Caregiving in U.S. Gulf States During Natural Disasters and COVID-19.

Objectives: To ascertain common experiences and needs of a diverse group of caregivers challenged by hurricanes/floods and COVID-19. Methods: In-depth interviews with unpaid caregivers in U.S. Southeast/Gulf Coast states who had experienced caregiving during a natural disaster and during COVID-19. Results: Caregivers report challenges including daily living disruption, altered social supports, complicated health management, additional disaster planning, and emotional/financial impacts. Caregivers suggested helpful resources, policy options, and preparatory tools at individual, local, and health system levels to mediate discontinuity. Conclusions: Our data describe combined caregiver experiences of hurricanes/floods and the pandemic. Caregivers experience unique burdens related to care recipient diagnosis, location, and veteran status. Access to community supports varies as they manage the tasks required for care recipients' health and safety. Our findings indicate the need for public health reinforcement of caregiving though caregiver pre-planning and targeted support. Bolstering understanding of communities' caregiving capacity though first responder trainings and caregiver registries may enhance health and safety.

Stakeholder Experiences with the Single IRB Review Process and Recommendations for Food and Drug Administration Guidance.

The revised Common Rule requires using a single institutional review board (sIRB) for U.S.-based, multisite, nonexempt, federally conducted or supported research with human participants. The 21st Century Cures Act directs the Department of Health and Human Services (HHS) to harmonize differences between HHS and the U.S. Food and Drug Administration (FDA) regulations governing research with humans. Anticipating that the FDA may update its 2006 centralized IRB guidance, we conducted interviews with 34 stakeholders engaged in FDA-regulated clinical research to identify benefits and challenges of using sIRBs and to gather recommendations for revising the FDA's guidance. The main benefits were consistency and standardization, speed and efficiency, and streamlining and simplification. The main challenges were uncertainty at local institutions, including addressing local context; decreased timeliness of the research review process; variable processes; and insufficient communication. Several recommendations for FDA guidance focused on the local context and communication plans. Findings suggest that the sIRB review process may be gaining efficiency although challenges remain.

Pregnancy vs. paycheck: a qualitative study of patient's experience with employment during pregnancy at high risk for preterm birth.

BACKGROUND: Pregnant women with a history of preterm birth are at risk for recurrence, often requiring frequent prenatal visits for close monitoring and/or preventive therapies. Employment demands can limit uptake and adherence to recommended monitoring and preterm birth prevention therapies. METHOD: We conducted a qualitative descriptive study using in-depth interviews (IDIs) of pregnant women with a history of preterm birth. IDIs were conducted by trained qualitative interviewers following a semi-structured interview guide focused on uncovering barriers and facilitators to initiation of prenatal care, including relevant employment experiences, and soliciting potential interventions to improve prompt prenatal care initiation. The IDIs were analyzed via applied thematic analysis. RESULTS: We described the interview findings that address women's employment experiences. The current analysis includes 27 women who are majority self-described as non-Hispanic Black (74%) and publically insured (70%). Participants were employed in a range of professions; food services, childcare and retail were the most common occupations. Participants described multiple ways that being pregnant impacted their earning potential, ranging from voluntary work-hour reduction, involuntary duty hour reductions by employers, truncated promotions, and termination of employment. Participants also shared varying experiences with workplace accommodations to their work environment and job duties based on their pregnancy. Some of these accommodations were initiated by a collaborative employee/employer discussion, others were initiated by the employer's perception of safe working conditions in pregnancy, and some accommodations were based on medical recommendations. Participants described supportive and unsupportive employer reactions to requests for accommodations. CONCLUSIONS: Our findings provide novel insights into women's experiences balancing a pregnancy at increased risk for preterm birth with employment obligations. While many women reported positive experiences, the most striking insights came from women who described negative situations that ranged from challenging to potentially unlawful. Many of the findings suggest profound misunderstandings likely exist at the patient, employer and clinical provider level about the laws surrounding employment in pregnancy, safe employment responsibilities during pregnancy, and the range of creative accommodations that often allow for continued workplace productivity even during high risk pregnancy.

Continued investigator engagement: Reasons principal investigators conduct multiple FDA-regulated drug trials.

BACKGROUND/AIMS: Numerous reasons have been identified for why U.S.-based principal investigators choose to not continue participating in FDA-regulated trials. However, unexplored are reasons why a substantial number of principal investigators, facing the same challenges, remain engaged in clinical research. This study aimed to both describe barriers and identify factors that contribute to active investigators' success in conducting multiple FDA-regulated trials. METHODS: We conducted qualitative in-depth interviews (IDIs) with "active" multi-trial investigators. Interviews focused on investigators' experiences with FDA-regulated drug trials, challenges faced, and factors contributing to success. Investigators also reflected on previously identified barriers and shared advice for new investigators. Narratives were analyzed using applied thematic analysis. RESULTS: We interviewed 23 experienced investigators, representing a variety of backgrounds. Most reported that demonstrated ability to conduct a trial led to being approached again by sponsors. Investigators cited infrastructure, staff support, advance planning, and personal qualities as key factors in successfully conducting multiple trials. Nearly all cited difficulties related to trial finances. Three-quarters pointed to challenges with patient recruitment; others described challenges related to data and safety reporting and to the time that trial implementation takes away from other activities. Aspiring investigators were advised to engage in research-specific training and seek out mentorship opportunities. CONCLUSION: Investigators in our sample faced many of the same challenges identified in previous research, yet they had evolved strategies to overcome them. The amount and type of support to which investigators have access may represent a crucial difference between "active" investigators and principal investigators who leave FDA-regulated trials.

Assessment of the Perceived Acceptability of an Early Enrollment Strategy Using Advance Consent in Health Care-Associated Pneumonia.

Importance: Better treatment options are needed in life-threatening infections, including health care-associated pneumonia. Enrolling patients in antibacterial clinical trials before diagnosis may circumvent existing time-to-enrollment constraints. However, the acceptability of an early enrollment strategy using advance consent is unknown. Objective: To assess the perceived acceptability of an early enrollment strategy for enrolling patients in an antibacterial clinical trial before a pneumonia diagnosis. Design, Setting, and Participants: This qualitative, descriptive study used semistructured telephone interviews. Framed within a planned noninferiority pneumonia antibiotic trial, an early enrollment strategy was described and perceptions were assessed. Using this strategy, patients give consent to enroll before developing pneumonia, to be monitored by study staff, and to be randomly assigned a study antibiotic if pneumonia develops. All interviews were audiorecorded, transcribed verbatim, and analyzed using applied thematic analysis. Fifty-two key stakeholders from across the United States, including 18 patients at risk of pneumonia, 12 caregivers, 10 representatives of institutional review boards, 7 investigators, and 5 study coordinators, were interviewed from June 20 to August 19, 2016. Main Outcomes and Measures: Perceived acceptability of the early enrollment strategy. Results: Among the 52 stakeholders interviewed (ages 29-75 years; 14 women), patients and caregivers expressed no concerns about patients being approached about participation before developing pneumonia; however, some patients may experience anxiety on learning about their risk for pneumonia. No concerns with study staff accessing patients' medical records were expressed. The clarity of consent information was important for understanding the study rather than having the condition under investigation. Among patients, caregivers, and institutional review board representatives, preferences varied regarding opt-out and precedent autonomy procedures. Nearly all patients would be willing to join a trial using the early enrollment strategy and caregivers would be willing to provide proxy consent. Institutional review board representatives were supportive of the strategy and made recommendations for the study protocol, primarily around informed consent. Investigators and study coordinators believed the strategy would not be burdensome and offered suggestions to ensure its feasibility. Conclusion and Relevance: Results of the study suggest that the early enrollment strategy is acceptable. Future research should evaluate whether the strategy improves enrollment rates in registrational pneumonia trials and in trials of other acute infection syndromes with narrow enrollment windows and/or patients with transient decisional incapacity.

Improving biobank consent comprehension: a national randomized survey to assess the effect of a simplified form and review/retest intervention.

PURPOSE: To determine the individual and combined effects of a simplified form and a review/retest intervention on biobanking consent comprehension. METHODS: We conducted a national online survey in which participants were randomized within four educational strata to review a simplified or traditional consent form. Participants then completed a comprehension quiz; for each item answered incorrectly, they reviewed the corresponding consent form section and answered another quiz item on that topic. RESULTS: Consistent with our first hypothesis, comprehension among those who received the simplified form was not inferior to that among those who received the traditional form. Contrary to expectations, receipt of the simplified form did not result in significantly better comprehension compared with the traditional form among those in the lowest educational group. The review/retest procedure significantly improved quiz scores in every combination of consent form and education level. Although improved, comprehension remained a challenge in the lowest-education group. Higher quiz scores were significantly associated with willingness to participate. CONCLUSION: Ensuring consent comprehension remains a challenge, but simplified forms have virtues independent of their impact on understanding. A review/retest intervention may have a significant effect, but assessing comprehension raises complex questions about setting thresholds for understanding and consequences of not meeting them.Genet Med advance online publication 13 October 2016.

Development and Initial Validation of the PROMIS(®) Sexual Function and Satisfaction Measures Version 2.0.

INTRODUCTION: The Patient-Reported Outcomes Measurement Information System (PROMIS)(®) Sexual Function and Satisfaction measure (SexFS) version 1.0 was developed with cancer populations. There is a need to expand the SexFS and provide evidence of its validity in diverse populations. AIM: The aim of this study was to describe the development of the SexFS v2.0 and present preliminary evidence for its validity. METHODS: Development built on version 1.0, plus additional review of extant items, discussions with 15 clinical experts, 11 patient focus groups (including individuals with diabetes, heart disease, anxiety, depression, and/or are lesbian, gay, bisexual, or aged 65 or older), 48 cognitive interviews, and psychometric evaluation in a random sample of U.S. adults plus an oversample for specific sexual problems (2281 men, 1686 women). We examined differential item functioning (DIF) by gender and sexual activity. We examined convergent and known-groups validity. RESULTS: The final set of domains includes 11 scored scales (interest in sexual activity, lubrication, vaginal discomfort, clitoral discomfort, labial discomfort, erectile function, orgasm ability, orgasm pleasure, oral dryness, oral discomfort, satisfaction), and six nonscored item pools (screeners, sexual activities, anal discomfort, therapeutic aids, factors interfering with sexual satisfaction, bother). Domains from version 1.0 were reevaluated and improved. Domains considered applicable across gender and sexual activity status, namely interest, orgasm, and satisfaction, were found to have significant DIF. We identified subsets of items in each domain that provided consistent measurement across these important respondent groups. Convergent and known-groups validity was supported. CONCLUSIONS: The SexFS version 2.0 has several improvements and enhancements over version 1.0 and other extant measures, including expanded evidence for validity, scores centered around norms for sexually active U.S. adults, new domains, and a final set of items applicable for both men and women and those sexually active with a partner and without. The SexFS is customizable, allowing users to select relevant domains and items for their study.

Informed consent for biobanking: consensus-based guidelines for adequate comprehension.

PURPOSE: Federal regulations and best practice guidelines identify categories of information that should be communicated to prospective biobank participants during the informed consent process. However, uncertainty remains about which of this information participants must understand to provide valid consent. METHODS: We conducted a Delphi process to define "adequate comprehension" in the context of biobanking consent. The process involved an iterative series of three online surveys of a diverse panel of 51 experts, including genome scientists, biobank managers, ethics and policy experts, and community and participant representatives. We sought consensus (>70% agreement) concerning what specific details participants should know about 16 biobank consent topics. RESULTS: Consensus was achieved for 15 of the 16 consent topics. The exception was the comprehension needed regarding the Genetic Information Nondiscrimination Act. CONCLUSION: Our Delphi process was successful in identifying a concise set of key points that prospective participants must grasp to provide valid consent for biobanking. Specifying the level of knowledge sufficient for individuals to make an informed choice provides a basis for improving consent forms and processes, as well as an absolute metric for assessing the effectiveness of other interventions to improve comprehension.Genet Med 17 3, 226-233.

Accuracy of 30-day recall for components of sexual function and the moderating effects of gender and mood.

INTRODUCTION: Despite the ubiquity of 1-month recall periods for measures of sexual function, there is limited evidence for how well recalled responses correspond to individuals' actual daily experiences. AIM: To characterize the correspondence between daily sexual experiences and 1-month recall of those experiences. METHODS: Following a baseline assessment of sexual functioning, health, and demographic characteristics, 202 adults from the general population (101 women, 101 men) were recruited to complete daily assessments of their sexual function online for 30 days and a single recall measure of sexual function at day 30. MAIN OUTCOME MEASURES: At the baseline and 30-day follow-ups, participants answered items asking about sexual satisfaction, sexual activities, interest, interfering factors, orgasm, sexual functioning, and use of therapeutic aids during the previous 30 days. Participants also completed a measure of positive and negative affect at follow-up. The main outcome measures were agreement between the daily and 1-month recall versions of the sexual function items. RESULTS: Accuracy of recall varied depending on the item and on the gender and mood of the respondent. Recall was better (low bias and higher correlations) for sexual activities, vaginal discomfort, erectile function, and more frequently used therapeutic aids. Recall was poorer for interest, affectionate behaviors (e.g., kissing), and orgasm-related items. Men more than women overestimated frequency of interest and masturbation. Concurrent mood was related to over- or underreporting for six items addressing the frequency of masturbation and vaginal intercourse, erectile function, and orgasm. CONCLUSIONS: A 1-month recall period seems acceptable for many aspects of sexual function in this population, but recall for some items was poor. Researchers should be aware that concurrent mood can have a powerful biasing effect on reports of sexual function.

Participants' perspectives on safety monitoring in clinical trials.

BACKGROUND: Minimizing the risk to study participants is an essential requirement of ethical research. Respecting the rights of subjects is also paramount, which includes respecting their autonomy by making available important information about the evolving safety profile of an investigational product as the trial progresses. Little is known about what trial participants understand and expect regarding monitoring and communication of serious adverse events during the conduct of a trial in which they have agreed to participate. PURPOSE: To explore understanding and expectations of potential trial participants concerning monitoring and communication of serious adverse events during a clinical trial. METHODS: A professional moderator led four 90-min, in-person focus groups: two groups with individuals who had never participated in a clinical trial and two groups with people who had. After relevant research terms were defined and existing regulations were explained, discussion focused on how participants expected safety to be monitored and communicated during the conduct of a clinical trial. Group comments were video-recorded and transcribed and then analyzed by the investigators. RESULTS: The 27 racially diverse focus group members were largely unaware of existing safeguards and regulations to manage risk in clinical trials. Many people expressed a desire for increased transparency about serious adverse events during the trial as well as shortened reporting deadlines. Focus group members also spontaneously expressed concerns about potential financial conflicts of interest in monitoring and reporting serious adverse events. LIMITATIONS: This was a single-site, qualitative study and is not meant to establish the prevalence of beliefs. CONCLUSIONS: Potential trial participants have limited understanding and a wide range of expectations about how safety monitoring in clinical trials should be managed and communicated. The overall tenor of opinion suggests unease about participant safety and a desire to have more information conveyed by sponsors to investigators and, in some cases, by investigators to participants. Additional study in other regions and settings may be useful to more broadly explore the range of participants' beliefs and expectations. In the meantime, engaging patient advocates in the design of clinical trials and clearly communicating to trial participants the plan for oversight of their safety may help ease the types of concerns expressed in this study.

Use of central institutional review boards for multicenter clinical trials in the United States: a review of the literature.

BACKGROUND: To improve the efficiency of conducting multicenter clinical trials, the Food and Drug Administration, the Office of Human Research Protections, and the Department of Health and Human Services have expressed support for using a centralized institutional review board (IRB) process. However, research institutions differ in their willingness to defer to central IRBs. PURPOSE: We aimed to review and describe peer-reviewed journal articles on the use of central IRBs for multicenter clinical trials in the United States in an effort to inform the policy discussion about central IRBs. METHODS: We used a PubMed search and consulted IRB experts and the bibliographies of other reviews to identify relevant commentaries and empirical studies. RESULTS: Our search identified 33 articles related to the use of central IRBs for multicenter trials in the United States. Of these, 22 were commentary pieces and 11 were empirical studies. LIMITATIONS: Our review was restricted to journal articles about the use of central IRBs for multicenter clinical trials in the United States. CONCLUSIONS: There is limited empirical work on the use of central IRBs for multicenter trials in the United States. Most published studies focused on problems in efficiency associated with redundant local reviews of multicenter studies and the potential benefits of a centralized system. Because the absence of studies on the use of central IRBs may be due to their infrequent use, additional work is needed to generate data on the use of central IRBs and to elucidate and address the concerns that research institutions have about deferring ethical review to a central IRB.

Development of the NIH PROMIS ® Sexual Function and Satisfaction measures in patients with cancer.

INTRODUCTION: We describe the development and validation of the Patient-Reported Outcomes Measurement Information System(®) Sexual Function and Satisfaction (PROMIS(®) SexFS; National Institutes of Health) measures, version 1.0, for cancer populations. AIM: To develop a customizable self-report measure of sexual function and satisfaction as part of the U.S. National Institutes of Health PROMIS Network. METHODS: Our multidisciplinary working group followed a comprehensive protocol for developing psychometrically robust patient-reported outcome measures including qualitative (scale development) and quantitative (psychometric evaluation) development. We performed an extensive literature review, conducted 16 focus groups with cancer patients and multiple discussions with clinicians, and evaluated candidate items in cognitive testing with patients. We administered items to 819 cancer patients. Items were calibrated using item-response theory and evaluated for reliability and validity. MAIN OUTCOME MEASURES: The PROMIS SexFS measures, version 1.0, include 81 items in 11 domains: Interest in Sexual Activity, Lubrication, Vaginal Discomfort, Erectile Function, Global Satisfaction with Sex Life, Orgasm, Anal Discomfort, Therapeutic Aids, Sexual Activities, Interfering Factors, and Screener Questions. RESULTS: In addition to content validity (patients indicate that items cover important aspects of their experiences) and face validity (patients indicate that items measure sexual function and satisfaction), the measure shows evidence for discriminant validity (domains discriminate between groups expected to be different) and convergent validity (strong correlations between scores on PROMIS and scores on conceptually similar older measures of sexual function), as well as favorable test-retest reliability among people not expected to change (interclass correlations from two administrations of the instrument, 1 month apart). CONCLUSIONS: The PROMIS SexFS offers researchers a reliable and valid set of tools to measure self-reported sexual function and satisfaction among diverse men and women. The measures are customizable; researchers can select the relevant domains and items comprising those domains for their study.

Using central IRBs for multicenter clinical trials in the United States.

Research institutions differ in their willingness to defer to a single, central institutional review board (IRB) for multicenter clinical trials, despite statements from the FDA, OHRP, and NIH in support of using central IRBs to improve the efficiency of conducting trials. The Clinical Trials Transformation Initiative (CTTI) supported this project to solicit current perceptions of barriers to the use of central IRBs and to formulate potential solutions. We held discussions with IRB experts, interviewed representatives of research institutions, and held an expert meeting with diverse stakeholder groups and thought leaders. We found that many perceived barriers relate to conflating responsibilities of the institution with the ethical review responsibilities of the IRB. We identified the need for concrete tools to help research institutions separate institutional responsibilities from ethical responsibilities required of the IRB. One such tool is a document we created that delineates these responsibilities and how they might be assigned to each entity, or, in some cases, both entities. This tool and project recommendations will be broadly disseminated to facilitate the use of central IRBs in multicenter trials. The ultimate goal is to increase the nation's capacity to efficiently conduct the large number of high-quality trials.

Patient experiences with communication about sex during and after treatment for cancer.

OBJECTIVE: We studied patients' experiences with oncology providers regarding communication about sexual issues during and after treatment for cancer. METHODS: During development of the Patient-Reported Outcomes Measurement Information System (PROMIS(®)) Sexual Function measure, we collected focus group and survey data on communication with oncology professionals about sexual problems. We conducted 16 focus groups with patients and survivors (n = 109) and analyzed the discussions for major themes, including experiences discussing sex during oncology visits. During testing of the PROMIS Sexual Function measure, we assessed experiences discussing sexual problems with oncology professionals (n = 819) and measured bivariate associations between asking for information from clinicians and sexual function and satisfaction with sex life. RESULTS: Most patients and survivors (74%) thought that discussions with oncology professionals about sexual problems were important, but whether they had ever received information about sexual function from a provider varied by cancer type (23% lung, 29% breast, 39% colorectal, and 79% prostate). Those who had asked an oncology professional about sexual problems had significantly greater interest in sexual activity as well as more sexual dysfunction. CONCLUSIONS: Sexual problems are a widespread concern among patients and survivors, but there is much variation in experiences of communication about sexual issues, and many patients do not receive the information they need from their oncology providers. There are large differences in sexual function between patients who do and do not ask providers about sexual problems. Sexual health has yet to be fully integrated into oncology care, even for cancers involving sex organs.

Using item banks to construct measures of patient reported outcomes in clinical trials: investigator perceptions.

BACKGROUND: Item response theory (IRT) promises more sensitive and efficient measurement of patient-reported outcomes (PROs) than traditional approaches; however, the selection and use of PRO measures from IRT-based item banks differ from current methods of using PRO measures. PURPOSE: To anticipate barriers to the adoption of IRT item banks into clinical trials. METHODS: We conducted semistructured telephone or in-person interviews with 42 clinical researchers who published results from clinical trials in the Journal of the American Medical Association, the New England Journal of Medicine, or other leading clinical journals from July 2005 through May 2006. Interviews included a brief tutorial on IRT item banks. RESULTS: After the tutorial, 39 of 42 participants understood the novel products available from an IRT item bank, namely customized short forms and computerized adaptive testing. Most participants (38/42) thought that item banks could be useful in their clinical trials, but they mentioned several potential barriers to adoption, including economic and logistical constraints, concerns about whether item banks are better than current PRO measures, concerns about how to convince study personnel or statisticians to use item banks, concerns about FDA or sponsor acceptance, and the lack of availability of item banks validated in specific disease populations. LIMITATIONS: Selection bias might have led to more positive responses to the concept of item banks in clinical trials. CONCLUSIONS: Clinical investigators are open to a new method of PRO measurement offered in IRT item banks, but bank developers must address investigator and stakeholder concerns before widespread adoption can be expected.

Brain morphometry, T2-weighted hyperintensities, and IQ in children with neurofibromatosis type 1.

BACKGROUND: Larger gray matter (GM) volume in healthy children is correlated with higher IQ. Children with neurofibromatosis type 1 (NF1) have larger brains, their magnetic resonance images frequently show T2-weighted hyperintensities, and their IQs are lower. OBJECTIVES: To confirm the hypotheses that (1) children with NF1 have larger GM and white matter volumes, (2) the greatest volume differences are in the frontal and parietal regions and in children with NF1 with hyperintensities, and (3) GM volume is inversely related to IQ in children with NF1. DESIGN: Wechsler Intelligence Scale for Children-Third Edition IQ testing and measurement of cerebral volumes and hyperintensities in brain magnetic resonance images were performed on 36 children with NF1 and on 36 matched relatives who served as control subjects. RESULTS: Gray matter and white matter volumes were significantly larger in children with NF1. The greatest difference was observed in cerebral white matter volume, predominantly in the frontal lobes, whereas the greatest difference in GM volume was in the temporal, parietal, and occipital regions. In controls, IQ was significantly related to GM volume, but in children with NF1, IQ was not inversely associated with GM volume, although IQs of children with NF1 were significantly lower. CONCLUSIONS: Children with NF1 do not have the normal relationship between GM volume and IQ. Larger GM volume in the posterior brain regions and larger white matter volumes in the frontal brain regions contribute to the larger brain volume in children with NF1.

Anatomic location and laterality of MRI signal hyperintensities in late-life depression.

OBJECTIVES: Evidence is mounting linking cerebrovascular disease with the development of major depression in the elderly. Lesions in both white and gray matter have been associated with geriatric depression. In addition, the literature on poststroke depression suggests that left-sided lesions are associated with depression. We sought to examine the severity and location of white- and gray-matter lesions in a group of elderly depressives and nondepressed control subjects. METHOD: 115 depressed patients (69 with late onset, 46 with early onset) and 37 controls, all over age 45, received magnetic resonance imaging (MRI). Semiquantitative severity ratings and quantitative measurements of number and size of MRI hyperintensities were obtained, and groups were compared using Cochran-Mantel-Haenszel (CMH) analyses and repeated-measures analyses of covariance adjusting for age. RESULTS: Late-onset depressed patients had more severe hyperintensity ratings in deep white matter than early-onset patients and controls. Late- and early-onset patients had more severe subcortical gray-matter hyperintensities (particularly in the putamen) compared with controls. Left-sided white-matter lesions were significantly associated with older age of depression onset, whereas right-anterior white matter and left-subcortical lesions (particularly in the putamen) were associated with melancholia in the depressed group. CONCLUSION: These findings extend previous reports of an association between cerebrovascular disease and depression, as well as recent studies showing lateralized lesion involvement in geriatric depression. Such vascular pathology may disrupt neural pathways involved in affective processing and the maintenance of a normal mood and psychomotor state.