Introdução: As lesões periapicais de origem endodôntica decorrem de uma infeção persistente, consequência de necrose pulpar. A persistência da infeção induz uma resposta imune inflamatória que culmina na formação de granulomas, abcessos, ou quistos. A partir dos 5 mm de dimensão no seu maior eixo, estas lesões são consideradas de tamanho crítico. Atualmente, não existe um protocolo terapêutico definido, contudo preconiza-se o tratamento endodôntico como abordagem de primeira linha. Porém, face às suas dimensões, na maioria dos casos torna-se fundamental associar um método adjuvante para o controlo da infeção, destacando-se a enucleação, a marsupialização e a descompressão, sendo este último o mais conservador. A presente série de casos relata a abordagem terapêutica de quinze casos clínicos de lesões periapicais extensas de origem endodôntica, submetidos ao tratamento endodôntico não cirúrgico, descompressão e, quando necessário, microcirurgia apical. Descrição dos Casos Clínicos: A maioria das lesões situava-se no maxilar, com sintomatologia associada e sinais de abaulamento e/ou edema. Como exames complementares de diagnóstico destaca-se o uso de testes de sensibilidade e vitalidade pulpar, que confirmaram a tendência de associação destas lesões à presença de dentes necrosados ou previamente endodonciados; tomografia computorizada de feixe cónico, para cálculo do volume inicial e pós-descompressão das lesões, e análise microbiológica. A abordagem terapêutica incluiu o tratamento ou retratamento endodôntico não cirúrgico em todos os pacientes. Adicionalmente, realizou-se o procedimento de descompressão com colocação de dreno (em seis pacientes), através da técnica de irrigação e aspiração simultâneas (em três pacientes) ou associação de ambas as técnicas (em seis pacientes). O período de descompressão via dreno foi, em média, 9 meses. Oito pacientes foram posteriormente submetidos a microcirurgia apical. Os casos clínicos apresentam um período de seguimento de 3 meses a 6 anos (média de 15 meses). Discussão e Conclusões: A combinação do tratamento endodôntico não cirúrgico com o procedimento de descompressão, independentemente da(s) técnica(s) utilizada( s), permitiu taxas de redução significativas do volume das lesões. Independentemente da resolução das lesões, a descompressão possibilitou a redução do tamanho e o espessamento da membrana da lesão, minimizando os riscos, invasividade e complexidade da intervenção cirúrgica subsequente, quando necessária.
The determination of the direction of a stellar core collapse via its neutrino emission is crucial for the identification of the progenitor for a multimessenger follow-up. A highly effective method of reconstructing supernova directions within the Deep Underground Neutrino Experiment (DUNE) is introduced. The supernova neutrino pointing resolution is studied by simulating and reconstructing electron-neutrino charged-current absorption on $^{40}$Ar and elastic scattering of neutrinos on electrons. Procedures to reconstruct individual interactions, including a newly developed technique called ``brems flipping'', as well as the burst direction from an ensemble of interactions are described. Performance of the burst direction reconstruction is evaluated for supernovae happening at a distance of 10 kpc for a specific supernova burst flux model. The pointing resolution is found to be 3.4 degrees at 68% coverage for a perfect interaction-channel classification and a fiducial mass of 40 kton, and 6.6 degrees for a 10 kton fiducial mass respectively. Assuming a 4% rate of charged-current interactions being misidentified as elastic scattering, DUNE's burst pointing resolution is found to be 4.3 degrees (8.7 degrees) at 68% coverage.
Objectives: To perform an economic evaluation comparing urinary and recombinant gonadotropins in ovarian stimulation for in vitro fertilisation (IVF) in the National Health Service perspective. Pituitary suppression was achieved through the use of gonadotropin-releasing hormone (GnRH) agonists in a long protocol. Incremental cost-effectiveness ratios of one alternative versus the other were calculated for three different age groups. Effectiveness was measured in deliveries.Methods: Effectiveness data came from the combination of results provided by two large, international, multicentric randomized controlled trials and the Portuguese Assisted Reproductive Technologies (ART) National Registry. Medication costs and reimbursement rates were obtained from official sources. Medication usage levels were the most efficient to achieve reported consumption levels. Considered ART treatment costs were obtained from government published prices.Results: Urinary gonadotropins are the dominant treatment strategy, with higher effectiveness and lower costs. Cost differences ranged from 95,83€ to 159,90€ in the analysed age groups. Incremental cost-effectiveness ratios obtained were -2886,21€ (≤34 years old), -3386,89€ (35-39 years old) and -21575,52€ (≥40 years old) per delivery. Sensitivity analysis showed that the main results did not change substantially after key parameters in the model were varied.Conclusions: Urinary gonadotropins are the most cost-effective alternative in IVF treatments after long protocol with GnRH agonist. The cost-savings achieved using urinary gonadotropins would allow for the delivery of an additional IVF cycle for every 20 cycles.
DUNE is an international experiment dedicated to addressing some of the questions at the forefront of particle physics and astrophysics, including the mystifying preponderance of matter over antimatter in the early universe. The dual-site experiment will employ an intense neutrino beam focused on a near and a far detector as it aims to determine the neutrino mass hierarchy and to make high-precision measurements of the PMNS matrix parameters, including the CP-violating phase. It will also stand ready to observe supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector implements liquid argon time-projection chamber (LArTPC) technology, and combines the many tens-of-kiloton fiducial mass necessary for rare event searches with the sub-centimeter spatial resolution required to image those events with high precision. The addition of a photon detection system enhances physics capabilities for all DUNE physics drivers and opens prospects for further physics explorations. Given its size, the far detector will be implemented as a set of modules, with LArTPC designs that differ from one another as newer technologies arise. In the vertical drift LArTPC design, a horizontal cathode bisects the detector, creating two stacked drift volumes in which ionization charges drift towards anodes at either the top or bottom. The anodes are composed of perforated PCB layers with conductive strips, enabling reconstruction in 3D. Light-trap-style photon detection modules are placed both on the cryostat's side walls and on the central cathode where they are optically powered. This Technical Design Report describes in detail the technical implementations of each subsystem of this LArTPC that, together with the other far detector modules and the near detector, will enable DUNE to achieve its physics goals.
Abstract Background Ibandronate is effective in reducing the risk of vertebral fractures, but experimental evidence offers conflicting results regarding nonvertebral fractures. Real-world evidence has been published evaluating the anti-nonvertebral fracture effect of ibandronate. Aim This meta-analysis of observational studies assessed the effectiveness of ibandronate in reducing the risk of nonvertebral fractures in women with osteoporosis. Method Pubmed/Embase databases were searched for observational studies. Risks of nonvertebral fractures and hip fractures were the outcomes. Meta-analyses were performed pooling rate ratios (RRs), using random-effects models. Data were reanalysed in sensitivity analyses considering Knapp–Hartung method and Bayesian random-effects. Results Six cohort studies were included. Overall, once-monthly 150 mg oral ibandronate reduced the risk of nonvertebral fractures (RR 0.84; 95% CI 0.76–0.94). Similar results were obtained when the comparison was restricted to once-monthly 150 mg risedronate, but no differences were found when the comparator was other oral bisphosphonates (weekly alendronate/risedronate). Ibandronate didn’t significantly change the risk of hip fractures (RR 1.25; 95% CI 0.89–1.76). The risk of hip fracture was comparable between once monthly, 150 mg oral ibandronate and other oral bisphosphonates. Intravenous ibandronate was not effective in reducing hip fractures comparing to intravenous zoledronate. The low number of studies diminished the robustness of sensitivity analyses. Conclusion Results suggest that once-monthly 150 mg oral ibandronate may be as effective as other oral bisphosphonates in reducing the risk of nonvertebral fractures. However, uncertainty associated to the small number of included studies, which are characterized by heterogeneous demographics and methodologies, precluded definitive conclusions.
During the COVID-19 pandemic, EMA set-up a large-scale cohort event monitoring (CEM) system to estimate incidence rates of patient-reported adverse drug reactions (ADRs) of different COVID-19 vaccines across the participating countries. This study aims to give an up to date and in-depth analysis of the frequency of patient-reported ADRs after the 1st, 2nd, and booster vaccination, to identify potential predictors in developing ADRs and to describe time-to-onset (TTO) and time-to-recovery (TTR) of ADRs. A CEM study was rolled out in a period ranging from February 2021 to February 2023 across multiple European countries; The Netherlands, Belgium, France, the United Kingdom, Italy, Portugal, Romania, Slovakia and Spain. Analysis consisted of a descriptive analyses of frequencies of COVID-19 vaccine-related ADRs for 1st, 2nd and booster vaccination, analysis of potential predictors in developing ADRs with a generalized linear mixed-effects model, analysis of TTO and TTR of ADRs and a sensitivity analysis for loss to follow-up (L2FU). A total of 29,837 participants completed at least the baseline and the first follow-up questionnaire for 1st and 2nd vaccination and 7,250 participants for the booster. The percentage of participants who reported at least one ADR is 74.32% (95%CI 73.82–74.81). Solicited ADRs, including injection site reactions, are very common across vaccination moments. Potential predictors for these reactions are the brand of vaccine used, the patient's age, sex and prior SARS-CoV-2 infection. The percentage of serious ADRs in the study is low for 1st and 2nd vaccination (0.24%, 95%CI 0.19––0.31) and booster (0.26%, 95%CI 0.15, 0.41). The TTO was 14 h (median) for dose 1 and slightly longer for dose 2 and booster dose. TTR is generally also within a few days. The effect of L2FU on estimations of frequency is limited. Despite some limitations due to study design and study-roll out, CEM studies can allow prompt and almost real-time observations of the safety of medications directly from a patient-centered perspective, which can play a crucial role for regulatory bodies during an emergency setting such as the COVID-19 pandemic.
Objectives The aim of this study was to analyze and characterize the outcomes of the Central Portugal Regional Pharmacovigilance Unit over a 6-year period. Methods Spontaneous reports received between January 2009 and December 2014 were considered. The annual reporting ratios were estimated. The cases were characterized according to their seriousness, previous description, causality assessment, reporting professional, pharmacotherapeutic groups of the suspected drugs, and type of adverse drug reactions most frequently reported. Results The Pharmacovigilance Unit received 1277 reports that contained 3222 adverse events. In 2014, the reporting rate was estimated at 124 reports per million inhabitants. Sixty-five percent of the reports were assessed as serious. Seventy-three percent of the cases were assessed as being at least possibly related with the suspected drug. Physicians reported 49% of the cases. The suspected drugs most frequently reported were “anti-infectives for systemic use” (n = 494, 38%). The most frequently reported adverse events were “general disorders and administration site conditions” (n = 667, 21%). Conclusions Despite the continuous efforts carried out by the Central Portugal Regional Pharmacovigilance Unit in promoting spontaneous reports of suspected adverse drug reactions, the results, although representing a contribution to the postmarketing safety monitoring of drugs, are still modest illustrating the need to promote the adherence of health-care professionals to the pharmacovigilance system and to increase their reporting rates of suspected ADRs.
Objective: To explore the usefulness of number needed to treat to be harmed (NNTH), in benefit-risk assessments, by studying the agreement between NNTH values and withdrawals of medicines from European market due to safety reasons.Methods: Medicines with data from longitudinal studies were included. Studies were identified from European Medicines Agency's Reports. Meta-analyses were performed to pool odds ratios (OR) with 95% confidence-intervals (CI). Published control event rates were applied to ORs to calculate NNTHs (95%CI) for selected adverse events.Results: NNTH (95%CI) decreased from pre- to post-marketing for the eight medicines included: peripheral neuropathy (∞ vs. 12[non-significant; NS] with almitrine; heart valve disease with benfluorex (∞ vs. NNTH ranging from 7[4–13] to 7[5–9]); myopathy (−4096[NS] vs. 797[421–1690]), new-onset diabetes (113[NS] vs. 390[425–778]), bleeding (∞ vs. 517[317–1153]), and infection (∞ vs. 253[164–463]) with niacin-laropiprant; psychiatric disorders (12[7–34] vs. 9[5–24]) with rimonabant; myocardial infarction (MI) [−1305 vs. 270[89–4362]) with rofecoxib; MI (−510 vs. NNTH ranging from 152[55–4003] to 568[344–1350]) with rosiglitazone; cardiovascular events (∞ vs. 245[129–1318]) with sibutramine; and liver injury (∞ vs. 5957[NS]) with ximelagatran.Conclusion: NNTH have potential of use as a supportive tool in benefit-risk re-evaluations of medicines and may help regulators to making decisions on drug safety.
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