A simple platelet biomarker is associated with symptom severity in major depressive disorder
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Extravascular coagulation regulates haemostasis independently of activated platelet surfaces in an in vivo mouse model
While the conventional understanding of haemostatic plug formation is that coagulation proceeds efficiently on the surface of activated platelets at the vascular injury site to form a robust haemostatic plug, this understanding does not explain the clinical reality that platelet dysfunction results in a mild bleeding phenotype, whereas coagulation disorders exhibit severe bleeding phenotypes, particularly in deep tissues. Here, we introduce an in vivo imaging method to observe internal bleeding and subsequent haemostatic plug formation in mice and report that haemostatic plug formation after internal bleeding, coagulation occurs primarily outside the blood vessel rather than on platelets. Experiments in mice with impaired platelet surface coagulation, depleted platelets, haemophilia A or reduced tissue factor expression suggest that this extravascular coagulation triggers and regulates haemostatic plug formation. Our discovery of the important role of extravascular coagulation in haemostasis may contribute to refining the treatment of haemostatic abnormalities and advancing antithrombotic therapy.
Comparison of recognition of symptom burden in MPN between patient- and physician-reported assessment – an intraindividual analysis by the German Study Group for MPN (GSG-MPN)
Myeloproliferative neoplasms (MPN) are associated with a variety of symptoms that severely impact patients’ quality of life and ability to perform daily activities. Recent studies showed differences in the perception of physician- versus patient-reported symptom burden. However, studies directly comparing patient- and physician-reported ratings are lacking. Here, a retrospective analysis on symptom burden of 3979 MPN patients of the Bioregistry of the German Study Group for MPN was conducted to intra-individually compare physician and patient reports collected at the same time. Cohen’s kappa was calculated to assess the degree of agreement between patient and physician reports. Factors influencing baseline symptom severity were identified using linear regression and adjusted Cox models were calculated to investigate the effect of symptom burden on survival. MPN patients had a high symptom burden, which neither decreased over time nor upon cytoreductive therapy. All symptoms were more frequently reported by patients compared to physicians. Agreement remained low and only slightly improved when considering a higher threshold for patient symptom severity. Patients with severe symptom burden had inferior survival compared to patients with less severe symptoms. Assessment of symptom burden in MPN is therefore insufficient and patient-reported outcome tools need to be implemented into clinical routine.
Beclin 1 of megakaryocytic lineage cells is locally dispensable for platelet hemostasis but functions distally in bone homeostasis
The crosstalk between megakaryocytic lineage cells and the skeletal system has just begun to be explored but remains largely elusive. Using conditional gene knockout mouse models, we demonstrated that loss of Beclin 1 (Becn1), a major regulator of mammalian autophagy, exclusively in the megakaryocytic lineage disrupted autophagy in platelets but did not compromise megakaryopoiesis or the formation and function of platelets. Unexpectedly, conditional Becn1 deletion in male mice led to a remarkable increase in bone mass with improved bone quality, in association with a decrease in sex hormone binding globulin (SHBG) and an increase in free testosterone (FT). In vivo Becn1 overexpression in megakaryocytic lineage-specific cells reduced bone mass and quality, along with an increase in SHBG and a decrease in FT. Transplantation of wild-type bone marrow cells into megakaryocytic lineage Becn1-deficient male mice restored bone mass and normalized SHBG and FT. Furthermore, bilateral orchiectomy of Becn1f/f;Pf4-iCre mice, which are crippled with the production of testosterone, resulted in a reduction in bone mass and quality, whereas in vivo overexpression of SHBG, specifically in the liver of Becn1f/f;Pf4-iCre mice, decreased FT and reduced bone mass and quality. In addition, metformin treatment, which induces SHBG expression, reduced FT and normalized bone mass in Becn1f/f;Pf4-iCre mice. We thus concluded that Becn1 of the megakaryocytic lineage is dispensable locally for platelet hemostasis but limits bone mass by increasing SHBG, which in turn reduces the FT of male mice. Our findings highlight a mechanism by which Becn1 from megakaryocytic lineage cells distally balances bone growth.
Task-sharing and telemedicine delivery of psychotherapy to treat perinatal depression: a pragmatic, noninferiority randomized trial
Task-sharing and telemedicine can increase access to effective psychotherapies. Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) is pragmatic, multisite, noninferiority, four-arm trial that tested the non-inferiority of provider (non-specialist vs. specialist providers) and modality (telemedicine vs. in-person) in delivering psychotherapy for perinatal depressive symptoms. Across three university-affiliated networks in the United States and Canada, pregnant and postpartum adult participants were randomized 1:1:1:1 to each arm (472 nonspecialist telemedicine, 145 nonspecialist in-person, 469 specialist telemedicine and 144 specialist in-person) and offered weekly behavioral activation treatment sessions. The primary outcome was depressive symptoms (Edinburgh Postnatal Depression Scale (EPDS)) and the secondary outcome was anxiety (Generalized Anxiety Disorder (GAD-7)) symptoms at 3 months post-randomization. Between 8 January 2020 and 4 October 2023, 1,230 participants were recruited. Noninferiority was met for the primary outcome comparing provider (EPDS: nonspecialist 9.27 (95% CI 8.85–9.70) versus specialist 8.91 (95% CI 8.49–9.33)) and modality (EPDS: telemedicine 9.15 (95% CI 8.79–9.50) versus in-person 8.92 (95% CI 8.39–9.45)) for both intention-to-treat and per protocol analyses. Noninferiority was also met for anxiety symptoms in both comparisons. There were no serious or adverse events related to the trial. This trial suggests compelling evidence for task-sharing and telemedicine to improve access to psychotherapies for perinatal depressive and anxiety symptoms. ClinicalTrials.gov NCT04153864
Periodontitis impacts on thrombotic diseases: from clinical aspect to future therapeutic approaches
Periodontitis is a chronic inflammatory disease initiated by biofilm microorganisms and mediated by host immune imbalance. Uncontrolled periodontal infections are the leading cause of tooth loss in adults. Thrombotic diseases can lead to partial or complete obstruction of blood flow in the circulatory system, manifesting as organ or tissue ischemia and necrosis in patients with arterial thrombosis, and local edema, pain and circulatory instability in patients with venous thrombosis, which may lead to mortality or fatality in severe case. Recent studies found that periodontitis might enhance thrombosis through bacterial transmission or systemic inflammation by affecting platelet-immune cell interactions, as well as the coagulation, and periodontal therapy could have a prophylactic effect on patients with thrombotic diseases. In this review, we summarized clinical findings on the association between periodontitis and thrombotic diseases and discussed several novel prothrombotic periodontitis-related agents, and presented a perspective to emphasize the necessity of oral health management for people at high risk of thrombosis.
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