Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease.

Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) with small molecules has been pursued as a treatment to ameliorate many disease complications but with limited success. Herein, we report the discovery of , a novel, potent, and selective molecular glue degrader of the transcription factor WIZ that robustly induces HbF expression as a potential treatment for SCD.

Dynamical forces drive organ morphology changes during embryonic development.

Organs and tissues must change shape in precise ways during embryonic development to execute their functions. Multiple mechanisms including biochemical signaling pathways and biophysical forces help drive these morphology changes, but it has been difficult to tease apart their contributions, especially from tissue-scale dynamic forces that are typically ignored. We use a combination of mathematical models and experiments to study a simple organ in the zebrafish embryo called Kupffer's vesicle.

A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia.

Azacitidine/venetoclax is an active regimen in patients with newly diagnosed acute myeloid leukemia (AML). However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML.

Improvements in Quality, Safety and Costs Associated with Use of Implant Registries Within a Health System.

Background: Clinical quality registries (CQRs) are intended to enhance quality, safety, and cost reduction using real-world data for a self-improving health system. Starting in 2001, Kaiser Permanente established several medical device CQRs as a quality improvement initiative. This report examines the contributions of these CQRs on improvement in health outcomes, changes in clinical practice, and cost-effectiveness over the past 20 years.

Implementation of a hotline ("S-T-I-C-K") to expedite management of occupational bloodborne pathogen exposures at an academic medical center: A Process Improvement Initiative.

Previously, blood and body fluid exposures were managed by a visit to the University Employee Health Clinic during normal business hours and the Emergency Department after hours. We implemented the "S-T-I-C-K" program where health care personnel were evaluated immediately after exposure by a nurse-driven 24/7 hotline. Increasing accessibility to care and a simplified process for exposure management led to a significant decrease in Emergency Department utilization and time between the exposure and receipt of post-exposure prophylaxis.

Utilization of Total Joint Arthroplasty by Rural-Urban Designation in Patients With Osteoarthritis in a Universal Coverage System.

Background: Utilization of total joint arthroplasty (TJA) is affected by differences linked to sex, race, and socioeconomic status; there is little information about how geographic variation contributes to these differences. We sought to determine whether discrepancies in TJA utilization exist in patients diagnosed with osteoarthritis (OA) based upon urban-rural designation in a universal coverage system.

Methods: We conducted a cohort study using data from a US-integrated healthcare system (2015 to 2019).

Association Between Race/Ethnicity and 90-Day Emergency Department Visits in Patients Undergoing Elective Total Knee Arthroplasty or Total Hip Arthroplasty in a Universally Insured Population.

Background: Research has identified disparities in returns to care by race/ethnicity following primary total joint arthroplasty. We sought to identify risk factors for 90-day emergency department (ED) returns following primary total knee arthroplasty (TKA) or total hip arthroplasty (THA) for these populations.

Methods: Black, Hispanic, and non-Hispanic White patients who underwent elective primary unilateral TKA and THA in an integrated US healthcare system were identified.

TLR2 is non-redundant in the population and subpopulation responses to in macrophages and .

Tuberculosis (TB), caused by the pathogenic bacterium (Mtb), is a global health threat. Targeting host pathways that modulate protective or harmful components of inflammation has been proposed as a therapeutic strategy that could aid sterilization or mitigate TB-associated permanent tissue damage. In purified form, many Mtb components can activate innate immune pathways.

Understanding laterality disorders and the left-right organizer: Insights from zebrafish.

Vital internal organs display a left-right (LR) asymmetric arrangement that is established during embryonic development. Disruption of this LR asymmetry-or laterality-can result in congenital organ malformations. (SIT) is a complete concordant reversal of internal organs that results in a low occurrence of clinical consequences.

shox2 is required for vestibular statoacoustic neuron development.

Homeobox genes act at the top of genetic hierarchies to regulate cell specification and differentiation during embryonic development. We identified the short stature homeobox domain 2 (shox2) transcription factor that is required for vestibular neuron development. shox2 transcripts are initially localized to the otic placode of the developing inner ear where neurosensory progenitors reside.

Temporal Trends in Deep Surgical Site Infections After Six Orthopaedic Procedures Over a 12-year Period Within a US-based Healthcare System.

Introduction: Centers of excellence and bundled payment models have driven perioperative optimization and surgical site infection (SSI) prevention with decolonization protocols and antibiotic prophylaxis strategies. We sought to evaluate time trends in the incidence of deep SSI and its causative organisms after six orthopaedic procedures in a US-based integrated healthcare system.

Methods: We conducted a population-level time-trend study using data from Kaiser Permanente's orthopaedic registries.

Association Between Race/Ethnicity and Total Joint Arthroplasty Utilization in a Universally Insured Population.

Introduction: Previous studies have documented racial and ethnic disparities in total joint arthroplasty (TJA) utilization in the United States. A potential mediator of healthcare disparities is unequal access to care, and studies have suggested that disparities may be ameliorated in systems of universal access. The purpose of this study was to assess whether racial/ethnic disparities in TJA utilization persist in a universally insured population of patients enrolled in a managed healthcare system.

Postoperative Acute Kidney Injury With Dual NSAID Use After Outpatient Primary Total Joint Arthroplasty.

Background: NSAIDs have been shown to be highly effective analgesic agents in the postoperative period. NSAIDs do have several potential adverse effects, including kidney injury (AKI). Little is known about AKI in the outpatient total joint arthroplasty (TJA) setting, where patient labs are not closely monitored.

Is There Harm in Debridement, Antibiotics, and Implant Retention Versus Two-Stage Revision in the Treatment of Periprosthetic Knee Infection? Experiences Within a Large US Health Care System.

Background: When faced with a periprosthetic joint infection (PJI) following total knee arthroplasty, the treating surgeon must determine whether 2-stage revision or "liner exchange," aka debridement, antibiotics, exchange of the modular polyethylene liner, and retention of fixed implants (DAIR), offers the best balance of infection eradication versus treatment morbidity. We sought to determine septic re-revision risk following DAIR compared to initial 2-stage revision.

Methods: We conducted a cohort study using data from Kaiser Permanente's total joint replacement registry.

Making Security Viral: Shifting Engineering Biology Culture and Publishing.

The ability to construct, synthesize, and edit genes and genomes at scale and with speed enables, in synergy with other tools of engineering biology, breakthrough applications with far-reaching implications for society. As SARS-CoV-2 spread around the world in early spring of 2020, researchers rapidly mobilized, using these tools in the development of diagnostics, therapeutics, and vaccines for COVID-19. The sharing of knowledge was crucial to making rapid progress.

canonical virulence factors interfere with a late component of the TLR2 response.

For many intracellular pathogens, the phagosome is the site of events and interactions that shape infection outcome. Phagosomal membrane damage, in particular, is proposed to benefit invading pathogens. To define the innate immune consequences of this damage, we profiled macrophage transcriptional responses to wild-type (Mtb) and mutants that fail to damage the phagosomal membrane.

Revision Risk in a Cohort of US Patients Younger Than 55 Undergoing Primary Elective Total Hip Arthroplasty.

Background: As indications for elective total hip arthroplasty (THA) expand to younger patients, we sought to (1) compare revision risk following primary elective THA in patients <55 years at the time of their THA to patients aged ≥65 years and (2) identify specific risk factors for revision in patients <55 years.

Methods: A Kaiser Permanente's total joint replacement registry was used to conduct a cohort study including primary elective THA patients aged ≥18 (2001-2018). In total, 11,671 patients <55 years and 53,106 patients ≥65 years were included.

Cause-Specific Stem Revision Risk in Primary Total Hip Arthroplasty Using Cemented vs Cementless Femoral Stem Fixation in a US Cohort.

Background: We sought to evaluate the cause-specific revision risk following hybrid (cemented stem mated to a cementless acetabular implant) vs cementless total hip arthroplasty (THA) in a US cohort.

Methods: Primary elective THA for osteoarthritis was identified using Kaiser Permanente's Total Joint Replacement Registry (2001-2018). Multivariable Cox regression was used to evaluate cause-specific revision, including aseptic loosening, infection, instability, and periprosthetic fracture (PPF), for hybrid vs cementless THA.

Association Between Same-Day Discharge Total Joint Arthroplasty and Risk of 90-Day Adverse Events in Patients with ASA Classification of ≥3.

Background: Although safety in same-day discharge total joint arthroplasty (TJA) has been reported, findings are limited to healthier patients, specific surgeons, and/or specific institutions. Indications for same-day discharge TJA have expanded to include patients with multiple comorbidities; however, safety in this specific patient population remains unknown. Therefore, we sought to compare the risk of 90-day adverse events in higher-risk patients undergoing same-day discharge versus inpatient TJA.

DSB-3 reveals conservation and divergence among protein complexes promoting meiotic double-strand breaks.

Meiotic recombination plays dual roles in the evolution and stable inheritance of genomes: Recombination promotes genetic diversity by reassorting variants, and it establishes temporary connections between pairs of homologous chromosomes that ensure their future segregation. Meiotic recombination is initiated by generation of double-strand DNA breaks (DSBs) by the conserved topoisomerase-like protein Spo11. Despite strong conservation of Spo11 across eukaryotic kingdoms, auxiliary complexes that interact with Spo11 complexes to promote DSB formation are poorly conserved.