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OBJECTIVE: Genetic high-resolution analyses and improved diagnostic imaging have impacted the ability to detect fetal disorders. It is unknown if this resulted in an alteration in the number of terminations of pregnancy due to fetal anomalies (TOPFA). The objective was to describe the incidence and indication of TOPFA. METHODS: A descriptive study based on records from the Regional Abortion Council in the Central Denmark Region from 2008 to 2021 consisting of 1895 TOPFA. RESULTS: A consistent incidence of TOPFA was observed, accounting for 0.96% of the total births during that period. When examining fetal indications, there was a small increase in the occurrence of genetic aberrations, primarily caused by deletions, duplications, and single nucleotide variations, whereas the number of chromosomal aberrations remained stable. Of 35.5% of the cases with malformations, the central nervous system was the most affected organ system, followed by malformations of the heart 29.6%. Overall, the total number of cases remained stable. DISCUSSION AND CONCLUSION: Unexpectedly, despite the development of new diagnostic tools, the incidence of TOPFA from 2008 to 2021 remained stable. However, the number of cases with genetic aberrations increased. This may be attributed to increased genetic testing for fetuses with identified malformations, resulting in more accurate diagnoses.
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Aborto Inducido , Aborto Espontáneo , Enfermedades Fetales , Embarazo , Femenino , Humanos , Aborto Inducido/métodos , Enfermedades Fetales/epidemiología , Aberraciones Cromosómicas , Feto , Diagnóstico PrenatalRESUMEN
OBJECTIVES: We developed a rat model of prosthetic vascular graft infection to assess, whether the fibrinolytic tissue plasminogen activator (tPA) could increase the efficacy of antibiotic therapy. MATERIALS AND METHODS: Rats were implanted a polyethylene graft in the common carotid artery, pre-inoculated with approx. 6 log10 colony forming units (CFU) of methicillin resistant Staphylococcus aureus. Ten days after surgery, rats were randomized to either: 0.9% NaCl (n = 8), vancomycin (n = 8), vancomycin + tPA (n = 8), vancomycin + rifampicin (n = 18) or vancomycin + rifampicin + tPA (n = 18). Treatment duration was seven days. Approximately 36 hours after the end of treatment, the rats were euthanized, and grafts and organs were harvested for CFU enumeration. RESULTS: All animals in the control group had significantly higher CFU at the time of euthanization compared to bacterial load found on the grafts prior to inoculation (6.45 vs. 4.36 mean log10 CFU/mL, p = 0.0011), and both the procedure and infection were well tolerated. Vancomycin and rifampicin treatment were superior to monotherapy with vancomycin, as it lead to a marked decrease in median bacterial load on the grafts (3.50 vs. 6.56 log10 CFU/mL, p = 0.0016). The addition of tPA to vancomycin and rifampicin combination treatment did not show a further decrease in bacterial load (4.078 vs. 3.50 log10 CFU/mL, p = 0.26). The cure rate was 16% in the vancomycin + rifampicin group vs. 37.5% cure rate in the vancomycin + rifampicin + tPA group. Whilst interesting, this trend was not significant at our sample size (p = 0.24). CONCLUSION: We developed the first functional model of an arterial prosthetic vascular graft infection in rats. Antibiotic combination therapy with vancomycin and rifampicin was superior to vancomycin monotherapy, and the addition of tPA did not significantly reduce bacterial load, nor significantly increase cure rate.
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Staphylococcus aureus Resistente a Meticilina , Infecciones Relacionadas con Prótesis , Infecciones Estafilocócicas , Animales , Ratas , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Infecciones Relacionadas con Prótesis/microbiología , Rifampin/farmacología , Rifampin/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Activador de Tejido Plasminógeno/uso terapéutico , Vancomicina/farmacología , Vancomicina/uso terapéuticoRESUMEN
Biliary tract cancer (BTC) is a rare gastrointestinal cancer with a dismal prognosis. Biomarkers with clinical utility are needed. In this study, we investigated the association between survival and 89 immuno-oncology-related proteins, with the aim of identifying prognostic biomarkers for BTC. The study included patients with BTC (n = 394) treated at three Danish hospitals. Patients were divided into four cohorts: the first-line discovery cohort (n = 202), first-line validation cohort (n = 118), second-line cohort (n = 56), and surgery cohort (n = 41). Plasma protein levels were measured using a proximity extension assay (Olink Proteomics). Twenty-seven proteins were associated with overall survival (OS) in a multivariate analysis in the discovery cohort. In the first-line validation cohort, high levels of interleukin (IL)-6, IL-15, mucin 16, hepatocyte growth factor, programmed cell death ligand 1, and placental growth factor were significantly associated with poor OS in univariate Cox regression analyses. When adjusting for performance status, location, and stage, the association was significant only for IL-6 (hazard ratio (HR) = 1.25, 95% confidence interval (CI) 1.08-1.46) and IL-15 (HR = 2.23, 95% CI 1.48-3.35). Receiver operating characteristic analyses confirmed IL-6 and IL-15 as the strongest predictors of survival. Combining several proteins into signatures further improved the ability to distinguish between patients with short (<6 months) and long survival (>18 months). The study identified several circulating proteins as prognostic biomarkers in patients, with BTC, IL-6, and IL-15 being the most promising markers. Combining proteins in a prognostic signature improved prognostic performance, but future studies are needed to determine the optimal combination and thresholds.
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Background & Aims: Biliary tract cancer (BTC) is associated with a dismal prognosis, partly because it is typically diagnosed late, highlighting the need for diagnostic biomarkers. The purpose of this project was to identify and validate multiprotein signatures that could differentiate patients with BTC from non-cancer controls. Methods: In this study, we included treatment-naïve patients with BTC, healthy controls, and patients with benign conditions including benign biliary tract disease. Participants were divided into three non-overlapping cohorts: a case-control-based discovery cohort (BTC = 186, controls = 249); a case-control-based validation cohort (validation cohort 1: BTC = 113, controls = 241); and a cohort study-based validation cohort including participants (BTC = 8, controls = 132) referred for diagnostic work-up for suspected cancer (validation cohort 2). Immuno-Oncology (I-O)-related proteins were measured in serum and plasma using a proximity extension assay (Olink Proteomics). Lasso and Ridge regressions were used to generate protein signatures of I-O-related proteins and carbohydrate antigen 19-9 (CA19-9) in the discovery cohort. Results: Sixteen protein signatures, including 2 to 82 proteins, were generated. All signatures included CA19-9 and chemokine C-C motif ligand 20. Signatures discriminated between patients with BTC vs. controls, with AUCs ranging from 0.95 to 0.99 in the discovery cohort and 0.94 to 0.97 in validation cohort 1. In validation cohort 2, AUCs ranged from 0.84 to 0.94. Nine signatures achieved a specificity of 82% to 84% while keeping a sensitivity of 100% in validation cohort 2. All signatures performed better than CA19-9, and signatures including >15 proteins showed the best performance. Conclusion: The study demonstrated that it is possible to generate protein signatures that can successfully differentiate patients with BTC from non-cancer controls. Impact and implications: We attempted to find blood sample-based protein profiles that could differentiate patients with biliary tract cancer from those without cancer. Several profiles were found and tested in different groups of patients. The profiles were successful at identifying most patients with biliary tract cancer, pointing towards the utility of multiprotein signatures in this context.
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Biliary tract cancer (BTC) is characterized by a desmoplastic extracellular matrix (ECM). We tested the diagnostic and prognostic use of seven circulating biomarkers of ECM remodeling: pro-peptides of type III collagen (PRO-C3), VI (PRO-C6) and XI (PRO-C11), matrix metalloprotease (MMP) degraded type III collagen (C3M) and type IV collagen (C4M) fragments, granzyme B degraded type IV collagen fragments (C4G) and MMP degraded and citrullinated vimentin (VICM) a marker of macrophage activation. The study included 269 patients with all stages of BTC and 49 patients with benign biliary tract diseases. Serum samples from BTC patients were collected before surgery, or before first- or second-line chemotherapy. C3M, C4M, PRO-C3, PRO-C6, PRO-C11 and VICM levels were elevated in patients with BTC compared to patients with benign disease. Receiver operating characteristics curve analyses identified PRO-C3 (area under curve [AUC] = 0.87) as the ECM marker with the best diagnostic performance. The ECM biomarkers correlated with inflammation biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6] and YKL-40) but not with CA19-9. To investigate prognostic performance, patients were split into three cohorts (first-line, second-line and surgery). Elevated ECM biomarker levels were associated with short overall survival (OS), but only pretreatment PRO-C3 and PRO-C6 were associated with OS in both the first-line and second-line settings when adjusting for CA19-9, performance status and stage in a multivariate Cox-regression analyses. Our results indicate that collagen remodeling is increased in patients with BTC and associated with survival. The collagen pro-peptides (PRO-C3 and PRO-C6) could be used as novel biomarkers in these patients.
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Neoplasias del Sistema Biliar , Colágeno Tipo IV , Humanos , Colágeno Tipo III , Pronóstico , Biomarcadores de Tumor , Antígeno CA-19-9 , Complemento C3 , Biomarcadores , Fibrosis , Neoplasias del Sistema Biliar/diagnóstico , PéptidosRESUMEN
BACKGROUND: Men with Klinefelter syndrome (KS) are routinely offered testosterone replacement therapy (TRT) suggested to potentially promote platelet aggregation and increase cardiovascular risk. OBJECTIVE: We investigated platelet aggregation in men with KS before and during TRT. MATERIALS AND METHODS: Forty-one adult men with KS participated, of which 20 had no history of TRT at baseline, with 15 completing follow-up after 18 months TRT. Further, we included 21 adult men with KS on long-term TRT (>10 years) and a male reference population. We assessed platelet impedance aggregometry using adenosine diphosphate (6.5 µM), thrombin-receptor-activating-peptide-6 (TRAP 32 µM), and arachidonic acid (ASPI 0.5 mM) as agonists in KS compared to a male reference population and stratified by route of TRT administration. RESULTS: Platelet aggregation among men with KS at baseline or during TRT was not increased compared with the male reference population. For all three agonist, no change was seen in platelet aggregation in KS at follow-up compared with baseline (p ≥ 0.2). Platelet aggregation was not associated with total testosterone and furthermore, platelet count was not affected by treatment with testosterone. Men with KS treated with testosterone gel showed slightly increased TRAP- and ASPI-induced platelet aggregation compared with those treated with testosterone injection (p = 0.02 and p = 0.04, respectively). DISCUSSION AND CONCLUSIONS: We observed normal platelet aggregation in men with KS before TRT and following both short and long term treatment. Our findings do not support an independent role of platelets in driving the cardiovascular risk in KS.
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Hipogonadismo , Síndrome de Klinefelter , Adulto , Humanos , Masculino , Síndrome de Klinefelter/tratamiento farmacológico , Síndrome de Klinefelter/complicaciones , Estudios de Seguimiento , Testosterona/uso terapéutico , Plaquetas , Terapia de Reemplazo de Hormonas , Hipogonadismo/tratamiento farmacológicoRESUMEN
Human speech production obeys the same acoustic principles as vocal production in other animals but has distinctive features: A stable vocal source is filtered by rapidly changing formant frequencies. To understand speech evolution, we examined a wide range of primates, combining observations of phonation with mathematical modeling. We found that source stability relies upon simplifications in laryngeal anatomy, specifically the loss of air sacs and vocal membranes. We conclude that the evolutionary loss of vocal membranes allows human speech to mostly avoid the spontaneous nonlinear phenomena and acoustic chaos common in other primate vocalizations. This loss allows our larynx to produce stable, harmonic-rich phonation, ideally highlighting formant changes that convey most phonetic information. Paradoxically, the increased complexity of human spoken language thus followed simplification of our laryngeal anatomy.
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Evolución Biológica , Laringe , Fonación , Primates , Habla , Pliegues Vocales , Animales , Humanos , Laringe/anatomía & histología , Fonética , Acústica del Lenguaje , Pliegues Vocales/anatomía & histologíaRESUMEN
We studied systemic ceftriaxone, and free/local tobramycin and doxycycline in a controlled rat model representing a generic acute exogenous joint infection. We hypothesized that evidence of infection (quantitative colony forming units [CFU], qualitative scanning electron microscopy [SEM], histopathology) (1a) would be reduced with local versus systemic antibiotic, (1b) any antibiotic would be superior to control, (2) there would be a difference among antibiotics, and (3) antibiotic would not be detectable in serum at 4-week euthanasia. Study groups included infected and noninfected (1) control (no treatment), (2) systemic ceftriaxone (daily), (3) local tobramycin, and (4) local doxycycline (10 rats/group; power = 0.8). With IACUC approval, a reliable acute exogenous joint infection was created by slowly injecting 50-µl, 104 CFU Staphylococcus aureus, into the distal femoral medullary canal. The antibiotic formulation was introduced locally to the femoral canal and joint space. After 4 weeks, serum, pin, bone, and synovium were obtained. CFU/ml of bone and synovium were quantified using macrotiter method. SEM imaged biofilm on the surface of the pin, histopathology identified tissue response, liquid chromatography/mass spectrometry quantified plasma antibiotic. (1) Groups receiving any antibiotic reported lower CFU/ml in synovium compared with no treatment. (2) In the synovium, free/local tobramycin reduced CFU/ml to a greater extent than free/local doxycycline (p < 0.05). (3) Antibiotic in plasma after the local application was nondetectable in all groups after 4 weeks. SEM revealed no difference in biofilm on pin among all groups.
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Infecciones Relacionadas con Prótesis , Infecciones Estafilocócicas , Animales , Antibacterianos , Ceftriaxona , Doxiciclina , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Infecciones Relacionadas con Prótesis/prevención & control , Ratas , Ratas Sprague-Dawley , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/prevención & control , TobramicinaRESUMEN
Protein S (PS) deficiency is a risk factor for venous thromboembolism (VTE) and can be caused by variants of the gene encoding PS ( PROS1 ). This study aimed to evaluate the clinical value of molecular analysis of the PROS1 gene in PS-deficient participants. We performed Sanger sequencing of the coding region of the PROS1 gene and multiplex ligation-dependent probe amplification to exclude large structural rearrangements. Free PS was measured by a particle-enhanced immunoassay, while PS activity was assessed by a clotting method. A total of 87 PS-deficient participants and family members were included. In 22 index participants, we identified 13 PROS1 coding variants. Five variants were novel. In 21 index participants, no coding sequence variants or structural rearrangements were identified. The free PS level was lower in index participants carrying a PROS1 variant compared with index participants with no variant (0.51 [0.32-0.61] vs. 0.62 [0.57-0.73] × 10 3 IU/L; p < 0.05). The p.(Thr78Met) variant was associated with only slightly decreased free PS levels (0.59 [0.53-0.66] × 10 3 IU/L) compared with the p.(Glu390Lys) variant (0.27 [0.24-0.37] × 10 3 IU/L, p < 0.01). The frequency of VTE in participants with a coding PROS1 variant was 43 and 17% in the group with normal PROS1 gene ( p = 0.05). In conclusion, we report 13 PROS1 coding variants including five novel variants. PS levels differ by PROS1 variant and the frequency of VTE was higher when a coding PROS1 variant was present. Hence, molecular analysis of the PROS1 gene may add clinical value in the diagnostic work-up of PS deficiency.
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INTRODUCTION: Vaginal colonization with Streptococcus agalactiae (group B streptococci) is hypothesized to constitute a risk factor for preterm prelabor rupture of membranes. In vitro studies have shown that S. agalactiae strains isolated from infants with neonatal sepsis adhere to chorion cells of the human chorioamniotic membrane. However, it is still unknown whether S. agalactiae strains penetrate the chorioamniotic membranes and whether S. agalactiae colonization affects the biomechanical properties of the membranes and thus contributes to increased risk of preterm prelabor rupture. The aim of this in vitro study was to explore if different strains of S. agalactiae penetrate and affect the biomechanical properties of human chorioamniotic membranes. MATERIAL AND METHODS: Three different strains of S. agalactiae were obtained, one from an early-onset neonatal infection, one from a case of preterm prelabor rupture of membranes and one from a healthy pregnant carrier. Chorioamniotic membranes from elective cesarean deliveries were either incubated with S. agalactiae or mounted in a two-chamber incubation cell generating a "maternal" and a "fetal" chamber and incubated with S. agalactiae in the maternal chamber. Subsequently the membranes were examined to evaluate S. agalactiae attachment, penetration and the effect on the biomechanical properties. RESULTS: At 5 h after incubation, S. agalactiae adhered to the chorioamniotic membranes with increased number at 20 h. Streptococcus agalactiae did not penetrate the membranes even after 20 h of incubation. Streptococcus agalactiae increased the ultimate tensile stress needed to rupture the membranes and increased the work needed to rupture the membranes as well as the elastic modulus. CONCLUSIONS: Human chorioamniotic membranes constitute a physical barrier against S. agalactiae infections. Moreover, S. agalactiae infection leads to increased strength of the membranes.
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Corion/microbiología , Rotura Prematura de Membranas Fetales/microbiología , Complicaciones Infecciosas del Embarazo , Infecciones Estreptocócicas , Streptococcus agalactiae/patogenicidad , Femenino , Humanos , Técnicas In Vitro , EmbarazoRESUMEN
Male walruses produce some of the longest continuous reproductive displays known among mammals to convey their physical fitness to potential rivals and possibly to potential mates. Here, we document the ability of a captive walrus to produce intense, rhythmic sounds through a non-vocal pathway involving deliberate, regular collision of the fore flippers. High-speed videography linked to an acoustic onset marker revealed sound production through cavitation, with the acoustic impulse generated by each forceful clap exceeding a peak-to-peak sound level of 200 dB re. 1 µPa. This clapping display is in some ways quite similar to the knocking display more commonly associated with walruses in rut but is produced through a very different mechanism and with much higher amplitudes. While this clapping behaviour has not yet been documented in wild individuals, it has been observed among other mature male walruses living in human care. Production of intense sounds through cavitation has previously been documented only in crustaceans but may also be an effective means of sound production for some aquatic mammals.
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Intra-articular injection of vancomycin may be an important antimicrobial prophylactic supplement to systemic administration in the prevention of prosthetic joint infections. In eight female pigs, 500 mg of diluted vancomycin was given by intra-articular injection into the knee joint. Microdialysis was used for dense sampling of vancomycin concentrations over 12 hours in the synovial fluid of the knee joint, and in the adjacent femoral and tibial cancellous bone and subcutaneous tissue. Venous blood samples were obtained as reference. The mean (standard deviation [SD]) peak drug concentration of vancomycin in the synovial fluid of the knee joint was 5,277 (5,668) µg/mL. Only one pig failed to reach a peak drug concentration above 1,000 µg/mL. The concentration remained high throughout the sampling interval with a mean (SD) concentration of 337 (259) µg/mL after 690 minutes. For all extraarticular compartments, the pharmacokinetic parameters (area under the concentration time-curve, peak drug concentration, and time to peak drug concentration) were comparable. The highest extraarticular mean (SD) peak drug concentration of 4.4 (2.3) µg/mL was found in subcutaneous tissue. An intra-articular injection of 500 mg diluted vancomycin was found to provide significant prophylactic mean concentrations for at least 12 hours in the synovial fluid of the knee joint. Correspondingly, the adjacent tissue and plasma concentrations were low but remained stable, signifying low risk of systemic toxic side effects and a slow release or uptake from the synovium to the systemic circulation.
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Articulación de la Rodilla , Animales , Antibacterianos/uso terapéutico , Femenino , Inyecciones Intraarticulares , Porcinos , Líquido Sinovial , VancomicinaRESUMEN
Platelet aggregation measured by impedance aggregometry is highly dependent on platelet count. We previously developed a tool to interpret impedance aggregometry based on the strong linear correlation between platelet counts and platelet aggregation at reduced platelet counts. The present study aimed to optimize the tool by expanding the model to include normal platelet counts. We combined data from three previous studies on 266 healthy individuals measuring impedance aggregometry with four agonists (collagen, adenosine diphosphate, thrombin receptor activating peptide-6, and ristocetin). Reduced platelet counts were established in vitro. The investigated platelet counts ranged from 26-425x109/L. A positive linear correlation was found between platelet counts and platelet aggregation across normal and reduced platelet counts (all p-values <0.001). We established 95% prediction intervals for healthy platelet aggregation in relation to platelet count. The new expanded model serves as an optimized tool for evaluation of platelet aggregation at normal and reduced platelet counts.
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Plaquetas/metabolismo , Impedancia Eléctrica/uso terapéutico , Pruebas de Función Plaquetaria/métodos , Femenino , Humanos , MasculinoRESUMEN
Circulating cell-free DNA (cfDNA) has spurred much interest as a biomarker in oncology. However, inter- and intra-individual cfDNA levels vary greatly. Consequently, in order to base clinical decisions on cfDNA measurements, normal reference intervals are essential to avoid that ordinary variation is confused with clinically relevant change. The lack of reference intervals may potentially explain the ambiguous results reported in the field. Our study aimed to establish reference intervals and to evaluate the association between cfDNA and demographic and clinical variables, including colorectal cancer (CRC). Plasma samples and clinical data from 2817 subjects were collected including 1930 noncancer individuals and 887 CRC patients. cfDNA was measured using droplet digital polymerase chain reaction (PCR). The large cohort combined with robust cfDNA quantification enabled establishment of reference intervals (<67 years: 775-4860 copies/mL; ≥67 years: 807-6561 copies/mL). A cfDNA level above the age-stratified 90% percentile was prognostic of reduced survival in both noncancer individuals and CRC patients, with HR values of 2.56 and 2.01, respectively. Moreover, cfDNA levels increased significantly with age, elevated BMI and chronic diseases. In CRC, the cfDNA level was increased for Stage IV, but not Stage I to Stage III cancer. In summary, the use of reference intervals revealed that high cfDNA levels were predictive of shorter survival in both noncancer individuals and CRC patients, and that CRC development did not affect the cfDNA level until metastatic dissemination. Furthermore, cfDNA levels were impacted by age and chronic diseases. Conclusively, our study presents reference intervals that will help pave the way for clinical utilization of cfDNA.
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Biomarcadores de Tumor/sangre , Ácidos Nucleicos Libres de Células/sangre , Neoplasias Colorrectales/sangre , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Índice de Masa Corporal , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/metabolismo , Estudios de Cohortes , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , PronósticoRESUMEN
BACKGROUND: In March 2020, the World Health Organization elevated the coronavirus disease (COVID-19) epidemic to a pandemic and called for urgent and aggressive action worldwide. Public health experts have communicated clear and emphatic strategies to prevent the spread of COVID-19. Hygiene rules and social distancing practices have been implemented by entire populations, including 'stay-at-home' orders in many countries. The long-term health and economic consequences of the COVID-19 pandemic are not yet known. MAIN TEXT: During this time of crisis, some chiropractors made claims on social media that chiropractic treatment can prevent or impact COVID-19. The rationale for these claims is that spinal manipulation can impact the nervous system and thus improve immunity. These beliefs often stem from nineteenth-century chiropractic concepts. We are aware of no clinically relevant scientific evidence to support such statements. We explored the internet and social media to collect examples of misinformation from Europe, North America, Australia and New Zealand regarding the impact of chiropractic treatment on immune function. We discuss the potential harm resulting from these claims and explore the role of chiropractors, teaching institutions, accrediting agencies, and legislative bodies. CONCLUSIONS: Members of the chiropractic profession share a collective responsibility to act in the best interests of patients and public health. We hope that all chiropractic stakeholders will view the COVID-19 pandemic as a call to action to eliminate the unethical and potentially dangerous claims made by chiropractors who practise outside the boundaries of scientific evidence.
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Quiropráctica/ética , Información de Salud al Consumidor/ética , Decepción , Pandemias/ética , Mala Conducta Profesional , Betacoronavirus , COVID-19 , Comunicación , Infecciones por Coronavirus , Humanos , Manipulación Espinal/ética , Neumonía Viral , SARS-CoV-2RESUMEN
PURPOSE: Biliary tract cancer (BTC) is a heterogeneous group of rare gastrointestinal malignancies with dismal prognosis often associated with inflammation. We assessed the prognostic value of IL6 and YKL-40 compared with CA19-9 before and during palliative chemotherapy. We also investigated in mice whether IL6R inhibition in combination with gemcitabine could prolong chemosensitivity. EXPERIMENTAL DESIGN: A total of 452 Danish participants with advanced (locally advanced and metastatic) BTC were included from six clinical trials (February 2004 to March 2017). Serum CA19-9, IL6, and YKL-40 were measured before and during palliative treatment. Associations between candidate biomarkers and progression-free survival (PFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression. Effects of inhibiting IL6R and YKL-40 were assessed in vitro, and of IL6R inhibition in vivo. RESULTS: High pretreatment levels of CA19-9, IL6, and YKL-40, and increasing levels during treatment, were associated with short PFS and OS in patients with advanced BTC. IL6 provided independent prognostic information, independent of tumor location and in patients with normal serum CA19-9. ROC analyses showed that IL6 and YKL-40 were predictive of very short OS (OS < 6 months), whereas CA19-9 was best to predict OS > 1.5 years. Treatment with anti-IL6R and gemcitabine significantly diminished tumor growth when compared with gemcitabine monotherapy in an in vivo transplant model of BTC. CONCLUSIONS: Serum IL6 and YKL-40 are potential new prognostic biomarkers in BTC. IL6 provides independent prognostic information and may be superior to CA19-9 in certain contexts. Moreover, anti-IL6R should be considered as a new treatment option to sustain gemcitabine response in patients with BTC.
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Neoplasias del Sistema Biliar/tratamiento farmacológico , Proteína 1 Similar a Quitinasa-3/genética , Desoxicitidina/análogos & derivados , Interleucina-6/sangre , Receptores de Interleucina-6/sangre , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antígenos de Carbohidratos Asociados a Tumores/sangre , Antígenos de Carbohidratos Asociados a Tumores/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Biliar/sangre , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/patología , Biomarcadores de Tumor/sangre , Proliferación Celular/efectos de los fármacos , Proteína 1 Similar a Quitinasa-3/sangre , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Interleucina-6/genética , Masculino , Ratones , Persona de Mediana Edad , Cuidados Paliativos , Pronóstico , Supervivencia sin Progresión , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/genética , GemcitabinaRESUMEN
BACKGROUND: Pathogenic variants in STK11, also designated as LKB1, cause Peutz-Jeghers syndrome, which is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation changes, polyposis, and a high risk of cancer. METHODS: A male meeting the clinical diagnostic criteria for Peutz-Jeghers syndrome underwent next-generation sequencing. To validate the predicted splicing impact of a detected STK11 variant, we performed RNA-Seq on mRNA extracted from patient-derived Epstein-Barr virus-transformed lymphocytes treated with cycloheximide to inhibit nonsense-mediated decay ex vivo. RESULTS: Blood testing identified a novel single-nucleotide substitution, NM_000455.4:c.735-10C>A, at the end of the 3' polypyrimidine tract of intron five in STK11. RNA-Seq confirmed a predicted eight base pair insertion in the mRNA transcript. Following inhibition of nonsense-mediated decay, the out-of-frame insertion was detected in 50% of all RNA-Seq reads. This confirmed a strong, deleterious splicing impact of the variant. CONCLUSION: We characterized a novel likely pathogenic germline variant in intron five of STK11 associated with Peutz-Jeghers syndrome. The study highlights RNA-Seq as a useful supplement in hereditary cancer predisposition testing.
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Intrones , Síndrome de Peutz-Jeghers/genética , Mutación Puntual , Proteínas Serina-Treonina Quinasas/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Peutz-Jeghers/patología , Empalme del ARNRESUMEN
Hearing is vital for birds as they rely on acoustic communication with parents, mates, chicks and conspecifics. Amphibious seabirds face many ecological pressures, having to sense cues in air and underwater. Natural noise conditions have helped shape this sensory modality but anthropogenic noise is increasingly impacting seabirds. Surprisingly little is known about their hearing, despite their imperiled status. Understanding sound sensitivity is vital when we seek to manage the impacts of man-made noise. We measured the auditory sensitivity of nine wild Atlantic puffins, Fratercula arctica, in a capture-and-release setting in an effort to define their audiogram and compare these data with the hearing of other birds and natural rookery noise. Auditory sensitivity was tested using auditory evoked potential (AEP) methods. Responses were detected from 0.5 to 6â kHz. Mean thresholds were below 40â dBâ re. 20â µPa from 0.75 to 3â kHz, indicating that these were the most sensitive auditory frequencies, similar to other seabirds. Thresholds in the 'middle' frequency range 1-2.5â kHz were often down to 10-20 dB re. 20â µPa. The lowest thresholds were typically at 2.5â kHz. These are the first in-air auditory sensitivity data from multiple wild-caught individuals of a deep-diving alcid seabird. The audiogram was comparable to that of other birds of similar size, thereby indicating that puffins have fully functioning aerial hearing despite the constraints of their deep-diving, amphibious lifestyles. There was some variation in thresholds, yet animals generally had sensitive ears, suggesting aerial hearing is an important sensory modality for this taxon.
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Audición , Agua , Estimulación Acústica , Animales , Umbral Auditivo , Potenciales Evocados Auditivos , Pruebas Auditivas , RuidoRESUMEN
Novel and minimally-invasive prostate cancer (PCa)-specific biomarkers are needed to improve diagnosis and risk stratification. Here, we investigated the biomarker potential in localized and de novo metastatic PCa (mPCa) of methylated circulating tumor DNA (ctDNA) in plasma. Using the Marmal-aid database and in-house datasets, we identified three top candidates specifically hypermethylated in PCa tissue: DOCK2,HAPLN3, and FBXO30 (specificity/sensitivity: 80%-100%/75-94%). These candidates were further analyzed in plasma samples from 36 healthy controls, 61 benign prostatic hyperplasia (BPH), 102 localized PCa, and 65 de novo mPCa patients using methylation-specific droplet digital PCR. Methylated ctDNA for DOCK2/HAPLN3/FBXO30 was generally not detected in healthy controls, BPH patients, nor in patients with localized PCa despite a positive signal in 98%-100% of matched radical prostatectomy tissue samples. However, ctDNA methylation of DOCK2,HAPLN3, and/or FBXO30 was detected in 61.5% (40/65) of de novo mPCa patients and markedly increased in high- compared to low-volume mPCa (89.3% (25/28) vs. 32.1% (10/31), p < 0.001). Moreover, detection of methylated ctDNA was associated with significantly shorter time to progression to metastatic castration resistant PCa, independent of tumor-volume. These results indicate that methylated ctDNA (DOCK2/HAPLN3/FBXO30) may be potentially useful for identification of hormone-naïve mPCa patients who could benefit from intensified treatment.
Asunto(s)
Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/genética , Epigénesis Genética , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Metilación de ADN/genética , Progresión de la Enfermedad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Modelos de Riesgos Proporcionales , Neoplasias de la Próstata/patología , Análisis de Supervivencia , Carga Tumoral/genéticaRESUMEN
Wildlife species are often host to a diversity of parasites, but our knowledge of their diversity and ecology is extremely limited, especially for reptiles. Little is known about the host-parasite ecology of the Australian lizard, the King's skink (Egernia kingii). In spring of 2015, we carried out a field-based study of a population of King's skinks on Penguin Island (Western Australia). We documented five species of parasites, including two ectoparasitic mites (an undescribed laelapid mite and Mesolaelaps australiensis), an undescribed coccidia species, and two nematode species (Pharyngodon tiliquae and Capillaria sp.). The laelapid mite was the most abundant parasite, infesting 46.9% of the 113 captured lizards. This mite species increased in prevalence and abundance over the course of the study. Infection patterns of both mites varied with lizard life-stage; sub-adults were more commonly infested with laelapid mites than adults or juveniles, and sub-adults and adults were infested by more laelapid mites than juveniles. By contrast, adults had a higher prevalence of M. australiensis than juveniles or sub-adults. Among the gastrointestinal parasites, P. tiliquae was relatively common among the sampled lizards (35.3%). These results give new important information about reptiles as parasite hosts and what factors influence infection patterns.