Perfluoroalkyl Substances and Incident Natural Menopause in Midlife Women: The Mediating Role of Sex Hormones.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been associated with earlier natural menopause; however, the underlying mechanisms are not well understood, particularly the extent to which this relationship is mediated by sex hormones. We analyzed data (1999-2017) on 1,120 premenopausal women from the Study of Women's Health Across the Nation (SWAN). Causal mediation analysis was applied to quantify the degree to which follicle-stimulating hormone (FSH) and estradiol levels could mediate the associations between PFAS and incident natural menopause. Participants with higher PFAS concentrations had shorter times to natural menopause, with a relative survival of 0.82 (95% confidence interval (CI): 0.69, 0.96) for linear perfluorooctane sulfonate (n-PFOS), 0.84 (95% CI: 0.69, 1.00) for sum of branched-chain perfluorooctane sulfonate (Sm-PFOS), 0.79 (95% CI: 0.66, 0.93) for linear-chain perfluorooctanoate (n-PFOA), and 0.84 (95% CI: 0.71, 0.97) for perfluorononanoate (PFNA), comparing the highest tertile of PFAS concentrations with the lowest. The proportion of the effect mediated through FSH was 8.5% (95% CI: -11.7, 24.0) for n-PFOS, 13.2% (95% CI: 0.0, 24.5) for Sm-PFOS, 26.9% (95% CI: 15.6, 38.4) for n-PFOA, and 21.7% (6.8, 37.0) for PFNA. No significant mediation by estradiol was observed. The effect of PFAS on natural menopause may be partially explained by variations in FSH concentrations.

C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial.

PURPOSE: The complement pathway may play a key role in the pathogenesis of age-related macular degeneration (AMD). The safety and efficacy of avacincaptad pegol (Zimura, IVERIC bio Inc, New York, NY), a C5 inhibitor, were assessed in participants with geographic atrophy (GA) secondary to AMD (GATHER1 Study). DESIGN: International, prospective, randomized, double-masked, sham-controlled, pivotal phase 2/3 clinical trial. PARTICIPANTS: A total of 286 participants with GA secondary to AMD. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the mean rate of change in GA over 12 months measured by fundus autofluorescence (FAF) at 3 timepoints: baseline, month 6, and month 12. RESULTS: The reduction in the mean rate of GA growth (square root transformation) over 12 months was 27.4% (P = 0.0072) for the avacincaptad pegol 2 mg cohort and 27.8% (P = 0.0051) for the avacincaptad pegol 4 mg cohort compared with their corresponding sham cohorts. The results for both dose groups were statistically significant. Avacincaptad pegol was generally well tolerated after monthly administration over 12 months. There were no avacincaptad pegol-related adverse events (AEs) or inflammation. Further, there were no ocular serious AEs (SAEs) and no cases of endophthalmitis. The most frequent ocular AEs were related to the injection procedure. CONCLUSIONS: Intravitreal administration of avacincaptad pegol 2 mg and 4 mg led to a significant reduction of GA growth in eyes with AMD over a 12-month period. Because C5 inhibition theoretically preserves C3 activity, it may offer additional safety advantages. A second confirmatory pivotal clinical trial is underway to confirm the efficacy and safety of avacincaptad pegol in slowing the GA growth (GATHER2 Study).

Discovery of 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs for delivering nucleoside HCV NS5B polymerase inhibitors.

Our HCV research program investigated novel 2'-dihalogenated nucleoside HCV polymerase inhibitors and identified compound 1, a 5'-phosphoramidate prodrug of 2'-deoxy-2'-α-bromo-ß-chloro uridine. Although 1 had a favorable in vitro activity profile in HCV replicons, oral dosing in dog resulted in low levels of the active 5'-triphosphate (TP) in liver. Metabolism studies using human hepatocytes provided a simple assay for screening alternative phosphoramidate prodrug analogs. Compounds that produced high TP concentrations in hepatocytes were tested in dog liver biopsy studies. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrug 14, which provided 100-fold higher TP concentrations in dog liver in comparison to 1 (4 and 24 h after 5 mg/kg oral dose).

Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.

Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.

Gender-Affirming Hormone Therapy for Transgender Females.

The provision of hormone therapy, both estrogens and antiandrogens, to adult transgender females is well within the scope of practice of the obstetrician gynecologist. The goal is to induce feminizing changes and suppress previously developed masculinization. Estrogens in sufficient doses will usually achieve both goals with augmentation by antiandrogens. The primary short-term risk of estrogens is thrombosis, but long-term risk in transgender females is unclear. Optimal care requires pretreatment education and assessment, individualized dosing, ongoing routine monitoring, and standard breast and prostate cancer screening.

Role for OBGYNs in Gender-Affirming Surgical Care of Transgender and Gender Nonconforming Individuals.

Many transgender and gender nonconforming individuals have undergone, or plan to pursue, gender-affirming surgery as part of their transition. While not all gender-affirming surgeries are provided by Obstetricians and Gynecologists (OBGYNs), OBGYNs are uniquely skilled to perform certain gender-affirming surgeries such as hysterectomies, bilateral oophorectomies, and vaginectomies. OBGYNs are also well positioned to provide anatomy-specific cancer screening as dictated by patient's hormonal and surgical status, and to address postsurgical or natal vulvovaginal concerns.

In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir.

Pibrentasvir (ABT-530) is a novel and pan-genotypic hepatitis C virus (HCV) NS5A inhibitor with 50% effective concentration (EC50) values ranging from 1.4 to 5.0 pM against HCV replicons containing NS5A from genotypes 1 to 6. Pibrentasvir demonstrated similar activity against a panel of chimeric replicons containing HCV NS5A of genotypes 1 to 6 from clinical samples. Resistance selection studies were conducted using HCV replicon cells with NS5A from genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a, or 6a at a concentration of pibrentasvir that was 10- or 100-fold over its EC50 for the respective replicon. With pibrentasvir at 10-fold over the respective EC50, only a small number of colonies (0.00015 to 0.0065% of input cells) with resistance-associated amino acid substitutions were selected in replicons containing genotype 1a, 2a, or 3a NS5A, and no viable colonies were selected in replicons containing NS5A from other genotypes. With pibrentasvir at 100-fold over the respective EC50, very few colonies (0.0002% of input cells) were selected by pibrentasvir in genotype 1a replicon cells while no colonies were selected in other replicons. Pibrentasvir is active against common resistance-conferring substitutions in HCV genotypes 1 to 6 that were identified for other NS5A inhibitors, including those at key amino acid positions 28, 30, 31, or 93. The combination of pibrentasvir with HCV inhibitors of other classes produced synergistic inhibition of HCV replication. In summary, pibrentasvir is a next-generation HCV NS5A inhibitor with potent and pan-genotypic activity, and it maintains activity against common amino acid substitutions of HCV genotypes 1 to 6 that are known to confer resistance to currently approved NS5A inhibitors.

Discovery of fluorobenzimidazole HCV NS5A inhibitors.

Research toward a next-generation HCV NS5A inhibitor has identified fluorobenzimidazole analogs that demonstrate potent, broad-genotype in vitro activity against HCV genotypes 1-6 replicons as well as HCV NS5A variants that are orders of magnitude less susceptible to inhibition by first-generation NS5A inhibitors in comparison to wild-type replicons. The fluorobenzimidazole inhibitors have improved pharmacokinetic properties in comparison to non-fluorinated benzimidazole analogs. Discovery of these inhibitors was facilitated by exploring SAR in a structurally simplified inhibitor series.

Longitudinal analysis of the structural pattern of pseudophakic cystoid macular edema using multimodal imaging.

PURPOSE: To describe the relationship between pseudophakic cystoid macular edema (CME) progression and retinal structural changes observed by spectral-domain optical coherence tomography (SD-OCT) and fluorescein angiography. METHODS: Retrospective, consecutive, longitudinal imaging analysis of patients with acute pseudophakic cystoid macular edema. Two observers at two study centers evaluated all images and categorized the macular structural features based on the retinal layer involved with cystic changes and/or subretinal fluid. A time series of the structural pattern and visual acuity was constructed for 1-month intervals over a 6-month study period. RESULTS: Thirty nine patients presented with CME. The mean time since cataract extraction was 48 ±38 days (range 5-71). CME included inner nuclear layer (INL) cystic changes, outer plexiform layer (OPL) cystic changes, and subretinal fluid. Isolated INL changes were observed in four phakic fellow eyes. Isolated OPL morphology was not observed, and additional inner layers remained uninvolved. Resolution occurred rapidly following administration of periocular glucocorticoids, and typically demonstrated a reverse structural pattern or delayed subretinal fluid resolution. Isolated subretinal fluid or a combined INL and subretinal fluid structure indicated CME resolution. CONCLUSION: Acute and recurrent pseudophakic CME involves a directional progression of the retinal layer involved with cystic changes and a clinical course. CME begins with INL cystic changes, progresses to combined INL and OPL morphology, and may continue to involve subretinal fluid. The inner nuclear layer is the most frequently involved layer, and isolated INL cysts may occur in phakic fellow eyes. A three-layer structure, the presence of OPL morphology, or isolated INL early in the postoperative period indicates disease activity.

25-gauge pars plana vitrectomy with medium-term postoperative perfluoro-n-octane for the repair of giant retinal tears.

PURPOSE: The purpose of this study was to describe the treatment of giant retinal tears (GRTs) with 25-gauge pars plana vitrectomy (PPV) and medium-term postoperative perfluoro-n-octane (MT-PFO). METHODS: The study was a retrospective interventional case series of consecutive patients with GRTs treated with 25-gauge PPV and postoperative MT-PFO for a period of 2-3 weeks. A second, staged procedure was performed in all patients for PFO removal. RESULTS: Twenty-three eyes of 22 patients were studied, with a mean follow-up of 33.04 ± 19.74 months. Successful reattachment was achieved in 91.3 % of eyes (21/23) after MT-PFO. Retinal re-detachment occurred in five eyes, which was caused by proliferative vitreoretinopathy. Additional complications included cataract progression (n = 10), foreign body response (30.4 %, 7/23), and transient intraocular pressure (IOP) elevation (8/23, 34.8 %). Transient IOP elevation was associated with worse visual outcome (p = 0.01). CONCLUSIONS: MT-PFO was found to be an effective and safe technique for operative management of GRTs. In the majority of patients, retinas remained attached without further surgical intervention. Cataract progression, intraocular inflammation, and associated increased intraocular pressure are potential complications of MT-PFO.

Updated assays for inhibin B and AMH provide evidence for regular episodic secretion of inhibin B but not AMH in the follicular phase of the normal menstrual cycle.

STUDY QUESTION: What is the daily variation in serum inhibin B (InhB) and anti-Müllerian hormone (AMH) in relation to the LH surge in women of reproductive age. SUMMARY ANSWER: AMH is secreted in a biphasic follicular/luteal pattern in women with higher AMH secretion, while InhB secretion is episodic in the early to mid-follicular phase and immediately after the LH surge but not in the luteal phase. WHAT IS KNOWN ALREADY: In women of reproductive age with a mean serum AMH >1 ng/ml, levels are highest in Days 2-7 of the cycle. InhB concentrations are highest in the follicular phase of the cycle. STUDY DESIGN, SIZE, DURATION: In this cohort study conducted in an academic center, blood samples were collected daily from 20 women during one normal menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Regularly menstruating 30- to 40-year-old women had daily serum InhB, AMH, LH and FSH levels measured. Intracycle variability of InhB and AMH were assessed after aligning to the LH surge. MAIN RESULTS AND THE ROLE OF CHANCE: When classified into quartiles of AMH concentration, the lowest AMH levels did not vary across the cycle; the highest AMH levels showed a mid-follicular increase, mid-cycle decrease and mid-luteal increase. A surge of InhB was noted following the LH surge in 16/20 cycles. Episodic increases in InhB occurred in 17/20 cycles prior to the LH surge. In the luteal phase, InhB decreased or became undetectable and did not demonstrate episodic secretion. Old and new assays for AMH and InhB were compared in all samples, with the AMH assays demonstrating good correlation (Rsq = 0.9625) but the InhB assays showing less correlation (Rsq = 0.4903). LIMITATIONS, REASONS FOR CAUTION: The study population is small and in the mid-to-late reproductive age group. Single daily sampling may not detect more frequent variability (i.e. pulses) in hormone levels. WIDER IMPLICATIONS OF THE FINDINGS: These data suggest different regulatory mechanisms for InhB and AMH secretion, and confirm an 'aging ovary' pattern of AMH and InhB secretion, which is consistent with decreased ovarian reserve. We also demonstrated comparability of the AMH Gen II assay with the previous version in standard usage but our data raised concerns about comparability of the InhB Gen II assay. STUDY FUNDING/COMPETING INTEREST(S): General Clinical Research Center for phlebotomy work has been supported in part by NIH grant UL1RR024986. Recruitment and data analyses were supported by the Center for Integrated Approaches to Complex Diseases (SD Harlow, Director). The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Foreign body response within postoperative perfluoro-N-octane for retinal detachment repair: clinical features, grading system, and histopathology.

PURPOSE: To describe the clinical and histopathologic characteristics of inflammatory deposits occurring within intermediate duration postoperative perfluoro-n-octane (PFO) for inferior retinal detachment repair. METHODS: Prospective interventional case series of consecutive patients with inferior retinal detachment treated with intermediate duration postoperative vitreous cavity PFO endotamponade were analyzed by ophthalmoscopy for the presence of inflammation and white deposits. Ten consecutive samples developing white deposits were analyzed microscopically. Clinical variables were analyzed. RESULTS: One hundred and eighty-one eyes of 181 patients were included (mean age = 52.4 ± 14 years; mean follow-up = 29.7 ± 14 months). Fifty of 181 patients (28%) developed a characteristic foreign body response with abundant white deposits within indwelling PFO. Ten consecutive samples analyzed histologically contained abundant macrophages, the absence of additional inflammatory cells, and intracytoplasmic optically lucent inclusions. Foreign body response was associated with longer duration of PFO (P = 0.003). Perfluoro-n-octane foreign body response was not associated with age (P = 0.136), ethnicity (P = 0.101), visual outcome (P = 0.157), or persistent intraocular pressure elevation (P = 0.381). CONCLUSION: A stereotypical foreign body response occurs in ∼ 30% of patients with postoperative vitreous cavity PFO and becomes clinically apparent at 7 days to 10 days after initial placement for rhegmatogenous retinal detachment repair. The response consists almost exclusively of macrophages and does not seem to be related to either long-term intraocular pressure elevation or visual outcome. The response may be related to the duration of indwelling PFO and may limit visualization of the retina during PFO removal.

Comparison of morphologic features of macular proliferative vitreoretinopathy and idiopathic epimacular membrane.

BACKGROUND: To compare the spectral-domain optical coherence tomography morphologic features and visual characteristics of a series of patients with epimacular membrane with and without a history of retinal breaks. METHODS: Prospective, comparative case series of patients with epimacular membrane. All patients were evaluated with spectral-domain optical coherence tomography and detailed peripheral retinal examination. Symptomatic patients were treated with pars plana vitrectomy and epimacular membrane removal based on standard visual criteria. RESULTS: Macular proliferative vitreoretinopathy was present in 21 of 50 patients (42%). Approximately 18 of 21 patients had a previous retinal break, 5 of which were untreated before the initial examination. No retinal breaks were observed in the idiopathic group. Macular proliferative vitreoretinopathy was highly associated with a history of retinal breaks (P < 0.001). Presenting visual acuity was significantly worse (mean, 0.86 ± 0.44) for macular proliferative vitreoretinopathy than for the idiopathic group (mean, 0.44 ± 0.36). CONCLUSION: Epimacular membrane occurring in the context of previous retinal breaks or macular proliferative vitreoretinopathy has a characteristic morphologic feature in spectral-domain optical coherence tomography. Surgical removal typically results in significant visual improvement.

Anatomical and visual outcomes after two-port pars plana vitrectomy reoperation under silicone oil for epimacular membrane or recurrent retinal detachment.

PURPOSE: To describe the anatomical and visual outcomes in a series of patients undergoing two-port pars plana vitrectomy reoperation under silicone oil for recurrent retinal detachment (RD) due to proliferative vitreoretinopathy or epimacular membrane (EMM) after RD repair. METHODS: This study is a prospective, consecutive, interventional case series of patients presenting with recurrent RD or EMM under silicone oil. Two-port 25-gauge pars plana vitrectomy reoperation without an infusion port was performed in all cases. RESULTS: Thirty-nine patients were included. Reoperation pathology included recurrent RD with proliferative vitreoretinopathy (n = 33) and EMM alone (n = 6). The mean number of previous retinal surgeries was 2.4 ± 1.1 (range, 1-5). The mean overall follow-up was 24 ± 3.7 months. The mean visual acuity change from baseline at final follow-up was an improvement of 0.74 ± 0.63. Macular reattachment was achieved in 29 of 33 patients with RD, and EMMs were successfully removed in all patients. CONCLUSION: Two-port pars plana vitrectomy reoperation is an efficacious method for repair of consecutive RD due to proliferative vitreoretinopathy or EMM in patients with previous RD repair with silicone oil. Significant visual improvement with a low complication rate may be achieved in patients with advanced proliferative vitreoretinopathy or EMM under silicone oil.

Grandmothers' smoking in pregnancy and grandchildren's birth weight: comparisons by grandmother birth cohort.

This study examined whether grandmothers' smoking behavior during pregnancy was associated with birth weights in their grandchildren, considering possible birth cohort effects in the grandmothers' generation. The birth weights of 935 singleton children were compared by grandmothers' and mothers' smoking status during pregnancy. In 2008, women (n = 397) from the Michigan Bone Health and Metabolism Study were interviewed about their own birth history, including whether their own mother smoked while pregnant with them, and the birth histories of their offspring. While also accounting for family clustering, linear mixed models were used to evaluate whether birth weight differences in the grandchildren were associated with grandmothers' and mothers' smoking behavior during pregnancy. Associations were compared among grandmothers born from 1904 to 1928 versus grandmothers born from 1929 to 1945 to determine potential birth cohort effects. Forty-six (5 %) grandchildren had grandmothers and mothers who smoked while pregnant, while 455 (49 %) had grandmothers and mothers who did not smoke during pregnancy. After adjustment, birth weight was an average of 346 (95 % confidence interval 64-628) grams higher in grandchildren whose grandmother and mother both smoked during pregnancy relative to grandchildren whose grandmother and mother both did not smoke during pregnancy, but only among grandmothers who were born from 1929 to 1945. For grandmothers born from 1904 to 1928, grandchildren birth weights did not differ by grandmother and mother smoking status. Birth weight may be associated with grandmother and mother smoking behaviors during pregnancy, but birth cohort effects should be considered.

Impacts of management practices on habitat selection during juvenile mountain lion dispersal.

Dispersal is a complex series of movements before an individual establishes a home range. Animals must travel and forage in unfamiliar landscapes that include anthropogenic risks such as road crossings, harvest, and urban landscapes. We compare dispersal behavior of juvenile mountain lions (Puma concolor) from two geographically distinct populations in California and Nevada, USA. These two sites are ecologically similar but have different management practices; hunting is permitted in Nevada, whereas mountain lions are protected in California. We used GPS-collar data and net-squared displacement analysis to identify three dispersal states: exploratory, departure, and transient home range. We then compared each dispersal state of the two mountain lion populations using an integrated step selection analysis (iSSA). The model included explanatory variables hypothesized to influence one or more dispersal states, including distance to forest, shrub, water, hay and crop, developed lands, and four-wheel drive roads, as well as elevation and terrain ruggedness. Results revealed consistent habitat selection between sites across most landscape variables, with one notable exception: anthropogenic covariates, including distance to developed land, distance to hay and crop, and distance to four-wheeled drive roads, were only statistically significant on modeled habitat selection during dispersal in the population subject to hunting (i.e., Nevada). Results suggest that hunting (pursuit with hounds resulting in harvest) and non-lethal pursuit (pursuit with hounds but no harvest allowed) increase avoidance of anthropogenic landscapes during dispersal for juvenile mountain lions. By comparing populations, we provided valuable insights into the role of management in shaping dispersal behavior.

Heavy Metals and Trajectories of Anti-Müllerian Hormone During the Menopausal Transition.

BACKGROUND: Experimental and epidemiological studies have linked metals with women's reproductive aging, but the mechanisms are not well understood. Disrupted ovarian folliculogenesis and diminished ovarian reserve could be a pathway through which metals impact reproductive hormones and outcomes. OBJECTIVE: The study aimed to evaluate the associations of heavy metals with anti-Müllerian hormone (AMH), a marker of ovarian reserve. METHODS: The study included 549 women from the Study of Women's Health Across the Nation with 2252 repeated AMH measurements from 10 to 0 years before the final menstrual period (FMP). Serum AMH concentrations were measured using picoAMH ELISA. Urinary concentrations of arsenic, cadmium, mercury, and lead were measured using high-resolution inductively coupled plasma mass spectrometry. Multivariable linear mixed regressions modeled AMH as a function of time before the FMP interaction terms between metals and time to the FMP were also included. RESULTS: Adjusting for confounders, compared with those in the lowest tertile, women in the highest tertile of urinary arsenic or mercury concentrations had lower AMH concentrations at the FMP (percent change: -32.1%; 95% CI, -52.9 to -2.2, P-trend = .03 for arsenic; percent change: -40.7%; 95% CI, -58.9 to -14.5, P-trend = .005 for mercury). Higher cadmium and mercury were also associated with accelerated rates of decline in AMH over time (percent change per year: -9.0%; 95% CI, -15.5 to -1.9, P-trend = .01 for cadmium; -7.3%; 95% CI, -14.0 to -0.1, P-trend = .04 for mercury). CONCLUSION: Heavy metals including arsenic, cadmium, and mercury may act as ovarian toxicants by diminishing ovarian reserve in women approaching the FMP.

Integrating Lifestyle Factor Science into Neuropsychological Practice: A National Academy of Neuropsychology Education Paper.

OBJECTIVE: The primary aim of this paper is to review evidence and clinical implications related to lifestyle activities associated with promoting brain and cognitive health. Our review targets four key lifestyle factors: physical activity and exercise, social engagement, cognitively stimulating activity, and consuming Mediterranean-style diets. METHOD: We conducted a critical review of the lifestyle factor literature in the four domains listed earlier. We contextualize this literature review by translating findings, when possible, into evidence-based recommendations to consider when providing neuropsychological services. RESULTS: There is significant current evidence supporting the role of physical activity and exercise, social engagement, cognitively stimulating activity, and consuming Mediterranean-style diets on positive brain and cognitive health outcomes. While some null findings are present in all four areas reviewed, the weight of the evidence supports the notion that engaging in these activities may promote brain and cognitive functioning. CONCLUSIONS: Clinical neuropsychologists can have confidence in recommending engagement in physical activity, social activity, and cognitively stimulating activity, and adhering to a Mediterranean-style diet to promote brain and cognitive health. We discuss limitations in existing lifestyle factor research and future directions to enhance the existing evidence base, including additional research with historically underrepresented groups and individuals with neurological conditions.