Role of Aducanumab in the Treatment of Alzheimer's Disease: Challenges and Opportunities.

Aducanumab is a monoclonal antibody selective for amyloid ß (Aß) aggregates. In June 2021, aducanumab became the first drug underlying the pathophysiology of Alzheimer's disease (AD) approved by the US Food and Drug Administration (FDA), under the accelerated approval pathway. The decision was based on the ability of aducanumab to remove Aß plaques, without any evidence that the Aß clearance is correlated with less cognitive or functional decline. This decision has generated a considerable debate in the scientific community, especially because the results from the two Phase 3 trials, EMERGE and ENGAGE, were divergent and, even after the post hoc analysis, the data were insufficient to prove aducanumab efficacy. Moreover, some researchers think that this approval will be an obstacle to the progress and also demonstrated concerns about aducanumab cost and its safety profile. The European Medicines Agency's rejection of aducanumab in December 2021 just brought more controversy over FDA's decision. Now, Biogen is designing the FDA's required confirmatory study, named ENVISION, which should be complete in 2026. Despite the controversy, the aducanumab showed to affect downstream tau pathology, which could open doors for a combination therapy approach for AD (anti-tau and anti-amyloid drug). This review summarizes the clinical development of aducanumab until regulatory agencies' decisions, the available trials data and the controversy over aducanumab approval for AD.

Revisão de 5 anos (2015-2019) da reconstrução aloplástica imediata no Centro Hospitalar e Universitário de Coimbra, Portugal / 5-year revision (2015-2019) of immediate alloplastic reconstruction in Hospital and University Center of Coimbra, Portugal

■ RESUMO Introdução: Como o câncer de mama é a doença maligna mais prevalente em todo o mundo, o tratamento conservador é de extrema importância. No entanto, em muitos casos, a mastectomia continua sendo o procedimento cirúrgico indicado e, como qualquer outra amputação, leva um fardo significativo para essas pacientes. No caso da mastectomia, a reconstrução imediata da mama é o tratamento padrão. A reconstrução aloplástica continua sendo o tipo mais amplamente realizado de reconstrução mamária imediata. Métodos: Neste artigo, os autores apresentam uma série de 105 casos de reconstrução aloplástica imediata em 5 anos de 2015 a 2019 no Centro Hospitalar e Universitário de Coimbra, Portugal. Inclui mastectomias curativas e redutoras de risco realizadas por ginecologistas oncológicos. As opções de reconstrução oferecidas pela equipe de reconstrução plástica incluíram tanto a reconstrução direta no implante quanto a reconstrução em dois estágios com o uso de expansores de tecido. Resultados: Dados sobre a doença oncológica, tipo de mastectomia, critérios de seleção das pacientes e resultados pós-operatórios imediato e tardio com diferentes técnicas de reconstrução imediata foram coletados, analisados e comparados com a literatura. Em nosso estudo, o índice de massa corporal foi o único preditor mais significativo de complicações e seu impacto foi estatisticamente significativo. Conclusão: Os resultados obtidos representam uma etapa essencial para a melhoria da qualidade da assistência à mulher em reconstrução mamária.

■ ABSTRACT Introduction: With breast cancer being the most prevalent malignancy worldwide, conservative treatment is of tremendous importance. Nevertheless, in many cases, mastectomy remains the indicated surgical procedure, and like any other amputation, it carries a significant burden on those patients. In the case of mastectomy, immediate breast reconstruction is the standard of care. Alloplastic reconstruction remains the most widely performed type of immediate breast reconstruction. Methods: In this article, the authors present a series of 105 cases of immediate alloplastic reconstruction in 5 years from 2015 to 2019 in Centro Hospitalar e Universitário de Coimbra, Portugal. It includes curative and risk-reducing mastectomies performed by oncologic gynecologists. The reconstruction options offered by the plastic reconstructive team included both direct-to-implant reconstruction and two-stage reconstruction with the use of tissue expanders. Results: Data regarding the oncologic disease, type of mastectomy, patient selection criteria and immediate and late postoperative outcomes with different techniques of immediate reconstruction were collected, analyzed, and compared to literature. In our study, body mass index was the single most significant predictor of complications and, its impact was statistically significant. Conclusion: The results obtained represent an essential step to improving care quality for women undergoing breast reconstruction.

Alzheimer's disease: Recent treatment strategies.

Alzheimer Disease (AD) is a neurodegenerative disease characterized by two neuropathological hallmarks: extracellular deposition of amyloid plaques and intracellular neurofibrillary tangles. Current treatment for AD (donepezil, galantamine, rivastigmine and memantine) is only symptomatic and has modest benefits. Thus, the development of drugs with the potential to change the progression of the disease has been a priority. Therapies targeting amyloid ß have been the focus for almost 30 years. However, highly promising drugs recently failed to show clinical benefits in phase III trials. Even the positive findings presented by Biogen on Aducanumab are not entirely clear and further data is necessary to confirm its validity. Therefore, researchers are turning their efforts around to tau-targeting therapies, since tau protein appears to be better correlated with the severity of cognitive decline than amyloid ß. Currently, most anti-tau agents in clinical trials are immunotherapies and they are in the early stages of clinical research. Four monoclonal antibodies anti-tau (Gosuranemab, Tilavonemab, Semorinemab and Zagotenemab) and one anti-tau vaccine (AADvac1) have reached phase II, so far. In this review, we discuss the potential disease-modifying agents tested in clinical trials and update the information of drugs that are still under clinical evaluation.

Bilateral Lower Limb Salvage after Fourth-degree Burns: Subscapular Axis Free and Chimeric Flaps Effectiveness in Complex Reconstruction.

Microsurgery is usually required for reconstruction of complex lower limb defects, preserving otherwise unsalvageable injuries. Fourth-degree burns are severe traumatic injuries. A case of bilateral lower limb salvage through a resourceful use of subscapular axis free and chimeric flaps for acute burn reconstruction of extensive lower leg injuries is reported. A 48-year-old man sustained a 40% surface area flame burn, circumferential and full-thickness at the lower limbs. Debridement of fourth-degree burns of the anterior lower legs resulted in bone exposure of the left and right tibias, right medial malleolus, and Achilles tendon. A latissimus dorsi (LD) flap plus a chimeric subscapular axis free flap with 3 components (LD, serratus anterior (SA), and parascapular) were designed for reconstruction. LD insetting for left tibia coverage with anastomoses to anterior tibial vessels was performed. Right side flap insetting provided tibia coverage with LD; medial malleolus with SA; and Achilles tendon with parascapular flap. An anatomical variation required anastomoses to proximal (chimeric LD + SA) and distal (parascapular) ends of posterior tibial vessels because of an independent origin of the pedicles. At 10-months follow-up after intensive rehabilitation, the patient showed proper functional outcomes at daily-life and work activities with autonomous walking using a single crutch. This case highlights the importance of microsurgery and chimeric flaps for limb salvage in extreme situations. The authors review and discuss the surgical options, emphasizing specific considerations of microsurgical reconstruction in burn patients.

Índices de predição de mortalidade na unidade de queimados. Estudo comparativo / Mortality prediction models in the burn unit. Comparative study

INTRODUÇÃO E OBJECTIVO: Os índices de prognóstico em queimados determinam a mortalidade previsível da população, que permanece uma importante medida de avaliação dos cuidados prestados. O estudo visa comparar diferentes índices de predição de mortalidade numa unidade de queimados (UQ) e identificar potenciais aplicabilidades. MATERIAL E MÉTODOS: Estudo retrospetivo dos doentes internados na UQ entre 2016 e 2018 (n = 409). Avaliação da mortalidade e comparação das especificidades entre sobreviventes e falecidos, através de dados demográficos e clínicos na admissão. Avaliação de quatro índices (Abbreviated Burn Severity Index (ABSI), modelo de Ryan, Belgian Outcome in Burn Injury (BOBI) e revised-Baux) na determinação da mortalidade prevista versus observada, e análise da discriminação e ajuste dos modelos (curvas ROC e area under the curve, AUC; testes de Hosmer-Lemeshow). RESULTADOS: A média de idades dos doentes foi de 59.1 anos, sendo 56.5% homens, com superfície corporal queimada total (SCQT) média de 12%, queimaduras de terceiro grau presentes em 67% e lesão inalatória em 11.5%. A mortalidade global observada foi de 6.4% (n = 26). Os doentes falecidos eram significativamente mais velhos (71.7 vs. 58.3 anos; p < 0.001), apresentavam maior SCQT (23.2 vs. 11.2%; p < 0.001) e mais queimaduras de terceiro grau (92.3 vs. 65.3%; p = 0.005), sem diferenças significativas no género ou lesão inalatória. Os índices de mortalidade apresentaram ajuste e discriminação adequados. Todos os índices evidenciaram valores-p > 0.05 no teste de Hosmer-Lemeshow. O revised- Baux e o ABSI apresentaram um bom poder de discriminação (AUC 0.84 ± 0.04 e 0.81 ± 0.04, respectivamente), o BOBI moderado/bom (0.79 ± 0.04) e o Ryan moderado (0.73 ± 0.05). CONCLUSÕES: Os quatro índices de mortalidade revelaram um desempenho preditivo adequado, com o revised-Baux apresentando a melhor precisão na previsão da mortalidade. A sua utilização nas UQ constitui uma ferramenta preciosa na estratificação do risco, controlo da qualidade dos cuidados, comparação de novas estratégias terapêuticas e investigação científica

BACKGROUND AND OBJECTIVE: Prognostic scoring models in burn patients predict mortality risk in burn-injured populations. Mortality remains a main outcome measure for burn care. The study aims to compare different mortality prediction models in the burn unit (BU) and identify their potential applications. METHODS: Retrospective study of 409 burn patients admitted in the BU between 2016 and 2018, including mortality assessment and comparative analysis of survivors and deceased patients' characteristics based on admission demographic data and clinical criteria. Evaluation of four models (Abbreviated Burn Severity Index (ABSI), Ryan model, Belgian Outcome in Burn Injury (BOBI) and revised-Baux) on assessment of predicted mortality versus observed, and analysis of models' discriminative power and goodness-of-fit (ROC curves and area under the curve - AUC; and Hosmer-Lemeshow tests). RESULTS: Patients mean age was 59.1 years and mean total burned surface area (TBSA) was 12%; 56.5% were male; third degree burns were present in 67% and inhalation injury in 11.5%. Overall observed mortality rate was 6.4% (n = 26). Deceased patients were significantly older (71.7 vs. 58.3 years; p < 0.001), presented a larger TBSA (23.2 vs. 11.2%; p < 0.001) and higher frequency of third degree burns (92.3 vs. 65.3%; p = 0.005), with no significant difference on patient gender and inhalation injury. Mortality prediction models presented adequate goodness-of-fit and discrimination. All models showed p-values > 0.05 in Hosmer-Lemeshow test assessment. Revised-Baux and ABSI showed good discriminative power (AUC 0.84 ± 0.04 and 0.81 ± 0.04, respectively), BOBI discrimi¬nation was moderate / good (0.79 ± 0.04) and moderate with Ryan (0.73 ± 0.05). CONCLUSIONS: The four mortality indices revealed appropriate predictive performance, with revised-Baux presenting as the most accurate model for prediction of mortality. Their use in the BU represents a valuable tool for risk stratification, quality control of burn care, appraisal of new therapeutic strategies and scientific research purposes

Fournier's Gangrene: 10-Year Experience of a Plastic Surgery and Burns Department at a Tertiary Hospital.

INTRODUCTION: Fournier gangrene is a polymicrobial life threatening infection of perineal subcutaneous soft tissues with its point of origin in urologic, colorectal or skin diseases. Although more frequent in elderly and men, it can affect all genders and age groups. Perianal abscess, diabetes mellitus and Escherichia coli are the most frequent cause, predisposing comorbidity, and microorganism found in tissue culture analysis respectively. The objective of this study was to describe the experience of a Plastic Surgery Department of a tertiary Hospital in reconstructing Fournier's gangrene perineal defects and its detailed demography. MATERIAL AND METHODS: The sample is composed of all patients with Fournier gangrene admitted in the Plastic Surgery and Burns Department. The authors retrospectively collected and analyzed demographic and clinical data during a period of 10 years including gender, age, length of stay, cause, number of debridements, predisposing factors, microbial culture results, surgical reconstructive techniques and its associated complications, additional surgical procedures and outcomes. RESULTS: Fifteen patients were identified: 14 males (93%) and one female (7%); mean age was 66.9 years (range: 46 - 86); mean, length of stay was 46.8 days (range: 20 - 71 days) and mean number of debridements was 3.3 (range: 1 - 4). The most frequent predisposing factor was diabetes mellitus, the major cause was perianal (n = 2) and skin abscess (n = 2). Eight (53.3%) patients had no identifiable source of Fournier gangrene. Various types of reconstructive techniques were employed; and 5 additional surgical interventions (33.3%) were undertaken (one cystostomy, two orchidectomy, two ileostomy); six patients (40%) presented reconstructive technique complications with adequate final outcome. DISCUSSION: In contrast with the literature, where Escherichia coli was the most frequently isolated agent, Staphylococcus aureus was the most frequent microorganism found in tissue biopsy/pus collection analysis. A higher than expected number of patients (n = 8) had no identifiable source of Fournier gangrene. This findings can be explained by the retrospective non-multicentre study limitation, with a potencial source of bias patients that were transferred from other hospitals in advanced stage, without point of origin of Fournier's gangrene identified. CONCLUSION: Early recognition and extensive necrotic tissue debridement, along with prompt and adequate antimicrobial treatment, are the mainstay of Fournier gangrene management, thus reducing morbidity and mortality in these patients. Surgical reconstruction challenges derived from this condition should be addressed by specialized teams due to the risk of dysfunctional sequelae and conspicuous deformities. Taking in account the single-center and retrospective observational character of the present study, these premises require proper validation from a multicenter prospective study.

Introdução: A gangrena de Fournier é uma infeção polimicrobiana potencialmente fatal que afeta os tecidos moles do períneo com ponto de origem em patologias urológicas, coloretais ou cutâneas. Apesar de ser mais frequente no sexo masculino e em idosos, pode afetar ambos os géneros e qualquer idade. O abcesso perianal, a diabetes mellitus e a Escherichia coli são respetivamente a causa, a co-morbilidade e o micro-organismo mais frequentemente encontrados. Este estudo teve como objetivo descrever a experiência de um Serviço de Cirurgia Plástica e Queimados de um Hospital terciário no tratamento e reconstrução de defeitos perineais causados por gangrena de Fournier, disponibilizando detalhes sobre a sua demografia. Material e Métodos: A amostra é constituída por todos os doentes internados no serviço de Cirurgia Plástica e Queimados com o diagnóstico de gangrena de Fournier. Os autores realizaram uma colheita e análise retrospetiva de dados clínicos e demográficos durante um período de 10 anos incluindo género, idade, tempo de internamento, causa, número de desbridamentos, fatores predisponentes, resultados microbiológicos de culturas de pus, técnicas reconstrutivas cirúrgicas e suas complicações, intervenções cirúrgicas adicionais e o resultado final. Resultados: Foram identificados 15 doentes: 14 homens (93%) e uma mulher (7%); a idade média foi 66,9 anos (amplitude: 46 - 86); tempo médio de internamento foi 46,8 dias (amplitude: 20 - 71 dias) e o número médio de desbridamentos foi 3,3 (amplitude: 1 - 4). O fator predisponente mais frequente foi a diabetes mellitus, e as causas mais frequentes o abcesso perianal (n = 2) e o abcesso cutâneo (n = 2). Em oito (53,3%) doentes não foi identificada a causa da gangrena de Fournier. Foram utilizadas várias técnicas reconstrutivas e realizadas conco (33,3%) intervenções cirúrgicas adicionais (uma cistostomia, duas orquidectomias, duas ileostomias); seis doentes (40%) apresentaram complicações de técnicas reconstrutivas com resultado final adequado. Discussão: O micro-organismo mais frequentemente isolado nas culturas de pus foi o Staphylococcus aureus, o que contrasta com a literatura onde a Escherichia coli é o agente mais frequentemente isolado. Foi identificado um número superior ao esperado de doentes sem causa identificável (n = 8) de gangrena de Fournier. Estes achados podem ser explicados pelo facto de se tratar de um estudo retrospetivo multicêntrico, com um potencial viés por existirem doentes que foram transferidos de outras institucões em estado avançado de doença, sem foco de origem de gangrena de Fournier identificado. Conclusão: O precoce reconhecimento e extenso desbridamento do tecido necrosado, em conjunto com um adequado tratamento antibiótico, são os pilares do tratamento da gangrena de Fournier reduzindo assim a morbilidade e mortalidade destes doentes. Os desafios cirúrgicos reconstrutivos que advêm desta patologia devem ser abordados por uma equipa especializada, pelo risco de sequelas funcionais e estéticas. Tendo em conta o carater observacional, retrospetivo e unicêntrico do presente estudo, estas premissas requerem uma validação adequada através de um estudo prospetivo e multicêntrico.

Evaluation of Procalcitonin Accuracy for the Distinction Between Gram-Negative and Gram-Positive Bacterial Sepsis in Burn Patients.

Sepsis is the main cause of death in burns. Early institution of antimicrobial therapy is crucial to optimize outcomes but superfluous therapy increases adverse events, microbial resistance, and costs. Blood cultures are the gold standard for diagnosis but can take 48 to 72 hours. Biomarkers are used to help sepsis diagnosis and distinction between Gram-negative and Gram-positive bacterial cause. The aim of this work is to evaluate procalcitonin (PCT) accuracy for this distinction in burn patients. Retrospective observational study of adult septic burn patients with ≥15% total burn surface area admitted from January 2011 to December 2014 at a Burn Unit in Portugal. A statistical analysis was done, evaluating the correlation between PCT levels on the day of the first positive blood culture and microbiological data for Gram-negative and Grand-positive bacteria. Patients with mixed bacterial and/or fungal blood cultures were excluded. Data were summarized by quartiles statistics. Blood cultures were positive in 189 patients: 75 (39.7%) showed growth for Gram-negative and 114 (60.3%) for Gram-positive bacteria. Patients with Gram-negative bacteria have significantly higher PCT levels. Receiver operating characteristic curve analysis showed accuracy for Gram-negative discrimination with area under the curve = 0.687. Most elevated levels were related to nonfermentative Gram-negative bacteria and by Klebsiella pneumoniae and other Enterobacteriaceae. PCT levels were significantly higher in burn patients with Gram-negative sepsis comparing to patients with Gram-positive sepsis and controls. The determination of PCT levels may help the choice of empirical antimicrobial therapy while microbiological culture results are not available, despite not fully ensuring the desirable degree of precision.

Procalcitonin kinetics after burn injury and burn surgery in septic and non-septic patients - a retrospective observational study.

BACKGROUND: Early sepsis diagnosis is crucial for the correct management of burn patients, and it clearly influences outcomes. The systemic inflammatory response triggered by burns mimics sepsis presentation and complicates early sepsis diagnosis. Biomarkers were advocated to aid the diagnosis of early sepsis. Serum procalcitonin (PCT) exhibits fair accuracy and good correlation with sepsis severity, being used in diverse clinical settings. However, few studies have evaluated perioperative changes in PCT levels in burn patients. The present study evaluated PCT kinetics during the first days after burn injury and subsequent surgical interventions to assess PCT utility in distinguishing septic from non-septic inflammatory responses. METHODS: This study was a retrospective observational study of all burn patients admitted to the Coimbra Burns Unit (Portugal) between January 2011 and December 2014 who presented with a total burn surface area ≥ 15% and who underwent subsequent surgery. PCT kinetics were investigated a) during the first five days after burn injury and b) preoperatively during the five days after surgery in three subsets of patients, including those with no preoperative and no postoperative sepsis (NN), no preoperative but postoperative sepsis (NS), and preoperative and postoperative sepsis (SS). A total of 145 patients met the selection criteria and were included in the analysis. RESULTS: PCT levels in the first five days after burn injury were significantly higher in patients who developed at least one sepsis episode (n = 85) compared with patients who did not develop sepsis (n = 60). PCT values > 1.00 ng/mL were clearly associated with sepsis. Study participants (n = 145) underwent a total of 283 surgical interventions. Their distribution by preoperative/postoperative sepsis status was 142 (50.2%) in NN; 62 (21.9%) in NS; and 79 (27.9%) in SS. PCT values exhibited a parallel course in the three groups that peaked on the second postoperative day and returned to preoperative levels on the third day or later. The lowest PCT values were found in NN, and the highest values were observed in SS; the NS values were intermediate. CONCLUSIONS: PCT kinetics coupled with a clinical examination may be helpful for sepsis diagnosis during the first days after burn injury and burn surgery.

Checking procalcitonin suitability for prognosis and antimicrobial therapy monitoring in burn patients.

BACKGROUND: Due to greater infection susceptibility, sepsis is the main cause of death in burn patients. Quick diagnosis and patient stratification, early and appropriated antimicrobial therapy, and focus control are crucial for patients' survival. On the other hand, superfluous extension of therapy is associated with adverse events and arousal of microbial resistance. The use of biomarkers, necessarily coupled with close clinical examination, may predict outcomes, stratifying patients who need more intensive care, and monitor the efficacy of antimicrobial therapy, allowing faster de-escalation or stop, reducing the development of resistance and possibly the financial burden, without increasing mortality. The aim of this work is to check the suitability of procalcitonin (PCT) to fulfill these goals in a large sample of septic burn patients. METHODS: One hundred and one patients, with 15% or more of total body surface area (TBSA) burned, admitted from January 2011 to December 2014 at Coimbra Burns Unit (CBU), in Portugal were included in the sample. All patients had a diagnosis of sepsis, according to the American Burn Association (ABA) criteria. The sample was factored by survival (68 survivors and 33 non-survivors). The maximum value of PCT in each day was used for statistical analysis. Data were summarized by location measures (mean, median, minimum, maximum, quartiles) and dispersion measures (standard error and range measures). Statistical analysis was performed with SPSS© 23.0 IBM© for Windows©. RESULTS: There were statistically significant differences between PCT levels of patients from the survivor and non-survivor groups during the first and the last weeks of hospitalization as well as during the first week after sepsis suspicion, being slightly higher during this period. During the first 7 days of antimicrobial therapy, PCT was always higher in the non-survivor, still without reaching statistical significance, but when the analysis was extended till the 15th day, PCT increased significantly, rapidly, and steadily, denouncing therapy failure. CONCLUSION: Despite being not an ideal biomarker, PCT proved to have good prognostic power in septic burn patients, paralleling the evolution of the infectious process and reflecting the efficacy of antimicrobial therapy, and the inclusion of its serial dosing may be advised to reinforce antimicrobial stewardship programs at burn units; meanwhile, more accurate approaches are not available.

Uterine cavity calcifications: a report of 7 cases and a systematic literature review.

We report 7 uterine cavity calcification cases and systematically review the literature on cases presenting this finding. In our series of cases, the mean age of patients was 31.6 ± 5.4 years, with an infertility period ranging from 2 to 8 years. None of our patients had a history of intrauterine contraceptive device use, and 3 had undergone operative termination of pregnancy. Diagnostic and therapeutic hysteroscopy with complete removal of the calcifications was performed in all patients with fertility restoration in 5 of them. Our review included 35 articles published from 1989 to 2013 reporting endometrial calcification cases, with a total of 85 cases. Analyzed variables included patient age, abortion antecedents, clinical presentation, diagnostic method, treatment, and outcome. The mean age of the analyzed cases was 34.3 years, ranging from 19 to 62 years. Abortion antecedents were present in most patients (76.5%). The most frequently used diagnostic methods were ultrasound (88.5% of articles) and hysteroscopy (85.7%). Regarding the clinical presentation, infertility was the most common feature (72.9% of cases) followed by menstrual abnormalities (30.3%). Hysteroscopic removal, whether alone or combined with other techniques, was the most used method for the removal of osseous tissue (70.6% of cases) followed by curettage (27.1%). After removal of the bony fragments, 55.6% of the infertile patients achieved a pregnancy. A total of 14 cases reported relief of symptoms other than infertility. All of the data concerning outcome were stratified according to the treatment modality used. We conclude that endometrial calcifications in the uterine cavity are a relevant cause of secondary infertility, which can generally be properly diagnosed and treated through hysteroscopy, with successful restoration of fertility in most cases.