Public Priorities in Women's Health: Analysis of Request for Information Published to Inform "Advancing NIH Research on the Health of Women: A 2021 Conference".

Objectives: To assist with planning a congressionally requested conference on women's health research, the National Institutes of Health (NIH) Office of Research on Women's Health (ORWH) invited comments to characterize public concerns related to any or all of the specified public health issues: maternal morbidity and mortality (MMM); stagnant rates of cervical cancer survival; and the growing incidence of chronic debilitating conditions in women (CDCW). This analysis summarizes public priorities in women's health research. Materials and Methods: All comments received in response to a request for information were open coded and a master list of keywords was created, and comments were categorized. Comments addressing CDCW were categorized using a conceptual framework developed by the NIH. Results: Two hundred forty-seven comments were coded and analyzed. One hundred four comments (42%) addressed MMM; 182 comments (73%) discussed CDCW; and 27 comments (10%) addressed cervical cancer. Comments focused on CDCW most frequently addressed female-specific conditions (83%). The 10 most frequently identified keywords in order of frequency from the manual coding were as follows: (1) MMM, (2) racial disparities, (3) access to care, (4) provider training, (5) mental health, (6) Black or African American women, (7) screening, (8) quality of care, (9) time to diagnosis, and (10) social determinants of health. Conclusions: Comments demonstrate a broad range of concerns related to the health of women, including MMM, CDCW, and cervical cancer. A wide array of commenters included patients, advocacy groups, and academic and professional organizations originating from geographically diverse locations. These comments reflect a strong desire from the public to prioritize research on the health of women.

Multicenter prospective validation study for international chronic ocular graft-versus-host disease consensus diagnostic criteria.

PURPOSE: To validate the international chronic ocular graft-versus-host disease (GVHD) diagnostic criteria (ICCGVHD) compared to the National Institute of Health diagnostic criteria 2014 (NIH2014) for chronic ocular GVHD. METHODS: Between 2013 and 2019, the study enrolled 233 patients with or without chronic ocular GVHD combined with the presence or absence of systemic chronic GVHD in an internationally prospective multicenter and observational cohort from 9 institutions. All patients were evaluated for four clinical parameters of ICCGVHD. RESULTS: The relation between the ICCGVHD score (0-11) and NIH2014 eye score (0-4) was relatively high (r = 0.708, 95% CI: 0.637-0.767, p < 0.001). The sensitivity and specificity of ICCGVHD for NIH 2014 for 233 patients were 94.3% (95% CI: 89.6%-98.1%) and 71.7% (95% CI: 63.0-79.5%), respectively (cutoff value of the ICCGVHD score = 6). The positive predictive value was 77.1% (95% CI: 71.1%-82.1%), and the negative predictive value was 87.0% (95% CI:81.6-92.5%). For the patients with systemic GVHD (n = 171), the sensitivity and specificity were 94.2% and 67.2%, respectively (ICCGVHD-score cutoff value = 6). By receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.903 (95% CI: 0.859-0.948). For patients without systemic GVHD (n = 62), the sensitivity and specificity were 100% and 76.7%, respectively (ICCGVHD-score cutoff value = 6). The AUC was 0.891 (95% CI 0.673-1.000). CONCLUSIONS: Good sensitivity, specificity, predictive value and correlation were found between ICCGVHD and NIH2014. ICCGVHD scores ≥6 can be useful to diagnose ocular GVHD with or without systemic GVHD for clinical research.

Perspectives From Advancing National Institutes of Health Research to Inform and Improve the Health of Women: A Conference Summary.

The health of women remains understudied. In response to a request from Congress, the Office of Research on Women's Health of the National Institutes of Health (NIH) evaluated research on the health of women currently underway related to 1) rising rates of maternal morbidity and mortality, 2) rising rates of chronic debilitating conditions in women, and 3) stagnant cervical cancer survival rates. Input on the three priority areas was obtained from experts in women's health, members of the public, and federal stakeholders. The NIH research portfolios on these three topics were reviewed. On October 20, 2021, a conference on advancing NIH research on women's health was held to present, discuss, and delineate gaps and opportunities in the current portfolio. Across the life course, significant gaps in evidence regarding conditions, disorders, and diseases that occur in women were illustrated. Fundamental basic and translational knowledge gaps in many female-specific conditions and diseases with sex-specific presentations, symptoms, or responses to treatments have hampered the generation of robust scientific data needed to provide high-quality, evidence-based care to women. Key opportunities identified to improve the health of women include enhanced implementation of existing best practices and interventions to reduce disparities. Undertaking intentional clinical research on the health of women will produce significant returns on investment and has the potential to greatly improve human health.

Female Sex and Gender in Lung/Sleep Health and Disease. Increased Understanding of Basic Biological, Pathophysiological, and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease.

Female sex/gender is an undercharacterized variable in studies related to lung development and disease. Notwithstanding, many aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. These may manifest as differential gene expression or peculiar organ development. Some conditions are more prevalent in women, such as asthma and insomnia, or, in the case of lymphangioleiomyomatosis, are seen almost exclusively in women. In other diseases, presentation differs, such as the higher frequency of exacerbations experienced by women with chronic obstructive pulmonary disease or greater cardiac morbidity among women with sleep-disordered breathing. Recent advances in -omics and behavioral science provide an opportunity to specifically address sex-based differences and explore research needs and opportunities that will elucidate biochemical pathways, thus enabling more targeted/personalized therapies. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the NIH Office of Research on Women's Health and the Office of Rare Diseases Research, convened a workshop of investigators in Bethesda, Maryland on September 18 and 19, 2017. At the workshop, the participants reviewed the current understanding of the biological, behavioral, and clinical implications of female sex and gender on lung and sleep health and disease, and formulated recommendations that address research gaps, with a view to achieving better health outcomes through more precise management of female patients with nonneoplastic lung disease. This report summarizes those discussions.

Taking cardiology clinical trials to the next level: A call to action.

Physicians previously perceived heart disease to be a man's disease; yet, since 1984, more women have died of ischemic heart disease. Because women who develop obstructive coronary heart disease and heart failure tend to do so 10 years later than men, cardiology clinical trials that use arbitrary age cutoffs or exclusion criteria based on comorbidities and polypharmacy often limit the pool of potential participants to a greater extent for women. Issues related to trial design and insufficient accounting for female-predominant disease patterns have contributed to low rates of enrollment of women in certain domains of cardiology research. Accordingly, women do not benefit from as rich an evidence base for cardiology as men. Here, we review major sex differences in heart disease and discuss areas of cardiology research in which women have been underrepresented. Considering the widespread sex differences in cardiovascular structure and function, it is important to include balanced numbers of women and men in cardiovascular clinical trials. Beyond inclusion, sex-specific reporting is also essential. Moreover, with ongoing developments of clinical-trial methodology, it is imperative to seek innovative ways to learn as much as possible about how interventions behave in women and men. Adaptive trials are specifically identified as promising opportunities to consider sex-based analyses at interim stages, allowing sex-specific flexibility as these trials unfold. Finally, we emphasize the importance of factoring sex as a biological variable into the design, analysis, and reporting of preclinical research, because this research critically informs the design and execution of clinical trials.

TFOS DEWS II Sex, Gender, and Hormones Report.

One of the most compelling features of dry eye disease (DED) is that it occurs more frequently in women than men. In fact, the female sex is a significant risk factor for the development of DED. This sex-related difference in DED prevalence is attributed in large part to the effects of sex steroids (e.g. androgens, estrogens), hypothalamic-pituitary hormones, glucocorticoids, insulin, insulin-like growth factor 1 and thyroid hormones, as well as to the sex chromosome complement, sex-specific autosomal factors and epigenetics (e.g. microRNAs). In addition to sex, gender also appears to be a risk factor for DED. "Gender" and "sex" are words that are often used interchangeably, but they have distinct meanings. "Gender" refers to a person's self-representation as a man or woman, whereas "sex" distinguishes males and females based on their biological characteristics. Both gender and sex affect DED risk, presentation of the disease, immune responses, pain, care-seeking behaviors, service utilization, and myriad other facets of eye health. Overall, sex, gender and hormones play a major role in the regulation of ocular surface and adnexal tissues, and in the difference in DED prevalence between women and men. The purpose of this Subcommittee report is to review and critique the nature of this role, as well as to recommend areas for future research to advance our understanding of the interrelationships between sex, gender, hormones and DED.

A Report of the Women's Health Congress Workshop on The Health of Women of Color: A Critical Intersection at the Corner of Sex/Gender and Race/Ethnicity.

Women of color face unique health challenges that differ significantly from those of other women and men of color. To bring these issues to light, the National Institutes of Health (NIH) Office of Research on Women's Health sponsored a preconference workshop at the 23rd Annual Women's Health Congress, which was held in Washington, DC, in April 2015. The workshop featured presentations by NIH intramural and extramural scientists who provided insight on the disparities of a wide range of conditions, including cancer, cardiovascular disease, the risk of HIV infection, and disability in an aging population. In this study, we highlight the major points of each presentation and the ensuing discussion.

International Chronic Ocular Graft-vs-Host-Disease (GVHD) Consensus Group: proposed diagnostic criteria for chronic GVHD (Part I).

The International Chronic Ocular GVHD Consensus Group held 4 working meetings to define new diagnostic metrics for chronic ocular graft-versus-host disease (GVHD). After considering the factors currently used to diagnose chronic ocular GVHD, the Consensus Group identified 4 subjective and objective variables to measure in patients following allogeneic hematopoietic stem cell transplantation (HSCT): OSDI, Schirmer's score without anesthesia, corneal staining, and conjunctival injection. Each variable was scored 0-2 or 0-3, with a maximum composite score of 11. Consideration was also given to the presence or the absence of systemic GVHD. On the basis of their composite score and the presence or absence of systemic GVHD, patients were assigned to one of three diagnostic categories: NO, PROBABLE, or DEFINITE ocular GVHD. New diagnostic criteria for chronic ocular GVHD are presented by the Consensus Group. Validation studies are needed to identify the best combination of the proposed metrics to maximize diagnostic sensitivity and specificity.

Web-based versus paper administration of common ophthalmic questionnaires: comparison of subscale scores.

OBJECTIVE: To compare participants' responses to Web-based and paper-and-pencil versions of an ophthalmic, patient-reported outcome (PRO) questionnaire. DESIGN: Questionnaire development. PARTICIPANTS: Matched subjects with ocular surface disease (OSD) (n = 68) and without OSD (controls, n = 50). METHODS: Subjects completed a standard, paper-and-pencil and a Web-based version of the same questionnaire in randomized order. The administered questionnaire included several ophthalmic PRO subscales: the National Eye Institute's (NEI's) Refractive Error Quality of Life Instrument's Clarity of Vision, Near Vision, Far Vision, Glare, Symptoms, Worry, and Satisfaction with Correction subscales; the Ocular Surface Disease Index's (OSDI's) Symptoms subscale; and the NEI's Visual Function Questionnaire's Driving subscale. Possible scores for each subscale ranged from 0 (no difficulty) to 100 (most difficulty). Agreement of subscale scores between modes of administration was assessed using the Bland-Altman approach and multivariable logistic regression. MAIN OUTCOME MEASURES: Subscale scores and an unweighted average total score for each mode of administration. RESULTS: Mean differences in scores between modes of administration ranged from -2.1 to +2.3 units. Although no differences were found to be statistically significant, the Worry and Satisfaction with Correction subscales approached statistical significance (P = 0.07 and 0.08, respectively). Although most subscale mean differences in score did not differ significantly by gender, age (≥40 vs. <40 years), disease status (OSD vs. control), order of administration, or time between completion of the questionnaires, women had slightly greater score differences than men for the Driving (P = 0.04) and Clarity of Vision (P = 0.03) subscales; those with OSD had greater score differences for Clarity of Vision than did controls (P = 0.0006); and those aged ≥40 years had slightly greater differences in OSDI Symptoms subscale than those aged <40 years (P = 0.04). CONCLUSIONS: To our knowledge, this Food and Drug Administration and NEI collaboration is the first study to evaluate the equivalence of Web-based and paper versions of ophthalmic PRO questionnaires. We found no evidence of clinically significant differences between scores obtained by the 2 modes for any of the examined subscales. A Web-based instrument should yield scores equivalent to those obtained by standard methods, providing a useful tool that may facilitate ophthalmic innovation. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Ocular manifestations of xeroderma pigmentosum: long-term follow-up highlights the role of DNA repair in protection from sun damage.

OBJECTIVE: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations in DNA repair genes. Clinical manifestations of XP include mild to extreme sensitivity to ultraviolet radiation resulting in inflammation and neoplasia in sun-exposed areas of the skin, mucous membranes, and ocular surfaces. This report describes the ocular manifestations of XP in patients systematically evaluated in the Clinical Center at the National Institutes of Health. DESIGN: Retrospective observational case series. PARTICIPANTS: Eighty-seven participants, aged 1.3 to 63.4 years, referred to the National Eye Institute (NEI) for examination from 1964 to 2011. Eighty-three patients had XP, 3 patients had XP/Cockayne syndrome complex, and 1 patient had XP/trichothiodystrophy complex. METHODS: Complete age- and developmental stage-appropriate ophthalmic examination. MAIN OUTCOME MEASURES: Visual acuity; eyelid, ocular surface, and lens pathology; tear film and tear production measures; and cytologic analysis of conjunctival surface swabs. RESULTS: Of the 87 patients, 91% had at least 1 ocular abnormality. The most common abnormalities were conjunctivitis (51%), corneal neovascularization (44%), dry eye (38%), corneal scarring (26%), ectropion (25%), blepharitis (23%), conjunctival melanosis (20%), and cataracts (14%). Thirteen percent of patients had some degree of visual axis impingement, and 5% of patients had no light perception in 1 or both eyes. Ocular surface cancer or a history of ocular surface cancer was present in 10% of patients. Patients with an acute sunburning skin phenotype were less likely to develop conjunctival melanosis and ectropion but more likely to develop neoplastic ocular surface lesions than nonburning patients. Some patients also showed signs of limbal stem cell deficiency. CONCLUSIONS: Our longitudinal study reports the ocular status of the largest group of patients with XP systematically examined at 1 facility over an extended period of time. Structural eyelid abnormalities, neoplasms of the ocular surface and eyelids, tear film and tear production abnormalities, ocular surface disease and inflammation, and corneal abnormalities were present in this population. Burning and nonburning patients with XP exhibit different rates of important ophthalmologic findings, including neoplasia. In addition, ophthalmic characteristics can help refine diagnoses in the case of XP complex phenotypes. DNA repair plays a major role in protection of the eye from sunlight-induced damage.

Ocular manifestations of trichothiodystrophy.

OBJECTIVE: Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and multisystem abnormalities. Many TTD patients have a defect in known DNA repair genes. This report systematically evaluates the ocular manifestations of the largest-to-date cohort of TTD patients and xeroderma pigmentosum (XP)/TTD patients. DESIGN: Case series. PARTICIPANTS: Thirty-two participants, ages 1 to 30 years, referred to the National Eye Institute for examination from 2001 to 2010; 25 had TTD and 7 had XP/TTD. METHODS: Complete, age- and developmental stage-appropriate ophthalmic examination. MAIN OUTCOME MEASURES: Visual acuity (VA), best-corrected VA, ocular motility, state of the ocular surface and corneal endothelial cell density, corneal diameter, and lens assessment. RESULTS: Developmental abnormalities included microcornea (44% TTD), microphthalmia (8% TTD, 14% XP/TTD), nystagmus (40% TTD), and infantile cataracts (56% TTD, 86% XP/TTD). Corrective lenses were required by 65% of the participants, and decreased best-corrected VA was present in 28% of TTD patients and 71% of XP/TTD patients. Degenerative changes included dry eye (32% TTD, 57% XP/TTD) and ocular surface disease identified by ocular surface staining with fluorescein (32% TTD) that usually are exhibited by much older patients in the general population. The 2 oldest TTD patients exhibited clinical signs of retinal/macular degeneration. Four XP/TTD patients presented with corneal neovascularization. CONCLUSIONS: These TTD and XP/TTD study participants had a wide variety of ocular findings including refractive error, infantile cataracts, microcornea, nystagmus, and dry eye/ocular surface disease. Although many of these can be ascribed to abnormal development--likely owing to abnormalities in basal transcription of critical genes--patients may also have a degenerative course. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosures may be found after the references.

A multicenter pilot evaluation of the National Institutes of Health chronic graft-versus-host disease (cGVHD) therapeutic response measures: feasibility, interrater reliability, and minimum detectable change.

The lack of standardized criteria for measuring therapeutic response is a major obstacle to the development of new therapeutic agents for chronic graft-versus-host disease (cGVHD). National Institutes of Health (NIH) consensus criteria for evaluating therapeutic response were published in 2006. We report the results of 4 consecutive pilot trials evaluating the feasibility and estimating the interrater reliability and minimum detectable change of these response criteria. Hematology-oncology clinicians with limited experience in applying the NIH cGVHD response criteria (n = 34) participated in a 2.5-hour training session on response evaluation in cGVHD. Feasibility and interrater reliability between subspecialty cGVHD experts and this panel of clinician raters were examined in a sample of 25 children and adults with cGVHD. The minimum detectable change was calculated using the standard error of measurement. Clinicians' impressions of the brief training session, the photo atlas, and the response criteria documentation tools were generally favorable. Performing and documenting the full set of response evaluations required a median of 21 minutes (range: 12-60 minutes) per rater. The Schirmer tear test required the greatest time of any single test (median: 9 minutes). Overall, interrater agreement for skin and oral manifestations was modest; however, in the third and fourth trials, the agreement between clinicians and experts for all dimensions except movable sclerosis approached satisfactory values. In the final 2 trials, the threshold for defining change exceeding measurement error was 19% to 22% body surface area (BSA) for erythema, 18% to 26% BSA for movable sclerosis, 17% to 21% BSA for nonmovable sclerosis, and 2.1 to 2.6 points on the 15-point NIH Oral cGHVD scale. Agreement between clinician-expert pairs was moderate to substantial for the measures of functional capacity and for the gastrointestinal and global cGVHD rating scales. These results suggest that the NIH response criteria are feasible for use, and these reliability estimates are encouraging, because they were observed following a single 2.5-hour training session given at multiple transplant centers, with no opportunity for iterative training and calibration. Research is needed to evaluate inter- and intrarater reliability in larger samples, and to evaluate these response criteria as predictors of outcomes in clinical trials.

Prevalence of posterior subcapsular cataracts in volunteer cytapheresis donors.

BACKGROUND: Granulocyte donors routinely receive dexamethasone orally before donation. Steroids may increase the risk of posterior subcapsular cataract (PSC) formation. STUDY DESIGN AND METHODS: We recruited 100 granulocyte donors (four or more granulocyte donations; any number of platelet [PLT] donations) and 100 age- and sex-matched PLT donors (zero to three granulocyte donations, any number of PLT donations) to examine the risk of PSC. PSC was assessed by a masked ophthalmologist and reading center lens photograph gradings or medical record documentation of PSC as the reason for cataract extraction. RESULTS: Fourteen eyes of 10 granulocyte donors and five eyes of four PLT donors had PSCs (odds ratio [OR], 2.82; 95% confidence interval [CI], 0.83-9.61; p = 0.10). Risk of PSC increased with number of granulocyte donations: compared to zero to three donations (4.0%), the risk for four to nine, 10 to 19, and 20 or more donations was 8.6% (OR, 2.25; 95% CI, 0.31-13.99; p = 0.30), 9.5% (OR, 2.53; 95% CI, 0.44-14.20; p = 0.21), and 13.0% (OR, 3.60; 95% CI, 0.48-22.81; p = 0.11), respectively (p = 0.06 for trend). CONCLUSION: We did not demonstrate a statistically significant increased risk of PSC associated with granulocyte donation. However, although this makes a large risk unlikely, we cannot rule out a small to moderate risk and there is biologic plausibility that the steroid administration associated with granulocyte donation could be associated with PSC formation. Transfusion medicine professionals should advise granulocyte apheresis donors to maintain an appropriate frequency of eye examinations.