ABSTRACT
Background: Life-long vitamin K antagonist (VKA) therapy is recommended as a standard of care in antiphospholipid syndrome (APS) patients with thrombosis. Concerns have been raised about the validity of international normalized ratio (INR) measurements in lupus anticoagulant (LA)-positive APS patients because LA may interfere with phospholipid-dependent coagulation tests and could elevate INR measurements. Objectives: Here, we aimed to determine the interference of antigen-specific monoclonal and isolated patient antibodies with LA activity on INR measurements. Methods: Pooled normal plasma and control plasma from patients on VKA (without LA) were incubated with monoclonal and isolated patient immunoglobulin G antiprothrombin and anti-beta-2-glycoprotein I antibodies that express LA activity. INR was determined before and after addition using 3 laboratory assays (Owren STA-Hepato Prest, Quick STA-NeoPTimal, and Quick STA-Neoplastine R) and 1 point-of-care test device (CoaguChek Pro II). Results: Antiprothrombin and anti-beta-2-glycoprotein I antibodies with LA activity interfered with recombinant human thromboplastin reagents (Quick STA-Neoplastine R and CoaguChek Pro II), particularly when added to plasma of VKA-treated controls. This effect was most evident on point-of-care test INR measurements, while the recombinant Quick reagent exhibited a lesser degree of interference. In contrast, tissue-derived thromboplastin reagents (Owren STA-Hepato Prest and Quick STA-NeoPTimal) remained largely unaffected by these antibodies, both in pooled normal plasma and VKA anticoagulated control plasma. Among these reagents, the Owren INR reagent exhibited the lowest sensitivity to the influence of LA antibodies. This observed difference in sensitivity is independent of the plasma dilution factor or the presence of factor V or fibrinogen in Owren reagent. Conclusion: INR reagents that utilize recombinant human thromboplastin are more sensitive to the presence of monoclonal and patient-derived antibodies with LA activity. Consequently, APS patients positive for LA should be monitored using tissue-derived thromboplastin reagents, given its reduced susceptibility to interference by LA-causing antibodies.
ABSTRACT
Some locomotor tasks involve steering at high speeds through multiple waypoints within cluttered environments. Although in principle actors could treat each individual waypoint in isolation, skillful performance would seem to require them to adapt their trajectory to the most immediate waypoint in anticipation of subsequent waypoints. To date, there have been few studies of such behavior, and the evidence that does exist is inconclusive about whether steering is affected by multiple future waypoints. The present study was designed to address the need for a clearer understanding of how humans adapt their steering movements in anticipation of future goals. Subjects performed a simulated drone flying task in a forest-like virtual environment that was presented on a monitor while their eye movements were tracked. They were instructed to steer through a series of gates while the distance at which gates first became visible (i.e., lookahead distance) was manipulated between trials. When gates became visible at least 1-1/2 segments in advance, subjects successfully flew through a high percentage of gates, rarely collided with obstacles, and maintained a consistent speed. They also approached the most immediate gate in a way that depended on the angular position of the subsequent gate. However, when the lookahead distance was less than 1-1/2 segments, subjects followed longer paths and flew at slower, more variable speeds. The findings demonstrate that the control of steering through multiple waypoints does indeed depend on information from beyond the most immediate waypoint. Discussion focuses on the possible control strategies for steering through multiple waypoints.
Subject(s)
Eye Movements , Psychomotor Performance , Humans , Male , Adult , Female , Eye Movements/physiology , Psychomotor Performance/physiology , Young Adult , Automobile Driving , Motion Perception/physiology , Virtual RealityABSTRACT
OBJECTIVE: The term 'vulnerable' is often used to describe women facing psychosocial adversity during pregnancy, implying a heightened risk of experiencing suboptimal pregnancy outcomes. While this label might facilitate the pathway to appropriate care, it can be perceived as stigmatizing by the women it intends to help, which could deter their interaction with healthcare services. This study explores how women facing psychosocial adversity before, during and after pregnancy perceive the concept of vulnerability and experience being labeled as such. METHODS: We conducted a thematic analysis of semi-structured, in-depth interviews. Through purposive sampling targeting maximum variation, ten women of diverse backgrounds were included. RESULTS: Three central themes emerged: defining vulnerability, embracing vulnerability and the feeling of being stigmatized. Women perceived vulnerability as an inability to adequately care for themselves or their children, necessitating additional support alongside routine antenatal care. Acceptance of the 'vulnerable' label came when it also acknowledged their proactive efforts and strengths to improve their situation. Conversely, if discussions surrounding vulnerability failed to recognize women's agency - specifically, their personal journeys and the courage needed to seek support - the label was perceived as stigmatizing. CONCLUSIONS: Addressing vulnerability effectively in maternity care requires a nuanced, patient-centered approach, acknowledging both the challenges and strengths of women facing psychosocial adversities. Emphasizing personal narratives and their courage in seeking support can mitigate the stigmatizing effects of the 'vulnerable' label. Integrating these narratives into maternal healthcare practices can foster deeper connections with the women involved, enhancing the overall quality of care.
ABSTRACT
A 28-year-old patient with severe haemophilia A presented to the emergency department with significant and painful swelling of the left cheek, an extensive haematoma extending from the left ear to the anterior thoracic region, an intraoral haematoma over the soft palate with deviation of the uvula to the right, and complaints of shortness of breath when lying down. Three days prior, his dentist had performed a restoration of the 36 molar under local anaesthesia. Due to pain, the general practitioner had administered an intramuscular injection of a non-steroidal anti-inflammatory drug (NSAID) two days post-procedure. The patient was admitted for treatment with coagulation factors and pain management. Dental procedures and local anaesthesia in patients with a severe coagulation disorder require specific preparatory measures, such as administration of coagulation factors. Collaboration and consultation with a patient's haematologist or haemophilia treatment centre are essential requirements for safe dental care.
Subject(s)
Hemophilia A , Humans , Hemophilia A/complications , Hemophilia A/drug therapy , Male , Adult , Hematoma/etiology , Dental Care for Chronically IllABSTRACT
BACKGROUND: Early preterm (EP) born children are at risk of neurocognitive impairments persisting into adulthood. Less is known about moderately to late (MLP) preterm born children, especially after early childhood. The aim of this study was to assess neurocognitive functioning of MLP adolescents regarding intelligence, executive and attentional functioning, compared with EP and full-term (FT) adolescents. METHODS: This study was part of the Longitudinal Preterm Outcome Project (LOLLIPOP), a large community-based observational cohort study. In total 294 children (81 EP, 130 MLP, and 83 FT) were tested at age 14 to 16 years, regarding intelligence, speed of processing, attention, and executive functions. We used the Dutch version of the Wechsler Intelligence Scale for Children-Third Edition-Dutch Version (WISC-III-NL), the Test of Everyday Attention for Children, and the Behavioural Assessment of the Dysexecutive Syndrome for Children. We assessed differences between preterm-born groups with the FT group as a reference. RESULTS: Compared to the FT group, MLP adolescents scored significantly lower on two subtasks of the WISC-III-NL, i.e. Similarities and Symbol Search. EP adolescents performed significantly lower on all neuropsychological tests than their FT peers, except for the subtask Vocabulary. The MLP adolescents scored in between FT and EP adolescents on all tasks, except for three WISC-III-NL subtasks. CONCLUSIONS: Neurocognitive outcomes of MLP adolescents fell mostly in between outcomes of their EP and FT peers. MLPs generally performed on a low-average to average level, and appeared susceptible to a variety of moderate neurodevelopmental problems at adolescent age, which deserves attention in clinical practice.
Subject(s)
Executive Function , Infant, Premature , Humans , Adolescent , Female , Male , Infant, Premature/psychology , Infant, Premature/growth & development , Infant, Premature/physiology , Attention , Intelligence , Infant, Newborn , CognitionABSTRACT
ABSTRACT: Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of ≥50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts ≥30 × 109/L and ≥50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals. This trial is registered at www.clinicaltrials.gov as #NCT03395210 and www.clinicaltrialsregister.eu as EudraCT 2017-004012-19.
Subject(s)
Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Humans , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Treatment Outcome , Receptors, Fc , Thrombopoietin/therapeutic use , Thrombocytopenia/chemically induced , Hemorrhage/chemically inducedABSTRACT
OBJECTIVE: Physical therapists are well-positioned to prescribe exercise outside of a clinical setting to promote positive health behaviors in people with Parkinson disease (PD). Traditionally, a barrier to precise exercise prescription has been reliance on participant self-reported exercise adherence and intensity. Home-based, commercially available exercise platforms offer an opportunity to remotely monitor exercise behavior and facilitate adherence based on objective performance metrics. The primary aim of this project was to characterize the feasibility and processes of remote aerobic exercise data monitoring from a home-based, commercially available platform in individuals participating in the 12-month Cyclical Lower Extremity Exercise for PD II (CYCLE-II) randomized clinical trial. Secondary aims focused on using exercise behavior to classify the cohort into exercise archetypes and describing a shared decision-making process to facilitate exercise adherence. METHODS: Data from each exercise session were extracted, visualized, and filtered to ensure ride integrity. Weekly exercise frequency was used to determine exercise archetypes: Adherent (2-4 exercise sessions per week), Over-adherent (>4 exercise sessions per week), and Under-adherent (<2 exercise sessions per week). RESULTS: A total of 123 people with PD completed 22,000+ exercise sessions. Analysis of exercise frequency indicated that 79% of participants were adherent; 8% were over-adherent; and 13% were under-adherent. Three case reports illustrate how shared decision-making with the use of exercise performance data points guided exercise prescription. CONCLUSIONS: The number of exercise sessions and completeness of the data indicate that people with PD were able to utilize a commercial, home-based exercise platform to successfully engage in long-term aerobic exercise. Physical therapists can use objective data as a part of a shared decision-making process to facilitate exercise adherence. IMPACT: Commercially available exercise platforms offer a unique approach for physical therapists to monitor exercise behavior outside of a clinical setting. The methods used in this project can serve as a roadmap to utilizing data from consumer-based platforms.
Subject(s)
Parkinson Disease , Humans , Exercise , Exercise Therapy/methods , Health BehaviorABSTRACT
Multiple studies have reported immune thrombocytopenia (ITP) relapse following SARS-CoV-2 vaccination, however baseline ITP relapse rate and antibody response to vaccination are not known. Patients with ITP who received at least one of the first three SARS-CoV-2 vaccination doses were included in the study. One hundred and twenty-four patients met the inclusion criteria. Relapse rate was 4.2% following a first vaccine dose, 9.1% after a second and 2.9% after a third; baseline relapse rate was 7.6%. Ninety-four per cent of patients who received three vaccine doses developed a clinical antibody response. SARS-CoV-2 vaccination appears to be safe and effective in patients with ITP.
Subject(s)
COVID-19 Vaccines , COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Humans , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Purpura, Thrombocytopenic, Idiopathic/complications , Recurrence , VaccinationABSTRACT
OBJECTIVE: Identify patient experience and preference towards thrombopoietin-receptor agonists (TPO-RAs) in treatment of immune thrombocytopenia (ITP) in the Netherlands. METHODS: The Thrombopoietin-Receptor Agonist Patient experience (TRAPeze) survey used a discrete choice experiment (DCE) to elicit patient preferences and a patient burden survey (PBS) to evaluate the clinical and social impact of ITP. TRAPeze collected responses from 6th October to 19th November 2021. RESULTS: Seventy-six respondents completed the DCE: treatment preference appeared to be driven by method of administration (odds ratio [OR] 4.33; 95% confidence interval [CI] 2.88-6.52), frequency of dosing (OR 2.33; 95% CI 1.86-2.92) and drug-food interactions (OR 1.91; 95% CI 1.54-2.37). Respondents preferred therapies delivered orally over subcutaneous injection (OR 4.22; 95% CI 2.76-6.46), dosed once weekly over once daily (OR 2.37; 95% CI 1.58-3.54) and without food restrictions over with restrictions (OR 1.90; 95% CI 1.52-2.38). Sixty-nine respondents completed the DCE and PBS (mean [range] age 53 [19-83] years, 65% female). Seven incomplete PBS responses were excluded from analysis. Respondents were currently, or most recently, receiving eltrombopag (n = 43) or romiplostim (n = 26), of which 30% (n = 21/69) had previously received another TPO-RA. Loss (29%, n = 6/21) and lack (29%, n = 6/21) of response were the most common reasons for switching TPO-RA. Only 28% (n = 18/65) of respondents felt their TPO-RA increased energy levels. CONCLUSION: Patients preferred therapies delivered orally, dosed less frequently and without food restrictions. QoL of ITP patients on TPO-RAs can be improved; the burden analyses presented can inform future efforts towards this.
Subject(s)
Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Female , Humans , Male , Middle Aged , Benzoates/therapeutic use , Hydrazines/therapeutic use , Netherlands , Patient Preference , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Quality of Life , Receptors, Fc/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Thrombopoietin/metabolism , Thrombopoietin/therapeutic use , Young Adult , Adult , Aged , Aged, 80 and overABSTRACT
BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency disease (PID) characterized by a regulatory T cell defect resulting in immune dysregulation and autoimmunity. We present two siblings born to consanguineous parents of North African descent with LRBA deficiency and central nervous system (CNS) manifestations. As no concise overview of these manifestations is available in literature, we compared our patient's presentation with a reviewed synthesis of the available literature. CASE PRESENTATIONS: The younger brother presented with enteropathy at age 1.5 years, and subsequently developed Evans syndrome and diabetes mellitus. These autoimmune manifestations led to the genetic diagnosis of LRBA deficiency through whole exome sequencing with PID gene panel. At 11 years old, he had two tonic-clonic seizures. Brain MRI showed multiple FLAIR-hyperintense lesions and a T2-hyperintense lesion of the cervical medulla. His sister presented with immune cytopenia at age 9 years, and developed diffuse lymphadenopathy and interstitial lung disease. Genetic testing confirmed the same mutation as her brother. At age 13 years, a brain MRI showed multiple T2-FLAIR-hyperintense lesions. She received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) 3 months later. Follow-up MRI showed regression of these lesions. CONCLUSIONS: Neurological disease is documented in up to 25% of patients with LRBA deficiency. Manifestations range from cerebral granulomas to acute disseminating encephalomyelitis, but detailed descriptions of neurological and imaging phenotypes are lacking. LRBA deficiency amongst other PIDs should be part of the differential diagnosis in patients with inflammatory brain lesions. We strongly advocate for a more detailed description of CNS manifestations in patients with LRBA deficiency, when possible with MR imaging. This will aid clinical decision concerning both anti-infectious and anti-inflammatory therapy and in considering the indication for allo-HSCT.
Subject(s)
Anemia, Hemolytic, Autoimmune , Siblings , Male , Female , Humans , Autoimmunity , Mutation , Central Nervous System , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolismABSTRACT
A State of the Art lecture titled "coagulation biomarkers for ischemic stroke" was presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2022. Ischemic stroke (IS) is a common disease with major morbidity and mortality. It is a challenge to determine which patients are at risk for IS or have poor clinical outcome after IS. An imbalance of coagulation markers may contribute to the progression and prognosis of IS. Therefore, we now discuss studies on the association of selected coagulation biomarkers from the hemostasis, inflammation, and immunothrombosis systems with the risk of IS, stroke severity at the acute phase, and clinical outcome after treatment. We report on coagulation biomarker-induced risk of IS, stroke severity, and outcomes following IS derived from prospective population studies, case-control studies, and acute-phase IS studies. We found indications that many coagulation and inflammation biomarkers are associated with IS, but it is early to conclude that any of these biomarkers can be applied in a therapeutic setting to predict patients at risk of IS, stroke severity at the acute phase, and clinical outcome after treatment. The strongest evidence for a role in IS was found for beta-thromboglobulin, von Willebrand factor, factor VIII, fibrinogen, thrombin-activatable fibrinolysis inhibitor, D-dimer, and neutrophil extracellular traps, and therefore, they are promising candidates. Further research and validation in large-size populations using well-defined study designs are warranted. Finally, we provide a selection of recent data relevant to this subject that was presented at the 2022 ISTH Congress.
ABSTRACT
BACKGROUND: Earlier work within the physical domain showed that acute inflammation changes motivational prioritization and effort allocation rather than physical abilities. It is currently unclear whether a similar motivational framework accounts for the mental fatigue and cognitive symptoms of acute sickness. Accordingly, this study aimed to assess the relationship between fatigue, cytokines and mental effort-based decision making during acute systemic inflammation. METHODS: Eighty-five participants (41 males; 18-30 years (M = 23.0, SD = 2.4)) performed a mental effort-based decision-making task before, 2 h after, and 5 h after intravenous administration of 1 ng/kg bacterial lipopolysaccharide (LPS) to induce systemic inflammation. Plasma concentrations of cytokines (interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)) and fatigue levels were assessed at similar timepoints. In the task, participants decided whether they wanted to perform (i.e., 'accepted') arithmetic calculations of varying difficulty (3 levels: easy, medium, hard) in order to obtain rewards (3 levels: 5, 6 or 7 points). Acceptance rates were analyzed using a binomial generalized estimated equation (GEE) approach with effort, reward and time as independent variables. Arithmetic performance was measured per effort level prior to the decisions and included as a covariate. Associations between acceptance rates, fatigue (self-reported) and cytokine concentration levels were analyzed using partial correlation analyses. RESULTS: Plasma cytokine concentrations and fatigue were increased at 2 h post-LPS compared to baseline and 5 h post-LPS administration. Acceptance rates decreased for medium, but not for easy or hard effort levels at 2 h post-LPS versus baseline and 5 h post-LPS administration, irrespective of reward level. These reductions in acceptance rates occurred despite improved accuracy on the arithmetic calculations itself. Reduced acceptance rates for medium effort were associated with increased fatigue, but not with increased cytokine concentrations. CONCLUSION: Fatigue during acute systemic inflammation is associated with alterations in mental effort allocation, similarly as observed previously for physical effort-based choice. Specifically, willingness to exert mental effort depended on effort and not reward information, while task accuracy was preserved. These results extend the motivational account of inflammation to the mental domain and suggest that inflammation may not necessarily affect domain-specific mental abilities, but rather affects domain-general effort-allocation processes.
Subject(s)
Health Expenditures , Lipopolysaccharides , Male , Humans , Lipopolysaccharides/pharmacology , Motivation , Cytokines , Inflammation , Decision MakingABSTRACT
BACKGROUND: Transfusion guidelines regarding platelet-count thresholds before the placement of a central venous catheter (CVC) offer conflicting recommendations because of a lack of good-quality evidence. The routine use of ultrasound guidance has decreased CVC-related bleeding complications. METHODS: In a multicenter, randomized, controlled, noninferiority trial, we randomly assigned patients with severe thrombocytopenia (platelet count, 10,000 to 50,000 per cubic millimeter) who were being treated on the hematology ward or in the intensive care unit to receive either one unit of prophylactic platelet transfusion or no platelet transfusion before ultrasound-guided CVC placement. The primary outcome was catheter-related bleeding of grade 2 to 4; a key secondary outcome was grade 3 or 4 bleeding. The noninferiority margin was an upper boundary of the 90% confidence interval of 3.5 for the relative risk. RESULTS: We included 373 episodes of CVC placement involving 338 patients in the per-protocol primary analysis. Catheter-related bleeding of grade 2 to 4 occurred in 9 of 188 patients (4.8%) in the transfusion group and in 22 of 185 patients (11.9%) in the no-transfusion group (relative risk, 2.45; 90% confidence interval [CI], 1.27 to 4.70). Catheter-related bleeding of grade 3 or 4 occurred in 4 of 188 patients (2.1%) in the transfusion group and in 9 of 185 patients (4.9%) in the no-transfusion group (relative risk, 2.43; 95% CI, 0.75 to 7.93). A total of 15 adverse events were observed; of these events, 13 (all grade 3 catheter-related bleeding [4 in the transfusion group and 9 in the no-transfusion group]) were categorized as serious. The net savings of withholding prophylactic platelet transfusion before CVC placement was $410 per catheter placement. CONCLUSIONS: The withholding of prophylactic platelet transfusion before CVC placement in patients with a platelet count of 10,000 to 50,000 per cubic millimeter did not meet the predefined margin for noninferiority and resulted in more CVC-related bleeding events than prophylactic platelet transfusion. (Funded by ZonMw; PACER Dutch Trial Register number, NL5534.).
Subject(s)
Catheterization, Central Venous , Platelet Transfusion , Thrombocytopenia , Humans , Platelet Count , Platelet Transfusion/methods , Thrombocytopenia/diagnosis , Thrombocytopenia/therapy , Catheterization, Central Venous/adverse effects , Catheterization, Central Venous/methods , Ultrasonography, Interventional , Hemorrhage/etiology , Hemorrhage/prevention & controlABSTRACT
BACKGROUND: Von Willebrand factor (VWF) and VWF propeptide (VWFpp) are stored in eccentric nanodomains within platelet alpha-granules. VWF and VWFpp can undergo differential secretion following Weibel-Palade body exocytosis in endothelial cells; however, it is unclear if the same process occurs during platelet alpha-granule exocytosis. Using a high-throughput 3-dimensional super-resolution imaging workflow for quantification of individual platelet alpha-granule cargo, we studied alpha-granule cargo release in response to different physiological stimuli. OBJECTIVES: To investigate how VWF and VWFpp are released from alpha-granules in response to physiological stimuli. METHODS: Platelets were activated with protease-activated receptor 1 (PAR-1) activating peptide (PAR-1 ap) or collagen-related peptide (CRP-XL). Alpha-tubulin, VWF, VWFpp, secreted protein acidic and cysteine rich (SPARC), and fibrinogen were imaged using 3-dimensional structured illumination microscopy, followed by semiautomated analysis in FIJI. Uptake of anti-VWF nanobody during degranulation was used to identify alpha-granules that partially released content. RESULTS: VWFpp overlapped with VWF in eccentric alpha-granule subdomains in resting platelets and showed a higher degree of overlap with VWF than SPARC or fibrinogen. Activation of PAR-1 (0.6-20 µM PAR-1 ap) or glycoprotein VI (GPVI) (0.25-1 µg/mL CRP-XL) signaling pathways caused a dose-dependent increase in alpha-granule exocytosis. More than 80% of alpha-granules remained positive for VWF, even at the highest agonist concentrations. In contrast, the residual fraction of alpha-granules containing VWFpp decreased in a dose-dependent manner to 23%, whereas SPARC and fibrinogen were detected in 60% to 70% of alpha-granules when stimulated with 20 µM PAR-1 ap. Similar results were obtained using CRP-XL. Using an extracellular anti-VWF nanobody, we identified VWF in postexocytotic alpha-granules. CONCLUSION: We provide evidence for differential secretion of VWF and VWFpp from individual alpha-granules.
Subject(s)
Endothelial Cells , von Willebrand Factor , Humans , von Willebrand Factor/metabolism , Endothelial Cells/metabolism , Weibel-Palade Bodies/metabolism , Blood Platelets/metabolism , Fibrinogen/metabolism , ExocytosisABSTRACT
OBJECTIVES: The purpose of this systematic review and meta-analysis was to evaluate the proportion and risk factors of lymphoceles and symptomatic lymphoceles after PLND in early-stage cervical and early-stage high or high-intermediate risk endometrial cancer. METHODS: Studies reporting on the proportion of lymphocele after PLND were conducted in PubMed, Embase and Cochrane Library. Retrieved studies were screened on title/abstract and full text by two reviewers independently. Quality assessment was conducted using the Newcastle Ottowa Scale and the Cochrane risk-of-bias tool. Proportion of lymphocele and possible risk factors were pooled through random-effects meta-analyses. RESULTS: From the 233 studies retrieved, 24 studies were included. The pooled proportion of lymphocele was 14% and of symptomatic lymphocele was 3%. Routinely performing diagnostics was associated with a significantly higher proportion of lymphocele compared to diagnostics performed on indication (21% versus 4%, p < 0.01). Laparotomic surgical approach led to a significantly higher proportion of lymphoceles than laparoscopic surgical approach (18% versus 7%, p = 0.05). The proportion of lymphocele was significantly higher when >15% of the study population underwent additional paraaortic lymph node dissection (PAOLND) opposed to <15% (15% versus 3%, p < 0.01). A mean number of lymph nodes dissected of <21 resulted in a significantly higher pooled proportion of lymphoceles opposed to when the mean number was 21 or higher (19% versus 5%, p = 0.02). Other risk factors analysed were BMI, lymph node metastasis, adjuvant radiotherapy and follow up. There was no sufficient data to detect significant risk factors for the development of symptomatic lymphoceles. CONCLUSION: The pooled proportion of lymphocele was 14% of which symptomatic lymphoceles occurred in 3%. Significant risk factors for the total proportion of lymphoceles were laparotomic approach, decreased number of lymph nodes dissected and additional PAOLND.
Subject(s)
Endometrial Neoplasms , Laparoscopy , Lymphocele , Female , Humans , Lymphocele/etiology , Lymph Node Excision/methods , Lymph Nodes/pathology , Laparoscopy/methods , Endometrial Neoplasms/pathology , Pelvis , Postoperative Complications/etiologyABSTRACT
Paleontology has provided invaluable basic knowledge on the history of life on Earth. The discipline can also provide substantial knowledge to societal challenges such as climate change. The long-term perspective of climate change impacts on natural systems is both a unique selling point and a major obstacle to becoming more pertinent for policy-relevant bodies like the Intergovernmental Panel on Climate Change (IPCC). Repeated experiments on the impacts of climate change without anthropogenic disturbance facilitate the extraction of climate triggers in biodiversity changes. At the same time, the long timescales over which paleontological changes are usually assessed are beyond the scope of policymakers. Based on first-hand experience with the IPCC and a quantitative analysis of its cited literature, we argue that the differences in temporal scope are less of an issue than inappropriate framing and reporting of most paleontological publications. Accepting that some obstacles will remain, paleontology can quickly improve its relevance by targeting climate change impacts more directly and focusing on effect sizes and relevance for projections, particularly on higher-end climate change scenarios.
ABSTRACT
Lowe syndrome (LS) is a rare, X-linked disorder characterised by numerous symptoms affecting the brain, the eyes, and the kidneys. It is caused by mutations in the oculocerebrorenal syndrome of Lowe (OCRL) protein, a 5-phosphatase localised in different cellular compartments that dephosphorylates phosphatidylinositol-4,5-bisphosphate into phosphatidylinositol-4-monophosphate. Some patients with LS also have bleeding disorders, with normal to low platelet (PLT) count and impaired PLT function. However, the mechanism of PLT dysfunction in patients with LS is not completely understood. The main function of PLTs is to activate upon vessel wall injury and stop the bleeding by clot formation. PLT activation is accompanied by a shape change that is a result of massive cytoskeletal rearrangements. Here, we show that OCRL-inhibited human PLTs do not fully spread, form mostly filopodia, and accumulate actin nodules. These nodules co-localise with ARP2/3 subunit p34, vinculin, and sorting nexin 9. Furthermore, OCRL-inhibited PLTs have a retained microtubular coil with high levels of acetylated tubulin. Also, myosin light chain phosphorylation is decreased upon OCRL inhibition, without impaired degranulation or integrin activation. Taken together, these results suggest that OCRL contributes to cytoskeletal rearrangements during PLT activation that could explain mild bleeding problems in patients with LS.
Subject(s)
Oculocerebrorenal Syndrome , WAGR Syndrome , Humans , Oculocerebrorenal Syndrome/genetics , Actins , Kidney/metabolism , MutationABSTRACT
Field courses provide transformative learning experiences that support success and improve persistence for science, technology, engineering, and mathematics majors. But field courses have not increased proportionally with the number of students in the natural sciences. We conducted a scoping review to investigate the factors influencing undergraduate participation in and the outcomes from field courses in the United States. Our search yielded 61 articles, from which we classified the knowledge, affect, behavior, and skill-based outcomes resulting from field course participation. We found consistent reporting on course design but little reporting on demographics, which limits our understanding of who takes field courses. Cost was the most commonly reported barrier to student participation, and knowledge gains were the most commonly reported outcome. This scoping review underscores the need for more rigorous and evidence-based investigations of student outcomes in field courses. Understanding how field courses support or hinder student engagement is necessary to make them more accessible to all students.
ABSTRACT
Von Willebrand disease (VWD) is a bleeding disorder caused by quantitative (type 1 or 3) or qualitative (type 2A/2B/2M/2N) defects of circulating von Willebrand factor (VWF). Circulating VWF levels not always fully explain bleeding phenotypes, suggesting a role for alternative factors, like platelets. Here, we investigated platelet factor 4 (PF4) in a large cohort of patients with VWD. PF4 levels were lower in type 2B and current bleeding phenotype was significantly associated with higher PF4 levels, particularly in type 1 VWD. Based on our findings we speculate that platelet degranulation and cargo release may play a role across VWD subtypes.