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1.
J Biol Chem ; : 107551, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-39002671

RESUMO

Isoforms of microtubule associated protein 2 (MAP2) differ from their homologue Tau in the sequence and interactions of the N-terminal region. Binding of the N-terminal region of MAP2c (N-MAP2c) to the dimerization/docking domains of the regulatory subunit RIIα of cAMP-dependent protein kinase (RIIDD2) and to the Src-homology domain 2 of growth factor receptor-bound protein 2 (Grb2) have been described long time ago. However, the structural features of the complexes remained unknown due to the disordered nature of MAP2. Here we provide structural description of the complexes. We have solved solution structure of N-MAP2c in complex with RIIDD2, confirming formation of an amphiphilic α-helix of MAP2c upon binding, defining orientation of the α-helix in the complex and showing that its binding register differs from previous predictions. Using chemical shift mapping, we characterized the binding interface of SH2-Grb2 and rat MAP2c phosphorylated by the tyrosine kinase Fyn in their complex, and proposed a model explaining differences between SH2-Grb2 complexes with rat MAP2c and phosphopeptides with a Grb2-specific sequence. The results provide the structural basis of a potential role of MAP2 in regulating cAMP-dependent phosphorylation cascade via interactions with RIIDD2 and Ras signaling pathway via interactions with SH2-Grb2.

2.
Mol Phylogenet Evol ; 199: 108144, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38972494

RESUMO

Phylogenomic approaches have recently helped elucidate various insect relationships, but large-scale comprehensive analyses on relationships within sawflies and woodwasps are still lacking. Here, we infer the relationships and long-term biogeographic history of these hymenopteran groups using a large dataset of 354 UCE loci collected from 385 species that represent all major lineages. Early Hymenoptera started diversifying during the Early Triassic âˆ¼249 Ma and spread all over the ancient supercontinent Pangaea. We recovered Xyeloidea as a monophyletic sister group to other Hymenoptera and Pamphilioidea as sister to Unicalcarida. Within the diverse family Tenthredinidae, our taxonomically and geographically expanded taxon sampling highlights the non-monophyly of several traditionally defined subfamilies. In addition, the recent removal of Athalia and related genera from the Tenthredinidae into the separate family Athaliidae is supported. The deep historical biogeography of the group is characterised by independent dispersals and re-colonisations between the northern (Laurasia) and southern (Gondwana) palaeocontinents. The breakup of these landmasses led to ancient vicariance in several Gondwanan lineages, while interchange across the Northern Hemisphere has continued until the Recent. The little-studied African sawfly fauna is likewise a diverse mixture of groups with varying routes of colonization. Our results reveal interesting parallels in the evolution and biogeography of early hymenopterans and other ancient insect groups.

3.
Int J Cancer ; 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38938062

RESUMO

Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain-infiltrating growth in concert with a pronounced therapy resistance particularly of mesenchymal glioblastoma stem-like cells (GSCs) has been proposed to contribute to therapy failure. Recently, we have shown that a mesenchymal-to-proneural mRNA signature of patient derived GSC-enriched (pGSC) cultures associates with in vitro radioresistance and gel invasion. Importantly, this pGSC mRNA signature is prognostic for patients' tumor recurrence pattern and overall survival. Two mesenchymal markers of the mRNA signature encode for IKCa and BKCa Ca2+-activated K+ channels. Therefore, we analyzed here the effect of IKCa- and BKCa-targeting concomitant to (fractionated) irradiation on radioresistance and glioblastoma spreading in pGSC cultures and in pGSC-derived orthotopic xenograft glioma mouse models. To this end, in vitro gel invasion, clonogenic survival, in vitro and in vivo residual DNA double strand breaks (DSBs), tumor growth, and brain invasion were assessed in the dependence on tumor irradiation and K+ channel targeting. As a result, the IKCa- and BKCa-blocker TRAM-34 and paxilline, respectively, increased number of residual DSBs and (numerically) decreased clonogenic survival in some but not in all IKCa- and BKCa-expressing pGSC cultures, respectively. In addition, BKCa- but not IKCa-blockade slowed-down gel invasion in vitro. Moreover, systemic administration of TRAM-34 or paxilline concomitant to fractionated tumor irradiation increased in the xenograft model(s) residual number of DSBs and attenuated glioblastoma brain invasion and (numerically) tumor growth. We conclude, that KCa-blockade concomitant to fractionated radiotherapy might be a promising new strategy in glioblastoma therapy.

4.
Sci Rep ; 14(1): 14487, 2024 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-38914628

RESUMO

Analyzing irregularities in walking patterns helps detect human locomotion abnormalities that can signal health changes. Traditional observation-based assessments have limitations due to subjective biases and capture only a single time point. Ambient and wearable sensor technologies allow continuous and objective locomotion monitoring but face challenges due to the need for specialized expertise and user compliance. This work proposes a seismograph-based algorithm for quantifying human gait, incorporating a step extraction algorithm derived from mathematical morphologies, with the goal of achieving the accuracy of clinical reference systems. To evaluate our method, we compared the gait parameters of 50 healthy participants, as recorded by seismographs, and those obtained from reference systems (a pressure-sensitive walkway and a camera system). Participants performed four walking tests, including traversing a walkway and completing the timed up-and-go (TUG) test. In our findings, we observed linear relationships with strong positive correlations (R2 > 0.9) and tight 95% confidence intervals for all gait parameters (step time, cycle time, ambulation time, and cadence). We demonstrated that clinical gait parameters and TUG mobility test timings can be accurately derived from seismographic signals, with our method exhibiting no significant differences from established clinical reference systems.


Assuntos
Algoritmos , Marcha , Humanos , Marcha/fisiologia , Masculino , Feminino , Adulto , Análise da Marcha/métodos , Caminhada/fisiologia , Adulto Jovem , Pessoa de Meia-Idade
5.
Animals (Basel) ; 14(12)2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38929437

RESUMO

Conflicts between human populations and Nile crocodiles are widespread with crocodiles posing significant threats to fisherfolk and riverine communities across r-Saharan Africa. Hundreds of deadly attacks take place annually, and mortality rates may range from 50% to 100%. Attitudes and perceptions towards crocodiles were studied using structured questionnaires among fisherfolk along the River Nile and the Sudd wetlands in South Sudan. Local communities used crocodiles for their meat and skin/leather trades. The meat is regarded to enhance longevity, sexual potency, and protection against witchcraft. Crocodiles are perceived as a main threat to lives and livelihoods as they restrict people's freedom of movement along water bodies, attack livestock and humans, and devastate fishing equipment. To assess whether responses were influenced by the intensity of crocodile threats, published data on fatal crocodile attacks on humans and livestock were analysed using Generalised Linear Models (GLMs). This analysis indicated a direct link between the number of crocodile attacks and human attitudes. Crocodiles were generally feared and hated, and there was the agreement of the need to destroy breeding habitats. However, some attitudes were complex and nuanced as highlighted by the agreement of local communities on the need to destroy Nile Crocodile breeding habitats on the one hand and the need to establish crocodile sanctuaries as the the preferred strategy to mitigate risks and conflict on the other hand. There is a need for the creation of a crocodile sanctuary in the Sudd wetlands to minimise the risks of illegal hunting and to buffer the increasing pressure on crocodiles due to human population growth and economic upturn after the civil war.

6.
Vet Sci ; 11(6)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38922025

RESUMO

The integration of deep learning-based tools into diagnostic workflows is increasingly prevalent due to their efficiency and reproducibility in various settings. We investigated the utility of automated nuclear morphometry for assessing nuclear pleomorphism (NP), a criterion of malignancy in the current grading system in canine pulmonary carcinoma (cPC), and its prognostic implications. We developed a deep learning-based algorithm for evaluating NP (variation in size, i.e., anisokaryosis and/or shape) using a segmentation model. Its performance was evaluated on 46 cPC cases with comprehensive follow-up data regarding its accuracy in nuclear segmentation and its prognostic ability. Its assessment of NP was compared to manual morphometry and established prognostic tests (pathologists' NP estimates (n = 11), mitotic count, histological grading, and TNM-stage). The standard deviation (SD) of the nuclear area, indicative of anisokaryosis, exhibited good discriminatory ability for tumor-specific survival, with an area under the curve (AUC) of 0.80 and a hazard ratio (HR) of 3.38. The algorithm achieved values comparable to manual morphometry. In contrast, the pathologists' estimates of anisokaryosis resulted in HR values ranging from 0.86 to 34.8, with slight inter-observer reproducibility (k = 0.204). Other conventional tests had no significant prognostic value in our study cohort. Fully automated morphometry promises a time-efficient and reproducible assessment of NP with a high prognostic value. Further refinement of the algorithm, particularly to address undersegmentation, and application to a larger study population are required.

7.
Nature ; 630(8018): 831-835, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38768633

RESUMO

Observations of transiting gas giant exoplanets have revealed a pervasive depletion of methane1-4, which has only recently been identified atmospherically5,6. The depletion is thought to be maintained by disequilibrium processes such as photochemistry or mixing from a hotter interior7-9. However, the interiors are largely unconstrained along with the vertical mixing strength and only upper limits on the CH4 depletion have been available. The warm Neptune WASP-107b stands out among exoplanets with an unusually low density, reported low core mass10, and temperatures amenable to CH4, though previous observations have yet to find the molecule2,4. Here we present a JWST-NIRSpec transmission spectrum of WASP-107b that shows features from both SO2 and CH4 along with H2O, CO2, and CO. We detect methane with 4.2σ significance at an abundance of 1.0 ± 0.5 ppm, which is depleted by 3 orders of magnitude relative to equilibrium expectations. Our results are highly constraining for the atmosphere and interior, which indicate the envelope has a super-solar metallicity of 43 ± 8 × solar, a hot interior with an intrinsic temperature of Tint = 460 ± 40 K, and vigorous vertical mixing which depletes CH4 with a diffusion coefficient of Kzz = 1011.6±0.1 cm2 s-1. Photochemistry has a negligible effect on the CH4 abundance but is needed to account for the SO2. We infer a core mass of 11.5 - 3.6 + 3.0 M ⊕ , which is much higher than previous upper limits10, releasing a tension with core-accretion models11.

8.
Nucl Med Commun ; 45(8): 683-689, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38726601

RESUMO

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains uniformly lethal. Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in prostate cancer. 131 I-PSMA-1095 (also known as 131 I-MIP-1095) is a PSMA-targeted radioligand which selectively delivers therapeutic radiation to cancer cells and the tumor microenvironment. METHODS: We conducted a single-arm, phase 2 trial to assess efficacy and tolerability of 131 I-PSMA-1095 in mCRPC patients who had exhausted all lines of approved therapy. All patients underwent 18 F-DCFPyL PET and 18 F-FDG PET to determine PSMA-positive tumor volume, and patients with >50% PSMA-positive tumor volume were treated with up to four doses of 131 I-PSMA-1095. The primary endpoint was the response rate of prostate specific antigen (PSA). Secondary endpoints included rates of radiographic response and adverse events. Overall and radiographic progression-free survival were also analyzed. RESULTS: Eleven patients were screened for inclusion and nine patients received 131 I-PSMA-1095. The median baseline PSA was 162 µg/l, and six patients demonstrated a >50% PSA decrease. One patient demonstrated a confirmed radiographic response. Median overall survival was 10.3 months, and median progression-free survival was 5.4 months. Four patients experienced adverse events of grade 3 or higher, the most frequent being thrombocytopenia and anemia. CONCLUSION: 131 I-PSMA-1095 is highly active against heavily-pretreated PSMA-positive mCRPC, significantly decreasing tumor burden as measured by PSA. Adverse events, mainly hematologic toxicity, were not infrequent, likely related to off-target irradiation. This hematologic toxicity, as well as a higher logistical burden associated with use, could represent relative disadvantages of 131 I-PSMA-1095 compared to 177 Lu-PSMA-617.


Assuntos
Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Idoso , Pessoa de Meia-Idade , Ligantes , Idoso de 80 Anos ou mais , Glutamato Carboxipeptidase II/metabolismo , Resultado do Tratamento , Lutécio , Antígeno Prostático Específico
9.
Artigo em Inglês | MEDLINE | ID: mdl-38795108

RESUMO

BACKGROUND: Functional mitral regurgitation induces adverse effects on the left ventricle and the left atrium. Left atrial (LA) dilatation and reduced LA strain are associated with poor outcomes in heart failure (HF). Transcatheter edge-to-edge repair (TEER) of the mitral valve reduces heart failure hospitalization (HFH) and all-cause death in selected HF patients. OBJECTIVES: The aim of this study was to evaluate the impact of LA strain improvement 6 months after TEER on the outcomes of patients enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial. METHODS: The difference in LA strain between baseline and the 6-month follow-up was calculated. Patients with at least a 15% improvement in LA strain were labeled as "LA strain improvers." All-cause death and HFH were assessed between the 6 and 24-month follow-up. RESULTS: Among 347 patients (mean age 71 ± 12 years, 63% male), 106 (30.5%) showed improvement of LA strain at the 6-month follow-up (64 [60.4%] from the TEER + guideline-directed medical therapy [GDMT] group and 42 [39.6%] from the GDMT alone group). An improvement in LA strain was significantly associated with a reduction in the composite of death or HFH between the 6-month and 24-month follow-up, with a similar risk reduction in both treatment arms (Pinteraction = 0.27). In multivariable analyses, LA strain improvement remained independently associated with a lower risk of the primary composite endpoint both as a continuous variable (adjusted HR: 0.94 [95% CI: 0.89-1.00]; P = 0.03) and as a dichotomous variable (adjusted HR: 0.49 [95% CI: 0.27-0.89]; P = 0.02). The best outcomes were observed in patients treated with TEER in whom LA strain improved. CONCLUSIONS: In symptomatic HF patients with severe mitral regurgitation, improved LA strain at the 6-month follow-up is associated with subsequently lower rates of the composite endpoint of all-cause mortality or HFH, both after TEER and GDMT alone. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [COAPT]; NCT01626079).

10.
J Med Chem ; 67(10): 7935-7953, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38713163

RESUMO

The integration of diverse chemical tools like small-molecule inhibitors, activity-based probes (ABPs), and proteolysis targeting chimeras (PROTACs) advances clinical drug discovery and facilitates the exploration of various biological facets of targeted proteins. Here, we report the development of such a chemical toolbox for the human Parkinson disease protein 7 (PARK7/DJ-1) implicated in Parkinson's disease and cancers. By combining structure-guided design, miniaturized library synthesis, and high-throughput screening, we identified two potent compounds, JYQ-164 and JYQ-173, inhibiting PARK7 in vitro and in cells by covalently and selectively targeting its critical residue, Cys106. Leveraging JYQ-173, we further developed a cell-permeable Bodipy probe, JYQ-196, for covalent labeling of PARK7 in living cells and a first-in-class PARK7 degrader JYQ-194 that selectively induces its proteasomal degradation in human cells. Our study provides a valuable toolbox to enhance the understanding of PARK7 biology in cellular contexts and opens new opportunities for therapeutic interventions.


Assuntos
Proteína Desglicase DJ-1 , Proteólise , Compostos de Boro/farmacologia , Compostos de Boro/química , Compostos de Boro/síntese química , Proteína Desglicase DJ-1/metabolismo , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-Atividade
11.
Acta Orthop ; 95: 256-267, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38819193

RESUMO

Opening remarks: These guidelines are the result of discussions within a diverse group of RSA researchers. They were approved in December 2023 by the board and selected members of the International Radiostereometry Society to update the guidelines by Valstar et al. [1]. By adhering to these guidelines, RSA studies will become more transparent and consistent in execution, presentation, reporting, and interpretation. Both authors and reviewers of scientific papers using RSA may use these guidelines, summarized in the Checklist, as a reference. Deviations from these guidelines should have the underlying rationale stated.


Assuntos
Análise Radioestereométrica , Tomografia Computadorizada por Raios X , Humanos , Falha de Prótese , Guias de Prática Clínica como Assunto
12.
Sci Total Environ ; 934: 173046, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38735326

RESUMO

Although marine environments represent huge reservoirs of the potent greenhouse gas methane, they currently contribute little to global net methane emissions. Most of the methane is oxidized by methanotrophs, minimizing escape to the atmosphere. Aerobic methanotrophs oxidize methane mostly via the copper (Cu)-bearing enzyme particulate methane monooxygenase (pMMO). Therefore, aerobic methane oxidation depends on sufficient Cu acquisition by methanotrophs. Because they require both oxygen and methane, aerobic methanotrophs reside at oxic-anoxic interfaces, often close to sulphidic zones where Cu bioavailability can be limited by poorly soluble Cu sulphide mineral phases. Under Cu-limiting conditions, certain aerobic methanotrophs exude Cu-binding ligands termed chalkophores, such as methanobactin (mb) exuded by Methylosinus trichosporium OB3b. Our main objective was to establish whether chalkophores can mobilise Cu from Cu sulphide-bearing marine sediments to enhance Cu bioavailability. Through a series of kinetic batch experiments, we investigated Cu mobilisation by mb from a set of well-characterized sulphidic marine sediments differing in sediment properties, including Cu content and phase distribution. Characterization of solid-phase Cu speciation included X-ray absorption spectroscopy and a targeted sequential extraction. Furthermore, in batch experiments, we investigated to what extent adsorption of metal-free mb and Cu-mb complexes to marine sediments constrains Cu mobilisation. Our results are the first to show that both solid phase Cu speciation and chalkophore adsorption can constrain methanotrophic Cu acquisition from marine sediments. Only for certain sediments did mb addition enhance dissolved Cu concentrations. Cu mobilisation by mb was not correlated to the total Cu content of the sediment, but was controlled by solid-phase Cu speciation. Cu was only mobilised from sediments containing a mono-Cu-sulphide (CuSx) phase. We also show that mb adsorption to sediments limits Cu acquisition by mb to less compact (surface) sediments. Therefore, in sulphidic sediments, mb-mediated Cu acquisition is presumably constrained to surface-sediment interfaces containing mono-Cu-sulphide phases.


Assuntos
Cobre , Sedimentos Geológicos , Imidazóis , Methylosinus trichosporium , Oligopeptídeos , Cobre/metabolismo , Sedimentos Geológicos/química , Oligopeptídeos/metabolismo , Imidazóis/metabolismo , Imidazóis/química , Methylosinus trichosporium/metabolismo , Oxirredução , Metano/metabolismo , Oxigenases/metabolismo , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/análise
13.
Nat Commun ; 15(1): 4523, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38806464

RESUMO

Interest in gene therapy medicines is intensifying as the first wave of gene-correcting drugs is now reaching patient populations. However, efficacy and safety concerns, laborious manufacturing protocols, and the high cost of the therapeutics are still significant barriers in gene therapy. Here we describe liquid foam as a vehicle for gene delivery. We demonstrate that embedding gene therapy vectors (nonviral or viral) in a methylcellulose/xanthan gum-based foam formulation substantially boosts gene transfection efficiencies in situ, compared to liquid-based gene delivery. We further establish that our gene therapy foam is nontoxic and retained at the intended target tissue, thus minimizing both systemic exposure and targeting of irrelevant cell types. The foam can be applied locally or injected to fill body cavities so the vector is uniformly dispersed over a large surface area. Our technology may provide a safe, facile and broadly applicable option in a variety of clinical settings.


Assuntos
Terapia Genética , Vetores Genéticos , Terapia Genética/métodos , Vetores Genéticos/genética , Animais , Humanos , Camundongos , Técnicas de Transferência de Genes , Metilcelulose/química , Transfecção/métodos , Feminino , Polissacarídeos Bacterianos
14.
J Nutr ; 154(6): 1815-1826, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38599385

RESUMO

BACKGROUND: Evidence of the effectiveness of biofortified maize with higher provitamin A (PVA) to address vitamin A deficiency in rural Africa remains scant. OBJECTIVES: This study projects the impact of adopting PVA maize for a diversity of households in an area typical of rural Zimbabwe and models the cost and composition of diets adequate in vitamin A. METHODS: Household-level weighed food records were generated from 30 rural households during a week in April and November 2021. Weekly household intakes were calculated, as well as indicative costs of diets using data from market surveys. The impact of PVA maize adoption was modeled assuming all maize products contained observed vitamin A concentrations. The composition and cost of the least expensive indicative diets adequate in vitamin A were calculated using linear programming. RESULTS: Very few households would reach adequate intake of vitamin A with the consumption of PVA maize. However, from a current situation of 33%, 50%-70% of households were projected to reach ≥50% of their requirements (the target of PVA), even with the modest vitamin A concentrations achieved on-farm (mean of 28.3 µg RAE per 100 g). This proportion would increase if higher concentrations recorded on-station were achieved. The estimated daily costs of current diets (mean ± standard deviation) were USD 1.43 ± 0.59 in the wet season and USD 0.96 ± 0.40 in the dry season. By comparison, optimization models suggest that diets adequate in vitamin A could be achieved at daily costs of USD 0.97 and USD 0.79 in the wet and dry seasons, respectively. CONCLUSIONS: The adoption of PVA maize would bring a substantial improvement in vitamin A intake in rural Zimbabwe but should be combined with other interventions (e.g., diet diversification) to fully address vitamin A deficiency.


Assuntos
Biofortificação , Dieta , População Rural , Vitamina A , Zea mays , Zea mays/química , Zimbábue , Vitamina A/administração & dosagem , Humanos , Deficiência de Vitamina A/prevenção & controle , Deficiência de Vitamina A/dietoterapia , Provitaminas , Alimentos Fortificados , Estado Nutricional , Feminino , Masculino
15.
J Control Release ; 370: 310-317, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38677524

RESUMO

Adoptive cell therapy with tumor-infiltrating T cells (TILs) has generated exciting clinical trial results for the treatment of unresectable solid tumors. However, solid tumors remain difficult targets for adoptively transferred T cells, due in part to poor migration of TILs to the tumor, physical barriers to infiltration, and active suppression of TILs by the tumor. Furthermore, a highly skilled team is required to obtain tumor tissue, isolate and expand the TILs ex vivo, and reinfuse them into the patient, which drives up costs and limits patient access. Here, we describe a cell-free polymer implant designed to recruit, genetically reprogram and expand host T cells at tumor lesions in situ. Importantly, the scaffold can be fabricated on a large scale and is stable to lyophilization. Using a mouse breast cancer model, we show that the implants quickly and efficiently amass cancer-specific host lymphocytes at the tumor site in quantities sufficient to bring about long-term tumor regression. Given that surgical care is the mainstay of cancer treatment for many patients, this technology could be easily implemented in a clinical setting as an add-on to surgery for solid tumors. Furthermore, the approach could be broadened to recruit and genetically reprogram other therapeutically desirable host cells, such as macrophages, natural killer cells or dendritic cells, potentially boosting the antitumor effectiveness of the implant even more.


Assuntos
Materiais Biocompatíveis , Linfócitos do Interstício Tumoral , Alicerces Teciduais , Animais , Linfócitos do Interstício Tumoral/imunologia , Feminino , Materiais Biocompatíveis/química , Camundongos , Linhagem Celular Tumoral , Imunoterapia Adotiva/métodos , Linfócitos T/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos BALB C
16.
J Crit Care ; 82: 154814, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38643569

RESUMO

PURPOSE: Intensive care requires extensive resources. The ICUs' resource use can be compared using standardized resource use ratios (SRURs). We assessed the effect of mortality prediction models on the SRURs. MATERIALS AND METHODS: We compared SRURs using different mortality prediction models: the recent Finnish Intensive Care Consortium (FICC) model and the SAPS-II model (n = 68,914 admissions). We allocated the resources to severity of illness strata using deciles of predicted mortality. In each risk and year stratum, we calculated the expected resource use per survivor from our modelling approaches using length of ICU stay and Therapeutic Intervention Scoring System (TISS) points. RESULTS: Resource use per survivor increased from one length of stay (LOS) day and around 50 TISS points in the first decile to 10 LOS-days and 450 TISS in the tenth decile for both risk scoring systems. The FICC model predicted mortality risk accurately whereas the SAPS-II grossly overestimated the risk of death. Despite this, SRURs were practically identical and consistent. CONCLUSIONS: SRURs provide a robust tool for benchmarking resource use within and between ICUs. SRURs can be used for benchmarking even if recently calibrated risk scores for the specific population are not available.


Assuntos
Benchmarking , Mortalidade Hospitalar , Unidades de Terapia Intensiva , Tempo de Internação , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Finlândia/epidemiologia , Medição de Risco , Índice de Gravidade de Doença , Escore Fisiológico Agudo Simplificado , Recursos em Saúde/estatística & dados numéricos
18.
Artigo em Inglês | MEDLINE | ID: mdl-38576165

RESUMO

BACKGROUND: Variation in usual practice in fluid trials assessing lower versus higher volumes may affect overall comparisons. To address this, we will evaluate the effects of heterogeneity in treatment intensity in the Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care trial. This will reflect the effects of differences in site-specific intensities of standard fluid treatment due to local practice preferences while considering participant characteristics. METHODS: We will assess the effects of heterogeneity in treatment intensity across one primary (all-cause mortality) and three secondary outcomes (serious adverse events or reactions, days alive without life support and days alive out of hospital) after 90 days. We will classify sites based on the site-specific intensity of standard fluid treatment, defined as the mean differences in observed versus predicted intravenous fluid volumes in the first 24 h in the standard-fluid group while accounting for differences in participant characteristics. Predictions will be made using a machine learning model including 22 baseline predictors using the extreme gradient boosting algorithm. Subsequently, sites will be grouped into fluid treatment intensity subgroups containing at least 100 participants each. Subgroups differences will be assessed using hierarchical Bayesian regression models with weakly informative priors. We will present the full posterior distributions of relative (risk ratios and ratios of means) and absolute differences (risk differences and mean differences) in each subgroup. DISCUSSION: This study will provide data on the effects of heterogeneity in treatment intensity while accounting for patient characteristics in critically ill adult patients with septic shock. REGISTRATIONS: The European Clinical Trials Database (EudraCT): 2018-000404-42, ClinicalTrials. gov: NCT03668236.

19.
Crit Care Med ; 52(4): e217-e218, 2024 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-38483239
20.
J Orthop Res ; 42(8): 1820-1830, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38433320

RESUMO

Minimally invasive sacroiliac joint fusion has become increasingly prevalent and is described to reduce pain and improve function. In some patients, pain can recur several months after primary surgery. Lack of early implant osseointegration might be a cause of pain and hence an indication for revision surgery. Triangular titanium implants are the most documented implant for minimally invasive sacroiliac joint fusion. There is, however, no knowledge of how triangular titanium implants osseointegrate in humans and whether fusion is induced over the sacroiliac joint. During planned revision surgery due to recurrent pain, six triangular titanium implants were retrieved from six different patients at median 9 months from primary surgery. All six implants were scanned using microcomputed tomography. The presence or absence of bone in-growth, on-growth, and through-growth of the implants was evaluated as an indication of implant osseointegration. Three of six implants showed no or minor signs of osseointegration. Of the three remaining implants, one showed partial osseointegration and two implants showed high degrees of osseointegration. This study showed that triangular titanium implants can osseointegrate into host bone in humans. When osseointegration occurs, triangular titanium implants can give fusion across the sacroiliac joint.


Assuntos
Osseointegração , Articulação Sacroilíaca , Titânio , Humanos , Articulação Sacroilíaca/cirurgia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Idoso , Microtomografia por Raio-X , Fusão Vertebral/métodos , Fusão Vertebral/instrumentação
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