Repurposing the Antihypertensive Agent Hydralazine As an Inhibitor of the Base Excision Repair Enzyme APE1.

Apurinic/apyrimidinic endonuclease 1 (APE1) is a central enzyme in the base excision repair (BER) pathway. APE1 catalyzes incision of the phosphodiester linkage on the 5'-side of apurinic/apyrimidinic (AP) sites during the repair of damaged nucleobases in cellular DNA. Inhibition of this enzyme can potentiate the action of DNA-damaging chemotherapeutic agents.

Demographic changes in COVID-19 mortality during the pandemic: analysis of trends in disparities among workers using California's mortality surveillance system.

Background: There is limited information on the extent and patterns of disparities in COVID-19 mortality throughout the pandemic. We aimed to examine trends in disparities by demographics over variants in the pre- and post-vaccine availability period among Californian workers using a social determinants of health lens.

Methods: Using death certificates, we identified all COVID-19 deaths that occurred between January 2020 and May 2022 among workers aged 18-64 years in California (CA).

Dynamic gait stability and stability symmetry for people with transfemoral amputation: A case-series of 19 individuals with bone-anchored limbs.

For some individuals with severe socket-related problems, prosthesis osseointegration directly connects a prosthesis to the residual limb creating a bone-anchored limb (BAL). We compared dynamic gait stability and between-limb stability symmetry, as measured by the Margin of Stability (MoS) and the Normalized Symmetry Index (NSI), for people with unilateral transfemoral amputation before and one-year after BAL implantation. The MoS provides a mechanical construct to assess dynamic gait stability and infer center of mass and limb control by relating the center of mass and velocity to the base of support.

CalScope: methodology and lessons learned for conducting a remote statewide SARS-CoV-2 seroprevalence study in California using an at-home dried blood spot collection kit and online survey.

Background: To describe the methodology for conducting the CalScope study, a remote, population-based survey launched by the California Department of Public Health (CDPH) to estimate SARS-CoV-2 seroprevalence and understand COVID-19 disease burden in California.

Methods: Between April 2021 and August 2022, 666,857 randomly selected households were invited by mail to complete an online survey and at-home test kit for up to one adult and one child. A gift card was given for each completed survey and test kit.

IAPP Marks Mono-hormonal Stem-cell Derived β Cells that Maintain Stable Insulin Production and .

Islet transplantation for treatment of diabetes is limited by availability of donor islets and requirements for immunosuppression. Stem cell-derived islets might circumvent these issues. SC-islets effectively control glucose metabolism post transplantation, but do not yet achieve full function with current published differentiation protocols.

How Comprehensive and Efficient Are Patient-Reported Outcome Measures for Individuals with Lower Extremity Amputation Undergoing Implantation of Osseointegrated Bone Anchored Limbs?

» Patient-reported outcome measures (PROMs) are essential for measuring quality and functional outcomes after implantation of osseointegrated bone anchored limbs for patients with lower extremity amputation.» Using a novel assessment criterion with 8 domains, this study assessed all commonly used PROMs for their efficiency and comprehensiveness.» Comprehensiveness was scored according to the presence or absence of PROM questions related to these 8 domains (maximum score = 60): mobility (15 items), prosthesis (14 items), pain (10 items), psychosocial status (10 items), independence/self-care (4 items), quality of life/satisfaction (4 items), osseoperception (1 item), general information (1 item), and vitality (1 item).

Lifetime cost-effectiveness analysis osseointegrated transfemoral versus socket prosthesis using Markov modelling.

Aims: Prior cost-effectiveness analyses on osseointegrated prosthesis for transfemoral unilateral amputees have analyzed outcomes in non-USA countries using generic quality of life instruments, which may not be appropriate when evaluating disease-specific quality of life. These prior analyses have also focused only on patients who had failed a socket-based prosthesis. The aim of the current study is to use a disease-specific quality of life instrument, which can more accurately reflect a patient's quality of life with this condition in order to evaluate cost-effectiveness, examining both treatment-naïve and socket refractory patients.

The Amputated Limb Gluteus Medius is Biomechanically Disadvantaged in Patients with Unilateral Transfemoral Amputation.

Patients with transfemoral amputation (TFA) are at an increased risk of secondary musculoskeleteal comorbidities, primarily due to asymmetric joint loading. Amputated limb muscle weakness is also prevalent in the TFA population, yet all factors that contribute to muscle strength and thus joint loading are not well understood. Our objective was to bilaterally compare gluteus medius (GMED) muscle factors (volume, fatty infiltration, moment arm) that all contribute to joint loading in patients with TFA.

Unilateral transfemoral osseointegrated prostheses improve joint loading during walking.

People with unilateral transfemoral amputation using socket prostheses are at increased risk for developing osteoarthritis in both the residual hip and intact lower-limb joints. Osseointegrated prostheses are a surgical alternative to socket prostheses that directly attach to the residual femur via a bone-anchored implant, however their multi-joint loading effect is largely unknown. Our objective was to establish how osseointegrated prostheses influence joint loading during walking.

Daily steps and stepping cadence increase one-year following prosthesis osseointegration in people with lower-limb amputation.

Purpose: People with lower-limb loss participate in less physical activity than able-bodied individuals, which increases the mortality risk and incidence of metabolic syndromes. This study evaluated the effect of lower-limb prosthesis osseointegration on physical activity, including daily steps and stepping cadence.

Methods: Free-living walking activity was assessed from 14 patients scheduled to undergo prosthesis osseointegration at two time points (within 2 weeks prior to osseointegration surgery and 12-months following).

Matters arising: Insufficient evidence that pancreatic β cells are derived from adult ductal Neurog3-expressing progenitors.

Understanding the origin of pancreatic β cells has profound implications for regenerative therapies in diabetes. For over a century, it was widely held that adult pancreatic duct cells act as endocrine progenitors, but lineage-tracing experiments challenged this dogma. Gribben et al.

Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance.

Immunological protection of transplanted stem cell-derived islet (SC-islet) cells is yet to be achieved without chronic immunosuppression or encapsulation. Existing genetic engineering approaches to produce immune-evasive SC-islet cells have so far shown variable results. Here, we show that targeting human leukocyte antigens (HLAs) and PD-L1 alone does not sufficiently protect SC-islet cells from xenograft (xeno)- or allograft (allo)-rejection.

Whole-genome CRISPR screening identifies genetic manipulations to reduce immune rejection of stem cell-derived islets.

Human embryonic stem cells (hESCs) provide opportunities for cell replacement therapy of insulin-dependent diabetes. Therapeutic quantities of human stem cell-derived islets (SC-islets) can be produced by directed differentiation. However, preventing allo-rejection and recurring autoimmunity, without the use of encapsulation or systemic immunosuppressants, remains a challenge.

Extracellular mitochondria drive CD8 T cell dysfunction in trauma by upregulating CD39.

Rationale: The increased mortality and morbidity seen in critically injured patients appears associated with systemic inflammatory response syndrome (SIRS) and immune dysfunction, which ultimately predisposes to infection. Mitochondria released by injury could generate danger molecules, for example, ATP, which in turn would be rapidly scavenged by ectonucleotidases, expressed on regulatory immune cells.

Objective: To determine the association between circulating mitochondria, purinergic signalling and immune dysfunction after trauma.

Genetic manipulation of stress pathways can protect stem-cell-derived islets from apoptosis in vitro.

The in vitro production of stem-cell-derived islets (SC-islets) has brought forth the potential of transplanting these cells to restore glycemic control in people with diabetes. Nonetheless, alloimmune and autoimmune responses remain considerable challenges for a broad clinical implementation of β-cell replacement therapies. β-cell stress has been implicated in the onset of β-cell immunogenicity and death and is likely to contribute to β-cell failure following transplantation.

Cell maturation: Hallmarks, triggers, and manipulation.

How cells become specialized, or "mature," is important for cell and developmental biology. While maturity is usually deemed a terminal fate, it may be more helpful to consider maturation not as a switch but as a dynamic continuum of adaptive phenotypic states set by genetic and environment programing. The hallmarks of maturity comprise changes in anatomy (form, gene circuitry, and interconnectivity) and physiology (function, rhythms, and proliferation) that confer adaptive behavior.

Cognitive-Behavioral-Based Physical Therapy for Improving Recovery After Traumatic Orthopaedic Lower Extremity Injury (CBPT-Trauma).

Physical and psychological impairment resulting from traumatic injuries is often significant and affects employment and functional independence. Extremity trauma has been shown to negatively affect long-term self-reported physical function, the ability to work, and participation in recreational activities and contributes to increased rates of anxiety and/or depression. High pain levels early in the recovery process and psychosocial factors play a prominent role in recovery after traumatic lower extremity injury.

A human ESC line for efficient CRISPR editing of pluripotent stem cells.

Human pluripotent stem cells (hPSC) can be directed to differentiate in vitro into insulin-prorducing beta cells (SC-β). Although these cells accurately respond to glucose and can reverse diabetes in preclinical models improvments in the final cell products are desirable. For example, safety, controlling the cellular compositions and protection against immune rejection may be addressed by genetic modifications of SC-β pre-transplantation.

A therapeutic convection-enhanced macroencapsulation device for enhancing β cell viability and insulin secretion.

Islet transplantation for type 1 diabetes treatment has been limited by the need for lifelong immunosuppression regimens. This challenge has prompted the development of macroencapsulation devices (MEDs) to immunoprotect the transplanted islets. While promising, conventional MEDs are faced with insufficient transport of oxygen, glucose, and insulin because of the reliance on passive diffusion.

Generation of a heterozygous GAPDH-Luciferase human ESC line (HVRDe008-A-1) for in vivo monitoring of stem cells and their differentiated progeny.

Human stem cell-derived beta (SC-β) cells are a candidate for cell replacement therapy for type 1 diabetes. Whilst refinements to the differentiation protocol have resulted in the production of SC-β cells that resemble adult beta cells, the unsolved challenge to protect transplanted SC-β cells from the host immune system remains. To monitor the survival of SC-β cells in vivo, we knocked-in the Firefly luciferase gene into the GAPDH locus of the HUES8 human embryonic stem cell (hESC) line, such that differentiated islet cells constitutively express luciferase.

Building Biomimetic Potency Tests for Islet Transplantation.

Diabetes is a disease of insulin insufficiency, requiring many to rely on exogenous insulin with constant monitoring to avoid a fatal outcome. Islet transplantation is a recent therapy that can provide insulin independence, but the procedure is still limited by both the availability of human islets and reliable tests to assess their function. While stem cell technologies are poised to fill the shortage of transplantable cells, better methods are still needed for predicting transplantation outcome.

The promise of stem cell-derived islet replacement therapy.

Present-day treatments for people that are insulin dependent require multiple insulin injections, sometimes with an insulin pump, coupled with regular blood glucose monitoring. The availability of modified insulins, each with peaks of activity at varying times, has improved diabetes management. On the other hand, there have been impressive results leading to insulin independence by transplantation of cadaveric islets coupled with immune suppression.