Assessing barriers to the career ladder and professional development for ethnic minority genetic counselors in the United States.

Ethnic diversity is not reflected within healthcare professions, including genetic counseling, where lack of growth and membership among minority colleagues extends to upper-level and executive roles. While diversity and inclusion-based topics have been emphasized, studies on potential barriers to career advancement in the field of genetic counseling have not received the same attention. Our study examined the current state of mentorship and sponsorship programs, the presence of diversity and inclusion initiatives, and opportunities for career advancement through the lens of a minority genetic counselor. Practicing genetic counselors in the United States identifying as part of any racial group, other than non-Hispanic White alone, were recruited through the Minority Genetics Professionals Network for survey participation. A 31-item survey was fully completed by 19 practicing genetic counselors from a variety of ethnic backgrounds. Data were analyzed using descriptive statistics and thematic analysis, allowing for individual stories and accounts to be amplified. Results showed 16 of 19 participants had never been promoted in their current employment setting. Additionally, 7 out of 19 respondents disagreed or strongly disagreed that their company had a commitment to an ethnically diverse workforce within upper-level positions. Prominent themes identified from open-ended responses included lack of social connection with supervisors and the cross-race effect, a term referencing a tendency for individuals to better recognize members of their own race or ethnicity than others. Additional themes revealed feelings of isolation, need for support from White colleagues, as well as desired emphasis on sponsorship tailored toward professional growth. These findings demonstrate a need for proactive involvement in reaching ethnic and racial minority genetic counselors through companywide policy efforts, support and advocacy from White colleagues, and modification of cultural perception frameworks. Further focus and emphasis on these distinct but critical topics may be important in promoting increased diversity in upper-level positions in the field of genetic counseling.

Transitioning to telegenetics in the COVID-19 era: Patient satisfaction with remote genetic counseling in adult neurology.

The COVID-19 pandemic rapidly changed genetic counseling services across the United States. At the University of Pennsylvania (UPenn), a large academic hospital in an urban setting, nearly all genetic counseling (GC) visits for adult-onset disorders within the Department of Neurology were conducted via secure videoconferencing (telegenetics) or telephone between March and December 2020. Although telemedicine services have been steadily emerging, many clinical programs, including the neurogenetics program at UPenn, had not built infrastructure or widely utilized these services prior to the pandemic. Thus, little is known about patient attitudes toward receiving clinical GC services remotely. From May 18 to October 18, 2020, all individuals seen remotely for GC in adult neurology via telephone or telegenetics were surveyed about their satisfaction with telehealth GC (N = 142), with a response rate of 42% (N = 60/142). Telephone and telegenetics services were referred to as 'telehealth' in the surveys to capture patient perspectives on all remote GC services, though the majority (N = 49/60) of these visits were completed via telegenetics. Surveys included the modified telehealth usability questionnaire (MTUQ), genetic counseling satisfaction scale (GCSS), and novel questions about future telehealth use. Preliminary results suggest that patients were satisfied with receiving remote GC services in adult neurology, with most participants strongly agreeing to all items about satisfaction with telehealth. Just 2% of participants preferred only in-person visits in the future, but every participant was willing to consider using telehealth for future visits if their genetic counselor felt it was appropriate. Most participants preferred a hybrid model (73%), and some (25%) preferred only telehealth for future visits. Additionally, we found no differences in satisfaction with remote services based on visit type (initial vs. results disclosure) nor age. We conclude that remote GC is an acceptable method for the provision of services in adult neurology that is well-received by patients.

Effect of incorporating aromatic and chiral groups on the dielectric properties of poly(dimethyltin esters).

High-dielectric constant materials are critical for numerous applications such as photovoltaics, photonics, transistors, and capacitors. There are numerous polymers used as dielectric layers in these applications but can suffer from having a low dielectric constant, small band gap, or ferroelectricity. Here, the structure-property relationship of various poly(dimethyltin esters) is described that look to enhance the dipolar and atomic polarization component of the dielectric constant. These polymers are also modeled using first principles calculations based on density functional theory (DFT) to predict such values as the total, electronic, and ionic dielectric constant as well as structure. A strong correlation is achieved between the theoretical and experimental values with the polymers exhibiting dielectric constants >4.5 with dissipation on the order of 10(-3) -10(-2) .

Genetic testing in adults with neurologic disorders: indications, approach, and clinical impacts.

The role of genetic testing in neurologic clinical practice has increased dramatically in recent years, driven by research on genetic causes of neurologic disease and increased availability of genetic sequencing technology. Genetic testing is now indicated for adults with a wide range of common neurologic conditions. The potential clinical impacts of a genetic diagnosis are also rapidly expanding, with a growing list of gene-specific treatments and clinical trials, in addition to important implications for prognosis, surveillance, family planning, and diagnostic closure. The goals of this review are to provide practical guidance for clinicians about the role of genetics in their practice and to provide the neuroscience research community with a broad survey of current progress in this field. We aim to answer three questions for the neurologist in practice: Which of my patients need genetic testing? What testing should I order? And how will genetic testing help my patient? We focus on common neurologic disorders and presentations to the neurology clinic. For each condition, we review the most current guidelines and evidence regarding indications for genetic testing, expected diagnostic yield, and recommended testing approach. We also focus on clinical impacts of genetic diagnoses, highlighting a number of gene-specific therapies recently approved for clinical use, and a rapidly expanding landscape of gene-specific clinical trials, many using novel nucleotide-based therapeutic modalities like antisense oligonucleotides and gene transfer. We anticipate that more widespread use of genetic testing will help advance therapeutic development and improve the care, and outcomes, of patients with neurologic conditions.

Disparities in Genetic Testing for Neurologic Disorders.

BACKGROUND AND OBJECTIVES: Genetic testing is now the standard of care for many neurologic conditions. Health care disparities are unfortunately widespread in the US health care system, but disparities in the utilization of genetic testing for neurologic conditions have not been studied. We tested the hypothesis that access to and results of genetic testing vary according to race, ethnicity, sex, socioeconomic status, and insurance status for adults with neurologic conditions. METHODS: We analyzed retrospective data from patients who underwent genetic evaluation and testing through our institution's neurogenetics program. We tested for differences between demographic groups in 3 steps of a genetic evaluation pathway: (1) attending a neurogenetic evaluation, (2) completing genetic testing, and (3) receiving a diagnostic result. We compared patients on this genetic evaluation pathway with the population of all neurology outpatients at our institution, using univariate and multivariable logistic regression analyses. RESULTS: Between 2015 and 2022, a total of 128,440 patients were seen in our outpatient neurology clinics and 2,540 patients underwent genetic evaluation. Black patients were less than half as likely as White patients to be evaluated (odds ratio [OR] 0.49, p < 0.001), and this disparity was similar after controlling for other demographic factors in multivariable analysis. Patients from the least wealthy quartile of zip codes were also less likely to be evaluated (OR 0.67, p < 0.001). Among patients who underwent evaluation, there were no disparities in the likelihood of completing genetic testing, nor in the likelihood of a diagnostic result after adjusting for age. Analyses restricted to specific indications for genetic testing supported these findings. DISCUSSION: We observed unequal utilization of our clinical neurogenetics program for patients from marginalized and minoritized demographic groups, especially Black patients. Among patients who do undergo evaluation, all groups benefit similarly from genetic testing when it is indicated. Understanding and removing barriers to accessing genetic testing will be essential to health care equity and optimal care for all patients with neurologic disorders.

Electrospinning covalently cross-linking biocompatible hydrogelators.

Many hydrogel materials of interest are homogeneous on the micrometer scale. Electrospinning, the formation of sub-micrometer to micrometer diameter fibers by a jet of fluid formed under an electric field, is one process being explored to create rich microstructures. However, electrospinning a hydrogel system as it reacts requires an understanding of the gelation kinetics and corresponding rheology near the liquid-solid transition. In this study, we correlate the structure of electrospun fibers of a covalently cross-linked hydrogelator with the corresponding gelation transition and kinetics. Polyethylene oxide (PEO) is used as a carrier polymer in a chemically cross-linking poly(ethylene glycol)-high molecular weight heparin (PEG-HMWH) hydrogel. Using measurements of gelation kinetics from multiple particle tracking microrheology (MPT), we correlate the material rheology with the the formation of stable fibers. An equilibrated, cross-linked hydrogel is then spun and the PEO is dissolved. In both cases, microstructural features of the electrospun fibers are retained, confirming the covalent nature of the network. The ability to spin fibers of a cross-linking hydrogel system ultimately enables the engineering of materials and microstructural length scales suitable for biological applications.

Poly(2-methoxyethyl acrylate) (PMEA) improves the thromboresistance of FRED flow diverters: a thrombogenic evaluation of flow diverters with human blood under flow conditions.

BACKGROUND: Surface modification of flow-diverting stents has been explored to reduce thrombus-related complications that may arise under clinical use. This study investigated the thromboresistant properties of the flow redirection endoluminal device (FRED) X, a flow diverter treated with a copolymer of poly(2-methoxyethyl acrylate) (PMEA; X Technology). METHODS: The performance of FRED, FRED X, and Pipeline Flex with Shield Technology (sPED) was evaluated in an in vitro blood loop model. Blood activation level was assessed by the concentration of thrombin-antithrombin complex (TAT), ß-thromboglobulin (ß-TG), and platelet count, and qualitatively by scanning electron microscopy (SEM). Cellular adhesion characteristics were measured using human aortic endothelial cells that were seeded on flat sheets mimicking the surface of FRED, FRED X, and sPED, and evaluated with fluorescence microscopy. Statistical comparisons were conducted using one-way analysis of variance (ANOVA) with Tukey post hoc tests. RESULTS: FRED X, sPED, and control blood loops showed significantly reduced blood activation levels (TAT and ß-TG) compared with FRED (p<0.01). Consequently, FRED showed a significant decrease in platelet count compared with FRED X, sPED, and control loops (p<0.01). SEM imaging showed the lowest accumulation of blood cell-like deposits on FRED X compared with sPED and FRED, while FRED had the highest accumulation. Endothelial cells adhered and were widely spread on X Technology-treated sheets, while minimal cell adhesion was observed on phosphorylcholine-treated sheets. CONCLUSION: The X Technology surface modification of FRED X demonstrated superior thromboresistant properties over untreated FRED while maintaining comparable cellular adhesion. Taken together, these properties may help mitigate material-related thromboembolic complications.

Preimplantation Genetic Testing for Adult-Onset Neurodegenerative Disease: Considerations for Access, Utilization, and Counseling.

Preimplantation genetic testing for monogenic conditions (PGT-M), formerly called preimplantation genetic diagnosis, is a specialized assisted reproduction technique that aims to reduce the risk of a pregnancy inheriting a monogenic condition. Despite calls to increase awareness and prepare neurologists for discussing PGT-M with patients and their families, no guidelines currently exist. When introducing PGT-M to those who may be interested in using it, there are major factors for discussion, including (1) genetic considerations (e.g., requirement for a confirmed genetic diagnosis; timing of genetic test results); (2) practical considerations (e.g., access to PGT-M and genetic services); (3) technical considerations (e.g., factors that can affect the success rate of PGT-M); and (4) psychosocial and ethical considerations (e.g., predictive testing for asymptomatic family members; family dynamics and values). Here, our team of neurologists and specialized genetic counselors discusses the current state of genetic characterization in adult-onset neurodegenerative conditions and highlights the major factors that should be considered when discussing PGT-M with families.

A role for aberrant protein palmitoylation in FFA-induced ER stress and ß-cell death.

Exposure of insulin-producing cells to elevated levels of the free fatty acid (FFA) palmitate results in the loss of ß-cell function and induction of apoptosis. The induction of endoplasmic reticulum (ER) stress is one mechanism proposed to be responsible for the loss of ß-cell viability in response to palmitate treatment; however, the pathways responsible for the induction of ER stress by palmitate have yet to be determined. Protein palmitoylation is a major posttranslational modification that regulates protein localization, stability, and activity. Defects in, or dysregulation of, protein palmitoylation could be one mechanism by which palmitate may induce ER stress in ß-cells. The purpose of this study was to evaluate the hypothesis that palmitate-induced ER stress and ß-cell toxicity are mediated by excess or aberrant protein palmitoylation. In a concentration-dependent fashion, palmitate treatment of RINm5F cells results in a loss of viability. Similar to palmitate, stearate also induces a concentration-related loss of RINm5F cell viability, while the monounsaturated fatty acids, such as palmoleate and oleate, are not toxic to RINm5F cells. 2-Bromopalmitate (2BrP), a classical inhibitor of protein palmitoylation that has been extensively used as an inhibitor of G protein-coupled receptor signaling, attenuates palmitate-induced RINm5F cell death in a concentration-dependent manner. The protective effects of 2BrP are associated with the inhibition of [(3)H]palmitate incorporation into RINm5F cell protein. Furthermore, 2BrP does not inhibit, but appears to enhance, the oxidation of palmitate. The induction of ER stress in response to palmitate treatment and the activation of caspase activity are attenuated by 2BrP. Consistent with protective effects on insulinoma cells, 2BrP also attenuates the inhibitory actions of prolonged palmitate treatment on insulin secretion by isolated rat islets. These studies support a role for aberrant protein palmitoylation as a mechanism by which palmitate enhances ER stress activation and causes the loss of insulinoma cell viability.

Tunable degradation of maleimide-thiol adducts in reducing environments.

Addition chemistries are widely used in preparing biological conjugates, and in particular, maleimide-thiol adducts have been widely employed. Here, we show that the resulting succinimide thioether formed by the Michael-type addition of thiols to N-ethylmaleimide (NEM), generally accepted as stable, undergoes retro and exchange reactions in the presence of other thiol compounds at physiological pH and temperature, offering a novel strategy for controlled release. Model studies ((1)H NMR, HPLC) of NEM conjugated to 4-mercaptophenylacetic acid (MPA), N-acetylcysteine, or 3-mercaptopropionic acid (MP) incubated with glutathione showed half-lives of conversion from 20 to 80 h, with extents of conversion from 20% to 90% for MPA and N-acetylcysteine conjugates. After ring-opening, the resultant succinimide thioether did not show retro and exchange reactions. The kinetics of the retro reactions and extent of exchange can be modulated by the Michael donor's reactivity; therefore, the degradation of maleimide-thiol adducts could be tuned for controlled release of drugs or degradation of materials at time scales different than those currently possible via disulfide-mediated release. Such approaches may find a new niche for controlled release in reducing environments relevant in chemotherapy and subcellular trafficking.

Rapid, high resolution screening of biomaterial hydrogelators by µ2rheology.

A combination of sample manipulation and rheological characterization at the microscale is used to identify the gelation of poly(ethylene glycol)-heparin hydrogels over a wide range of compositions. A microfluidic device produces 50-100 droplet samples, each with a different composition. Multiple particle tracking microrheology is used to measure the rheological state of each sample. This combination requires little material and enables efficient and rapid screening of gelation conditions. The high resolution data identifies the gelation reaction percolation boundaries and a lower limit of the total hydrogelator concentration for gelation to occur, which can be used for the subsequent engineering, testing, and processing of these materials.

Rapid rheological screening to identify conditions of biomaterial hydrogelation.

Hydrogels engineered for biomedical applications consist of numerous components, each of which can affect the material assembly and final mechanical properties. We present methods that rapidly generate rheological libraries to identify regimes of hydrogel assembly in a large composition parameter space. This method conserves both material and time, and leads to critical insight into assembly mechanisms and mechanics, which can then be used for further materials development and optimization.

Rash associated with pregabalin use.

OBJECTIVE: To report a case of extensive rash induced by orally administered pregabalin in a patient with neuropathic pain. CASE SUMMARY: A 35-year-old white female with a diffuse, erythematous, maculopapular rash localized to her back and extremities presented to the preoperative holding area for planned exploratory nerve surgery. Prior to presentation, she had been receiving oral pregabalin 50 mg 3 times a day for approximately 2 weeks to treat her neuropathy. Prior to pregabalin therapy, the patient indicated that she had taken gabapentin for approximately 3 weeks for the pain, but had discontinued it due to adverse effects and perceived lack of efficacy. Pregabalin was discontinued and diphenhydramine and methylprednisolone were given to treat the rash. The rash almost completely resolved one week after pregabalin was discontinued. DISCUSSION: Pregabalin-induced rash was rarely reported in Phase 3 trials, and a clinical description of such events has not been published. Pregabalin exhibits pharmacokinetics different from those of most other antiepileptic agents. Presently, there are no clear mechanisms known for rash associated with pregabalin. The Naranjo probability scale indicates a probable relationship between the development of rash and use of pregabalin by our patient. CONCLUSIONS: There are currently no other available reports of the development of a rash coinciding with the use of pregabalin. As both Food and Drug Administration-approved and off-label use of this drug increases, further consideration of risk factors associated with the development of rash is needed.

Cation-Independent Mannose 6-Phosphate Receptor Deficiency Enhances ß-Cell Susceptibility to Palmitate.

Palmitate attenuates insulin secretion and reduces the viability of insulin-producing cells. Previous studies identified the aberrant palmitoylation or mispalmitoylation of proteins as one mechanism by which palmitate causes ß-cell damage. In this report, we identify a role for lysosomal protein degradation as a mechanism by which ß cells defend themselves against excess palmitate. The cation-independent mannose 6-phosphate receptor (CI-MPR) is responsible for the trafficking of mannose 6-phosphate-tagged proteins to lysosomes via Golgi sorting and from extracellular locations through endocytosis. RINm5F cells, which are highly sensitive to palmitate, lack CI-MPR. The reconstitution of CI-MPR expression attenuates the induction of endoplasmic reticulum (ER) stress and the toxic effects of palmitate on RINm5F cell viability. INS832/13 cells express CI-MPR and are resistant to the palmitate-mediated loss of cell viability. The reduction of CI-MPR expression increases the sensitivity of INS832/13 cells to the toxic effects of palmitate treatment. The inhibition of lysosomal acid hydrolase activity by weak base treatment of islets under glucolipotoxic conditions causes islet degeneration that is prevented by the inhibition of protein palmitoylation. These findings indicate that defects in lysosomal function lead to the enhanced sensitivity of insulin-producing cells to palmitate and support a role for normal lysosomal function in the protection of ß cells from excess palmitate.

Poly(dimethyltin glutarate) as a prospective material for high dielectric applications.

Poly(dimethyltin glutarate) is presented as the first organometallic polymer, a high dielectric constant, and low dielectric loss material. Theoretical results correspond well in terms of the dielectric constant. More importantly, the dielectric constant can be tuned depending on the solvent a film of the polymer is cast from. The breakdown strength is increased through blending with a second organometallic polymer.

IL-1 and TNF-alpha play a pivotal role in the host immune response in a mouse model of Staphylococcus aureus-induced experimental brain abscess.

Brain abscesses represent a significant medical problem despite recent advances made in detection and therapy. Using an established Staphylococcus aureus-induced brain abscess model, we have sought to define the functional importance of interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and IL-6 in the host anti-bacterial immune response using cytokine gene knockout (KO) mice. Previous studies from our laboratory revealed that these cytokines are among the main proinflammatory mediators produced during the acute stage of brain abscess development. The results presented here demonstrate that although they share many redundant activities, IL-1 and TNF-alpha are important for containing bacterial infection in evolving brain abscesses as evident by increased mortality and bacterial burdens in IL-1 and TNF-alpha KO mice compared to wild type (WT) animals. In contrast, IL-6 was not found to be a major contributor to the host anti-bacterial immune response. Microarray analysis was used to evaluate the downstream consequences originating from the lack of IL-1 on subsequent proinflammatory mediator expression in brain abscesses from IL-1 KO and WT animals. Although numerous genes were significantly induced following S. aureus infection, only IL-1beta and 2 chemokines, CCL9 (macrophage inflammatory protein-1 gamma/MIP-1gamma) and CXCL13 (B lymphocyte chemoattractant/BLC), were differentially regulated in IL-1 KO versus WT animals. These results suggest that IL-1 and TNF-alpha play a pivotal role during the acute stage of brain abscess development through regulating the ensuing anti-bacterial inflammatory response.

Persistent immune activation associated with a mouse model of Staphylococcus aureus-induced experimental brain abscess.

We have established a mouse experimental brain abscess model using Staphylococcus aureus where lesion sites are greatly exaggerated compared to the localized area of initial infection, reminiscent of an overactive immune response. Here we demonstrate the prolonged expression of IL-1 beta, TNF-alpha, and macrophage inflammatory protein-2 (MIP-2/CXCL2), concomitant with a chronic disruption of the blood-brain barrier (BBB) in mice with S. aureus-induced brain abscess. These changes correlated with the continued presence of infiltrating neutrophils and macrophages/microglia. Collectively these findings suggest that the excessive tissue damage that often results from brain abscess may be mediated, in part, by the perpetuation of antibacterial immune responses that are not downregulated in a timely manner.

A 48-hour exposure of pancreatic islets to calpain inhibitors impairs mitochondrial fuel metabolism and the exocytosis of insulin.

Genetic variation in the gene for a cytosolic cysteine protease, calpain-10, increases the susceptibility to type 2 diabetes apparently by altering levels of gene expression. In view of the importance of altered beta-cell function in the pathophysiology of type 2 diabetes, the present study was undertaken to define the effects on insulin secretion of exposing pancreatic islets to calpain inhibitors for 48 hours. Exposure of mouse islets to calpain inhibitors (ALLN, ALLM, E-64-d, MDL 18270, and PD147631) of different structure and mechanism of action for 48 hours reversibly suppresses glucose-induced insulin secretion by 40% to 80%. Exposure of islets to inhibitors of other proteases, ie, cathepsin B and proteasome, did not affect insulin secretion. The 48-hour incubation with calpain inhibitors also attenuates insulin secretory responses to the mitochondrial fuel alpha-ketoisocaproate (KIC). The same incubation also suppresses glucose metabolism and intracellular calcium ([Ca(2+)](i)) responses to glucose or KIC in islets. In summary, long-term inhibition of islet calpain activity attenuates insulin secretion possibly by limiting the rate of glucose metabolism. A reduction of calpain activity in islet could contribute to the development of beta-cell failure in type 2 diabetes thereby providing a link between genetic susceptibility to diabetes and the pathophysiologic manifestations of the disease.

Rationally designed polyimides for high-energy density capacitor applications.

Development of new dielectric materials is of great importance for a wide range of applications for modern electronics and electrical power systems. The state-of-the-art polymer dielectric is a biaxially oriented polypropylene (BOPP) film having a maximal energy density of 5 J/cm(3) and a high breakdown field of 700 MV/m, but with a limited dielectric constant (∼2.2) and a reduced breakdown strength above 85 °C. Great effort has been put into exploring other materials to fulfill the demand of continuous miniaturization and improved functionality. In this work, a series of polyimides were investigated as potential polymer materials for this application. Polyimide with high dielectric constants of up to 7.8 that exhibits low dissipation factors (<1%) and high energy density around 15 J/cm(3), which is 3 times that of BOPP, was prepared. Our syntheses were guided by high-throughput density functional theory calculations for rational design in terms of a high dielectric constant and band gap. Correlations of experimental and theoretical results through judicious variations of polyimide structures allowed for a clear demonstration of the relationship between chemical functionalities and dielectric properties.

Reversible maleimide-thiol adducts yield glutathione-sensitive poly(ethylene glycol)-heparin hydrogels.

We have recently reported that retro Michael-type addition reactions can be employed for producing labile chemical linkages with tunable sensitivity to physiologically relevant reducing potentials. We reasoned that such strategies would also be useful in the design of glutathione-sensitive hydrogels for a variety of targeted delivery and tissue engineering applications. In this report, we describe hydrogels in which maleimide-functionalized low molecular weight heparin (LMWH) is crosslinked with various thiol-functionalized poly(ethylene glycol) (PEG) multi-arm star polymers. Judicious selection of the chemical identity of the thiol permits tuning of degradation via previously unstudied, but versatile chemical methods. Thiol pKa and hydrophobicity affected both the gelation and degradation of these hydrogels. Maleimide-thiol crosslinking reactions and retro Michael-type addition reactions were verified with 1H NMR during the crosslinking and degradation of hydrogels. PEGs esterified with phenylthiol derivatives, specifically 4-mercaptophenylpropionic acid or 2,2-dimethyl-3-(4-mercaptophenyl)propionic acid, induced sensitivity to glutathione as shown by a decrease in hydrogel degradation time of 4-fold and 5-fold respectively, measured via spectrophotometric quantification of LMWH. The degradation proceeded through the retro Michael-type addition of the succinimide thioether linkage, with apparent pseudo-first order reaction constants derived from oscillatory rheology experiments of 0.039 ± 0.006 h-1 and 0.031 ± 0.003 h-1. The pseudo-first order retro reaction constants were approximately an order of magnitude slower than the degradation rate constants for hydrogels crosslinked via disulfide linkages, indicating the potential use of these Michael-type addition products for reduction-mediated release and/or degradation, with increased blood stability and prolonged drug delivery timescales compared to disulfide moieties.