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PURPOSE: The primary aim of our study was to identify the absolute incidence and implant survival of multiply revised knee arthroplasties based on nationwide register data. The secondary aim was to determine the change in the absolute incidence and implant survival of multiply revised knee arthroplasties Methods: We performed a retrospective observational study of primary knee arthroplasties using several nationwide Danish registers. All primary knee arthroplasties performed in Denmark from 1998 to 2021 were identified. From these primary arthroplasties, revision procedures were identified. Kaplan-Meier plots were used in survival analysis to estimate the likelihood of implant survival. RESULTS: 161,384 primary knee arthroplasties and their revisions performed between 1998 and 2021 were identified; of 13,786 (8.5%) revisions there were 10,638 1st revisions, 2,148 2nd revisions, 624 3rd revisions, 223 4th revisions, and 153 procedures that had been revised more than 4 times. The 10-year revision-free survival of primary arthroplasties was 92.3% (95% confidence interval [CI] 92.2-92.5). First-time revisions had a 10-year revision-free survival of 75.9% (CI 74.9-76.9). The 10-year survival of second- and third-time revisions was 65.1% (CI 62.6-67.6) and 57.8% (CI 53.4-62.5), respectively. The 10-year implant survival probabilities of primary knee arthroplasties were 91.4% in 1998-2009 and 93.3% in 2010-2021 (difference 2.2%). The 10-year implant survival probabilities of 1st revisions were 77% in 1998-2009 and 75% in 2010-2021 (difference -2.4%). CONCLUSION: We found that 0.3% of all primary knee arthroplasties resulted in 3 or more revisions. The implant survival decreased for each consecutive revision, with almost half of the 3rd revisions being re-revised within 10 years. The 10-survival of the primary implant was higher in 2010-2021, and the 10-year survival of the 1st revision was higher in 1998-2009.
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Artroplastia do Joelho , Falha de Prótese , Sistema de Registros , Reoperação , Humanos , Artroplastia do Joelho/estatística & dados numéricos , Artroplastia do Joelho/mortalidade , Reoperação/estatística & dados numéricos , Dinamarca/epidemiologia , Feminino , Masculino , Estudos Retrospectivos , Idoso , Incidência , Pessoa de Meia-Idade , Prótese do Joelho , Idoso de 80 Anos ou mais , Adulto , Estimativa de Kaplan-MeierRESUMO
Aims: The aim of this study was to perform a systematic review and bias evaluation of the current literature to create an overview of risk factors for re-revision following revision total knee arthroplasty (rTKA). Methods: A systematic search of MEDLINE and Embase was completed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The studies were required to include a population of index rTKAs. Primary or secondary outcomes had to be re-revision. The association between preoperative factors and the effect on the risk for re-revision was also required to be reported by the studies. Results: The search yielded 4,847 studies, of which 15 were included. A majority of the studies were retrospective cohorts or registry studies. In total, 26 significant risk factors for re-revision were identified. Of these, the following risk factors were consistent across multiple studies: age at the time of index revision, male sex, index revision being partial revision, and index revision due to infection. Modifiable risk factors were opioid use, BMI > 40 kg/m2, and anaemia. History of one-stage revision due to infection was associated with the highest risk of re-revision. Conclusion: Overall, 26 risk factors have been associated with an increased risk of re-revision following rTKA. However, various levels of methodological bias were found in the studies. Future studies should ensure valid comparisons by including patients with identical indications and using clear definitions for accurate assessments.
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Background: The renin-angiotensin system involves many more enzymes, receptors and biologically active peptides than originally thought. With this study, we investigated whether angiotensin-(1-5) [Ang-(1-5)], a 5-amino acid fragment of angiotensin II, has biological activity, and through which receptor it elicits effects. Methods: The effect of Ang-(1-5) (1µM) on nitric oxide release was measured by DAF-FM staining in human aortic endothelial cells (HAEC), or Chinese Hamster Ovary (CHO) cells stably transfected with the angiotensin AT 2 -receptor (AT 2 R) or the receptor Mas. A potential vasodilatory effect of Ang-(1-5) was tested in mouse mesenteric and human renal arteries by wire myography; the effect on blood pressure was evaluated in normotensive C57BL/6 mice by Millar catheter. These experiments were performed in the presence or absence of a range of antagonists or inhibitors or in AT 2 R-knockout mice. Binding of Ang-(1-5) to the AT 2 R was confirmed and the preferred conformations determined by in silico docking simulations. The signaling network of Ang-(1-5) was mapped by quantitative phosphoproteomics. Results: Key findings included: (1) Ang-(1-5) induced activation of eNOS by changes in phosphorylation at Ser1177 eNOS and Tyr657 eNOS and thereby (2) increased NO release from HAEC and AT 2 R-transfected CHO cells, but not from Mas-transfected or non-transfected CHO cells. (3) Ang-(1-5) induced relaxation of preconstricted mouse mesenteric and human renal arteries and (4) lowered blood pressure in normotensive mice - effects which were respectively absent in arteries from AT 2 R-KO or in PD123319-treated mice and which were more potent than effects of the established AT 2 R-agonist C21. (5) According to in silico modelling, Ang-(1-5) binds to the AT 2 R in two preferred conformations, one differing substantially from where the first five amino acids within angiotensin II bind to the AT 2 R. (6) Ang-(1-5) modifies signaling pathways in a protective RAS-typical way and with relevance for endothelial cell physiology and disease. Conclusions: Ang-(1-5) is a potent, endogenous AT 2 R-agonist.
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Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discover a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network.
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Tecido Adiposo , Resistência à Insulina , Obesidade , Receptores Acoplados a Proteínas G , Transdução de Sinais , Animais , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Tecido Adiposo/metabolismo , Camundongos , Obesidade/metabolismo , Insulina/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Adipócitos/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Músculos/metabolismo , Masculino , Músculo Esquelético/metabolismo , Drosophila melanogaster/metabolismo , Dieta Hiperlipídica/efeitos adversos , Neurônios/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Evolutionary relationships among parasites of the subfamily Leishmaniinae, which comprises pathogen agents of leishmaniasis, were inferred based on differential protein expression profiles from mass spectrometry-based quantitative data using the PhyloQuant method. Evolutionary distances following identification and quantification of protein and peptide abundances using Proteome Discoverer and MaxQuant software were estimated for 11 species from six Leishmaniinae genera. Results clustered all dixenous species of the genus Leishmania, subgenera L. (Leishmania), L. (Viannia), and L. (Mundinia), sister to the dixenous species of genera Endotrypanum and Porcisia. Placed basal to the assemblage formed by all these parasites were the species of genera Zelonia, Crithidia, and Leptomonas, so far described as monoxenous of insects although eventually reported from humans. Inferences based on protein expression profiles were congruent with currently established phylogeny using DNA sequences. Our results reinforce PhyloQuant as a valuable approach to infer evolutionary relationships within Leishmaniinae, which is comprised of very tightly related trypanosomatids that are just beginning to be phylogenetically unraveled. In addition to evolutionary history, mapping of species-specific protein expression is paramount to understand differences in infection processes, tissue tropisms, potential to jump from insects to vertebrates including humans, and targets for species-specific diagnostic and drug development.
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Targeted therapies against mutant BRAF are effectively used in combination with MEK inhibitors (MEKi) to treat advanced melanoma. However, treatment success is affected by resistance and adverse events (AEs). Approved BRAF inhibitors (BRAFi) show high levels of target promiscuity, which can contribute to these effects. The blood vessel lining is in direct contact with high plasma concentrations of BRAFi, but effects of the inhibitors in this cell type are unknown. Hence, we aimed to characterize responses to approved BRAFi for melanoma in the vascular endothelium. We showed that clinically approved BRAFi induced a paradoxical activation of endothelial MAPK signaling. Moreover, phosphoproteomics revealed distinct sets of off-targets per inhibitor. Endothelial barrier function and junction integrity were impaired upon treatment with vemurafenib and the next-generation dimerization inhibitor PLX8394, but not with dabrafenib or encorafenib. Together, these findings provide insights into the surprisingly distinct side effects of BRAFi on endothelial signaling and functionality. Better understanding of off-target effects could help to identify molecular mechanisms behind AEs and guide the continued development of therapies for BRAF-mutant melanoma.
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Melanoma , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Transdução de Sinais , Vemurafenib , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Humanos , Inibidores de Proteínas Quinases/farmacologia , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vemurafenib/farmacologia , Oximas/farmacologia , Sulfonamidas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Imidazóis/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Carbamatos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Linhagem Celular Tumoral , MutaçãoRESUMO
BACKGROUND AND PURPOSE: Mortality after major lower extremity amputations is high and may depend on amputation level. We aimed to examine the mortality risk in the first year after major lower extremity amputation divided into transtibial and transfemoral amputations. METHODS: This observational cohort study used data from the Danish Nationwide Health registers. 11,205 first-time major lower extremity amputations were included from January 1, 2010, to December 31, 2021, comprising 3,921 transtibial amputations and 7,284 transfemoral amputations. RESULTS: The 30-day mortality after transtibial amputation was overall 11%, 95% confidence interval (CI) 10-12 (440/3,921) during the study period, but declined from 10%, CI 7-13 (37/381) in 2010 to 7%, CI 4-11 (15/220) in 2021. The 1-year mortality was 29% overall, CI 28-30 (1,140 /3,921), with a decline from 31%, CI 21-36 (117/381) to 20%, CI 15-26 (45/220) during the study period. For initial transfemoral amputation, the 30-day mortality was overall 23%, CI 22-23 (1,673/7,284) and declined from 27%, CI 23-31 (138/509) to 22%, CI 19-25 (148/683) during the study period. The 1-year mortality was 48% overall, CI 46-49 (3,466/7,284) and declined from 55%, CI 50-59 (279/509) to 46%, CI 42-50 (315/638). CONCLUSION: The mortality after major lower extremity amputation declined in the 12-year study period; however, the 1-year mortality remained high after both transtibial and transfemoral amputations (20% and 46% in 2021). Hence, major lower extremity amputation patients constitute one of the most fragile orthopedic patient groups, emphasizing an increased need for attention in the pre-, peri-, and postoperative setting.
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Amputação Cirúrgica , Humanos , Amputação Cirúrgica/mortalidade , Amputação Cirúrgica/estatística & dados numéricos , Dinamarca/epidemiologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Estudos de Coortes , Extremidade Inferior/cirurgia , Idoso de 80 Anos ou mais , Sistema de Registros , Bases de Dados Factuais , Adulto , Tíbia/cirurgia , Fêmur/cirurgiaRESUMO
A considerable number of micropollutants from human activities enter the wastewater network for removal. However, at the wastewater treatment plant (WWTP), some proportion of these compounds is retained in the sewage sludge (biosolids), and due to its high content of nutrients, sludge is widely applied as an agricultural fertilizer and becomes a means for the micropollutants to be introduced to the environment. Accordingly, a holistic semiquantitative nontarget screening was performed on sewage sludges from five different WWTPs using nanoflow liquid chromatography coupled to high-resolution Orbitrap mass spectrometry. Sixty-one inorganic elements were measured using inductively coupled plasma mass spectrometry. Across all sludges, the nontarget analysis workflow annotated >21,000 features with chemical structures, and after strict prioritization and filtering, 120 organic micropollutants with diverse chemical structures and applications such as pharmaceuticals, pesticides, flame retardants, and industrial and natural compounds were identified. None of the tested sludges were free from organic micropollutants. Pharmaceuticals contributed the largest share followed by pesticides and natural products. The predicted concentration of identified contaminants ranged between 0.2 and 10,881 ng/g dry matter. Through quantitative nontarget analysis, this study comprehensively demonstrated the occurrence of cocktails of micropollutants in sewage sludges.
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Agricultura , Esgotos , Esgotos/química , Águas Residuárias/química , Monitoramento Ambiental , Poluentes Químicos da Água/análise , FertilizantesRESUMO
BACKGROUND: Periprosthetic knee fractures (PPKFs) following total knee arthroplasty (TKA) are uncommon, but potentially serious injuries. We analyze the risk and risk factors for a PPKF in standard primary TKA patients who have osteoarthritis and a minimally (cruciate-retaining TKAs without a femoral box cut) or posterior-stabilized TKA. In addition, we report the risk for patients who have other underlying knee disorders and/or a higher level of TKA constraint. METHODS: All primary TKAs were identified from the Danish National Patient Register and the Danish Knee Arthroplasty Register using data between 1997 and 2022. Subsequent fractures were identified through the International Classification of Diseases diagnosis code, Nordic Medico-Statistical Committee procedure code, or indication for revision TKA. RESULTS: We included 120,642 standard primary TKA patients who had 1,434 PPKFs. The cumulated proportions were 0.4% (95% confidence interval (CI) 0.3 to 0.4) at 2 years 0.8% (0.7 to 0.8) at 5 years. At 10 years, the cumulated proportion was 1.7% (1.6 to 1.8), with 1.3% in the femur, 0.2% in the patella, and 0.2% in the tibia. Significant risk factors were (hazard ratio [HR] [95% CI]); ipsilateral hip arthroplasty (2.3 [2.0 to 2.6]); women (2.1 [1.8 to 2.4]), osteoporosis (1.4 [1.2 to 1.7]); age 80+ (1.4 [1.3 to 1.6]), uncemented TKA (1.3 (1.1 to 1.5) and Charlson Comorbidity Index score 3+ (1.4 [1.1 to 1.8]). An additional 22,624 primary TKA patients who had other underlying knee disorders and/or a higher level of implant constraint were included with 485 PPKFs. The 10-year cumulated proportions were 8.3% (95% CI 6.9 to 9.8) when the underlying disorder was a previous fracture, 2.8% (2.2 to 3.5) for rheumatic disorders, and 5.2% (2.6 to 10.6) for osteonecrosis. In patients who had condylar constrained knees, it was 6.9% (5.1 to 9.4), and 12.4% (8.0 to 16.04) for hinges. CONCLUSIONS: In standard primary TKA patients, the 10-year cumulated proportion of PPKFs was 1.7%, and ipsilateral hip arthroplasty, women, osteoporosis, advanced age, uncemented TKA and higher Charlson Comorbidity Index increased the risk. Higher risks were observed in non-osteoarthritis patients and/or patients who had a higher level of TKA constraint.
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BACKGROUND AND PURPOSE: Few studies have examined the impact of comorbidity on functional and clinical knee scores after primary total knee arthroplasty (TKA). We compared the effect of having a high Charlson Comorbidity Index (CCI), relative to a low CCI, on changes in the American Knee Society Score (AKSS) functional and clinical scores from baseline to week 52 after TKA in patients with knee osteoarthritis (OA). METHODS: This population-based cohort study included 22,533 patients identified in the Danish Knee Arthroplasty Register from 1997 to 2021. Patients were classified as having low, medium, or high comorbidity based on CCI. The outcome was defined as the mean change (from preoperative to 1-year post-TKA) in functional and clinical knee scores measured by the AKSS (0-100). The association was analyzed using multiple linear regression by calculating mean change scores adjusting for sex, age, weight, cohabiting status, and baseline AKSS. RESULTS: The prevalence of patients with low, medium, and high comorbidity was 75%, 21%, and 4%, respectively. The mean change score in functional AKSS for patients with high comorbidity was -6 points (95% confidence interval [CI] -7 to -5) compared with low comorbidity. The mean change score in clinical AKSS for patients with high comorbidity was -1 point (CI -2 to 0) compared with low comorbidity. CONCLUSION: Patients with knee OA and medium or high comorbidity can expect similar improvements in functional and clinical AKSS after TKA to patients with low comorbidity.
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Artroplastia do Joelho , Comorbidade , Osteoartrite do Joelho , Humanos , Feminino , Masculino , Osteoartrite do Joelho/cirurgia , Idoso , Pessoa de Meia-Idade , Dinamarca/epidemiologia , Estudos de Coortes , Sistema de Registros , Recuperação de Função FisiológicaRESUMO
BACKGROUND AND PURPOSE: Length of hospital stay after hip and knee arthroplasty is about 1 day in Denmark with few patients discharged on the day of surgery. Hence, a protocol for multicenter implementation of discharge on day of surgery has been instituted. We aimed to describe the implementation of outpatient hip and knee arthroplasty in a multicenter public healthcare setting. METHODS: We performed a prospective multicenter study from 7 public hospitals across Denmark. Patients were screened using well-defined in- and exclusion criteria and were discharged on day of surgery when fulfilling functional discharge criteria. The study period was from September 2022 to February 2023 with variable start of implementation. Data from the same centers in a 6-month period before the COVID pandemic from July 2019 to December 2019 was used for baseline control. RESULTS: Of 2,756 primary hip and knee arthroplasties, 37% (95% confidence interval [CI] 35-39) were eligible (range 21-50% in centers) and 52% (range 24-62%) of these were discharged on day of surgery. 21% (CI 20-23) of all patients (eligible and non-eligible) were discharged on day of surgery with a range of 10-31% within centers. This was an additional 15% (CI 13-17, P < 0.001) compared with patients discharged in the control period (6% in 2019). CONCLUSION: We found it possible to perform outpatient hip and knee replacement in 21% of patients in a public healthcare setting, probably to be increased with further center experience.
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Artroplastia de Quadril , Artroplastia do Joelho , Humanos , Artroplastia do Joelho/métodos , Artroplastia de Quadril/métodos , Estudos Prospectivos , Dinamarca , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , COVID-19/prevenção & controle , COVID-19/epidemiologia , Procedimentos Cirúrgicos Ambulatórios , Tempo de Internação , Alta do Paciente , Hospitais Públicos/estatística & dados numéricos , Idoso de 80 Anos ou maisRESUMO
Importance: Despite increased use of antibiotic-loaded bone cement (ALBC) in joint arthroplasty over recent decades, current evidence for prophylactic use of ALBC to reduce risk of periprosthetic joint infection (PJI) is insufficient. Objective: To compare the rate of revision attributed to PJI following primary total knee arthroplasty (TKA) using ALBC vs plain bone cement. Design, Setting, and Participants: This international cohort study used data from 14 national or regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, New Zealand, Norway, Romania, Sweden, Switzerland, the Netherlands, the UK, and the US. The study included primary TKAs for osteoarthritis registered from January 1, 2010, to December 31, 2020, and followed-up until December 31, 2021. Data analysis was performed from April to September 2023. Exposure: Primary TKA with ALBC vs plain bone cement. Main Outcomes and Measures: The primary outcome was risk of 1-year revision for PJI. Using a distributed data network analysis method, data were harmonized, and a cumulative revision rate was calculated (1 - Kaplan-Meier), and Cox regression analyses were performed within the 10 registries using both cement types. A meta-analysis was then performed to combine all aggregated data and evaluate the risk of 1-year revision for PJI and all causes. Results: Among 2â¯168â¯924 TKAs included, 93% were performed with ALBC. Most TKAs were performed in female patients (59.5%) and patients aged 65 to 74 years (39.9%), fully cemented (92.2%), and in the 2015 to 2020 period (62.5%). All participating registries reported a cumulative 1-year revision rate for PJI of less than 1% following primary TKA with ALBC (range, 0.21%-0.80%) and with plain bone cement (range, 0.23%-0.70%). The meta-analyses based on adjusted Cox regression for 1â¯917â¯190 TKAs showed no statistically significant difference at 1 year in risk of revision for PJI (hazard rate ratio, 1.16; 95% CI, 0.89-1.52) or for all causes (hazard rate ratio, 1.12; 95% CI, 0.89-1.40) among TKAs performed with ALBC vs plain bone cement. Conclusions and Relevance: In this study, the risk of revision for PJI was similar between ALBC and plain bone cement following primary TKA. Any additional costs of ALBC and its relative value in reducing revision risk should be considered in the context of the overall health care delivery system.
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Antibacterianos , Artroplastia do Joelho , Cimentos Ósseos , Infecções Relacionadas à Prótese , Sistema de Registros , Reoperação , Humanos , Artroplastia do Joelho/efeitos adversos , Cimentos Ósseos/uso terapêutico , Feminino , Idoso , Masculino , Antibacterianos/uso terapêutico , Infecções Relacionadas à Prótese/epidemiologia , Infecções Relacionadas à Prótese/etiologia , Reoperação/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos de CoortesRESUMO
Psychopharmacological treatment may be an independent risk factor for increased length of stay and readmission after hip and knee replacement. Thus, temporary perioperative discontinuation may be beneficial. However, little is known regarding the treatments, and not all are feasible to discontinue. Therefore, the aim of this study was to describe the treatments in terms of type, dose, duration, indication and initiating physician to assess the feasibility of temporary perioperative discontinuation. We included 482 patients planned for hip or knee replacement in psychopharmacological treatment for psychiatric disorders from 2021 to 2023 at five orthopaedic departments in Denmark. Most patients were treated with antidepressants (89%); most frequently, either selective serotonin reuptake inhibitors (SSRIs; 48%) or serotonin-norepinephrine reuptake inhibitors (SNRIs; 21%). The majority received monotherapy (70%); most frequently, an SSRI (36%) or an SNRI (12%). Most antidepressants were initiated by general practitioners (71%), and the treatments had lasted for more than a year (87%). The doses of SSRIs/SNRIs were moderate, and the most frequent indication for antidepressants was depression (77%). These results imply that temporary perioperative SSRI/SNRI discontinuation may be feasible in hip and knee replacement patients and support a future randomized controlled trial investigating the potential benefits of temporary discontinuation.
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Antidepressivos , Artroplastia de Quadril , Artroplastia do Joelho , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Masculino , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Feminino , Idoso , Pessoa de Meia-Idade , Dinamarca , Antidepressivos/uso terapêutico , Antidepressivos/administração & dosagem , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Transtornos Mentais/tratamento farmacológico , Idoso de 80 Anos ou mais , Tempo de Internação/estatística & dados numéricos , Depressão/tratamento farmacológico , AdultoRESUMO
Intellectual disability is a heterogeneous disorder, diagnosed using intelligence quotient (IQ) score criteria. Currently, no specific clinical test is available to diagnose the disease and its subgroups due to inadequate understanding of the pathophysiology. Therefore, current study was designed to explore the molecular mechanisms involved in disease perturbation, and to identify potential biomarkers for disease diagnosis and prognosis. A total of 250 participants were enrolled in this study, including 200 intellectually disabled (ID) subjects from the subgroups (mild, moderate, and severe) with age and gender matched healthy controls (n = 50). Initially, IQ testing score and biochemical profile of each subject was generated, followed by label-free quantitative proteomics of subgroups of IQ and healthy control group through nano-LC/MS- mass spectrometry. A total of 310 proteins were identified, among them198 proteins were common among all groups. Statistical analysis (ANOVA) of the subgroups of ID showed 142 differentially expressed proteins, in comparison to healthy control group. From these, 120 proteins were found to be common among all subgroups. The remaining 22 proteins were categorized as exclusive proteins found only in disease subgroups. Furthermore, the hierarchical cluster analysis (HCL) of common significant proteins was also performed, followed by PANTHER protein classification and GO functional enrichment analysis. Results provides that the datasets of differentially expressed proteins, belong to the categories of immune / defense proteins, transfer carrier proteins, apolipoproteins, complement proteins, protease inhibitors, hemoglobin proteins etc., they are known to involvein immune system, and complement and coagulation pathway cascade and cholesterol metabolism pathway. Exclusively expressed 22 proteins were found to be disease stage specific and strong PPI network specifically those that have significant role in platelets activation and degranulation, such as Filamin A (FLNA). Furthermore, to validate the mass spectrometric findings, four highly significant proteins (APOA4, SAP, FLNA, and SERPING) were quantified by ELISA in all the study subjects. AUROC analysis showed a significant association of APOA4 (0.830), FLNA (0.958), SAP (0.754) and SERPING (0.600) with the disease. Apolipoprotein A4 (APOA4) has a significant role in cholesterol transport, and in modulation of glucose and lipid metabolism in the CNS. Similarly, FLNA has a crucial role in the nervous system, especially in the functioning of synaptic network. Therefore, both APOA4, and FLNA proteins represent good potential for candidate biomarkers for the diagnosis and prognosis of the intellectual disability. Overall, serum proteome of ID patients provides valuable information of proteins/pathways that are altered during ID progression.
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Colesterol , Deficiência Intelectual , Proteômica , Humanos , Deficiência Intelectual/sangue , Masculino , Proteômica/métodos , Feminino , Colesterol/sangue , Adolescente , Biomarcadores/sangue , Criança , Adulto Jovem , Proteínas do Sistema Complemento/metabolismo , Coagulação Sanguínea/fisiologia , AdultoRESUMO
INTRODUCTION: Long-read whole genome sequencing like Oxford Nanopore Technology, is increasingly being introduced in clinical settings. With its ability to simultaneously call sequence variation and DNA modifications including 5-methylcytosine, nanopore is a promising technology to improve diagnostics of imprinting disorders. METHODS: Currently, no tools to analyze DNA methylation patterns at known clinically relevant imprinted regions are available. Here we present NanoImprint, which generates an easily interpretable report, based on long-read nanopore sequencing, to use for identifying clinical relevant abnormalities in methylation levels at 14 imprinted regions and diagnosis of common imprinting disorders. RESULTS AND CONCLUSION: NanoImprint outputs a summarizing table and visualization plots displays methylation frequency (%) and chromosomal positions for all regions, with phased data color-coded for the two alleles. We demonstrate the utility of NanoImprint using three imprinting disorder samples from patients with Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS) and Prader-Willi syndrome (PWS). NanoImprint script is available from https://github.com/carolinehey/NanoImprint.
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Síndrome de Angelman , Síndrome de Beckwith-Wiedemann , Metilação de DNA , Impressão Genômica , Sequenciamento por Nanoporos , Síndrome de Prader-Willi , Humanos , Sequenciamento por Nanoporos/métodos , Síndrome de Angelman/genética , Síndrome de Angelman/diagnóstico , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/diagnóstico , Análise de Sequência de DNA/métodos , Nanoporos , Transtornos da Impressão GenômicaRESUMO
BACKGROUND: Current clinical markers overestimate the recurrence risk in many lymph node negative (LNN) breast cancer (BC) patients such that a majority of these low-risk patients unnecessarily receive systemic treatments. We tested if differential microRNA expression in primary tumors allows reliable identification of indolent LNN BC patients to provide an improved classification tool for overtreatment reduction in this patient group. METHODS: We collected freshly frozen primary tumors of 80 LNN BC patients with recurrence and 80 recurrence-free patients (mean follow-up: 20.9 years). The study comprises solely systemically untreated patients to exclude that administered treatments confound the metastasis status. Samples were pairwise matched for clinical-pathological characteristics to minimize dependence of current markers. Patients were classified into risk-subgroups according to the differential microRNA expression of their tumors via classification model building with cross-validation using seven classification methods and a voting scheme. The methodology was validated using available data of two independent cohorts (n = 123, n = 339). RESULTS: Of the 80 indolent patients (who would all likely receive systemic treatments today) our ultralow-risk classifier correctly identified 37 while keeping a sensitivity of 100% in the recurrence group. Multivariable logistic regression analysis confirmed independence of voting results from current clinical markers. Application of the method in two validation cohorts confirmed successful classification of ultralow-risk BC patients with significantly prolonged recurrence-free survival. CONCLUSION: Profiles of differential microRNAs expression can identify LNN BC patients who could spare systemic treatments demanded by currently applied classifications. However, further validation studies are required for clinical implementation of the applied methodology.
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Biomarcadores Tumorais , Neoplasias da Mama , MicroRNAs , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Feminino , MicroRNAs/genética , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Idoso , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Adulto , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Medição de Risco/métodos , Metástase Neoplásica , PrognósticoRESUMO
BACKGROUND: Patients' postoperative quality of recovery (QOR) is an important outcome measurement and predicting and preventing impaired quality of recovery is essential. In this study, we aimed to investigate if patients Sense of Coherence (SOC) could be a potential predictor and screening instrument for impaired quality of recovery. We hypothesized that patients' SOC is positively related to their QOR. MATERIAL AND METHODS: The study was performed as a descriptive single-center prospective cohort study. Data was collected using digital questionnaires. Patients undergoing total hip (THA) or knee arthroplasty (TKA) received the SOC13 questionnaire prior to their surgery to establish their SOC and a questionnaire on postoperative day 2 and 7, respectively, establishing their QOR. Multiple linear regression was used to fit a model for the QOR score using SOC, age, sex, and type of surgery as potential explanatory variables. RESULTS: 206 patients were included in the study analysis. The results showed a highly significant positive correlation between patients' SOC and their postoperative QOR on both postoperative day 2 and 7 (p < 0.01). Patients with a lower SOC score also presented a significantly lower QOR score, meaning they experienced impaired QOR compared to patients with a higher SOC score. CONCLUSIONS: The results indicate that a weak SOC (low SOC score) can be considered a clinically important indicator for risk of impaired QOR (low QOR score) after THA and TKA. The SOC13 questionnaire may be a potential screening instrument identifying patients in risk of impaired postoperative QOR based on a low SOC score.
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Objective: To evaluate the validity of diagnosis codes for Major Osteoporotic Fracture (MOF) in the Danish National Patient Registry (NPR) and secondly to evaluate whether the fracture was incident/acute using register-based definitions including date criteria and procedural codes. Methods: We identified a random sample of 2400 records with a diagnosis code for a MOF in the NPR with dates in the year of 2018. Diagnoses were coded with the 10th revision of the International Classification of Diseases (ICD-10). The sample included 2375 unique fracture patients from the Region of Southern Denmark. Medical records were retrieved for the study population and reviewed by an algorithmic search function and medical doctors to verify the MOF diagnoses. Register-based definitions of incident/acute MOF was evaluated in NPR data by applying date criteria and procedural codes. Results: The PPV for MOF diagnoses overall was 0.99 (95% CI: 0.98;0.99) and PPV=0.99 for the four individual fracture sites, respectively. Further, analyses of incident/acute fractures applying date criteria, procedural codes and using patients' first contact in the NPR resulted in PPV=0.88 (95% CI: 0.84;0.91) for hip fractures, PPV=0.78 (95% CI: 0.74;0.83) for humerus fractures, PPV=0.78 (95% CI: 0.73;0.83) for clinical vertebral fractures and PPV=0.87 (95% CI: 0.83;0.90) for wrist fractures. Conclusion: ICD-10 coded MOF diagnoses are valid in the NPR. Furthermore, a set of register-based criteria can be applied to qualify if the MOF fracture was incident/acute. Thus, the NPR is a valuable and reliable data source for epidemiological research on osteoporotic fractures.
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INTRODUCTION: Perioperative glycaemic control is important. However, the complexity of guidelines for perioperative diabetes management is complicated due to different and novel antihyperglycaemic medications, limited procedure-specific data and lack of data from implemented fast-track regimens which otherwise are known to reduce morbidity and glucose homeostasis disturbances. Consequently, outcome in patients with diabetes mellitus (DM) after surgery and the influence of perioperative diabetes management on postoperative recovery remains poorly understood. METHODS AND ANALYSIS: A prospective observational multicentre study involving 8 arthroplasty centres across Denmark with a documented implemented fast-track programme (median length of hospitalisation (LOS) 1 day). We will collect detailed perioperative data including preoperative haemoglobin A1c and antidiabetic treatment in 1400 unselected consecutive patients with DM undergoing hip and knee arthroplasty from September 2022 to December 2025, enrolled after consent. Follow-up duration is 90 days after surgery. The primary outcome is the proportion of patients with DM with LOS >4 days and 90-day readmission rate after fast-track total hip arthroplasty (THA), total knee arthroplasty (TKA) and unicompartmental knee arthroplasty (UKA). The secondary outcome is the association between perioperative diabetes treatment and LOS >2 days, 90-day readmission rate, other patient demographics and Comprehensive Complication Index for patients with DM after THA/TKA/UKA in a fast-track regimen. ETHICS AND DISSEMINATION: The study will follow the principles of the Declaration of Helsinki and ICH-Good Clinical Practice guideline. Ethical approval was not necessary as this is a non-interventional observational study on current practice. The trial is registered in the Region of Southern Denmark and on ClinicalTrials.gov. The main results and all substudies of this trial will be published in peer-reviewed international medical journals. TRIAL REGISTRATION NUMBER: NCT05613439.
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Artroplastia de Quadril , Artroplastia do Joelho , Humanos , Dinamarca , Diabetes Mellitus , Hemoglobinas Glicadas/análise , Hipoglicemiantes/uso terapêutico , Tempo de Internação/estatística & dados numéricos , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Readmissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Multimodal postoperative analgesia following total hip arthroplasty is recommended, but the optimal combination of drugs remains uncertain. The aim of the RECIPE trial was to investigate the relative benefit and harm of the different combinations of paracetamol, ibuprofen, and the analgesic adjuvant dexamethasone for treatment of postoperative pain following total hip arthroplasty. METHODS: The RECIPE trial was a randomised, blinded, placebo-controlled trial conducted at nine Danish hospitals. Adults scheduled for total hip arthroplasty were randomly assigned (1:1:1:1) using a computer-generated list with stratification by site to receive combinations of oral paracetamol 1000 mg every 6 h, oral ibuprofen 400 mg every 6 h, or a single-dose of intravenous dexamethasone 24 mg in the following groups: paracetamol plus ibuprofen, ibuprofen plus dexamethasone, paracetamol plus dexamethasone, and paracetamol plus ibuprofen plus dexamethasone. The primary outcome was 24 h intravenous morphine consumption, analysed in a modified intention-to-treat population, defined as all randomly assigned participants who underwent total hip arthroplasty. The predefined minimal important difference was 8 mg. Safety outcomes included serious and non-serious adverse events within 90 days and 24 h. The trial was registered with ClinicalTrials.gov, NCT04123873. FINDINGS: Between March 5, 2020, and Nov 15, 2022, we randomly assigned 1060 participants, of whom 1043 (589 [56%] women and 454 [44%] men) were included in the modified intention-to-treat population. 261 were assigned to paracetamol plus ibuprofen, 262 to ibuprofen plus dexamethasone, 262 to paracetamol plus dexamethasone, and 258 to paracetamol plus ibuprofen plus dexamethasone. Median 24 h morphine consumption was 24 mg (IQR 12-38) in the paracetamol plus ibuprofen group, 20 mg (12-32) in the paracetamol plus dexamethasone group, 16 mg (10-30) in the ibuprofen plus dexamethasone group, and 15 mg (8-26) in the paracetamol plus ibuprofen plus dexamethasone group. The paracetamol plus ibuprofen plus dexamethasone group had a significantly reduced 24 h morphine consumption compared with paracetamol plus ibuprofen (Hodges-Lehmann median difference -6 mg [99% CI -10 to -3]; p<0·0001) and paracetamol plus dexamethasone (-4 mg [-8 to -1]; p=0·0013), however, none of the comparisons showed differences reaching the minimal important threshold of 8 mg. 91 (35%) of 258 participants in the paracetamol plus ibuprofen plus dexamethasone group had one or more adverse events, compared with 99 (38%) of 262 in the ibuprofen plus dexamethasone group, 103 (39%) of 262 in the paracetamol plus dexamethasone group, and 165 (63%) of 261 in the paracetamol plus ibuprofen group. INTERPRETATION: In adults undergoing total hip arthroplasty, a combination of paracetamol, ibuprofen, and dexamethasone had the lowest morphine consumption within 24 h following surgery and the most favourable adverse event profile, with a lower incidence of serious and non-serious adverse events (primarily driven by differences in nausea, vomiting, and dizziness) compared with paracetamol plus ibuprofen. FUNDING: The Novo Nordisk Foundation and Næstved-Slagelse-Ringsted Hospitals' Research Fund.