Bacterial flagellar motors and osmoelectric molecular rotation by an axially transmembrane well and turnstile mechanism

AbstractBacterial ion-driven flagellar motors are the smallest known rotatory mechanical devices, natural or artificial, their overall diameter being only about 25 nm or one millionth of an inch. They are unique in the fields of biology and engineering. This paper develops a possible osmoelectric or local electrokinetic mechanism of molecular rotatory motion in bilayer membranes, which may help to explain how bacterial flagellar motors work, and may incidentally encourage new developments in the bioenergetics and biomechanics of enzyme, osmoenzyme and porter action

Het diagnostisch instrument voor apraxie van de spraak

Momenteel is er geen gestandaardiseerd en genormeerd testinstrument voor de diagnose van apraxie van de spraak bij volwassenen voorhanden. De differentiaaldiagnose tussen apraxie van de spraak en andere neurogene stoornissen is dan ook uiterst complex. Een goede diagnosestelling is echter essentieel voor het bepalen van de inhoud van de therapie van apraxie van de spraak. Om de stoornis in de toekomst te kunnen diagnosticeren en differentiëren van overige neurogene stoornissen is gestart met de ontwikkeling van het Diagnostisch Instrument voor Apraxie van de Spraak (DIAS)

Phenotype, genotype, and laboratory assessment of congenital fibrinogen disorders:Data from the Rare Bleeding disorders in the Netherlands study

Introduction: Congenital fibrinogen disorders (CFDs), encompassing quantitative (hypo−/afibrinogenemia) and qualitative (dysfibrinogenemia) defects, can result in bleeding or thrombotic events. This study aimed to enhance understanding of the clinical and genetic characteristics of CFD patients. Methods: The Dutch cross-sectional RBiN study included 47 CFD patients (median age 38, 55 % women), categorized into (hypo)dysfibrinogenemia, severe (&lt;500 mg/L), moderate (500–1000 mg/L) and mild hypofibrinogenemia (1000–1800 mg/L) as well as carriers with pathogenic variants but normal fibrinogen levels (&gt;1800 mg/L). Clinical assessments included bleeding phenotype, thrombosis history, fibrinogen activity and antigen levels, thrombin and plasmin generation assays and genotypic analysis. Results: Patients with severe hypofibrinogenemia displayed the highest median ISTH-BAT score (16), followed by moderate hypofibrinogenemia (11), (hypo)dysfibrinogenemia (6), mild hypofibrinogenemia (4) and carriers (0). Female-specific bleeding (postpartum hemorrhage, heavy menstrual bleeding) was prevalent across all CFD subtypes, with moderate hypofibrinogenemia showing high average scores on these ISTH-BAT items (3.0 and 2.3). Postoperative bleeding was common in moderate and severe hypofibrinogenemia (average ISTH-BAT item scores of 2.5 and 2.8, respectively). Patients with biallelic variants had lower fibrinogen activity levels (median 200 mg/L) than those with monoallelic variants (935 mg/L, p &lt; 0.001). Fibrinogen activity levels correlated positively with plasmin peak height (R = 0.74, p &lt; 0.001) and inversely with thrombin potential (R = –0.55, p = 0.002). Thrombin potential was 1.77-fold higher in patients with a venous thrombosis history (n = 5, p = 0.03) than in healthy controls. Conclusions: In patients with CFDs, postoperative bleeding correlates with fibrinogen activity, while female-specific bleeding affects all CFD subtypes. Elevated thrombin generation might explain thrombosis risk in these patients.</p

High prevalence of heavy menstrual bleeding in women with rare bleeding disorders in the Netherlands:retrospective data from the RBiN study

Background: Heavy menstrual bleeding (HMB) is associated with a reduced quality of life and limitations in social and physical functioning. Data on HMB in women with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, are scarce. Objectives: To analyze the prevalence, severity, and treatment of HMB in Dutch women with an RBD. Methods:The Rare Bleeding Disorders in the Netherlands (RBiN) study included 263 patients with an RBD from all 6 hemophilia treatment centers (October 2017-November 2019). In this analysis, data of 111 women aged ≥16 years were studied. According to the International Society on Thrombosis and Haemostasis bleeding assessment tool, HMB symptoms were scored from 0 (no/trivial) to 4 (severe symptoms requiring medical intervention). HMB was defined as a score ≥1. Age at RBD diagnosis was extracted from patient files. Results: HMB was reported by 80% of women (89/111) and was more prevalent in women with a fibrinolytic disorder (33/35; 94%) than in women with a coagulation factor deficiency (56/76; 74%) (P = .011). Of the 89 women with HMB, 82% (n = 73) ever required treatment. Multiple treatment modalities were frequently used, both in severe and mild deficiencies. Hormonal treatment was mostly used (n = 64; 88%), while antifibrinolytics were prescribed less frequently (n = 18; 25%). In women with HMB since menarche (n = 61; 69%), median age at RBD diagnosis was 28 years (IQR, 14-41).Conclusion: HMB is common in women with RBDs. Women with mild deficiencies also frequently reported HMB. Only a minority of women were treated with hemostatic agents. A significant diagnostic delay was observed after the onset of HMB symptoms.</p

Desmopressin in nonsevere hemophilia A:patient perspectives on use and efficacy

Background: Desmopressin increases plasma factor VIII and von Willebrand factor levels in persons with nonsevere hemophilia A. Patients’ perspectives on desmopressin are relevant to increase and optimize its suboptimal use. However, patients’ views on desmopressin are not reported. Objectives: To evaluate the perspectives of persons with nonsevere hemophilia A on desmopressin use, barriers for its use, side effects, and their knowledge about desmopressin's efficacy and side effects. Methods: Persons with nonsevere hemophilia A were included in a cross-sectional, national, multicenter study. Questionnaires were filled out by adult patients and children aged ≥12 years themselves. Caretakers filled out questionnaires for children aged &lt;12 years. Results: In total, 706 persons with nonsevere hemophilia A were included (544 mild, 162 moderate, [age range, 0–88 years]). Of 508 patients, 234 (50%) patients reported previous desmopressin use. Desmopressin was considered as at least moderately effective in 171 of 187 (90%) patients. Intranasal administration was the modality of choice for 138 of 182 (76%) patients. Flushing was the most reported side effect in 54 of 206 (26%) adults and 7 of 22 (32%) children. The most frequently reported advantage and disadvantage were the convenience of intranasal, out-of-hospital administration by 56% (126/227) and side effects in 18% (41/227), respectively. Patients’ self-perceived knowledge was unsatisfactory or unknown in 28% (63/225). Conclusion: Overall, desmopressin was most often used intranasally and considered effective, with flushing as the most common side effect. The most mentioned advantage was the convenience of intranasal administration and disadvantage was side effects. More information and education on desmopressin could answer unmet needs in patients with current or future desmopressin treatment.</p

Desmopressin in nonsevere hemophilia A:patient perspectives on use and efficacy

Background: Desmopressin increases plasma factor VIII and von Willebrand factor levels in persons with nonsevere hemophilia A. Patients’ perspectives on desmopressin are relevant to increase and optimize its suboptimal use. However, patients’ views on desmopressin are not reported. Objectives: To evaluate the perspectives of persons with nonsevere hemophilia A on desmopressin use, barriers for its use, side effects, and their knowledge about desmopressin's efficacy and side effects. Methods: Persons with nonsevere hemophilia A were included in a cross-sectional, national, multicenter study. Questionnaires were filled out by adult patients and children aged ≥12 years themselves. Caretakers filled out questionnaires for children aged &lt;12 years. Results:In total, 706 persons with nonsevere hemophilia A were included (544 mild, 162 moderate, [age range, 0–88 years]). Of 508 patients, 234 (50%) patients reported previous desmopressin use. Desmopressin was considered as at least moderately effective in 171 of 187 (90%) patients. Intranasal administration was the modality of choice for 138 of 182 (76%) patients. Flushing was the most reported side effect in 54 of 206 (26%) adults and 7 of 22 (32%) children. The most frequently reported advantage and disadvantage were the convenience of intranasal, out-of-hospital administration by 56% (126/227) and side effects in 18% (41/227), respectively. Patients’ self-perceived knowledge was unsatisfactory or unknown in 28% (63/225). Conclusion:Overall, desmopressin was most often used intranasally and considered effective, with flushing as the most common side effect. The most mentioned advantage was the convenience of intranasal administration and disadvantage was side effects. More information and education on desmopressin could answer unmet needs in patients with current or future desmopressin treatment.</p

Safety of treating acute pulmonary embolism at home: an individual patient data meta-analysis

BACKGROUND AND AIMS: Home treatment is considered safe in acute pulmonary embolism (PE) patients selected by a validated triage tool (e.g. simplified PE severity index score or Hestia rule), but there is uncertainty regarding the applicability in underrepresented subgroups. The aim was to evaluate the safety of home treatment by performing an individual patient-level data meta-analysis. METHODS: Ten prospective cohort studies or randomized controlled trials were identified in a systematic search, totalling 2694 PE patients treated at home (discharged within 24 h) and identified by a predefined triage tool. The 14- and 30-day incidences of all-cause mortality and adverse events (combined endpoint of recurrent venous thromboembolism, major bleeding, and/or all-cause mortality) were evaluated. The relative risk (RR) for 14- and 30-day mortalities and adverse events is calculated in subgroups using a random effects model. RESULTS: The 14- and 30-day mortalities were 0.11% [95% confidence interval (CI) 0.0-0.24, I$^{2}$ = 0) and 0.30% (95% CI 0.09-0.51, I$^{2}$ = 0). The 14- and 30-day incidences of adverse events were 0.56% (95% CI 0.28-0.84, I$^{2}$ = 0) and 1.2% (95% CI 0.79-1.6, I$^{2}$ = 0). Cancer was associated with increased 30-day mortality [RR 4.9; 95% prediction interval (PI) 2.7-9.1; I$^{2}$ = 0]. Pre-existing cardiopulmonary disease, abnormal troponin, and abnormal (N-terminal pro-)B-type natriuretic peptide [(NT-pro)BNP] at presentation were associated with an increased incidence of 14-day adverse events [RR 3.5 (95% PI 1.5-7.9, I$^{2}$ = 0), 2.5 (95% PI 1.3-4.9, I$^{2}$ = 0), and 3.9 (95% PI 1.6-9.8, I$^{2}$ = 0), respectively], but not mortality. At 30 days, cancer, abnormal troponin, and abnormal (NT-pro)BNP were associated with an increased incidence of adverse events [RR 2.7 (95% PI 1.4-5.2, I$^{2}$ = 0), 2.9 (95% PI 1.5-5.7, I$^{2}$ = 0), and 3.3 (95% PI 1.6-7.1, I$^{2}$ = 0), respectively]. CONCLUSIONS: The incidence of adverse events in home-treated PE patients, selected by a validated triage tool, was very low. Patients with cancer had a three- to five-fold higher incidence of adverse events and death. Patients with increased troponin or (NT-pro)BNP had a three-fold higher risk of adverse events, driven by recurrent venous thromboembolism and bleeding

Phenotype, genotype, and laboratory assessment of congenital fibrinogen disorders: Data from the Rare Bleeding disorders in the Netherlands study

INTRODUCTION: Congenital fibrinogen disorders (CFDs), encompassing quantitative (hypo-/afibrinogenemia) and qualitative (dysfibrinogenemia) defects, can result in bleeding or thrombotic events. This study aimed to enhance understanding of the clinical and genetic characteristics of CFD patients. METHODS: The Dutch cross-sectional RBiN study included 47 CFD patients (median age 38, 55 % women), categorized into (hypo)dysfibrinogenemia, severe (1800 mg/L). Clinical assessments included bleeding phenotype, thrombosis history, fibrinogen activity and antigen levels, thrombin and plasmin generation assays and genotypic analysis. RESULTS: Patients with severe hypofibrinogenemia displayed the highest median ISTH-BAT score (16), followed by moderate hypofibrinogenemia (11), (hypo)dysfibrinogenemia (6), mild hypofibrinogenemia (4) and carriers (0). Female-specific bleeding (postpartum hemorrhage, heavy menstrual bleeding) was prevalent across all CFD subtypes, with moderate hypofibrinogenemia showing high average scores on these ISTH-BAT items (3.0 and 2.3). Postoperative bleeding was common in moderate and severe hypofibrinogenemia (average ISTH-BAT item scores of 2.5 and 2.8, respectively). Patients with biallelic variants had lower fibrinogen activity levels (median 200 mg/L) than those with monoallelic variants (935 mg/L, p < 0.001). Fibrinogen activity levels correlated positively with plasmin peak height (R = 0.74, p < 0.001) and inversely with thrombin potential (R = -0.55, p = 0.002). Thrombin potential was 1.77-fold higher in patients with a venous thrombosis history (n = 5, p = 0.03) than in healthy controls. CONCLUSIONS: In patients with CFDs, postoperative bleeding correlates with fibrinogen activity, while female-specific bleeding affects all CFD subtypes. Elevated thrombin generation might explain thrombosis risk in these patients