Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism.

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.

Do Sleep Problems Exacerbate the Mental Health Consequences of Discrimination Among Adults?

OBJECTIVE: An emerging literature suggests that sleep may play an important role in moderating the association between discrimination and mental health problems among adolescents. However, few if any studies have considered this topic among adults. Addressing this knowledge gap, the current study examined multiple sleep parameters as moderating variables in the association between discrimination and mental health problems among adults. METHODS: Participants were 874 adults residing in small towns and semirural contexts within the Southeastern region of the United States ( Mage = 41 years, SD = 7; 57% female; 31% Black, 69% White; 52% income-to-needs < 2). Sleep duration and night-to-night variability in duration were assessed using wrist actigraphy. Established self-report measures were used to assess global sleep problems, experiences of discrimination, and mental health problems (anxiety, depression, and externalizing symptoms). RESULTS: Experiences of discrimination were associated with more depression, anxiety, and externalizing problems. Two out of three sleep parameters were found to moderate the effects of discrimination on mental health. The association between discrimination and externalizing problems (but not anxiety or depression) was attenuated among those with less night-to-night variability in sleep duration. The associations between discrimination and anxiety and externalizing problems (but not depression) were attenuated among those with fewer global sleep problems. Less variability in sleep duration and fewer global sleep problems were also directly associated with lower levels of depression, anxiety, and externalizing problems. CONCLUSIONS: Greater consistency in sleep duration from night-to-night, and fewer overall sleep problems appear to mitigate risk of mental health problems among adults, particularly in contexts where discrimination is prevalent.

A daily diary study of discrimination and distress in Mexican-origin adolescents: Testing mediating mechanisms.

The present 21-day daily diary study (conducted 2021-2022) tested anger and racism-related vigilance as potential transdiagnostic mediators linking exposure to racial and ethnic discrimination (RED) to distress (negative affect and stress, respectively). The data analytic sample included N = 317 Mexican-origin adolescents (Mage = 13.5 years; 50.8% male, 46.7% female; 2.5% non-binary) from the Midwestern United States. Results from longitudinal mediation models revealed significant mediation effects through anger and racism-related vigilance, respectively, in the association between daily RED and daily distress, both within and across adolescents. Implications for theory, research, and practice are discussed so that future work can leverage these novel findings toward promoting the well-being of Mexican-origin adolescents, especially those who live in contexts of ethnoracial adversity.

Family-level moderators of daily associations between discrimination and distress among Mexican-origin youth.

The current study evaluated cultural values and family processes that may moderate associations between daily racial-ethnic discrimination and distress among Mexican-origin youth. Integrating micro-time (daily diary) and macro-time (longitudinal survey) research design features, we examined familism, family cohesion, and ethnic-racial socialization from youth-, mother-, and father- reports as potential buffers of daily associations between youth racial-ethnic discrimination and youth distress (negative affect and anger). The analytic sample, drawn from the Seguimos Avanzando study, included 317 Mexican-origin adolescents (Mage = 13.5 years) and their parents, recruited from the Midwestern United States. Results indicated that youth-reported familism and family cohesion significantly buffered daily associations between youth racial-ethnic discrimination and youth distress. In contrast, parent-reported familism and family cohesion and some aspects of ethnic-racial socialization exacerbated the discrimination to distress link. The implications of these results are discussed to inform efforts supporting the healthy development of Mexican-origin youth and their families.

Longitudinal Associations Between Friendship Ethnic/Racial Composition and Ethnic/Racial Identity: The Role of School Ethnic/Racial Diversity.

Schools and friendships represent important but distinct contexts for adolescent identity development. However, research has yet to explore the long-term interplay between these factors on ethnic/racial identity (ERI). This study included a sample of 640 adolescents from 9 public high schools in a diverse United States metropolis (Mage = 14.50, SD = 0.67; 44% Asian, 20% Black, 36% Latinx; female = 68%, male = 32%, non-binary = 0%). Latent growth curve modeling was conducted to investigate longitudinal associations in friendship ethnic/racial composition and ERI exploration. From the 9th-11th grades, same-race friends and ERI exploration increased linearly whereas friendship ethnic/racial diversity decreased linearly. Adolescents attending more ethnically/racially diverse schools maintained more ethnically/racially diverse friends over time but did not differ in changes in ERI exploration compared to adolescents in less diverse schools. There was no association between the rates at which adolescents' friendship ethnic/racial composition and ERI changed over time. More ethnically/racially diverse friends in the 9th-grade predicted faster increases in subsequent ERI exploration. The findings highlight important differences in the roles of friendship and school contexts on ERI, suggesting that friendship ethnic/racial diversity, but not school ethnic/racial diversity, facilitated ERI exploration over time. School ethnic/racial diversity did facilitate a slower decline in friendship ethnic/racial diversity, emphasizing the importance of school integration.

Corresponding Changes in Sleep and Discrimination: A Three-year Longitudinal Study Among Ethnically/Racially Diverse Adolescents.

Although research has established the immediate, detrimental impact of discrimination on sleep, how changes in experiences of discrimination may be related to changes in sleep duration over multiple years is less clear. This three-year longitudinal study investigated: (1) intercept-only and linear trajectories of sleep and everyday discrimination across three years of high school; (2) ethnic/racial differences in these trajectories; and (3) the associations between changes in sleep and changes in everyday discrimination. The sample consisted of ethnically/racially minoritized adolescents from five northeast U.S. public high schools (n = 329; 70% female, 30% male, 0% non-binary; 42% Asian, 21% Black, 37% Latiné; Mage = 14.72, SD = 0.54). Latent growth curve models found that both sleep duration and everyday discrimination declined linearly throughout the first three years of high school and varied by race/ethnicity. Asian adolescents reported longer sleep duration in the 9th grade relative to Black and Latiné adolescents but underwent a significant decline such that these differences were no longer significant in the 10th and 11th grades. In addition, Black and Latiné, but not Asian, adolescents reported a significant decline in discrimination from the 9th-11th grades. Although average sleep duration declined for the entire sample, slower declines in discrimination were associated with faster decreases in sleep duration. This was particularly salient among Black adolescents. The current study contributes to research on ethnic/racial disparities in sleep by highlighting that everyday discrimination can have both an immediate and cumulative detrimental impact on sleep duration.

Information-seeking preferences in diverse patients receiving a genetic testing result in the Clinical Sequencing Evidence-Generating Research (CSER) study.

PURPOSE: Accurate and understandable information after genetic testing is critical for patients, family members, and professionals alike. METHODS: As part of a cross-site study from the Clinical Sequencing Evidence-Generating Research consortium, we investigated the information-seeking practices among patients and family members at 5 to 7 months after genetic testing results disclosure, assessing the perceived utility of a variety of information sources, such as family and friends, health care providers, support groups, and the internet. RESULTS: We found that individuals placed a high value on information obtained from genetics professionals and health care workers, independent of genetic testing result case classifications as positive, inconclusive, or negative. The internet was also highly utilized and ranked. Study participants rated some information sources as more useful for positive results compared with inconclusive or negative outcomes, emphasizing that it may be difficult to identify helpful information for individuals receiving an uncertain or negative result. There were few data from non-English speakers, highlighting the need to develop strategies to reach this population. CONCLUSION: Our study emphasizes the need for clinicians to provide accurate and comprehensible information to individuals from diverse populations after genetic testing.

TRAPPC9-related neurodevelopmental disorder: Report of a homozygous deletion in TRAPPC9 due to paternal uniparental isodisomy.

TRAPPC9 loss-of-function biallelic variants are associated with an autosomal recessive intellectual disability syndrome (Online Mendelian Inheritance of Man no. 613192), also characterized by microcephaly, hypertelorism, obesity, growth delay, and behavioral differences. Here, we describe an 8-year-old Hispanic female with neurodevelopmental disorder, partial epilepsy, microcephaly, bilateral cleft lip and alveolus, growth delay, and dysmorphic features. She had abnormal myelination, mega cisterna magna, and colpocephaly on brain magnetic resonance imaging (MRI). Microarray showed a single ~146 Mb region of homozygosity (ROH) encompassing all of Chromosome 8, consistent with uniparental isodisomy (UPD). Exome sequencing performed in-house did not identify single nucleotide variants to explain her phenotype. Algorithms developed in-house and further evaluation of BAM files revealed a homozygous deletion overlapping Exon 2 in TRAPPC9 within the ROH. Subsequent del/dup analyses with exon-level oligo array confirmed a likely pathogenic deletion in TRAPPC9 (NM_031466.5): arr[GRCh37] 8q24.3(141460661_141461780)x0. Our case highlights the implications of downstream analyses from UPD/ROH given the increased risk for AR conditions, the strengths of combining orthologous molecular methods to establish a diagnosis and further delineates the TRAPPC9-related phenotype in an individual of Hispanic ancestry.

Insights into the perinatal phenotype of Kabuki syndrome in infants identified by genome-wide sequencing.

Increasing use of unbiased genomic sequencing in critically ill infants can expand understanding of rare diseases such as Kabuki syndrome (KS). Infants diagnosed with KS through genome-wide sequencing performed during the initial hospitalization underwent retrospective review of medical records. Human phenotype ontology terms used in genomic analysis were aggregated and analyzed. Clinicians were surveyed regarding changes in management and other care changes. Fifteen infants met inclusion criteria. KS was not suspected prior to genomic sequencing. Variants were classified as Pathogenic (n = 10) or Likely Pathogenic (n = 5) by American College of Medical Genetics and Genomics Guidelines. Fourteen variants were de novo (KMT2D, n = 12, KDM6A, n = 2). One infant inherited a likely pathogenic variant in KMT2D from an affected father. Frequent findings involved cardiovascular (14/15) and renal (7/15) systems, with palatal defects also identified (6/15). Three infants had non-immune hydrops. No minor anomalies were universally documented; ear anomalies, micrognathia, redundant nuchal skin, and hypoplastic nails were common. Changes in management were reported in 14 infants. Early use of unbiased genome-wide sequencing enabled a molecular diagnosis prior to clinical recognition including infants with atypical or rarely reported features of KS while also expanding the phenotypic spectrum of this rare disorder.

Ethnic/racial discrimination and academic grades among adolescents: moderation by sleep regularity.

This study investigates how sleep regularity moderates the association between ethnic/racial discrimination and academic grades among diverse adolescents. The study included a 14-day, daily diary and actigraphy study of ninth-grade adolescents in the United States (N = 265; mean [SD] age 15.26 [0.62] years, 41.51% Asian, 21.13% Black, 37.35% Latinx, 71.32% female) who completed measures of demographic information and ethnic/racial discrimination (Daily Life Experiences Racism and Bother subscale). Sleep data were collected for 14 consecutive days with wrist actigraphy, and sleep regularity was calculated using the Sleep Regularity Index (SRI). Academic grades were provided by the Department of Education. Discrimination frequency was associated with lower academic grades, and the SRI moderated this association. Compared to adolescents who had moderate and regular SRI profiles, adolescents with irregular SRI (i.e., lower sleep regularity) had stronger negative associations between discrimination and grades. On the other hand, for adolescents who had moderate to high sleep regularity, there was no significant association between discrimination and grades. This study underscores the importance of sleep regularity for adolescents' academic achievement.

The effects of COVID-19 victimization distress and racial bias on mental health among AIAN, Asian, Black, and Latinx young adults.

OBJECTIVE: U.S. young adult racial minorities have been disproportionately impacted by the coronavirus disease (COVID-19) pandemic in rates of infection and morbidity. Prepandemic racial discrimination has been associated with depression and general anxiety. However, the effect of coronavirus-specific forms of discrimination on mental health has not been examined. This study assessed the effect of social determinants of mental health and COVID-19-specific victimization and racial bias beliefs on depression and anxiety among young adults of color in the U.S. METHOD: A national online survey of 399 American Indian/Alaskan Natives, Asian, Black, and Latinx adults (18-25 years) included demographic variables, COVID-19-health risks, and standardized measures of depression, anxiety, coronavirus-related victimization distress and perceptions of coronavirus-related racial bias across a range of contexts. RESULTS: Employment, financial and prescription insecurity, COVID-19-health risks, coronavirus-victimization distress and coronavirus racial bias beliefs were positively correlated with depression and anxiety. Scores on the Coronavirus Racial Bias Scale were significantly higher among Asian and Black respondents. Structural equation modeling controlling for race/ethnicity and demographic variables indicated coronavirus racial bias mediated the effect of coronavirus victimization distress on both mental health indices. CONCLUSION: Results suggest the COVID-19 pandemic has created new pathways to mental health disparities among young adults of color by reversing formerly protective factors such as employment, and by exacerbating structural and societal inequities linked to race. Findings highlight the necessity of creating mental health services tailored to the specific needs of racial minorities during the current and future health crises. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Predicting genes from phenotypes using human phenotype ontology (HPO) terms.

The interpretation of genomic variants following whole exome sequencing (WES) can be aided using human phenotype ontology (HPO) terms to standardize clinical features and predict causative genes. We performed WES on 453 patients diagnosed prior to 18 years of age and identified 114 pathogenic (P) or likely pathogenic (LP) variants in 112 patients. We utilized PhenoDB to extract HPO terms from provider notes and then used Phen2Gene to generate a gene score and gene ranking from each list of HPO terms. We assigned Phen2Gene gene rankings to 6 rank classes, with class 1 covering raw gene rankings of 1 to 10 and class 2 covering rankings from 11 to 50 out of a total of 17,126 possible gene rankings. Phen2Gene ranked causative genes into rank class 1 or 2 in 27.7% of cases and the genes in rank class 1 were all associated with well-characterized phenotypes. We found significant associations between the gene score and the number of years, since the gene was first published, the number of HPO terms with an hierarchical depth greater or equal to 11, and the number of Online Mendelian Inheritance in Man terms associated with the phenotype and gene. We conclude that genes associated with recognizable phenotypes and terms deep in the HPO hierarchy have the best chance of producing a high gene score and ranking in class 1 to 2 using Phen2Gene software with HPO terms. Clinicians and laboratory staff should consider these results when HPO terms are employed to prioritize candidate genes.

Perspectives and preferences regarding genomic secondary findings in underrepresented prenatal and pediatric populations: A mixed-methods approach.

PURPOSE: Patients undergoing clinical exome sequencing (ES) are routinely offered the option to receive secondary findings (SF). However, little is known about the views of individuals from underrepresented minority pediatric or prenatal populations regarding SF. METHODS: We explored the preferences for receiving hypothetical categories of SF (H-SF) and reasons for accepting or declining actual SF through surveying (n = 149) and/or interviewing (n = 47) 190 families undergoing pediatric or prenatal ES. RESULTS: Underrepresented minorities made up 75% of the probands. In total, 150 families (79%) accepted SF as part of their child/fetus's ES. Most families (63%) wanted all categories of H-SF. Those who declined SF as part of ES were less likely to want H-SF across all categories. Interview findings indicate that some families did not recall their SF decision. Preparing for the future was a major motivator for accepting SF, and concerns about privacy, discrimination, and psychological effect drove decliners. CONCLUSION: A notable subset of families (37%) did not want at least 1 category of H-SF, suggesting more hesitancy about receiving all available results than previously reported. The lack of recollection of SF decisions suggests a need for alternative communication approaches. Results highlight the importance of the inclusion of diverse populations in genomic research.

Linking ethnic/racial discrimination to adolescent mental health: Sleep disturbances as an explanatory pathway.

Ethnic/racial discrimination is associated with negative psychosocial outcomes, and this study considered sleep disturbance as a mediating pathway. Employing a combination of daily diary and biannual surveys, multilevel structural equation models estimated the indirect effects of sleep/wake concerns on negative, anxious, and positive mood, rumination, and somatic symptoms. In a sample of 350 urban Asian (74% Chinese, 8% Korean, 4% Indian, 1% Filipinx, 1% Vietnamese, and 12% other), Black, and Latinx (25% Dominican, 24% South American, 22% Mexican, 15% Puerto Rican, 5% Central American, and 9% other) youth (M = 14.27 years, 69% female, 77% U.S. born, 76% monoethnic/racial, data collected from 2015 to 2018), there was evidence for sleep disturbances mediating the impact of ethnic/racial discrimination on adjustment. Nighttime disturbance, daytime dysfunction, and daytime sleepiness evidenced partial or full mediation for daily- and person-level outcomes (υ = 0.1%-17.9%). Reciprocal associations between sleep disturbances and negative mood and rumination were also observed.

Preference for secondary findings in prenatal and pediatric exome sequencing.

OBJECTIVE: We aimed to determine the frequency of accepting secondary findings in families undergoing exome sequencing in prenatal and pediatric settings. METHODS: This was a secondary analysis of prospectively enrolled patients undergoing trio exome sequencing for congenital anomalies or developmental disorders in prenatal and pediatric settings, in which families were offered receiving secondary findings (initially assessed in the proband and, if identified, then in the parents). The primary outcome was frequency of accepting secondary findings. Secondary outcomes included frequency of acceptance in prenatal versus pediatric settings, and sociodemographic differences between those who accepted versus declined secondary findings. RESULTS: There were 682 families included in the cohort (289 prenatal and 393 pediatric). Overall, 84% (576/682) of families accepted secondary findings: 86.2% (249/289) of families undergoing prenatal versus 83.2% (327/393) pediatric (p = 0.30) testing. Secondary findings were identified in 2.6% (15/576) of cases, with no difference between prenatal and pediatric settings. There were no differences in sociodemographics between families that accepted versus declined secondary findings. CONCLUSION: The majority of families undergoing exome sequencing accepted secondary findings; this did not differ in prenatal versus pediatric settings. This highlights the need for guidance surrounding the offer of secondary findings in the prenatal setting.

Vicarious racism, ethnic/racial identity, and sleep among Asian Americans.

OBJECTIVES: Vicarious racism-witnessing or hearing about other individuals of one's ethnic/racial group being the target of racism-has been salient among Asian Americans during the coronavirus disease (COVID-19) pandemic. There is emerging evidence that such experiences adversely impact several health-related outcomes, including sleep. The present study examines associations between vicarious racism and subjective sleep duration and quality, and the potential moderating role of ethnic/racial identity (ERI). METHOD: Multivariable regression models assessed the association between vicarious racism, private regard, and centrality on self-reported sleep disturbance and duration. The sample consisted of an online sample of 600 Asian American adults (Mage = 38.55, SDage = 17.11; 65.17% female; 60% ≥ Bachelor's degree) recruited from May to June 2020. RESULTS: Vicarious racism was associated with compromised sleep quality and duration, including after adjustment for sociodemographic variables that have been linked to sleep. Private regard toward one's own ethnic/racial group and centrality of ethnicity/race to self-identity buffered the association between vicarious racism and sleep quality and duration. Adverse effects of high vicarious racism on sleep quality and duration were lessened among respondents reporting high levels of ERI private regard and centrality. CONCLUSIONS: Findings from this study extend research on racism and sleep by examining vicarious racism, an understudied facet of racism, and by focusing specifically on Asian Americans and in the context of the COVID-19 pandemic. Future research and practice should consider expanding research on discrimination to include a broader range of unjust experiences. Vicarious racism contributes to health hazards experienced by Asian Americans during the COVID-19 pandemic. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Employment, coronavirus victimization distress, and substance use disorders among black and non-Hispanic White young adults during the COVID-19 pandemic.

Substance abuse among young adults increased during the COVID-19 pandemic. Although pre-pandemic data indicate non-Hispanic White adults had higher levels of substance use disorder (SUD), Black adults suffered more serious consequences. The COVID-19 pandemic has introduced new stressors that may contribute to SUD, especially among Black young adults, including employment as essential workers, which may be related to victimization distress associated with the coronavirus (i.e., coronavirus victimization distress). The current study administered an anonymous, cross-sectional, online survey to a national sample of 132 Black and 141 non-Hispanic White adults 18 - 25 years to assess the relationship between health, economic disparities, employment, coronavirus victimization distress, and substance use during the first wave of the pandemic. Controlling for COVID-19 health risks and income, structural equation models indicated that coronavirus victimization distress fully accounted for the positive association between employment and SUD risk, and this association was more pronounced among Black young adults. Findings underscore the urgency of considering disease-related victimization in SUD interventions involving employed young adults during infectious disease pandemics.

Third case of Bardet-Biedl syndrome caused by a biallelic variant predicted to affect splicing of IFT74.

Bardet-Biedl syndrome (BBS) is a rare ciliopathy characterized by rod-cone dystrophy, postaxial polydactyly, truncal obesity and renal anomalies with autosomal recessive inheritance. We describe a 6-year-old male with early onset retinal dystrophy, postaxial polydactyly, truncal obesity and motor delays. Exome sequencing revealed a homozygous variant predicted to affect splicing of the IFT74 gene, c.1685-1G > T. This is the third patient with BBS due to variants predicting loss of function in IFT74. All three patients have had retinal dystrophy, polydactyly, obesity, developmental differences, and a notable lack of renal anomalies. We recommend that IFT74 is added to gene panels for the diagnosis of BBS.

Oncolytic Adenovirus Armed with BiTE, Cytokine, and Checkpoint Inhibitor Enables CAR T Cells to Control the Growth of Heterogeneous Tumors.

No single cancer immunotherapy will likely defeat all evasion mechanisms of solid tumors, including plasticity of tumor antigen expression and active immune suppression by the tumor environment. In this study, we increase the breadth, potency, and duration of anti-tumor activity of chimeric antigen receptor (CAR) T cells using an oncolytic virus (OV) that produces cytokine, checkpoint blockade, and a bispecific tumor-targeted T cell engager (BiTE) molecule. First, we constructed a BiTE molecule specific for CD44 variant 6 (CD44v6), since CD44v6 is widely expressed on tumor but not normal tissue, and a CD44v6 antibody has been safely administered to cancer patients. We then incorporated this BiTE sequence into an oncolytic-helper binary adenovirus (CAdDuo) encoding an immunostimulatory cytokine (interleukin [IL]-12) and an immune checkpoint blocker (PD-L1Ab) to form CAdTrio. CD44v6 BiTE from CAdTrio enabled HER2-specific CAR T cells to kill multiple CD44v6+ cancer cell lines and to produce more rapid and sustained disease control of orthotopic HER2+ and HER2-/- CD44v6+ tumors than any component alone. Thus, the combination of CAdTrio with HER2.CAR T cells ensures dual targeting of two tumor antigens by engagement of distinct classes of receptor (CAR and native T cell receptor [TCR]), and significantly improves tumor control and survival.

The Impact of Daily Discrimination on Sleep/Wake Problem Trajectories Among Diverse Adolescents.

This study examines how everyday discrimination is associated with 6-day trajectories of sleep/wake problems, operationalized as sleep disturbance and daytime dysfunction, among 350 diverse adolescents (Mage  = 14.27, SD = 0.61, 69% female; 22% African American, 41% Asian American, 37% Latinx; 24% multiethnic/racial; across participating schools, 72% of students eligible for free/reduced price lunch) in the Northeastern United States. Adolescents encountering discrimination experienced changes in sleep/wake problem trajectories (i.e., significant increases in same-day sleep/wake problems), whereas adolescents reporting no discrimination experienced no changes in trajectories (Cohen's ds = .51-.55). Multiethnic/racial (compared to monoethnic/racial) adolescents experiencing everyday discrimination reported greater same-day sleep/wake problems, yet steeper decreases in sleep/wake problems suggesting stronger impact coupled with faster return to baseline levels.