Restauração transcirúrgica: passo a passo / Transsurgical restoration: step by step

Sabe-se que para uma restauração ser considerada um sucesso clínico é preciso que haja uma concomitância saudável entre a estrutura dentária, o material restaurador e as estruturas biológicas periodontais. As restaurações transcirúrgicas caracterizam-se como procedimentos alternativos para possibilitar a restauração de dentes com cárie dentária extensa, restaurações subgengivais desadaptadas e fraturas. O presente estudo teve como objetivo realizar um relato de caso de um procedimento cirúrgico-restaurador, através de uma técnica de restauração transcirúrgica. Este estudo tem como justificativa relatar um caso clínico, colaborando com maiores informações sobre a escolha da técnica a ser empregada, mostrando em quais situações devemos escolher uma restauração transcirúrgica e quais seus benefícios. Também, salientar se devemos fazer a recuperação do espaço biológico do periodonto ou não(AU)

It is known that for a restoration to be considered a clinical success, there must be a healthy concomitance between the tooth structure, the restorative material and the periodontal biological structures. Transsurgical restorations are characterized as alternative procedures to enable the restoration of teeth with extensive dental caries, maladapted subgingival restorations and fractures. The present study aims to carry out a case report of a surgical-restorative procedure, using a transsurgical restoration technique. This study is justified by reporting a clinical case, providing more information on the choice of technique to be used, showing in which situations we should choose a transsurgical restoration and what its benefits are. Also, highlight whether we should recover the biological space of the periodontium or not(AU)

Restauração indireta em resina composta: um relato de prontuário / Indirect resin composite restoration: a dental record report

Restaurações diretas em resina composta são amplamente utilizadas em odontologia para restaurar dentes posteriores. Todavia, quando há grande destruição coronária, onde a distância do istmo excede dois terços da distância intercuspídea, as restaurações indiretas em resina composta são indicadas. O presente estudo teve como objetivo relatar a análise de um prontuário de um paciente que recebeu uma restauração indireta em resina composta em dente posterior amplamente destruído. Através da análise de prontuários de pacientes atendidos nas disciplinas de Estágios Supervisionados do Curso de Odontologia da FSG Centro Universitário no ano de 2023, foi selecionado um prontuário de um paciente que compareceu a clínica odontológica da FSG com uma restauração em amálgama fraturada com reparo em resina composta que apresentou sintomatologia dolorosa. O procedimento diagnóstico ocorreu através de exame clínico e radiográfico, que constatou a indicação de substituição da restauração insatisfatória e realização de uma restauração indireta em resina composta. Os resultados estéticos e funcionais apresentados demostraram a viabilidade da técnica restauradora indireta em resina composta para reabilitar dentes posteriores com ampla destruição coronária(AU)

Direct composite resin restoration are widely used in dentistry to restore posterior teeth. However, when there is large coronary destruction, that the distance from the isthmus exceeds two- thirds of the intercuspal distance, indirect composite resin restorations are indicated. This study aimed to report the analysis of a dental record of a patient who received an indirect restoration in composite resin in a badly destroyed posterior tooth. Through the analysis of dental records of patients seen in the disciplines of Supervised Internship of the Dentistry Course at FSG Centro Universitário in the year 2023, the dental record of a patient who attended the FSG dental clinic with fractured amalgam restoration with composite resin repair was selected who had painful symptoms. The diagnostic procedure took place through clinical and radiographic examination, which revealed the indication of replacing the unsatisfactory restoration and carrying out an indirect restoration in composite resin.The aesthetic and functional results presented demonstrated the viability of the indirect composite resin restoration technique for rehabilitating posterior teeth with extensive coronal destruction(AU)

Termo de consentimento livre e esclarecido e sua relação com os procedimentos de preenchimento labial / Free and informed consent terms and its relationship with lip filling procedures

Introdução: Na medida em que envelhecemos os lábios estreitam-se, ocasionando perda de volume e contorno e como forma de minimizar este efeito fisiológico o preenchimento labial de escolha utilizado é o ácido hialurônico. É possível perceber efeitos adversos advindos do emprego deste material, e pelo fato da informação ao paciente ser assegurada pelo Código de Defesa do Consumidor e pelo fato da necessidade dos Cirurgiões-Dentistas terem de esclarecer seus pacientes, o Termo de Consentimento Livre e Esclarecido tornase necessário. Objetivo: identificar, por meio de aplicação de questionário, a percepção de profissionais que trabalham com Harmonização Orofacial em relação a necessidade do emprego do Termo de Consentimento Livre e Esclarecido (TCLE). O questionário apresentou 6 perguntas objetivas, que foram disponibilizadas na plataforma Google Forms®. Material e Método: os dados obtidos foram tabulados em uma planilha eletrônica do programa Microsoft Excel e após analisados descritivamente através de tabelas de frequência, porcentagens e gráficos estatísticos. Resultados: dentre os entrevistados foi constatado que a maioria, 87,5% dos especialistas em Harmonização Orofacial realizam o procedimento de preenchimento labial em sua rotina clínica, e 12,5% não. Conclusão: no presente estudo identificamos que os especialistas realizam o emprego do TCLE, em sua maioria, porém, alguns destes ainda negligenciam o seu uso(AU)

Introduction: As we age, the lips become thinner and to minimize this effect, the lip filler used is hyaluronic acid. It is possible to notice adverse effects arising from the use of this material, and it is extremely important that Dental Surgeons have to clarify their patients, the Free and Informed Consent Form becomes necessary. Objective: to identify, through the application of a questionnaire, the perception of professionals who work with Orofacial Harmonization in relation to the need to use the Free and Informed Consent Form (TCLE). The questionnaire presented 6 objective questions, which were made available on the Google Forms® platform. Materials and Methods: the data obtained were tabulated in a Microsoft Excel spreadsheet and then analyzed descriptively using frequency tables, percentages and graphs. Results: among those interviewed, it was found that the majority, 87.5% of specialists in Orofacial Harmonization perform the lip filling procedure in their clinical routine, and 12.5% do not. With the high percentage of 59.4%, it was possible to verify that the majority of professionals perform 1 to 3 procedures per month; 31.3% perform 4 to 9 procedures per month; and 9.4% of 10 or more monthly procedures. Conclusion: in the present study it was possible to identify that the majority of specialists in Orofacial Harmonization use the informed consent form, however, some of them still neglect its use(AU)

Restauração em resina composta semidireta em dente posterior: relato de caso / Semi-direct composite restoration in posterior toth: a case report

A escolha da técnica restauradora desempenha papel fundamental na eficácia e duração de um tratamento reabilitador. O objetivo deste relato de caso foi descrever a utilização da técnica semidireta para a confecção de uma restauração em resina composta em um primeiro molar inferior. A paciente apresentava uma restauração insatisfatória no dente 36, que necessitava ser substituída devido à infiltração por cárie. Optou-se pela técnica semidireta devido à amplitude da cavidade, que envolvia estruturas de suporte, e pela combinação das vantagens das abordagens direta e indireta. O procedimento envolveu a remoção de tecido cariado, a aplicação de hidróxido de cálcio pasta, seguida da aplicação de uma fina camada de ionômero de vidro e, posteriormente, resina fluída para realizar o selamento dentinário. O preparo foi realizado seguindo os princípios necessários. O elemento em questão foi moldado com silicone de adição e o arco antagonista, com alginato. Ambos modelos foram vertidos com silicone para modelos semirrígidos e montados em oclusor de peças de brinquedo. A restauração semidireta foi confeccionada em resina composta Filtek Z350 XT, respeitando a anatomia do dente 36. Pigmentos foram utilizados para aprimorar detalhes estéticos. Após acabamento e polimento, a peça foi condicionada e cimentada com cimento dual Relyx Ultimate. Pode-se concluir que a abordagem restauradora por meio da técnica semidireta construída em modelo semirrígido é uma opção terapêutica conservadora e vantajosa para dentes com extensa destruição coronária. Essa técnica possibilita a restauração de forma eficaz, garantindo tanto a estética quanto a função adequada do dente afetado(AU)

The choice of restorative technique plays a fundamental role in the effectiveness and duration of rehabilitation treatment. The objective of this case report was to describe the use of the semi-direct technique to create a composite resin restoration in a lower first molar. The patient had an unsatisfactory restoration on tooth 36, which needed to be replaced due to cavity infiltration. The semi-direct technique was chosen due to the amplitude of the cavity, which involved support structures, and the combination of advantages of the direct and indirect approaches. The procedure involved the removal of carious tissue, and the application of calcium hydroxide paste, followed by the application of a thin layer of glass ionomer and, subsequently, fluid resin to seal the dentin. The preparation was carried out following the necessary principles. The element in question was molded with addition silicone and the antagonist arch was molded with alginate. Both models were poured with silicone for semi-rigid models and mounted on toy parts occluders. The semi-direct restoration was made in Filtek Z350 XT composite resin, respecting the anatomy of tooth 36. Pigments were used to improve aesthetic details. After finishing and polishing, the piece was conditioned and cemented with Relyx Ultimate dual cement. It can be concluded that the restorative approach using the semi-direct technique built on a semi-rigid model is a conservative and advantageous therapeutic option for teeth with extensive coronal destruction. This technique allows for effective restoration, ensuring both the aesthetics and adequate function of the affected tooth(AU)

Drug screening and development cascade for Chagas disease: an update of in vitro and in vivo experimental models.

Chagas disease is a tropical neglected disease that affects millions of people worldwide, still demanding a more effective and safer therapy, especially in its chronic phase which lacks a treatment that promotes substantial parasitological cure. The technical note of Romanha and collaborators published in 2010 aimed establish a guideline with the set of minimum criteria and decision gates for the development of new agents against Trypanosoma cruzi with the focus on developing new antichagasic drugs. In this sense, the present review aims to update this technical note, bringing the state of the art and new advances on this topic in recent years.

Modeling groundwater redox conditions at national scale through integration of sediment color and water chemistry in a machine learning framework.

Redox conditions play a crucial role in determining the fate of many contaminants in groundwater, impacting ecosystem services vital for both the aquatic environment and human water supply. Geospatial machine learning has previously successfully modelled large-scale redox conditions. This study is the first to consolidate the complementary information provided by sediment color and water chemistry to enhance our understanding of redox conditions in Denmark. In the first step, the depth to the first redox interface is modelled using sediment color from 27,042 boreholes. In the second step, the depth of the first redox interface is compared against water chemistry data at 22,198 wells to classify redox complexity. The absence of nitrate containing water below the first redox interface is referred to as continuous redox conditions. In contrast, discontinuous redox conditions are identified by the presence of nitrate below the first redox interface. Both models are built using 20 covariate maps, encompassing diverse hydrologically relevant information. The first redox interface is modelled with a mean error of 0.0 m and a root-mean-squared error of 8.0 m. The redox complexity model attains an accuracy of 69.8 %. Results indicate a mean depth to the first redox interface of 8.6 m and a standard deviation of 6.5 m. 60 % of Denmark is classified as discontinuous, indicating complex redox conditions, predominantly collocated in clay rich glacial landscapes. Both maps, i.e., first redox interface and redox complexity are largely driven by the water table and hydrogeology. The developed maps contribute to our understanding of subsurface redox processes, supporting national-scale land-use and water management.

Electric Field-Responsive Gold Nanoantennas for the Induction of a Locoregional Tumor pH Change Using Electrolytic Ablation Therapy.

Electrolytic ablation (EA) is a burgeoning treatment for solid tumors, in which electrical energy catalyzes a chemical reaction to generate reactive species that can eradicate cancer cells. However, the application of this technique has been constrained owing to the limited spatial effectiveness and complexity of the electrode designs. Therefore, the incorporation of nanotechnology into EA is anticipated to be a significant improvement. Herein, we present a therapeutic approach based on difructose dianhydride IV-conjugated polyethylenimine-polyethylene glycol-modified gold nanorods as electric nanoantennas and nanoelectrocatalysts for EA. We demonstrate that square-wave direct current (DC) fields trigger a reaction between water molecules and chloride ions on the gold nanorod surface, generating electrolytic products including hydrogen, oxygen, and chlorine gases near the electrodes, changing the pH, and inducing cell death. These electric nanoantennas showed significant efficacy in treating colorectal cancer both in vitro and in vivo after DC treatment. These findings clearly indicate that gold nanoantennas enhance the effectiveness of EA by creating a localized electric field and catalyzing electrolytic reactions for the induction of locoregional pH changes within the tumor. By overcoming the limitations of traditional EA and offering an enhanced level of tumor specificity and control, this nanotechnology-integrated approach advances further innovations in cancer therapies.

Proximity-based activation of AURORA A by MPS1 potentiates error correction.

Faithfull cell division relies on mitotic chromosomes becoming bioriented with each pair of sister kinetochores bound to microtubules oriented toward opposing spindle poles. Erroneous kinetochore-microtubule attachments often form during early mitosis, but are destabilized through the phosphorylation of outer kinetochore proteins by centromeric AURORA B kinase (ABK) and centrosomal AURORA A kinase (AAK), thus allowing for re-establishment of attachments until biorientation is achieved. MPS1-mediated phosphorylation of NDC80 has also been shown to directly weaken the kinetochore-microtubule interface in yeast. In human cells, MPS1 has been proposed to transiently accumulate at end-on attached kinetochores and phosphorylate SKA3 to promote microtubule release. Whether MPS1 directly targets NDC80 and/or promotes the activity of AURORA kinases in metazoans remains unclear. Here, we report a novel mechanism involving communication between kinetochores and centrosomes, wherein MPS1 acts upstream of AAK to promote error correction. MPS1 on pole-proximal kinetochores phosphorylates the C-lobe of AAK thereby increasing its activation at centrosomes. This proximity-based activation ensures the establishment of a robust AAK activity gradient that locally destabilizes mal-oriented kinetochores near spindle poles. Accordingly, MPS1 depletion from Drosophila cells causes severe chromosome misalignment and erroneous kinetochore-microtubule attachments, which can be rescued by tethering either MPS1 or constitutively active AAK mutants to centrosomes. Proximity-based activation of AAK by MPS1 also occurs in human cells to promote AAK-mediated phosphorylation of the NDC80 N-terminal tail. These findings uncover an MPS1-AAK cross-talk that is required for efficient error correction, showcasing the ability of kinetochores to modulate centrosome outputs to ensure proper chromosome segregation.

Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN/GEM1802 phase II study).

BACKGROUND: Encorafenib plus binimetinib (EB) is a standard of care treatment for advanced BRAFV600-mutant melanoma. We assessed efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response. METHODS: E-BRAIN/GEM1802 was a prospective, multicenter, single arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression.Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%. RESULTS: The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After two months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial PFS and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grade 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%). CONCLUSION: Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.

Subtotal laparoscopic cholecystectomy versus conversion to open as a bailout procedure: a cohort study.

BACKGROUND: The aim of this study is to evaluate morbidity and mortality in patients taken to conversion to open procedure (CO) and subtotal laparoscopic cholecystectomy (SLC) as bailout procedures when performing difficult laparoscopic cholecystectomy. METHOD: This observational cohort study retrospectively analyzed patients taken to SLC or CO as bailout surgery during difficult laparoscopic cholecystectomy between 2014 and 2022. Univariable and multivariable logistic regression models were used to identify prognostic factors for morbimortality. RESULTS: A total of 675 patients were included. Of the 675 patients (mean [SD] age 63.85 ± 16.00 years; 390 [57.7%] male) included in the analysis, 452 (67%) underwent CO and 223 (33%) underwent SLC. Overall, neither procedure had an increased risk of major complications (89 [19.69%] vs 35 [15.69%] P.207). However, CO had an increased risk of bile duct injury (18 [3.98] vs 1 [0.44] P.009), bleeding (mean [SD] 165.43 ± 368.57 vs 43.25 ± 123.42 P < .001), intestinal injury (20 [4.42%] vs 0 [0.00] P.001), and wound infection (18 [3.98%] vs 2 [0.89%] P.026), while SLC had a higher risk of bile leak (15 [3.31] vs 16 [7.17] P.024). On the multivariable analysis, Charlson comorbidity index (odds ratio [OR], 1.20; CI95%, 1.01-1.42), use of anticoagulant agents (OR, 2.56; CI95%, 1.21-5.44), classification of severity of cholecystitis grade III (OR, 2.96; CI95%, 1.48-5.94), and emergency admission (OR, 6.07; CI95%, 1.33-27.74) were associated with presenting major complications. CONCLUSIONS: SLC was less associated with complications; however, there is scant evidence on its long-term outcomes. Further research is needed on SLC to establish if it is the safest in the long-term as a bailout procedure.

Leveraging technology to improve access to medical education in anatomy and physiology in resource-limited settings: A mixed methods study.

This study assesses the acceptability, appropriateness, feasibility, and efficacy of a novel asynchronous video-based intervention for teaching respiratory physiology and anatomy to medical students in resource-limited settings. A series of short video lectures on pleural anatomy, pulmonary physiology, and pathophysiology was created using Lightboard and screen capture technology. These were uploaded to YouTube and Google Drive and made available to 1st-3rd year medical students at two Latin American universities for 1 week. Employing a parallel-convergent mixed methods design, we conducted surveys, focus groups, interviews, and pre/post testing for qualitative and quantitative data. Thematic Analysis was used to analyze qualitative data and McNemar's test for quantitative analysis. Seventy-six students participated. The videos' short format, interactivity, and Lightboard style were highly valued for their flexibility, time efficiency, and educational impact. Students recognized their clinical relevance and trusted their content, suggesting potential applicability in similar settings. Despite infrastructure and connectivity challenges, the use of flexible streaming and downloadable options facilitated learning. Survey results indicated high levels of feasibility (99%), appropriateness (95%), and acceptability (95%), with significant knowledge gains observed (37% correct pre-test answers vs. 56% post-test, p < 0.0001). Our findings demonstrate high acceptability, appropriateness, feasibility, and efficacy of a targeted asynchronous education centered on short-format videos in resource-limited settings, enabling robust learning despite local barriers. Flexible access is key for overcoming localized barriers. Taking an adaptive, learner-centered approach to content creation and delivery to address constraints was pivotal to success. Our modular videos could serve as versatile models for flexible education in resource-constrained settings.

Treatment patterns and factors associated with adherence in pulmonary arterial hypertension.

OBJECTIVE: Improving understanding of actual pulmonary hypertension (PH) treatment adherence patterns is crucial to properly treating these patients. We aimed to primarily assess adherence to treatments used for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) specific therapies, identify potential factors related to it and secondly describe its treatment patterns. METHODS: A 6-month observational cross-sectional study in a tertiary care hospital was conducted. Patients with PH-targeted therapy who picked it up in the ambulatory hospital pharmacy and who had been on treatment with the same drug for at least 1 year were included. Adherence was assessed as: 1) Proportion of days covered (PDC); and 2) Simplified Medication Adherence Questionnaire (SMAQ). PDC ≥80% was considered adherent. Statistical analyses were performed to evaluate the study outcomes. Logistic regressions were estimated to identify the association between baseline characteristics and factors associated with adherence. P < 0.05 indicated statistical significance. RESULTS: A total of 63 patients with 127 different treatments were included, 71.4% were females with a mean age (SD) of 59 (15) years. PAH was the most common diagnosis (74.6%). Double therapy was used in 39.7% of patients, being the combination of Macitentan + Tadalafil and Ambrisentan + Tadalafil the most prescribed. Endothelin receptor antagonists were the most used treatment (40.2%). Adherence according to PDC was 93.7%, showing no great differences depending on the targeted drug used, and according to SMAQ 61.9%. The agreement degree of both methods was slight (65.1%; Kappa 0.12). Only female sex (OR: 0.23, 95% CI: 0.06-0.90; p = 0.035) was associated with worse adherence in the SMAQ method but not in the PDC. Adverse events were reported by a 55.6% of participants and the perception of effective treatment was high (95.2%). CONCLUSIONS: Adherence to PH therapy differs depending on the assessment method; PDC showed greater adherence rate than SMAQ. According to SMAQ, female sex may have a negative impact on adherence in this cohort, but PDC revealed no factors influencing it. No notable differences in adherence between treatment types were found and generally patients felt the treatments were effective in controlling their disease.

Synthesis, biosimulation and pharmacological evaluation of benzimidazole derivatives with antihypertensive multitarget effect.

In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT1R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1H NMR, 13C NMR and mass spectral data. Through biosimulation, compounds 1-7 were identified as computational safe hits, thus, best candidates underwent ex vivo testing against two distinct mechanisms implicated in hypertension: antagonism of the Ang II type 1 receptor and the blockade of calcium channel. Molecular docking studies helped to understand at the molecular level the dual vasorelaxant effects with the recognition sites of the AT1R and the L-type calcium channel. In an in vivo spontaneously hypertensive rat model (SHR), intraperitoneally administration of compound 1 at 20 mg/kg resulted in a 25 % reduction in systolic blood pressure, demonstrating both ex vivo vasorelaxant action and in vivo antihypertensive multitarget efficacy. ©2024 Elsevier.

Adolescent cannabinoid exposure rescues phencyclidine-induced social deficits through modulation of CA2 transmission.

Psychotic disorders entail intricate conditions marked by disruptions in cognition, perception, emotions, and social behavior. Notably, psychotic patients who use cannabis tend to show less severe deficits in social behaviors, such as the misinterpretation of social cues and the inability to interact with others. However, the biological underpinnings of this epidemiological interaction remain unclear. Here, we used the NMDA receptor blocker phencyclidine (PCP) to induce psychotic-like states and to study the impact of adolescent cannabinoid exposure on social behavior deficits and synaptic transmission changes in hippocampal area CA2, a region known to be active during social interactions. In particular, adolescent mice underwent 7 days of subchronic treatment with the synthetic cannabinoid, WIN 55, 212-2 (WIN) followed by one injection of PCP. Using behavioral, biochemical, and electrophysiological approaches, we showed that PCP persistently reduced sociability, decreased GAD67 expression in the hippocampus, and induced GABAergic deficits in proximal inputs from CA3 and distal inputs from the entorhinal cortex (EC) to CA2. Notably, WIN exposure during adolescence specifically restores adult sociability deficits, the expression changes in GAD67, and the GABAergic impairments in the EC-CA2 circuit, but not in the CA3-CA2 circuit. Using a chemogenetic approach to target EC-CA2 projections, we demonstrated the involvement of this specific circuit on sociability deficits. Indeed, enhancing EC-CA2 transmission was sufficient to induce sociability deficits in vehicle-treated mice, but not in animals treated with WIN during adolescence, suggesting a mechanism by which adolescent cannabinoid exposure rescues sociability deficits caused by enhanced EC-CA2 activity in adult mice.

Coping with the experience of frustration throughout life: Sex- and age-specific effects of early life stress on the susceptibility to reward devaluation.

Early life stress may lead to lifelong impairments in psychophysiological functions, including emotional and reward systems. Unpredicted decrease in reward magnitude generates a negative emotional state (frustration) that may be involved with susceptibility to psychiatric disorders. We evaluated in adolescents and adult rats of both sexes whether maternal separation (MS) alters the ability to cope with an unexpected reduction of reward later in life. Litters of Wistar rats were divided into controls (non handled - NH) or subjected to MS. Animals were trained to find sugary cereal pellets; later the amount was reduced. Increased latency to reach the reward-associated area indicates higher inability to regulate frustration. The dorsal hippocampus (dHC) and basolateral amygdala (BLA) were evaluated for protein levels of NMDA receptor subunits (GluN2A/GluN2B), synaptophysin, PSD95, SNAP-25 and CRF1. We found that adult MS males had greater vulnerability to reward reduction, together with decreased GluN2A and increased GluN2B immunocontent in the dHC. MS females and adolescents did not differ from controls. We concluded that MS enhances the response to frustration in males. The change in the ratio of GluN2A and GluN2B subunits in dHC could be related to a stronger, more difficult to update, memory of the aversive experience.

Cost-effectiveness analysis of levonorgestrel-releasing intrauterine system (LNG-IUS) 52 mg versus other long-acting reversible contraceptives for contraception in Spain.

INTRODUCTION: Condoms and combined oral contraceptive pills are widely used in Spain with high failure rates. Long-Acting Reversible Contraceptive (LARC) methods offer better efficacy and adherence and reduce unintended pregnancies (UP) compared with short-acting reversible contraceptive (SARC) methods. OBJECTIVE: To assess the cost-effectiveness of LNG-IUS 52 mg (Mirena®) versus other LARC for contraception in Spain. MATERIALS AND METHODS: A Markov model with annual cycles and an eight-year time horizon was developed from the Spanish national healthcare system (NHS) perspective, considering costs for contraceptive method acquisition, health care resources (HCR) and UP. Effectiveness was based on failure and discontinuation rates. Sensitivity analyses were performed to test the model's robustness. RESULTS: LNG-IUS 52 mg (Mirena®) resulted in lower costs and fewer UP versus LNG-IUS 13.5 mg (Jaydess®), Implant (Implanon®) and Copper IUD. LNG-IUS 52 mg (Levosert®) prevented the same UP events at a higher cost. LNG-IUS 19.5 mg (Kyleena®) was the most effective option, due to a lower discontinuation rate. CONCLUSIONS: LNG-IUS 52 mg (Mirena®) is the least costly LARC, driven by lower acquisition costs and reduced HCR utilisation. Increasing LNG-IUS 52 mg (Mirena®) uptake in contraception could generate further cost savings for the Spanish NHS and reduce economic burden of UP.

Levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena^®) is an effective and cost-saving long-acting reversible contraceptive (LARC) method compared with other similar methods in Spain over an eight-year time horizon, and Kyleena^® was the most effective option.

Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance.

Background: Ovarian cancer is the leading cause of mortality among gynecological malignancies. Carboplatin and poly (ADP-ribose) polymerase inhibitors (PARPi) are often implemented in the treatment of ovarian cancer. Homologous recombination deficient (HRD) tumors demonstrate increased sensitivity to these treatments; however, many ovarian cancer patients are homologous recombination proficient (HRP). TTFields are non-invasive electric fields that induce an HRD-like phenotype in various cancer types. The current study aimed to investigate the impact of TTFields applied together with carboplatin or PARPi (olaparib or niraparib) in preclinical ovarian cancer models. Methods: A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) human ovarian cancer cells were treated in vitro with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with various drug concentrations. Treated cells were measured for cell count, colony formation, apoptosis, DNA damage, expression of DNA repair proteins, and cell cycle. In vivo, ID8-fLuc (HRP) ovarian cancer cells were inoculated intraperitoneally to C57BL/6 mice, which were then treated with either sham, TTFields (200 kHz), olaparib (50 mg/kg), or TTFields plus olaparib; over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation; and survival analysis was performed. Results: The nature of TTFields-drug interaction was dependent on the drug's underlying mechanism of action and on the genetic background of the cells, with synergistic interactions between TTFields and carboplatin or PARPi seen in HRP and resistant cells. Treated cells demonstrated elevated levels of DNA damage, accompanied by G2/M arrest, and induction of an HRD-like phenotype. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to olaparib monotherapy and to control. Conclusion: By inducing an HRD-like phenotype, TTFields sensitize HRP and resistant ovarian cancer cells to treatment with carboplatin or PARPi, potentially mitigating a-priori and de novo drug resistance, a major limitation in ovarian cancer treatment.

Indications and outcomes of liver retransplantation in three medical centers.

INTRODUCTION: retransplantation is the only viable treatment for patients with irreversible graft loss. The objective of this study was to analyze the indications and outcomes of liver retransplantation in three medical centers. METHODS: a total of 66 patients who underwent liver retransplantation from September 1991 to December 2021 were included in the study. A retrospective analysis was performed evaluating patients demographic, clinical, primary diagnosis, indications for and time interval to retransplantation, complications and patient survival. RESULTS: from a total of 1293 primary liver transplants performed, 70 required one or more liver retransplant. The main indication for primary transplant was hepatitis C cirrhosis (21,2%). Hepatic artery thrombosis was the main cause of retransplantation (60,6%), with almost half (46,9%) of retransplants having occurred within 30 days from initial procedure. The average survival time after a repeat liver transplant, was 89,1 months, with confidence interval from 54 to 124,2. The 1-,5- and 10- year survival rate following liver retransplant were 48,4%, 38% and 30,1%, respectively. Male gender, primary non function as the cause for retransplant, prolonged operative time and higher MELD were associated with higher mortality. CONCLUSIONS: operative mortality and morbidity rates of liver retransplantation are higher than those of the first transplantation. Male gender, primary non function, prolonged operative time and higher MELD were associated with less favorable outcomes.

Loss of transient receptor potential channel 5 causes obesity and postpartum depression.

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.