Press-Fit Placement of a Rectangular Block Implant in the Resorbed Alveolar Ridge: Surgical and Biomechanical Considerations.

Rectangular Block Implant (RBIs) were manufactured, using computer-aided-design lathe turning, surface roughened with grit blasting and gamma irradiated. Implants were surgically placed into the resorbed edentulous mandibular ridges of both greyhound dogs (ex vivo and in vivo) and humans; the pooled total was 17 placements. The aim was to achieve mechanical stability and full implant submergence without damage to the mandibular canal and without bone fracture: fulfilment of all of these criteria was deemed to be a successful surgical outcome.

Improving kidney care for people with severe mental health difficulties: A thematic analysis of personal and family members' perspectives.

People with severe mental health difficulties (SMHDs) often have poorer access to kidney healthcare. To better understand the barriers and facilitators to kidney healthcare for this population, we conducted interviews with nine individuals with SMHDs and four family members. Through reflexive thematic analysis, we generated three themes: (1) '' describes the need for individualised kidney healthcare, adapted to meet the specific needs of each person with a SMHD.

Correction: Minimising the payload solvent exposed hydrophobic surface area optimises the antibody-drug conjugate properties.

[This corrects the article DOI: 10.1039/D3MD00540B.].

Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma.

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition.

Cryo-EM structure of human PAPP-A2 and mechanism of substrate recognition.

Pregnancy-Associated Plasma Protein A isoforms, PAPP-A and PAPP-A2, are metalloproteases that cleave insulin-like growth factor binding proteins (IGFBPs) to modulate insulin-like growth factor signaling. The structures of homodimeric PAPP-A in complex with IGFBP5 anchor peptide, and inhibitor proteins STC2 and proMBP have been recently reported. Here, we present the single-particle cryo-EM structure of the monomeric, N-terminal LG, MP, and the M1 domains (with the exception of LNR1/2) of human PAPP-A2 to 3.

Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients.

Background: MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902).

Methods: Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines.

Radiographic alveolar bone assessment in correlation with primary implant stability: A systematic review and meta-analysis.

Introduction: The radiographic examination of alveolar bone using 3D radiographic examination is essential in dental implant treatment planning. Our study aimed to systematically review and quantitatively analyze the correlation between alveolar bone parameters, specifically bone density and cortical bone thickness, assessed using cone beam computed tomography (CBCT) and/or multidetector computed tomography (MDCT); and primary implant stability (PIS) determined using implant stability quotient (ISQ), Periotest® value (PTV), and insertion torque value (ITV).

Methods: This review was registered in the PROSPERO database (registration number CRD42022307245).

Pseudohyperkalemia in chronic lymphocytic leukemia and diabetic ketoacidosis.

Pseudohyperkalemia can lead to inaccurate hyperkalemia diagnosis, inappropriate initiation of potassium-lowering therapies, and overall unnecessary treatment possibly inducing iatrogenic hypokalemia. Patients with leukocytosis and thrombocytosis should raise clinical suspicion that hyperkalemic laboratory results in the absence of other traditional signs of hyperkalemia may be indicative of pseudohyperkalemia. Here we present a case of severe leukocytosis with chronic lymphocytic leukemia (CLL) found to have critically elevated potassium levels on admission to the intensive care unit (ICU).

Therapeutic cyproheptadine regimen in serotonin syndrome: Complications after cardiovascular surgery.

Serotonin syndrome can be a life-threatening condition that occurs from the overactivity of serotonin in the central nervous system. This report describes the use of cyproheptadine for the management of serotonin syndrome in a patient taking fluoxetine and bupropion, who received methylene blue for vasoplegia syndrome. A 61-year-old female taking fluoxetine and bupropion preoperatively was given a total of three doses of methylene blue 100 mg IV within a brief time frame during and after a planned coronary artery bypass graft surgery.

Evidence-based appraisal of two guidelines for the diagnosis of suspected, uncomplicated urinary tract infections in primary care: a diagnostic accuracy validation study.

Objectives: Given the lack of accurate rapid diagnostics for urinary tract infection (UTI) in women, many countries have developed guidelines aiming to support appropriate antibiotic prescribing, but some guidelines have not been validated. We performed a diagnostic accuracy validation study of two guidelines: Public Health England (GW-1263) and Scottish Intercollegiate Guidelines Network (SIGN160).

Methods: We used data from women with symptoms suggestive of uncomplicated UTI from a randomized controlled trial comparing urine collection devices.

Modulation of MG-63 Osteogenic Response on Mechano-Bactericidal Micronanostructured Titanium Surfaces.

Despite recent advances in the development of orthopedic devices, implant-related failures that occur as a result of poor osseointegration and nosocomial infection are frequent. In this study, we developed a multiscale titanium (Ti) surface topography that promotes both osteogenic and mechano-bactericidal activity using a simple two-step fabrication approach. The response of MG-63 osteoblast-like cells and antibacterial activity toward and bacteria was compared for two distinct micronanoarchitectures of differing surface roughness created by acid etching, using either hydrochloric acid (HCl) or sulfuric acid (HSO), followed by hydrothermal treatment, henceforth referred to as either MN-HCl or MN-HSO.

The Biomechanical Profile of an Osseo-Integrated Rectangular Block Implant: A Pilot In Vivo Strain Analysis.

To load-test the osseo-integrated rectangular block implant (RBI), measure the generated cortical peri-implant strains, and relate these findings to known human physiological parameters. : Two RBIs were placed into the posterior mandibular saddle in a mature greyhound dog and allowed to osseo-integrate. The half mandible (implants in situ) was mounted in a servohydraulic system.

Structure of the PAPP-A complex reveals mechanism of substrate recognition.

Insulin-like growth factor (IGF) signaling is highly conserved and tightly regulated by proteases including Pregnancy-Associated Plasma Protein A (PAPP-A). PAPP-A and its paralog PAPP-A2 are metalloproteases that mediate IGF bioavailability through cleavage of IGF binding proteins (IGFBPs). Here, we present single-particle cryo-EM structures of the catalytically inactive mutant PAPP-A (E483A) in complex with a peptide from its substrate IGFBP5 (PAPP-A) and also in its substrate-free form, by leveraging the power of AlphaFold to generate a high quality predicted model as a starting template.

Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site.

Anti-IL17A therapies have proven effective for numerous inflammatory diseases including psoriasis, axial spondylitis and psoriatic arthritis. Modulating and/or antagonizing protein-protein interactions of IL17A cytokine binding to its cell surface receptors with oral therapies offers the promise to bring forward biologics-like efficacy in a pill to patients. We used an NMR-based fragment screen of recombinant IL17A to uncover starting points for small molecule IL17A antagonist discovery.

Research Note: Methods in detecting signs of life after gaseous stun in broilers.

To be compliant with religious requirements for poultry, slaughter facilities using controlled atmosphere stunning may require a reliable method for detecting signs of life. However, the production setting challenges methods utilized in veterinary and field use by generating excess sound and vibration, which can impact the effectiveness of typical measurement tools, such as the stethoscope or doppler ultrasound. In addition, it is required that the process be quick and efficient as to not interfere with the rapid pace of production.

An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy.

Costimulatory receptors such as glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) play key roles in regulating the effector functions of T cells. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect, which may be due to suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies.

Use of tocilizumab, remdesivir, and high-dose methylprednisolone prevents intubation in an ESRD patient with COVID-19 pneumonia.

Coronavirus disease 2019 (COVID-19) has affected over 200 million patients worldwide. COVID-19 is transmitted through respiratory droplets from patient to patient or by touching a surface that has been contaminated by an infected patient. Many COVID-19 patients have other comorbidities, such as end-stage renal disease.

The biomechanical profile of an osseo-integrated rectangular block implant: A pilot in vivo experimental study.

Objective: A novel implant design, the rectangular block implant (RBI), was investigated as a possible solution to the restoration of the posterior resorbed ridge.

Aim: To maximally load test the osseo-integrated RBI in shear and tensile loads and relate these findings to known human masticatory loads as biomechanical proof of the study concept.

Materials And Methods: Twelve RBIs were design-manufactured and placed into posterior mandibular saddles in 3 mature greyhound dogs.

Measuring tooth movement with treatment using the Dahl principle: An observational study.

Statement Of Problem: Research on the quantification of 3-dimensional tooth movements in patients undergoing treatment using the Dahl principle is lacking.

Purpose: The purpose of this observational clinical study was to measure the magnitude, direction, duration, and rate of tooth movement occurring in patients to reestablish tooth contact and create restorative space.

Material And Methods: A total of 104 paired preoperative and postoperative physical and virtual casts from 26 patients were obtained.

Structure-Based Design of A-1293102, a Potent and Selective BCL-X Inhibitor.

BCL-X, an antiapoptotic member of the BCL-2 family of proteins, drives tumor survival and maintenance and thus represents a key target for cancer treatment. Herein we report the rational design of a novel series of selective BCL-X inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-X inhibitor A-1155463 and the dual BCL-X/BCL-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation.

Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers.

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications.