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DNAJB6 is a suppressor of α-synuclein aggregation in vivo and in vitro. DNAJB6 is strongly expressed in the brain, and its overall protein expression is altered in neurodegenerative conditions such as Parkinson's Disease (PD) and Multiple System Atrophy (MSA). These two diseases are characterized by accumulation of aggregated α-synuclein in neurons and oligodendrocytes, respectively. To further explore this, we employed post-mortem normal human brain material to investigate the regional and cell type specific protein expression of DNAJB6. We found that the DNAJB6 protein is ubiquitously expressed across various regions of the brain. Notably, we demonstrate for the first time that DNAJB6 is present in nearly half (41%-53%) of the oligodendrocyte population and in the majority (68%-80%) of neurons. However, DNAJB6 was only sparsely present in other cell types such as astrocytes and microglia. Given that α-synuclein aggregation in oligodendrocytes is a hallmark of MSA, we investigated DNAJB6 presence in MSA brains compared to control brains. We found no significant difference in the percentage of oligodendrocytes where DNAJB6 was present in MSA brains relative to control brains. In conclusion, our results reveal an expression of the DNAJB6 protein across various regions of the human brain, and that DNAJB6 is almost exclusively present in neurons and oligodendrocytes. Since prior studies have shown that PD and MSA brains have altered levels of DNAJB6 relative to control brains, DNAJB6 may be an interesting target for drug development.
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Background: Mitochondrial DNA copy number (mtDNA-CN) is associated with aging. A relationship between mtDNA-CN and degenerative disorders, e.g. osteoarthritis (OA) and osteoporosis (OP), has been suggested. We aimed to investigate the relationship of mtDNA-CN and incident OA and OP. Materials and methods: MtDNA-CN was studied in relationship to incident OA and OP in a population-based cohort study of 6916 middle-aged women (52-63 years). Totally 2521 women with sufficient quality of mtDNA were analyzed. After exclusions, 1978 women remained in the study population. Four different endpoints obtained from the National Patient register were studied: 1) OA, 2) OP 3) OA surgery, and 4) OP fracture. In the multivariate model adjustments were made for potential OA and OP risk factors. Results: Women with low mtDNA-CN were older and had more activity at work. 125 women (6.32%) were affected by incident OP and 254 women (12.84%) had an OP fracture. Incident OA affected 451 women (22.80%) and 175 women (8.85%) had OA surgery. There were no associations between mtDNA-CN and incident risk of OA (Hazard ratio â= â1.00, 95% confidence interval 0.83-1.20), OA surgery (0.79, 0.58-1.07), OP (0.89, 0.62-1.27), or OP fracture (1.00, 0.78-1.29). However, incident OP was significantly associated with T-score (bone density), smoking, diabetes mellitus, and chronic obstructive bronchitis (COPD). OA was associated with body mass index and COPD. Conclusions: The present study suggests that mtDNA-CN, reflecting mitochondrial dysfunction, is not a major predictor for incident OA or OP. However, due to the limited study size minor associations cannot be excluded.
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Sweat chloride concentration, a diagnostic feature in cystic fibrosis (CF), reflects CF transmembrane conductance regulator (CFTR) activity. CFTR modulator therapies, especially elexacaftor/tezacaftor/ivacaftor (ETI), has improved CF outcomes. We report nationwide, real-world data on sweat chloride concentration in people with CF (pwCF) with and without modulator therapies. All Danish pwCF with a minimum of one F508del allele were included. Sweat chloride measurements were stratified by genotype and modulator treatment. Differences were assessed using mixed-effects models. We included 977 sweat chloride measurements from 430 pwCF, 71% of which were F508del homozygous. Heterozygous and homozygous ETI-treated pwCF had an estimated mean sweat chloride concentration of 43 mmol/L (95% confidence interval: 39; 48) and 43 mmol/L (39; 47), respectively-48% and 59% lower than those without treatment. High variation in concentrations remained regardless of treatment status. Despite ETI treatment, 27% heterozygous and 23% homozygous pwCF had elevated concentrations (≥60 mmol/L). These real-world data confirm a substantial decrease in sweat chloride concentration during modulator treatment, especially ETI, where mean concentrations halved. However, large variation remained, including persistently high concentrations. These findings emphasize the potential of sweat chloride concentration as a treatment response biomarker and the need to explore its heterogeneity and relationship with clinical outcomes.
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PURPOSE: The existing knee-specific pediatric patient-reported outcome measures (PROMs) lack content and construct validity for children with anterior cruciate ligament (ACL) injury. This impairs their accuracy which can lead to false interpretations of data and inaccurate clinical guidelines. The purpose of this study was to develop a content-valid PROM for children with an ACL injury. METHODS: The process adhered to the COnsensus-based Standards for the selection of health Measurement INstruments guidelines for PROM development. Informants were children with ACL deficiency and sampled based on age, sex, and treatment. Semistructured interviews were conducted exploring themes within the International Classification of Functioning, Disability and Health model. Interviews continued beyond data saturation. By thematic analysis and by probing items from the adult PROM 'KNEES-ACL', new themes and items emerged. Content coverage, relevance and understandability were continuously evaluated. All interviews were recorded and transcribed verbatim. The NVivo 12 software was used for data analysis and coding of items. RESULTS: A PROM of 60 items across nine subscales was formed. From cognitive interviews, 19 new items emerged. Forty-one of 55 items from KNEES-ACL were endorsed as relevant; however, all required rewording to ensure understandability. Substantial differences in the psychosocial impact between adults and children were observed. The children experienced a more considerable negative psychosocial impact caused by a loss of participation in sports, lower self-confidence and loss of social networks. This resulted in four new domains. The physical issues were similar to adults, with few exceptions. CONCLUSION: The 'KIDS-KNEES-ACL' 1.0 (qualitative version) was developed. This version will be subjected to psychometric analysis, resulting in adequate measurement properties of the final KIDS-KNEES-ACL 2.0. As the only adequate pediatric ACL-specific PROM, its use in clinical trials and databases will enhance PROM data quality, and strengthen clinical guidelines and thus the treatment of children with ACL injury. LEVEL OF EVIDENCE: Not applicable.
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INTRODUCTION: Diabetic polyneuropathy (DPN), a common complication of diabetes, can manifest as small, large, or mixed fiber neuropathy (SFN, LFN, and MFN, respectively), depending on the type of fibers involved. Despite evidence indicating small fiber involvement prior to large fiber involvement in type 1 diabetes mellitus (T1DM)-associated DPN, no evidence has been produced to determine the more prevalent subtype. We aim to determine the more prevalent type of nerve fiber damage-SFN, LFN, and MFN-in T1DM-associated DPN, both with and without pain. RESEARCH DESIGN AND METHODS: In this cross-sectional study, participants (n=216) were divided into controls; T1DM; T1DM with non-painful DPN (NP-DPN); and T1DM with painful DPN (P-DPN). DPN was further subgrouped based on neuropathy severity. The more prevalent type of fiber damage was determined applying small and large fiber-specific tests and three diagnostic models: model 1 (≥1 abnormal test); model 2 (≥2 abnormal tests); and model 3 (≥3 abnormal tests). RESULTS: MFN showed the highest prevalence in T1DM-associated DPN. No differences in neuropathy subtype were found between NP-DPN and P-DPN. DPN, with prevalent SFN plateaus between models 2 and 3. All models showed increased prevalence of MFN according to DPN severity. Model 3 showed increased DPN with prevalent LFN in early neuropathy. DPN with prevalent SFN demonstrated a similar, but non-significant pattern. CONCLUSIONS: DPN primarily manifests as MFN in T1DM, with no differentiation between NP-DPN and P-DPN. Additionally, we propose model 2 as an initial criterion for diagnosing DPN with a more prevalent SFN subtype in T1DM. Lastly, the study suggests that in mild stages of DPN, one type of nerve fiber (either small or large) is more susceptible to damage.
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Diabetes Mellitus Tipo 1 , Neuropatías Diabéticas , Humanos , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/epidemiología , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/etiología , Masculino , Estudios Transversales , Femenino , Adulto , Persona de Mediana Edad , Fibras Nerviosas/patología , Prevalencia , Estudios de Casos y Controles , Estudios de Seguimiento , Conducción Nerviosa/fisiología , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: Emergency care of critically ill patients in the trauma room is an integral part of interdisciplinary work in hospitals. Live threatening injuries require swift diagnosis, prioritization, and treatment; thus, different medical specialties need to work together closely for optimal patient care. Training is essential to facilitate smooth performance. This study presents a training tool for familiarization with trauma room algorithms in immersive virtual reality (VR), and a first qualitative assessment. MATERIALS AND METHODS: An interdisciplinary team conceptualized two scenarios and filmed these in the trauma room of the University Medical Center Mainz, Germany in 3D-360°. This video content was used to create an immersive VR experience. Participants of the Department of Anesthesiology were included in the study, questionnaires were obtained and eye movement was recorded. RESULTS: 31 volunteers participated in the study, of which 10 (32,2%) had completed specialist training in anesthesiology. Participants reported a high rate of immersion (immersion(mean) = 6 out of 7) and low Visually Induced Motion Sickness (VIMS(mean) = 1,74 out of 20). Participants agreed that VR is a useful tool for medical education (mean = 1,26; 1 very useful, 7 not useful at all). Residents felt significantly more secure in the matter after training (p < 0,05), specialist showed no significant difference. DISCUSSION: This study presents a novel tool for familiarization with trauma room procedures, which is especially helpful for less experienced residents. Training in VR was well accepted and may be a solution to enhance training in times of low resources for in person training.
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Realidad Virtual , Humanos , Grupo de Atención al Paciente , Alemania , Masculino , Femenino , Adulto , Heridas y Lesiones/terapia , Anestesiología/educación , Competencia ClínicaRESUMEN
Purpose: Autonomic nervous system dysfunction (ANSD), for which presently no treatment exists, has a negative impact on prognosis in people with type 2 diabetes (T2D). Periosteal pressure sensitivity (PPS) on sternum may be a measure of autonomic nervous system dysfunction (ANSD). We tested if a non-pharmacological PPS-feedback-guided treatment program based on non-noxious sensory nerve stimulation, known to reduce PPS, changed empowerment, treatment satisfaction, and quality of life in people with T2D, compared to usual treatment. Patients and Methods: Analysis of secondary endpoints in a single center, two-armed, parallel-group, observer-blinded, randomized controlled trial of individuals with T2D. Participants were randomized to non-pharmacological intervention as an add-on to treatment as usual. Endpoints were evaluated by five validated questionnaires: Diabetes specific Empowerment (DES-SF), Diabetes Treatment Satisfaction (DTSQ), quality of life (QOL) (WHO-5), clinical stress signs (CSS), and self-reported health (SF-36). Sample size calculation was based on the primary endpoint HbA1c. Results: We included 144 participants, 71 allocated to active intervention and 73 to the control group. Active intervention compared to control revealed improved diabetes-specific empowerment (p = 0.004), DTSQ (p = 0.001), and SF-36 self-reported health (p=0.003) and tended to improve quality of life (WHO-5) (p = 0.056). The findings were clinically relevant with a Cohen's effect size of 0.5 to 0.7. Conclusion: This non-pharmacological intervention, aiming to reduce PPS, and thus ANSD, improved diabetes-specific empowerment, treatment satisfaction, and self-reported health when compared to usual treatment. The proposed intervention may be a supplement to conventional treatment for T2D.
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BACKGROUND: During the 2023 Danish COVID-19 vaccination campaign, an updated monovalent mRNA vaccine targeting the SARS-CoV-2 omicron XBB.1.5 subvariant was administered. However, the rapid spread of a genetically divergent omicron BA.2.86 subvariant, JN.1, since September, 2023, poses potential challenges due to its rapid dominance and possible immune escape. Using national electronic health registry data from all regions of Denmark, we aimed to investigate whether the SARS-CoV-2 subvariant BA.2.86, and its descendant JN.1, differed from other circulating variants in terms of their ability to escape vaccine protection, the risk of infection leading to severe disease, and self-reported symptoms among infected people. METHODS: In this observational study, we included all residents of Denmark aged 65 years and older who tested positive for SARS-CoV-2 by PCR between Oct 1 and Dec 31, 2023, and for whom genomic data on the SARS-CoV-2 variant that had caused their infection were available. Data from clinical testing, sentinel, and self-sampling-based surveillance were linked with national electronic civil, vaccination, and hospitalisation registers. The relative protection of the XBB.1.5 updated COVID-19 vaccine against BA.2.86 infections versus infections with other variants was analysed in a case-only study, and the relative risk of hospitalisation in people infected with BA.2.86 versus other variants was analysed in a case-control study. Both analyses were adjusted for time, comorbidities, and previous vaccination history, among other potential confounders. Additionally, prevalence patterns in self-reported symptoms among people of all ages infected with SARS-CoV-2 were reported separately by subvariant. FINDINGS: Of the 7581 people in Denmark aged 65 years or older who tested positive for SARS-CoV-2 by PCR during the study period, 5882 (78%) samples were eligible for sequencing. 3862 (66%) of these passed quality control, were successfully sequenced, and the SARS-CoV-2 variant and subvariant identified, and these individuals were included in the study. Of these 3862 people, 2184 (57%) were infected with the BA.2.86 subvariant, including 1615 JN.1 infections. Participants infected with BA.2.86 had 1·52 (95% CI 1·25-1·86) times the odds, and those infected with JN.1 had 1·60 (1·27-2·02) times the odds, of having received the XBB.1.5 vaccine at least 7 days before their infection compared with participants infected with a non-BA.2.86 variant. The severity analysis showed no evidence of association between the infecting variant and the risk of COVID-19 hospitalisation (odds ratio 1·04 [95% CI 0·86-1·26] for BA.2.86 and 1·07 [0·85-1·34] for JN.1). Similarly, there was no evidence of differences in self-reported symptoms by variant strain. INTERPRETATION: Compared with other SARS-CoV-2 variants, BA.2.86 and the JN.1 sublineage were less sensitive to vaccine-induced immune protection from the XBB.1.5 updated COVID-19 vaccine; however, we found no evidence that infection with BA.2.86 or JN.1 resulted in increased disease severity or different symptom profiles. Although less effective against the new variants, XBB.1.5 vaccination remains protective and reduces the risk of infection and COVID-19 disease. FUNDING: The Danish Government and the EU's EU4Health programme.
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Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/prevención & control , COVID-19/epidemiología , COVID-19/virología , Dinamarca/epidemiología , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Anciano , Femenino , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Masculino , Anciano de 80 o más Años , Índice de Severidad de la Enfermedad , VacunaciónRESUMEN
AIM: The objective of this study was to evaluate whether patient biological sex influences treatment outcomes in patients with metastatic melanoma (MM) undergoing first-line immune checkpoint inhibitor (ICI) therapy. METHODS: The Danish Metastatic Melanoma Database (DAMMED) was employed to identify patients who underwent first-line ICI therapy for MM in Denmark from 2013 to 2021. Excluding adjuvant treatment, uveal and mucosal histological subtypes, the study conducted univariable and multivariable analyses to evaluate the influence of patient sex in survival analyses. Further, landmark survival of this real-world national cohort was described for progression free survival (PFS), overall survival (OS) and melanoma-specific survival (MSS). RESULTS: The analysis encompassed a cohort of 1378 patients with MM. Compared to male sex, females had significantly improved OS (p = 0.003) when tested in univariable testing. Multivariable analyses, controlling for age, performance status, lactate dehydrogenase level, BRAF status, M-stage, and number of metastatic sites revealed significant favourable outcomes associated with female sex irrespective of the considered survival metrics (pPFS = 0.014, pOS = 0.002, and pMSS = 0.03). The observed five-year OS rates of the entire cohort were 47% and 38%, while melanoma-specific survival were 50% and 45% for female and male, respectively. CONCLUSION: In this nationwide cohort of patients with MM undergoing first-line ICI treatment females exhibited superior treatment outcomes compared to males. Sex was identified as an independent predictive variable for treatment outcomes, irrespective of the chosen outcome measures considered. Our analyses are not able to conclude whether the differences in outcome is attributable to differences in biology or to treatment strategy.
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Inhibidores de Puntos de Control Inmunológico , Melanoma , Humanos , Melanoma/tratamiento farmacológico , Melanoma/mortalidad , Melanoma/patología , Masculino , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Dinamarca , Persona de Mediana Edad , Anciano , Factores Sexuales , Resultado del Tratamiento , Adulto , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Anciano de 80 o más AñosAsunto(s)
Neoplasias de Cabeza y Cuello , Variaciones Dependientes del Observador , Órganos en Riesgo , Humanos , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Cabeza y Cuello/patología , Órganos en Riesgo/efectos de la radiación , Guías de Práctica Clínica como Asunto , Planificación de la Radioterapia Asistida por Computador/métodos , Masculino , FemeninoRESUMEN
PURPOSE: Stereotactic body radiotherapy (SBRT) has emerged as a promising new modality for locally advanced pancreatic cancer (LAPC). The current study evaluated the efficacy and toxicity of SBRT in patients with LAPC (NCT03648632). METHODS: This prospective single institution phase II study recruited patients with histologically or cytologically proven adenocarcinoma of the pancreas after more than two months of combination chemotherapy with no sign of progressive disease. Patients were prescribed 50-60 Gy in 5-8 fractions. Patients were initially treated on a standard linac (n = 4). Since 2019, patients were treated using online magnetic resonance (MR) image-guidance on a 1.5 T MRI-linac, where the treatment plan was adapted to the anatomy of the day. The primary endpoint was resection rate. RESULTS: Twenty-eight patients were enrolled between August 2018 and March 2022. All patients had non-resectable disease at time of diagnosis. Median follow-up from inclusion was 28.3 months (95 % CI 24.0-NR). Median progression-free and overall survival from inclusion were 7.8 months (95 % CI 5.0-14.8) and 16.5 months (95 % CI 10.7-22.6), respectively. Six patients experienced grade III treatment-related adverse events (jaundice, nausea, vomiting and/or constipation). One of the initial four patients receiving treatment on a standard linac experienced a grade IV perforation of the duodenum. Six patients (21 %) underwent resection. A further one patient was offered resection but declined. CONCLUSION: This study demonstrates that SBRT in patients with LAPC was associated with promising overall survival and resection rates. Furthermore, SBRT was safe and well tolerated, with limited severe toxicities.
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Neoplasias Pancreáticas , Radiocirugia , Humanos , Radiocirugia/métodos , Radiocirugia/efectos adversos , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/diagnóstico por imagen , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Prospectivos , Anciano de 80 o más Años , Radioterapia Guiada por Imagen/métodos , Adenocarcinoma/patología , Adenocarcinoma/radioterapia , Adenocarcinoma/cirugía , Adenocarcinoma/diagnóstico por imagen , Imagen por Resonancia Magnética/métodosRESUMEN
Oceanic spreading centers north of Iceland are characterized by ultraslow spreading rates, and related hydrothermal activity has been detected in the water column and at the seafloor along nearly all ridge segments. An exception is the 500-km-long Knipovich Ridge, from where, until now, no hydrothermal vents were known. Here we report the investigation of the first hydrothermal vent field of the Knipovich Ridge, which was discovered in July 2022 during expedition MSM109. The newly discovered hydrothermal field, named Jøtul hydrothermal field, is associated with the eastern bounding fault of the rift valley rather than with an axial volcanic ridge. Guided by physico-chemical anomalies in the water column, ROV investigations on the seafloor showed a wide variety of fluid escape sites, inactive and active mounds with abundant hydrothermal precipitates, and chemosynthetic organisms. Fluids with temperatures between 8 and 316 °C as well as precipitates were sampled at four vent sites. High methane, carbon dioxide, and ammonium concentrations, as well as high 87Sr/86Sr isotope ratios of the vent fluids indicate strong interaction between magma and sediments from the Svalbard continental margin. Such interactions are important for carbon mobilization at the seafloor and the carbon cycle in the ocean.
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BACKGROUND: Rift Valley fever (RVF) is a zoonotic viral disease of increasing intensity among humans in Africa and the Arabian Peninsula. In Uganda, cases reported prior to 2016 were mild or not fully documented. We report in this paper on the severe morbidity and hospital-based mortality of human cases in Uganda. METHODS: Between November 2017 and March 2020 human cases reported to the Uganda Virus Research Institute (UVRI) were confirmed by polymerase chain reaction (PCR). Ethical and regulatory approvals were obtained to enrol survivors into a one-year follow-up study. Data were collected on socio-demographics, medical history, laboratory tests, potential risk factors, and analysed using Stata software. RESULTS: Overall, 40 cases were confirmed with acute RVF during this period. Cases were not geographically clustered and nearly all were male (39/40; 98%), median age 32 (range 11-63). The median definitive diagnosis time was 7 days and a delay of three days between presumptive and definitive diagnosis. Most patients (31/40; 78%) presented with fever and bleeding at case detection. Twenty-eight (70%) cases were hospitalised, out of whom 18 (64%) died. Mortality was highest among admissions in regional referral (11/16; 69%) and district (4/5; 80%) hospitals, hospitalized patients with bleeding at case detection (17/27; 63%), and patients older than 44 years (9/9; 100%). Survivors mostly manifested a mild gastro-intestinal syndrome with nausea (83%), anorexia (75%), vomiting (75%), abdominal pain (50%), and diarrhoea (42%), and prolonged symptoms of severe disease including jaundice (67%), visual difficulties (67%), epistaxis (50%), haemoptysis (42%), and dysentery (25%). Symptom duration varied between two to 120 days. CONCLUSION: RVF is associated with high hospital-based mortality, severe and prolonged morbidity among humans that present to the health care system and are confirmed by PCR. One-health composite interventions should be developed to improve environmental and livestock surveillance, prevent infections, promptly detect outbreaks, and improve patient outcomes.
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Fiebre del Valle del Rift , Humanos , Uganda/epidemiología , Fiebre del Valle del Rift/mortalidad , Fiebre del Valle del Rift/epidemiología , Masculino , Adulto , Persona de Mediana Edad , Adolescente , Femenino , Adulto Joven , Niño , Virus de la Fiebre del Valle del Rift/genética , Mortalidad Hospitalaria , Morbilidad , Factores de RiesgoRESUMEN
BACKGROUND: Population-based prevalence estimates of distal symmetric polyneuropathy (DPN) and diabetic autonomic neuropathy (DAN) are scares. Here we present neuropathy estimates and describe their overlap in a large cohort of people with type 1 and type 2 diabetes. METHODS: In a large population of outpatient participants, DPN was assessed using vibration perception threshold, sural nerve function, touch, pain and thermal sensation. Definite DPN was defined by the Toronto Consensus Criteria. Painful DPN was defined by Douleur Neuropathique 4 Questions. DAN measures were: cardiovascular reflex tests, electrochemical skin conductance, and gastroparesis cardinal symptom index. RESULTS: We included 822 individuals with type 1 (mean age (±SD) 54 ± 16 years, median [IQR] diabetes duration 26 [15-40] years) and 899 with type 2 diabetes (mean age 67 ± 11 years, median diabetes duration 16 [11-22] years). Definite DPN was prevalent in 54 % and 68 %, and painful DPN was in 5 % and 15 % of type 1 and type 2 participants, respectively. The prevalence of DAN varied between 6 and 39 % for type 1 and 9-49 % for type 2 diabetes. DPN without other neuropathy was present in 45 % with T1D and 50 % with T2D. CONCLUSION: The prevalence of DPN and DAN was high. DPN and DAN co-existed in only 50 % of cases.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Humanos , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/complicaciones , Persona de Mediana Edad , Femenino , Masculino , Prevalencia , Dinamarca/epidemiología , Adulto , Anciano , Estudios de Cohortes , Instituciones de Atención Ambulatoria/estadística & datos numéricos , Centros de Atención Terciaria/estadística & datos numéricosRESUMEN
BACKGROUND AND AIMS: Anterior quadratus lumborum block is a truncal block, applied in close proximity to the lumbar plexus, potentially causing lower limb weakness. This trial aimed to evaluate whether a unilateral anterior quadratus lumborum block caused quadriceps muscle weakness compared with placebo. METHODS: In this randomized, non-inferiority, triple-blind trial, 20 healthy volunteers received an active unilateral anterior quadratus lumborum block with 30 mL ropivacaine 0.75% and a placebo block on the contralateral side. Primary outcome was change in maximal quadriceps muscle strength from baseline to 60 min postblock compared with placebo. Secondary outcomes were change in single-leg 6 m timed hop test, change in Timed-Up and Go test, change in mean arterial pressure from baseline to 30 min postblock and dermatomal affection. RESULTS: There was no statistically significant difference in changes in maximal quadriceps muscle strength between active and placebo block; 15.88 N (95% CI -12.19 to +43.94), pnon-inf=0.003, indicating non-inferiority. Timed-Up and Go test was performed significantly faster 60 min postblock; -0.23 s (95% CI -0.38 to -0.08, p=0.005). Mean change in mean arterial pressure from baseline to 30 min postblock was 4.25 mm Hg (95% CI 0.24 to 8.26, p=0.04). Dermatome testing revealed an affection primarily of the lower abdomen (Th10-L1) with the active block. CONCLUSION: In this randomized controlled trial including healthy volunteers a unilateral anterior quadratus lumborum block does not cause statistical or clinical significant motor block of the quadriceps muscle compared with placebo. When administered correctly, the block can be used for procedures where early postoperative mobilization is essential. TRIAL REGISTRATION NUMBER: NCT05023343.
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INTRODUCTION: Treatment planning using a five-millimetre geometrical margin from GTV to high-dose CTV (CTV1) has been used in DAHANCA treatment centres since 2013. We aimed to evaluate changes in CTV1 volumes, local control (LC), and recurrence pattern after the implementation of five-millimetre geometrical margins nationally. MATERIALS AND METHODS: 1,948 patients with pharyngeal, and laryngeal squamous cell carcinomas completed definitive IMRT-based treatment in 2010-2012 and 2013-2015 in three centres. The patient-specific margin was calculated as median surface distance from primary tumour GTV (GTV-T) to CTV1. Radiologically verified local recurrences were analysed using a centre of mass (COM) of the delineated recurrence volume, measuring the shortest distance between COM to GTV-T and CTV1 boundaries. RESULTS: Median GTV-CTV1 was 0.9 (0.0-0.97) and 0.47 cm (0.4-0.5) for 2010-2012 and 2013-2015, respectively. Median CTV1 changed in three centres from 76, 28, 42 cm3 to 61, 53, 62 cm3 for 2010-2012 and 2013-2015, respectively. Local failures occurred at 247 patients during first three years after radiotherapy. The 3-year LC rate for 2010-2012 and 2013-2015 was 0.84 and 0.87 (p = 0.06). Out of 146 radiology-verified analysable local recurrences, 102 (69.9%) were inside the CTV1. In 74.6% and 91% of cases, the LRs were covered by 95% isodose in 2010-2012 and 2013-2015, respectively. CONCLUSION: DAHANCA radiotherapy guidelines based on a geometrically generated isotropic CTV1 margin led to less variation in treatment volumes and between centres than previous guidelines. The transition towards consensus GTV-CTV1 margins did not influence local tumour control. The majority of local recurrences were inside CTV1 and covered by the prescription dose.
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Neoplasias Laríngeas , Recurrencia Local de Neoplasia , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Radioterapia de Intensidad Modulada , Humanos , Masculino , Femenino , Recurrencia Local de Neoplasia/radioterapia , Persona de Mediana Edad , Anciano , Planificación de la Radioterapia Asistida por Computador/métodos , Neoplasias Laríngeas/radioterapia , Neoplasias Laríngeas/patología , Radioterapia de Intensidad Modulada/métodos , Guías de Práctica Clínica como Asunto , Neoplasias Faríngeas/radioterapia , Neoplasias Faríngeas/patología , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/patología , Anciano de 80 o más Años , AdultoRESUMEN
Introduction: Patients with failure after primary radiotherapy (RT) for head and neck squamous cell carcinoma (HNSCC) have a poor prognosis. This study investigates pattern of failure after primary curatively intended IMRT in a randomized controlled trial in relation to HPV/p16 status. Material and methods: Patients with HNSCC of the oral cavity, oropharynx (OPSCC), hypopharynx or larynx were treated with primary curative IMRT (+/-cisplatin) and concomitant nimorazole between 2007 and 12. Of 608 patients, 151 had loco-regional failure within five years, from whom 130 pairs of scans (planning-CT and diagnostic failure scan) were collected and deformably co-registered. Point of origin-based pattern of failure analysis was conducted, including distance to CTV1 and GTV, and estimated dose coverage of the point of origin. Results: Of 130 patients with pairs of scans, 104 (80 %) had at least one local or regional failure site covered by 95 % of prescribed dose and 87 (67 %) of the failures had point of origin within the high-dose CTV (CTV1). Of failures from primary p16 + OPSCC, the majority of both mucosal (84 %) and nodal (61 %) failures were covered by curative doses. For p16- tumors (oral cavity, OPSCC p16neg, hypopharynx and larynx), 75 % of mucosal and 66 % of nodal failures were high-dose failures. Conclusion: Radioresistance is the primary cause of failure after RT for HNSCC irrespective of HPV/p16 status. Thus, focus on predictors for the response to RT is warranted to identify patients with higher risk of high-dose failure that might benefit from intensified treatment regimens.
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INTRODUCTION: Diabetic retinopathy (DR), diabetic kidney disease (DKD) and distal symmetric polyneuropathy (DSPN) share common pathophysiology and pose an additive risk of early mortality. RESEARCH DESIGN AND METHODS: In adults with type 1 diabetes, 49 metabolites previously associated with either DR or DKD were assessed in relation to presence of DSPN. Metabolites overlapping in significance with presence of all three complications were assessed in relation to microvascular burden severity (additive number of complications-ie, presence of DKD±DR±DSPN) using linear regression models. Subsequently, the same metabolites were assessed with progression to endpoints: soft microvascular events (progression in albuminuria grade, ≥30% estimated glomerular filtration rate (eGFR) decline, or any progression in DR grade), hard microvascular events (progression to proliferative DR, chronic kidney failure, or ≥40% eGFR decline), and hard microvascular or macrovascular events (hard microvascular events, cardiovascular events (myocardial infarction, stroke, or arterial interventions), or cardiovascular mortality), using Cox models. All models were adjusted for sex, baseline age, diabetes duration, systolic blood pressure, HbA1c, body mass index, total cholesterol, smoking, and statin treatment. RESULTS: The full cohort investigated consisted of 487 participants. Mean (SD) follow-up was 4.8 (2.9, 5.7) years. Baseline biothesiometry was available in 202 participants, comprising the cross-sectional cohort. Eight metabolites were significantly associated with presence of DR, DKD, and DSPN, and six with additive microvascular burden severity. In the full cohort longitudinal analysis, higher levels of 3,4-dihydroxybutanoic acid (DHBA), 2,4-DHBA, ribonic acid, glycine, and ribitol were associated with development of events in both crude and adjusted models. Adding 3,4-DHBA, ribonic acid, and glycine to a traditional risk factor model improved the discrimination of hard microvascular events. CONCLUSIONS: While prospective studies directly assessing the predictive ability of these markers are needed, our results strengthen the role of clinical metabolomics in relation to risk assessment of diabetic complications in chronic type 1 diabetes.
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Diabetes Mellitus Tipo 1 , Neuropatías Diabéticas , Retinopatía Diabética , Adulto , Humanos , Diabetes Mellitus Tipo 1/complicaciones , Estudios Prospectivos , Estudios Transversales , Retinopatía Diabética/etiología , Retinopatía Diabética/complicaciones , Neuropatías Diabéticas/complicaciones , GlicinaRESUMEN
Using a common protocol across seven countries in the European Union/European Economic Area, we estimated XBB.1.5 monovalent vaccine effectiveness (VE) against COVID-19 hospitalisation and death in booster-eligible ≥ 65-year-olds, during October-November 2023. We linked electronic records to construct retrospective cohorts and used Cox models to estimate adjusted hazard ratios and derive VE. VE for COVID-19 hospitalisation and death was, respectively, 67% (95%CI: 58-74) and 67% (95%CI: 42-81) in 65- to 79-year-olds and 66% (95%CI: 57-73) and 72% (95%CI: 51-85) in ≥ 80-year-olds. Results indicate that periodic vaccination of individuals ≥ 65 years has an ongoing benefit and support current vaccination strategies in the EU/EEA.
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Vacunas contra la COVID-19 , COVID-19 , Unión Europea , Hospitalización , SARS-CoV-2 , Eficacia de las Vacunas , Humanos , COVID-19/prevención & control , COVID-19/epidemiología , Anciano , Masculino , Anciano de 80 o más Años , Femenino , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Estudios Retrospectivos , Hospitalización/estadística & datos numéricos , SARS-CoV-2/inmunología , Vacunación/estadística & datos numéricos , Europa (Continente)/epidemiología , Registros Electrónicos de SaludRESUMEN
OBJECTIVE: We investigated associations between gastrointestinal symptoms - evaluated as a combined weighted symptom score (CWSS) - Diabetic autonomic neuropathy (DAN), and distal symmetrical polyneuropathy (DSPN) in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Cross-sectional study in a tertiary outpatient clinic. CWSS was calculated based on questionnaires: gastroparesis composite symptom index (GCSI) and gastrointestinal symptom rating score (GSRS). DAN and DSPN were addressed using the composite autonomic symptom score 31 (COMPASS-31) questionnaire, cardiac autonomic reflex tests (CARTs), electrochemical skin conductance (ESC), vibration perception threshold (VPT), Michigan Neuropathy Screening Instrument (MNSI), pain- and thermal sensation. Analyses were adjusted for age, sex, diabetes duration, smoking, LDL-cholesterol, HbA1C and systolic blood pressure. Type 1 and type 2 diabetes were evaluated separately. RESULTS: We included 566 with type 1 diabetes and 377 with type 2 diabetes. Mean ± SD age was 58 ± 15 years and 565 (59.9 %) were women. A high CWSS was present in 143 (25 %) with type 1 and 142 (38 %) with type 2 diabetes. The odds of DAN by COMPASS-31 (p < 0.001) were higher in the high score group. For type 1 diabetes, odds of cardiac autonomic neuropathy were higher in the high CWSS group. The odds of DSPN by VPT and MNSI in type 1 diabetes, and by ESC, VPT and pain sensation in type 2 diabetes were higher in the high CWSS group. CONCLUSIONS: A high symptom score was associated with neuropathy by COMPASS-31 and vibration perception. Gastrointestinal symptom burden associated inconsistently with other neuropathy tests between diabetes types.