Pharmacotherapy for primary biliary cholangitis: an assessment of medication candidacy and rates of treatment.

Background: Ursodeoxycholic acid is the preferred first-line therapy for primary biliary cholangitis. Alternative therapies, such as obeticholic acid, are recommended for patients who cannot tolerate ursodeoxycholic acid or who have an inadequate response to ursodeoxycholic acid monotherapy. Prior investigations have suggested that as many as 30% of patients with primary biliary cholangitis may have never received treatment with ursodeoxycholic acid.

Computed Tomography Topographical Analysis of Incomplete Humeral Intracondylar Fissures in English Springer Spaniel Dogs.

Objective:  The aim of this study was to use computed tomography (CT) images obtained from English springer spaniels (ESS) with different sizes of humeral intracondylar fissure (HIF) to describe the typical shape, origin and a possible propagation pattern of HIF in this breed.

Study Design:  It is a retrospective analysis of 32 elbow CT from 27 ESS with incomplete HIF. Measurements included HIF articular surface length, centre of HIF at articular surface relative to the caudal edge of the supratrochlear foramen (CHIF), HIF depth and sagittal area of fissure.

Malaria transmission-blocking vaccines Pfs230D1-EPA and Pfs25-EPA in Alhydrogel in healthy Malian adults; a phase 1, randomised, controlled trial.

Background: Malaria transmission-blocking vaccines target mosquito-stage parasites and will support elimination programmes. Gamete vaccine Pfs230D1-EPA/Alhydrogel induced superior activity to zygote vaccine Pfs25-EPA/Alhydrogel in malaria-naive US adults. Here, we compared these vaccines in malaria-experienced Malians.

A ring-like accretion structure in M87 connecting its black hole and jet.

The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole.

Structural and immunological differences in Plasmodium falciparum sexual stage transmission-blocking vaccines comprised of Pfs25-EPA nanoparticles.

Development of a malaria vaccine that blocks transmission of different parasite stages to humans and mosquitoes is considered critical for elimination efforts. A vaccine using Pfs25, a protein on the surface of zygotes and ookinetes, is under investigation as a transmission-blocking vaccine (TBV) that would interrupt parasite passage from mosquitoes to humans. The most extensively studied Pfs25 TBVs use Pichia pastoris-produced recombinant forms of Pfs25, chemically conjugated to a recombinant carrier protein, ExoProtein A (EPA).

Stereotactic radiosurgery for cerebellopontine meningiomas: a systematic review and meta-analysis.

Objective: To (1) measure surgical outcomes associated with stereotactic radiosurgery treatment of cerebellopontine angle meningiomas, and (2) determine if differences in radiation dosages or preoperative tumor volumes affect surgical outcomes.

Methods: A systematic search was performed on the PubMed, Medline, Embase and Cochrane Library databases searching for patients under stereotactic radiosurgery for meningiomas of the cerebellopontine angle. After data extraction and Newcastle-Ottawa scale quality assessment, meta-analysis of the data was performed with Review Manager 3.

Principles of Hypotensive Shock: A Video Introduction to Pathophysiology and Treatment Strategies.

Audience: Emergency medicine interns, medical students, and mid-level providers (physician assistants, nurse practitioners).

Introduction: Shock is defined as a state of global tissue hypoxia and is typically the result of hypotension and circulatory system failure. A variety of disease states may ultimately culminate in hypotensive shock through one or more generally recognized mechanisms - hypovolemic, cardiogenic, obstructive, and/or distributive shock.

An Invariant Protein That Colocalizes With VAR2CSA on Plasmodium falciparum-Infected Red Cells Binds to Chondroitin Sulfate A.

Background: Plasmodium falciparum-infected red blood cells (iRBCs) bind and sequester in deep vascular beds, causing malaria-related disease and death. In pregnant women, VAR2CSA binds to chondroitin sulfate A (CSA) and mediates placental sequestration, making it the major placental malaria (PM) vaccine target.

Methods: In this study, we characterize an invariant protein associated with PM called P falciparum chondroitin sulfate A ligand (PfCSA-L).

Preerythrocytic Vaccine Antigens Enhance Sterile Protection in Mice Induced by Circumsporozoite Protein.

Preerythrocytic vaccines prevent malaria by targeting parasites in the clinically silent sporozoite and liver stages and preventing progression to the virulent blood stages. The leading preerythrocytic vaccine, RTS,S/AS01E (Mosquirix), entered implementation programs in 2019 and targets the major sporozoite surface antigen, circumsporozoite protein (CSP). However, in phase III clinical trials, RTS,S conferred partial protection with limited durability, indicating a need to improve CSP-based vaccination.

A human monoclonal antibody blocks malaria transmission and defines a highly conserved neutralizing epitope on gametes.

Malaria elimination requires tools that interrupt parasite transmission. Here, we characterize B cell receptor responses among Malian adults vaccinated against the first domain of the cysteine-rich 230 kDa gamete surface protein Pfs230, a key protein in sexual stage development of P. falciparum parasites.

Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice.

BACKGROUNDVaccines that block human-to-mosquito Plasmodium transmission are needed for malaria eradication, and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced serum functional activity in both US and Malian adults. However, antibody levels declined rapidly, and transmission-reducing activity required 4 vaccine doses.

Antimalarial antibody repertoire defined by plasma IG proteomics and single B cell IG sequencing.

Plasma antimalarial Ab can mediate antiparasite immunity but has not previously been characterized at the molecular level. Here, we develop an innovative strategy to characterize humoral responses by integrating profiles of plasma immunoglobulins (IGs) or Abs with those expressed on B cells as part of the B cell receptor. We applied this strategy to define plasma IG and to determine variable (V) gene usage after vaccination with the Plasmodium falciparum zygote antigen Pfs25.

Structure and function of a malaria transmission blocking vaccine targeting Pfs230 and Pfs230-Pfs48/45 proteins.

Proteins Pfs230 and Pfs48/45 are Plasmodium falciparum transmission-blocking (TB) vaccine candidates that form a membrane-bound protein complex on gametes. The biological role of Pfs230 or the Pfs230-Pfs48/45 complex remains poorly understood. Here, we present the crystal structure of recombinant Pfs230 domain 1 (Pfs230D1M), a 6-cysteine domain, in complex with the Fab fragment of a TB monoclonal antibody (mAb) 4F12.

A Just-in-Time Video Primer on Pneumothorax Pathophysiology and Early Management.

Audience: Emergency medicine residents (interns, junior residents), medical students, and mid-level providers (physician assistants, nurse practitioners).

Introduction: Pneumothorax refers to the presence of gas within the pleural space and is a relatively common clinical entity in the emergency department.1 Traumatic pneumothorax results from blunt or penetrating trauma to the thorax.

Large mediastinal haematoma after paraoesophageal hernia repair.

Mediastinal haematoma is a rare complication of laparoscopic paraoesophageal hernia repair with few documented cases in the current literature. Presentation of this unique clinical problem can range from extrinsic oesophageal obstruction to life-hreatening cardiac tamponade and therefore, warrants further discussion of at-risk population aetiology, diagnosis and successful management strategies. We present the case of a 71-year-old woman who underwent laparoscopic paraoesophageal hernia repair with nissen fundoplication complicated by severe dysphagia on postoperative day 12.

Naturally Acquired Antibody Response to Malaria Transmission Blocking Vaccine Candidate Pvs230 Domain 1.

malaria incidence has increased in Latin America and Asia and is responsible for nearly 74.1% of malaria cases in Latin America. Immune responses to are less well characterized than those to , partly because is more difficult to cultivate in the laboratory.

Graft Materials and Biologics for Spinal Interbody Fusion.

Spinal fusion is the most widely performed procedure in spine surgery. It is the preferred treatment for a wide variety of pathologies including degenerative disc disease, spondylolisthesis, segmental instability, and deformity. Surgeons have the choice of fusing vertebrae by utilizing cages containing autografts, allografts, demineralized bone matrices (DBMs), or graft substitutes such as ceramic scaffolds.

Assessment of the impact of manufacturing changes on the physicochemical properties of the recombinant vaccine carrier ExoProtein A.

Efforts to develop a vaccine for the elimination of malaria include the use of carrier proteins to assemble monomeric antigens into nanoparticles to maximize immunogenicity. Recombinant ExoProtein A (EPA) is a detoxified form of Pseudomonas aeruginosa Exotoxin A which has been used as a carrier in the conjugate vaccine field. A pilot-scale process developed for purification of EPA yielded product that consistently approached a preset upper limit for host cell protein (HCP) content per human dose.

Safety and immunogenicity of Pfs25H-EPA/Alhydrogel, a transmission-blocking vaccine against Plasmodium falciparum: a randomised, double-blind, comparator-controlled, dose-escalation study in healthy Malian adults.

Background: Pfs25H-EPA is a protein-protein conjugate transmission-blocking vaccine against Plasmodium falciparum that is safe and induces functional antibodies in malaria-naive individuals. In this field trial, we assessed Pfs25H-EPA/Alhydrogel for safety and functional immunogenicity in Malian adults.

Methods: This double-blind, randomised, comparator-controlled, dose-escalation trial in Bancoumana, Mali, was done in two staggered phases, an initial pilot safety assessment and a subsequent main phase.

Protein-protein conjugate nanoparticles for malaria antigen delivery and enhanced immunogenicity.

Chemical conjugation of polysaccharide to carrier proteins has been a successful strategy to generate potent vaccines against bacterial pathogens. We developed a similar approach for poorly immunogenic malaria protein antigens. Our lead candidates in clinical trials are the malaria transmission blocking vaccine antigens, Pfs25 and Pfs230D1, individually conjugated to the carrier protein Exoprotein A (EPA) through thioether chemistry.

Safety and Immunogenicity of Pfs25-EPA/Alhydrogel®, a Transmission Blocking Vaccine against Plasmodium falciparum: An Open Label Study in Malaria Naïve Adults.

Transmission-blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination. Pfs25 is a leading TBV candidate, and previous studies conducted in animals demonstrated an improvement of its functional immunogenicity after conjugation to EPA, a recombinant, detoxified ExoProtein A from Pseudomonas aeruginosa. In this report, we describe results of an open-label, dose-escalating Phase 1 trial to assess the safety and immunogenicity of Pfs25-EPA conjugates formulated with Alhydrogel®.

Structural and Immunological Characterization of Recombinant 6-Cysteine Domains of the Plasmodium falciparum Sexual Stage Protein Pfs230.

Development of a Plasmodium falciparum (Pf) transmission blocking vaccine (TBV) has the potential to significantly impact malaria control. Antibodies elicited against sexual stage proteins in the human bloodstream are taken up with the blood meal of the mosquitoes and inactivate parasite development in the mosquito. In a phase 1 trial, a leading TBV identified as Pfs25-EPA/Alhydrogel® appeared safe and immunogenic, however, the level of Pfs25-specific antibodies were likely too low for an effective vaccine.

VAR2CSA Domain-Specific Analysis of Naturally Acquired Functional Antibodies to Plasmodium falciparum Placental Malaria.

Background: Placental malaria is caused by Plasmodium falciparum-infected erythrocytes (IEs) that surface-express VAR2CSA and bind chondroitin sulfate A. The inflammatory response to placenta-sequestered parasites is associated with poor pregnancy outcomes, and protection may be mediated in part by VAR2CSA antibodies that block placental IE adhesion.

Methods: In this study, we used a new approach to assess VAR2CSA domains for functional epitopes recognized by naturally acquired antibodies.

Reversible Conformational Change in the Plasmodium falciparum Circumsporozoite Protein Masks Its Adhesion Domains.

The extended rod-like Plasmodium falciparum circumsporozoite protein (CSP) is comprised of three primary domains: a charged N terminus that binds heparan sulfate proteoglycans, a central NANP repeat domain, and a C terminus containing a thrombospondin-like type I repeat (TSR) domain. Only the last two domains are incorporated in RTS,S, the leading malaria vaccine in phase 3 trials that, to date, protects about 50% of vaccinated children against clinical disease. A seroepidemiological study indicated that the N-terminal domain might improve the efficacy of a new CSP vaccine.