Global Guidance Network (GG-Net) architectures were evaluated. The training was performed with a combination of the cross-entropy and Dice loss functions and the overall performance of the networks was assessed using the Dice coefficient, Jaccard index, accuracy, recall, specificity, and precision. Despite all networks having obtained Dice scores superior to 75%, the GG-Net and SegResNetVAE architectures outperform the remaining methods, achieving 82.56% and 81.90%, respectively. Clinical Relevance- The results of this study allowed to prove the potential of deep neural networks to be used in clinical practice for breast lesion segmentation also suggesting the best model choices.

Disclosing the Potential of Fluorinated Ionic Liquids as Interferon-Alpha 2b Delivery Systems.

Interferon-alpha 2b (IFN-α 2b) is a therapeutic protein used for the treatment of cancer, viral infections, and auto-immune diseases. Its application is hindered by a low bioavailability and instability in the bloodstream, and the search for new strategies for a target delivery and stabilization of IFN-α 2b to improve its therapeutic efficacy is crucial. Fluorinated ionic liquids (FILs) are promising biomaterials that: (i) can form self-assembled structures; (ii) have complete miscibility in water; and (iii) can be designed to have reduced toxicity. The influence of IFN-α 2b in the aggregation behaviour of FILs and the interactions between them were investigated through conductivity and surface tension measurements, and using electron microscopic and spectroscopy techniques to study FILs feasibility as an interferon-alpha 2b delivery system. The results show that the presence of IFN-α 2b influences the aggregation behaviour of FILs and that strong interaction between the two compounds occurs. The protein might not be fully encapsulated by FILs. However, the FIL can be tailored in the future to carry IFN-α 2b by the formation of a conjugate, which prevents the aggregation of this protein. This work constitutes a first step toward the design and development of FIL-based IFN-α 2b delivery systems.

Lung Auscultation Using the Smartphone-Feasibility Study in Real-World Clinical Practice.

Conventional lung auscultation is essential in the management of respiratory diseases. However, detecting adventitious sounds outside medical facilities remains challenging. We assessed the feasibility of lung auscultation using the smartphone built-in microphone in real-world clinical practice. We recruited 134 patients (median[interquartile range] 16[11-22.25]y; 54% male; 31% cystic fibrosis, 29% other respiratory diseases, 28% asthma; 12% no respiratory diseases) at the Pediatrics and Pulmonology departments of a tertiary hospital. First, clinicians performed conventional auscultation with analog stethoscopes at 4 locations (trachea, right anterior chest, right and left lung bases), and documented any adventitious sounds. Then, smartphone auscultation was recorded twice in the same four locations. The recordings (n = 1060) were classified by two annotators. Seventy-three percent of recordings had quality (obtained in 92% of the participants), with the quality proportion being higher at the trachea (82%) and in the children's group (75%). Adventitious sounds were present in only 35% of the participants and 14% of the recordings, which may have contributed to the fair agreement between conventional and smartphone auscultation (85%; k = 0.35(95% CI 0.26-0.44)). Our results show that smartphone auscultation was feasible, but further investigation is required to improve its agreement with conventional auscultation.

Adesão das pessoas com diabetes tipo 1 às atividades de autocuidado / Adherencia de las personas con diabetes tipo 1 a las actividades de autocuidado / Adherence of people with type 1 diabetes to self-care activities

Objective: to assess the adherence of people with type 1 diabetes to self-care activities. Method: quantitative study with 60 diabetics, from Porto, Portugal. The Self-Care Scale for Diabetes in its version translated and adapted to Portuguese was applied in January to February 2019. Results: respondents are mostly young (36.7%), employed (63.4%), female (73.3%), married (36.7%), high educated (60.0%) and diagnosed with recent diabetes (50.0%). Most have good mean adherence to self-care behaviors related to food (5.0), blood glucose monitoring (6.8), foot care (5.6) and medication (6.4). Regarding physical activity (2.6) and smoking, 73.3% of respondents say they smoked a cigarette in the last seven days lower adherence was identified. Conclusions: there is a need to develop educational programs to ensure a higher adherence to healthy lifestyles.(AU)

Objetivo: avaliar a adesão de pessoas com diabetes tipo 1 às atividades de autocuidado. Método: estudo com 60 diabéticos, do Porto, Portugal. Foi aplicada a Escala de Autocuidado para Diabetes traduzida e adaptada para o português em janeiro a fevereiro de 2019. Resultados: os inquiridos são maioritariamente jovens (36,7%), empregados (63,4%), mulheres (36,7%), casados (36,7%), com ensino superior (60,0%) e com diagnóstico recente de diabetes (50,0%). A maioria tem boa adesão aos comportamentos de autocuidado relacionados à alimentação (5,0), monitoramento da glicemia (6,8), cuidados com os pés (5,6) e medicamentos (6,4). Em relação à atividade física (2,6) e ao tabagismo, 73,3% dos entrevistados afirmam que fumaram um cigarro nos últimos sete dias foi identificada menor adesão. Conclusões: há necessidade de desenvolvimento de programas educativos que garantam uma maior adesão aos estilos de vida saudáveis.(AU)

Objetivo: evaluar la adherencia de las personas con diabetes tipo 1 a las actividades de autocuidado. Método: estudio cuantitativo con 60 diabéticos, de Porto, Portugal. Se aplicó la Escala de Autocuidado de la Diabetes y se tradujo al portugués en enero a febrero de 2019. Resultados: los encuestados son principalmente jóvenes (36,7%), empleados (63,4%), mujeres (36,7%), casados (36,7%), con estudios superiores (60,0%) y con diagnóstico reciente de diabetes (50,0%). La mayoría tiene una buena adherencia al autocuidado relacionado con la alimentación (5,0), control de la glucosa en sangre (6,8), cuidado de los pies (5,6) y medicación (6,4). En cuanto a actividad física (2,6) y tabaquismo, 73,3% de los encuestados dice haber fumado un cigarrillo en los últimos siete días, se identificó menor adherencia. Conclusiones: hay necesidad de desarrollar programas educativos que aseguren una mayor adherencia a los estilos de vida saludables.(AU)

A Potential Link Between Prolonged Cork Exposure and Intestinal-Type Sinonasal Adenocarcinoma - Special Findings of a Retrospective Cohort Analysis.

INTRODUCTION: intestinal-type sinonasal adenocarcinoma (ITAC) is a rare epithelium tumor of the nasal cavities and paranasal sinuses. Exposure to wood and leather dusts is a strong etiological factor related to its development. Prolonged cork exposure has rarely been associated. MATERIALS AND METHODS: thirty-seven-year (1981-2018) retrospective cohort analysis of all consecutive patients with sinonasal cancer (SNC) followed at our institution. Medical records were reviewed to determine patient demographics, occupational/environmental exposure, location and extent of the tumor, stage, histopathology findings, treatment strategies, and oncologic outcomes. Survival analysis was done using Kaplan-Meier method. RESULTS: we evaluated 379 patients with SNC, including 39 (10.3%) ITAC. Patient median age was 73 years (range 49-87), 56% male and 69% with identified professional occupational exposure (54% for cork; 69.2% considering only those for which an agent has been identified). Seventy-two percent had locally advanced disease (stage III or IVA-B). The initial treatment was surgery in 77%, and 54% received adjuvant radiotherapy. The median time to progression, progression-free survival, and overall-survival was 2.36 years (95% CI 1.54-8.70), 1.96 years (95% CI 1.43-3.74), and 3.51 years (95% CI 2.33-10.02), respectively. CONCLUSION: ITAC is an uncommon malignancy that grows silently, which contributes to delayed diagnosis, advanced stage and low survival rates. In our cohort, we observed a high prevalence of cork occupational exposure. This finding may lead to the implementation of protection measures and suggest a potential link to be further studied.

Improved long-term results of intensity-modulated radiotherapy for a non-endemic European nasopharyngeal carcinoma cohort: single-center retrospective study.

PURPOSE: Report our matured outcomes of European nasopharyngeal carcinoma (NPC) treatment from a non-endemic region in the IMRT era. METHODS: We reviewed 109 consecutive patients with biopsy proven NPC treated between 2009 and 2013. All received IMRT as per RTOG 0615. Toxicity was scored accordingly to CTCAE 4.03. Platinum-based chemotherapy was delivered following the Intergroup 0099. RESULTS: Median age of 53 years; 97% Caucasian; 74% male; 72% WHO grade III; 43% T1; 14% T2; 18% T3, 25% T4; 17% N0; 17% N1; 39% N2; 27% N3. Compliance to adjuvant chemotherapy was 88%. With a median follow up of 56 months, the 4-year local control was 90.2% (88.6% for T1; 100% for T2; 85% for T3; and 91.7% for T4), the 4-year distant metastases-free survival was 86% and an overall survival rate was 77%. Local control and survival were better in G3 (p < 0.001 and p = 0.032, respectively). Xerostomia was the most frequent late toxicity in 55% (n = 60). Hypothyroidism requiring hormonal reposition occurred in 15.5% (n = 17). From the 36 deaths, 20 were due to distant metastases, 3 grade 5 toxicity, 2 from local progression, 5 non-cancer deaths and unknown cause in the remaining 6. On multivariable analysis, age (p = 0.017), local recurrence and distant metastases were associated with death (p < 0.001, both). CONCLUSION: Our matured data from the IMRT era showed a major improvement from our 3D cohort series reaching excellent local and regional control, even in T4. Local recurrences, despite few, and distant metastases were correlated with the risk of death.

Recurrent midgut volvulus in an adult patient - The case for pexy? A case report and review of the literature.

INTRODUCTION: Intestinal malrotation is a rare condition, with an incidence estimated between 0,2 to 1%. Most cases are diagnosed and treated during childhood. Adult presentations are rare and most adults present with chronic nonspecific complaints. Midgut volvulus is the most feared complication of intestinal malrotation, far more common among the pediatric than the adult population. Presentation in adulthood with a midgut volvulus accounts for a minority of these patients (15%). The Ladd procedure is the standard surgical management of midgut volvulus and intestinal malrotation. Most evidence on the outcomes of the Ladd procedure originates from studies on pediatric population and the recurrence among children who have had a Ladd procedure is low (2-7%). PRESENTATION OF CASE: We report an exceedingly rare case of a patient who presented in adulthood with a midgut volvulus and less than two years after undergoing Ladd procedure presented with a recurrence of the midgut volvulus. The recurrent midgut volvulus was successfully treated by a fixation procedure (cecopexy and duodenopexy). CONCLUSION: Reports of midgut volvulus in adult patients are scarce and reports of recurrence even scarcer hence the rate of recurrence among adult patients has yet to be determined. The recurrence rate in some of the available adult series is much higher than the rate reported among children. Should the rate of recurrence among adult patients prove higher, it poses the question of whether the Ladd procedure should be modified to include bowel fixation when performed in adults.

Prospective Observational Study on acute Appendicitis Worldwide (POSAW).

Background: Acute appendicitis (AA) is the most common surgical disease, and appendectomy is the treatment of choice in the majority of cases. A correct diagnosis is key for decreasing the negative appendectomy rate. The management can become difficult in case of complicated appendicitis. The aim of this study is to describe the worldwide clinical and diagnostic work-up and management of AA in surgical departments. Methods: This prospective multicenter observational study was performed in 116 worldwide surgical departments from 44 countries over a 6-month period (April 1, 2016-September 30, 2016). All consecutive patients admitted to surgical departments with a clinical diagnosis of AA were included in the study. Results: A total of 4282 patients were enrolled in the POSAW study, 1928 (45%) women and 2354 (55%) men, with a median age of 29 years. Nine hundred and seven (21.2%) patients underwent an abdominal CT scan, 1856 (43.3%) patients an US, and 285 (6.7%) patients both CT scan and US. A total of 4097 (95.7%) patients underwent surgery; 1809 (42.2%) underwent open appendectomy and 2215 (51.7%) had laparoscopic appendectomy. One hundred eighty-five (4.3%) patients were managed conservatively. Major complications occurred in 199 patients (4.6%). The overall mortality rate was 0.28%. Conclusions: The results of the present study confirm the clinical value of imaging techniques and prognostic scores. Appendectomy remains the most effective treatment of acute appendicitis. Mortality rate is low.

Pelvic floor muscle training protocol for stress urinary incontinence in women: A systematic review / Protocolo de treino dos músculos do pavimento pélvico em mulheres com incontinência urinária de esforço: revisão sistemática

Summary Introduction: Strengthening exercises for pelvic floor muscles (SEPFM) are considered the first approach in the treatment of stress urinary incontinence (SUI). Nevertheless, there is no evidence about training parameters. Objective: To identify the protocol and/or most effective training parameters in the treatment of female SUI. Method: A literature research was conducted in the PubMed, Cochrane Library, PEDro, Web of Science and Lilacs databases, with publishing dates ranging from January 1992 to March 2014. The articles included consisted of English-speaking experimental studies in which SEPFM were compared with placebo treatment (usual or untreated). The sample had a diagnosis of SUI and their age ranged between 18 and 65 years. The assessment of methodological quality was performed based on the PEDro scale. Results: Seven high methodological quality articles were included in this review. The sample consisted of 331 women, mean age 44.4±5.51 years, average duration of urinary loss of 64±5.66 months and severity of SUI ranging from mild to severe. SEPFM programs included different training parameters concerning the PFM. Some studies have applied abdominal training and adjuvant techniques. Urine leakage cure rates varied from 28.6 to 80%, while the strength increase of PFM varied from 15.6 to 161.7%. Conclusion: The most effective training protocol consists of SEPFM by digital palpation combined with biofeedback monitoring and vaginal cones, including 12 week training parameters, and ten repetitions per series in different positions compared with SEPFM alone or a lack of treatment.

Resumo Introdução: Os exercícios de fortalecimento dos músculos do pavimento pélvico (EFMPP) são considerados a primeira intervenção no tratamento da incontinência urinária de esforço (IUE); porém, não existe evidência sobre os parâmetros de treino. Objetivo: Identificar o protocolo e/ou os parâmetros de treino mais eficazes no tratamento da IUE feminina. Método: A pesquisa bibliográfica foi realizada entre janeiro de 1992 e março de 2014 nas bases de dados PubMed, Cochrane Library, PEDro, Web of Science e Lilacs. Os artigos incluídos eram de língua inglesa, estudos experimentais, comparando EFMPP com tratamento placebo, usual ou sem tratamento, com idade compreendida entre 18 e 65 anos e diagnóstico de IUE. A avaliação da qualidade metodológica foi realizada por meio da escala PEDro. Resultados: Sete artigos de elevada qualidade metodológica foram incluídos na presente revisão. A amostra foi constituída por 331 mulheres, com idade média de 44,4±5,51 anos, duração média das perdas urinárias de 64±5,66 meses e gravidade da IUE variando entre ligeira e grave. Os programas de EFMPP eram distintos relativamente aos parâmetros de treino dos MPP. Alguns estudos incluíram treino abdominal e técnicas adjuvantes. A taxa de cura da quantidade de perda urinária variou entre 28,6 e 80%, enquanto o aumento da força dos MPP variou de 15,6 a 161,7%. Conclusão: O protocolo de treino mais eficaz consiste nos EFMPP por palpação digital e supervisão combinados com biofeedback e cones vaginais, incluindo os parâmetros de treino de 12 semanas de duração, dez repetições por série e em distintas posições comparados com os EFMPP isolados ou sem tratamento.

Endoscopic management of afferent loop syndrome caused by enteroliths and anastomotic stricture. A case report.

Afferent loop syndrome (ALS) is a rare complication of Billroth-II gastrojejunostomy. Causes of afferent loop obstruction include adhesions, internal hernias, intestinal strictures or malignancy. Obstruction caused by enteroliths is rare and usually requires surgery. We present the case of a 90-year-old man with a Billroth-II performed 50 years earlier and three acute pancreatitis. He presented with acute abdominal pain, without signs of pancreatitis. Upper digestive endoscopy revealed a punctiform anastomotic stricture of the afferent loop. Fluoroscopy-guided contrast injection showed a dilated loop with multiple filling defects. After through-the-scope balloon dilation, multiple calculi similar to gallstones were observed in the afferent loop and were removed with a basket. There were no signs of choledochoduodenal fistula or abnormalities in the ampulla of Vater, leading us to assume the formation of intestinal calculi. This case represents a rare cause of ALS, emphasizing the possibility of solely endoscopic treatment. The stone was removed and the anastomotic stricture which was the underlying cause of the enterolith formation was treated by endoscopy. Endoscopic management of enterolith-related ALS is technically difficult and rarely reported. To our knowledge, there are two cases in which electrohydraulic lithotripsy was used to fragment a large enterolith in the afferent loop. This includes one report of failed endoscopic retrieval of an enterolith and in another case a perforation after an attempt to grasp the stone with a basket. ALS has multiple causes and non-specific clinical manifestations. We highlight the importance of high clinical suspicion and individualized treatment according to the patient's condition, severity, ALS etiology and locally available treatment possibilities.

Clinical Development and Commercialization of Advanced Therapy Medicinal Products in the European Union: How Are the Product Pipeline and Regulatory Framework Evolving?

The research and development of advanced therapy medicinal products (ATMPs) has been active in Europe and worldwide during recent years. Yet, the number of licensed products remains low. The main expected legal change in the near future in the European Union (EU) concerns the regulation on clinical trials (536/2014), which will come into force in 2018. With this new framework, a more harmonized and swift process for approval of clinical trials is anticipated, which is expected to support the entry of new innovations into the EU market. A survey on ATMPs in clinical trials during 2010-2015 in the EU was conducted in order to study the trends of ATMP development since the earlier survey published in 2012. According to the results, the number of clinical trials using ATMPs is slowly increasing in the EU. Yet, the focus is still in early development, and the projects are mainly carried out by small and medium-sized enterprises, academia, and hospitals. Oncology is the main area of clinical development. Yet, the balance between cell-based products and gene therapy medicinal products in this area may be changing in the future due to the new T-cell technologies. Many limitations and challenges are identified for ATMP development, requiring proportionate regulatory requirements. On the other hand, for such a novel field, the developers should be active in considering possible constraints and actively engage with authorities to look for solutions. This article provides up to-date information on forthcoming regulatory improvements and discusses the main challenges hampering the commercialization of ATMPs in the EU.

Manufacturing, characterization and control of cell-based medicinal products: challenging paradigms toward commercial use.

During the past decade, a large number of cell-based medicinal products have been tested in clinical trials for the treatment of various diseases and tissue defects. However, licensed products and those approaching marketing authorization are still few. One major area of challenge is the manufacturing and quality development of these complex products, for which significant manipulation of cells might be required. While the paradigms of quality, safety and efficacy must apply also to these innovative products, their demonstration may be demanding. Demonstration of comparability between production processes and batches may be difficult for cell-based medicinal products. Thus, the development should be built around a well-controlled manufacturing process and a qualified product to guarantee reproducible data from nonclinical and clinical studies.

Functional hepatocellular regeneration in elderly patients undergoing hepatectomy.

BACKGROUND & AIMS: More than 50% of liver tumours occur in patients aged 65 years or more. Assessment of functional liver regeneration capacity is crucial to minimize postoperative liver failure. We aimed to study functional hepatocellular regeneration, through scintigraphic quantification of Mebrofenin hepatic extraction fraction (HEF), after partial hepatectomy, comparing elderly patients with younger ones. METHODS: One hundred and two patients undergoing partial hepatectomy for primary or secondary hepatic lesions were prospectively included and divided in two groups: Group A - 58 patients aged <65 years (33 men, 53.9 ± 8.7 years), Group B - 44 patients aged ≥65 years (32 men, 71 ± 5 years). Groups were comparable in several aspects except for the presence of cirrhosis (more common in Group B, all patients Child-Pugh score A) and the initial diagnosis (Group B - primary lesions, Group A - metastases). The scintigraphic evaluation of Mebrofenin-HEF was performed before surgery, on the 5th and 30th day post-hepatectomy. RESULTS: Mortality and morbidity were 3.4 and 12.1%, respectively, in Group A and 2.3 and 11.4% in Group B (n.s.). HEF values (%), T1/2 (min) and Tmax (min) showed no significant differences between the two groups: Group A (preoperative: HEF = 99.2 ± 1.5%, T1/2 = 36.7 ± 21.3, Tmax = 15 ± 6. Day 5: HEF = 96.3 ± 10.8%, T1/2 = 76.4 ± 75.9; Tmax = 13.3 ± 4.9. Day 30: HEF = 98.4 ± 5.5%, T1/2 = 38.6 ± 7.7, Tmax = 12.8 ± 3.6) and Group B (preoperative: HEF = 95.3 ± 13%, T1/2 = 38.1 ± 24.1; Tmax = 15.9 ± 9.4. Day 5: HEF = 98.4 ± 2.6%, T1/2 = 106.6 ± 131.7; Tmax = 15.1 ± 6.2. Day 30: HEF = 99 ± 2.1%, T1/2 = 40.5 ± 27; Tmax = 15.5 ± 6.7). CONCLUSION: Our results suggest that functional hepatocellular regeneration is early, fast and similar between elderly and younger patients. Thus, age alone, does not appear to represent an absolute contraindication to hepatectomy.

Reeducation of pelvic floor muscles in volleyball athletes / Reeducação dos músculos do pavimento pélvico em atletas de voleibol

Objective: to verify the effectiveness of the pelvic floor muscles rehabilitation program (PFMRP) in female volleyball athletes, analyzing the amount and frequency of urinary leakage. Methods: experimental study. The sample consisted of 32 female athletes from Famalicão Athletic Volleyball Club (Portugal). The athletes were selected by convenience and distributed randomly into two groups: experimental group (EG = 16 athletes) and the control group (CG = 16 athletes). The EG underwent PFMRP for three months. The PFMRP was the awareness and identification of the pelvic floor muscles (PFM), pre-timed PFM contraction prior to occasions of increased intra-abdominal pressure, and 30 daily contractions of MPP at home. The CG had only access to the pamphlet. The assessment instruments included the questionnaires, the Pad Test (amount of urinary leakage) and frequency record of urinary leakage (7-day diary) before and after PFMRP. Results: the amount of urine leakage decreased in 45.5% of athletes under PFMRP intervention, and in 4.9% of athletes in CG, with statistical differences between the groups (p < 0.001). The reduction in the frequency of urinary leakage was 14.3% in EG, and 0.05% in CG, a statistically significant difference between the groups (p < 0.001). Conclusion: PFMRP in this study was effective to reduce stress urinary incontinence in female volleyball athletes. The program allowed significant improvement of symptoms of quantity and frequency of urinary leakage. .

Objetivo: verificar a eficácia do programa de reeducação dos músculos do pavimento pélvico (PRMPP) em atletas femininas de voleibol, analisando a quantidade e a frequência das perdas urinárias. Métodos: estudo experimental. A amostra foi constituída por 32 atletas do sexo feminino do Atlético Voleibol Clube de Famalicão (Portugal). As atletas foram selecionadas por conveniência e distribuídas aleatoriamente em dois grupos: o grupo experimental (GE = 16 atletas) e o grupo-controle (GC = 16 atletas). O GE foi submetido ao PRMPP durante 3 meses; o programa consistiu na conscientização e identificação dos músculos do pavimento pélvico (MPP), na pré-contração dos MPP ao aumento da pressão intra-abdominal, e em 30 contrações diárias dos MPP no domicílio. O GC teve acesso unicamente ao panfleto. Os instrumentos de avaliação englobaram os questionários, o pad-test (quantidade de perda urinária) e o PRMPP. Resultados: a quantidade de perda urinária diminuiu 45,5% no GE, com intervenção do PRMPP, e 4,9% nas atletas do GC, verificando-se diferenças estatisticamente significativas entre os grupos (p<0,001). Na frequência das perdas urinárias, a redução foi de 14,3% no GE e de 0,05% no GC, verificando-se diferenças estatisticamente significativas entre os grupos (p<0,001). Conclusão: o PRMPP, nessa amostra, foi eficaz na incontinência urinária de esforço em atletas do sexo feminino de voleibol, pois permitiu melhorar significativamente os sintomas de quantidade e frequência das perdas urinárias. .