Platelet-Type von Willebrand Disease: Complex Pathophysiology and Insights on Novel Therapeutic and Diagnostic Strategies.

von Willebrand disease (VWD) is the most common well-studied genetic bleeding disorder worldwide. Much less is known about platelet-type VWD (PT-VWD), a rare platelet function defect, and a "nonidentical" twin bleeding phenotype to type 2B VWD (2B-VWD). Rather than a defect in the von Willebrand factor (VWF) gene, PT-VWD is caused by a platelet GP1BA mutation leading to a hyperaffinity of the glycoprotein Ibα (GPIbα) platelet surface receptor for VWF, and thus increased platelet clearing and high-molecular-weight VWF multimer elimination. Nine GP1BA gene mutations are known. It is historically believed that this enhanced binding was enabled by the ß-switch region of GPIbα adopting an extended ß-hairpin form. Recent evidence suggests the pathological conformation that destabilizes the compact triangular form of the R-loop-the GPIbα protein's region for VWF binding. PT-VWD is often misdiagnosed as 2B-VWD, even the though distinction between the two is crucial for proper treatment, as the former requires platelet transfusions, while the latter requires VWF/FVIII concentrate administration. Nevertheless, these PT-VWD treatments remain unsatisfactory, owing to their high cost, low availability, risk of alloimmunity, and the need to carefully balance platelet administration. Antibodies such as 6B4 remain undependable as an alternative therapy due to their questionable efficacy and high costs for this purpose. On the other hand, synthetic peptide therapeutics developed with In-Silico Protein Synthesizer to disrupt the association between GPIbα and VWF show preliminary promise as a therapy based on in vitro experiments. Such peptides could serve as an effective diagnostic technology for discriminating between 2B-VWD and PT-VWD, or potentially all forms of VWD, based on their high specificity. This field is rapidly growing and the current review sheds light on the complex pathology and some novel potential therapeutic and diagnostic strategies.

Epicardial delivery of a conductive membrane synchronizes conduction to reduce atrial fibrillation.

Conductive polymers have been investigated as a medium for the transmission of electrical signals in biological tissues, but their capacity to rewire cardiac tissue has not been evaluated. Myocardial tissue is unique in being able to generate an electrical potential at a fixed rate; this potential spreads rapidly among cells to trigger muscle contractions. Tissue injuries result in myocardial fibrosis and subsequent non-uniform conductivity, leading to arrhythmia. Atrial fibrillation (AF) is the most common sustained arrhythmia, associated with disruption of atrial electrical signaling, which can potentially be restored by the epicardial delivery of conductive polymers. In this work, poly-3-amino-4-methoxybenzoic acid, conjugated to gelatin, is fabricated as a membrane (PAMB-G) to support conductive velocities that are close to that of the myocardium. A cross-linked gelatin membrane (Gelatin) is used as a control. The as-fabricated PAMB-G has similar tensile elasticities, determined using the Young's modulus, as contracting myocardium; it can also transmit electrical signals to initiate cardiac cell and tissue excitation. Delivering PAMB-G onto the atrium of a rat AF model shortens AF duration and improves post-AF recovery for the duration of a 28-day-long study. Atrial tissue in the PAMB-G-implanted group has lower impedance, higher conduction velocity, and higher field potential amplitude than that in the Gelatin-implanted group. Therefore, the as-proposed PAMB-G is a suitable medium for restoring proper cardiac electrical signaling in AF hearts.

Characterization of chronic lung allograft dysfunction phenotypes using spectral and intrabreath oscillometry.

Background: Chronic lung allograft dysfunction (CLAD) is the major cause of death beyond 2 years after lung transplantation and develops in 50% of all patients by 5 years post-transplant. CLAD is diagnosed on the basis of a sustained drop of 20% for at least 3 months in the forced expiratory volume (FEV1), compared to the best baseline value achieved post-transplant. CLAD presents as two main phenotypes: bronchiolitis obliterans syndrome (BOS) is more common and has better prognosis than restrictive allograft syndrome (RAS). Respiratory oscillometry is a different modality of lung function testing that is highly sensitive to lung mechanics. The current study investigated whether spectral and intrabreath oscillometry can differentiate between CLAD-free, BOS- and RAS-CLAD at CLAD onset, i.e., at the time of the initial 20% drop in the FEV1. Methods: A retrospective, cross-sectional analysis of 263 double lung transplant recipients who underwent paired testing with oscillometry and spirometry at the Toronto General Pulmonary Function Laboratory from 2017 to 2022 was conducted. All pulmonary function testing and CLAD diagnostics were performed following international guidelines. Statistical analysis was conducted using multiple comparisons. Findings: The RAS (n = 6) spectral oscillometry pattern differs from CLAD-free (n = 225) by right-ward shift of reactance curve similar to idiopathic pulmonary fibrosis whereas BOS (n = 32) has a pattern similar to obstructive lung disease. Significant differences were found in most spectral and intrabreath parameters between BOS, RAS, and time-matched CLAD-free patients. Post-hoc analysis revealed these differences were primarily driven by BOS instead of RAS. While no differences were found between CLAD-free and RAS patients with regards to spectral oscillometry, the intrabreath metric of reactance at end-inspiration (XeI) was significantly different (p < 0.05). BOS and RAS were differentiated by spectral oscillometry measure R5, and intrabreath resistance at end expiration, ReE (p < 0.05 for both). Conclusion: Both spectral and intrabreath oscillometry can differentiate BOS-CLAD from CLAD-free states while intrabreath oscillometry, specifically XeI, can uniquely distinguish RAS-CLAD from CLAD-free. Spectral and intrabreath oscillometry offer complementary information regarding lung mechanics in CLAD patients to help distinguish the two phenotypes and could prove useful in prognostication.

Cervical Ripening Efficacy of Synthetic Osmotic Cervical Dilator Compared With Oral Misoprostol at Term: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether a synthetic osmotic cervical dilator is noninferior to oral misoprostol for cervical ripening. METHODS: In an open-label, noninferiority randomized trial, pregnant women undergoing induction of labor at 37 weeks of gestation or more with Bishop scores less than 6 were randomized to either mechanical cervical dilation or oral misoprostol. Participants in the mechanical dilation group underwent insertion of synthetic osmotic cervical dilator rods, and those in the misoprostol group received up to six doses of 25 micrograms orally every 2 hours. After 12 hours of ripening, oxytocin was initiated, with artificial rupture of membranes. Management of labor was at the physician's discretion. The primary outcome was the proportion of women achieving vaginal delivery within 36 hours of initiation of study intervention. Secondary outcomes included increase in Bishop score, mode of delivery, induction-to-delivery interval, total length of hospital stay, and patient satisfaction. On the basis of a noninferiority margin of 10%, an expected primary outcome frequency of 65% for misoprostol and 71% for mechanical methods, and 85% power, a sample size of 306 participants was needed. RESULTS: From November 2018 through January 2021, 307 women were randomized, with 151 evaluable participants in the synthetic osmotic cervical dilator group and 152 in the misoprostol group (there were four early withdrawals). The proportion of women achieving vaginal delivery within 36 hours was higher with mechanical cervical dilation compared with misoprostol (61.6% vs 59.2%), with an absolute difference of 2.4% (95% CI -9% to 13%), indicating noninferiority for the prespecified margin. No differences were noted in the mode of delivery. Tachysystole was more frequent in the misoprostol group (70 [46.4%] vs 35 [23.3%]; P=.01). Participants in the synthetic osmotic cervical dilator group reported better sleep, less unpleasant abdominal sensations, and lower pain scores (P<.05). CONCLUSION: Synthetic osmotic cervical dilator is noninferior to oral misoprostol for cervical ripening. Advantages of synthetic osmotic cervical dilator include a better safety profile and patient satisfaction, less tachysystole, lower pain scores, and U.S. Food and Drug Administration approval. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03670836. FUNDING SOURCE: Medicem Technology s.r.o., Czech Republic.

Bio-Conductive Polymers for Treating Myocardial Conductive Defects: Long-Term Efficacy Study.

Following myocardial infarction (MI), the resulting fibrotic scar is nonconductive and leads to ventricular dysfunction via electrical uncoupling of the remaining viable cardiomyocytes. The uneven conductive properties between normal myocardium and scar tissue result in arrhythmia, yielding sudden cardiac death/heart failure. A conductive biopolymer, poly-3-amino-4-methoxybenzoic acid-gelatin (PAMB-G), is able to resynchronize myocardial contractions in vivo. Intravenous PAMB-G injections into mice show that it does not cause any acute toxicity, up to the maximum tolerated dose (1.6 mL kg-1 ), which includes the determined therapeutic dose (0.4 mL kg-1 ). There is also no short- or long-term toxicity when PAMB-G is injected into the myocardium of MI rats, with no significant changes in body weight, organ-brain ratio, hematologic, and histological parameters for up to 12 months post-injection. At the therapeutic dose, PAMB-G restores electrical conduction in infarcted rat hearts, resulting in lowered arrhythmia susceptibility and improved cardiac function. PAMB-G is also durable, as mass spectrometry detected the biopolymer for up to 12 months post-injection. PAMB-G did not impact reproductive organ function or offspring characteristics when given intravenously into healthy adult rats. Thus, PAMB-G is a nontoxic, durable, and conductive biomaterial that is able to improve cardiac function for up to 1 year post-implantation.

Aging impairs human bone marrow function and cardiac repair following myocardial infarction in a humanized chimeric mouse.

Ventricular remodeling following myocardial infarction (MI) is a major cause of heart failure, a condition prevalent in older individuals. Following MI, immune cells are mobilized to the myocardium from peripheral lymphoid organs and play an active role in orchestrating repair. While the effect of aging on mouse bone marrow (BM) has been studied, less is known about how aging affects human BM cells and their ability to regulate repair processes. In this study, we investigate the effect aging has on human BM cell responses post-MI using a humanized chimeric mouse model. BM samples were collected from middle aged (mean age 56.4 ± 0.97) and old (mean age 72.7 ± 0.59) patients undergoing cardiac surgery, CD34+/- cells were isolated, and NOD-scid-IL2rγnull (NSG) mice were reconstituted. Three months following reconstitution, the animals were examined at baseline or subjected to coronary artery ligation (MI). Younger patient cells exhibited greater repopulation capacity in the BM, blood, and spleen as well as greater lymphoid cell production. Following MI, CD34+ cell age impacted donor and host cellular responses. Mice reconstituted with younger CD34+ cells exhibited greater human CD45+ recruitment to the heart compared to mice reconstituted with old cells. Increased cellular responses were primarily driven by T-cell recruitment, and these changes corresponded with greater human IFNy levels and reduced mouse IL-1ß in the heart. Age-dependent changes in BM function led to significantly lower survival, increased infarct expansion, impaired host cell responses, and reduced function by 4w post-MI. In contrast, younger CD34+ cells helped to limit remodeling and preserve function post-MI.

Neostigmine: an alternative treatment for constipation.

Constipation is a common complication of amyotrophic lateral sclerosis (ALS), especially as the disease progresses. While ALS patients may experience disturbed gastrointestinal motility due to the nature of the disease and decreased physical activity, the constipation is not usually caused by mechanical obstruction. Acute colonic pseudo-obstruction (ACPO) is a syndrome characterized by massive dilation of the colon without mechanical obstruction. Recent studies have shown neostigmine may be an effective treatment for ACPO. Through a case study, the author discusses the use of neostigmine and its nursing implications on a patient with ALS.

An integrated microfabricated cell sorter.

We have developed an integrated microfabricated cell sorter using multilayer soft lithography. This integrated cell sorter is incorporated with various microfluidic functionalities, including peristaltic pumps, dampers, switch valves, and input and output wells, to perform cell sorting in a coordinated and automated fashion. The active volume of an actuated valve on this integrated cell sorter can be as small as 1 pL, and the volume of optical interrogation is approximately 100 fL. Different algorithms of cell manipulation, including cell trapping, were implemented in these devices. We have also demonstrated sorting and recovery of Escherichia coli cells on the chip.