Increase of liver stiffness and altered bile acid metabolism after triple CFTR modulator initiation in children and young adults with cystic fibrosis.

BACKGROUND: Novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies (elexacaftor/tezacaftor/ivacaftor-ETI) promise clinically significant and sustained improvements for patients with cystic fibrosis (CF). In this study, we investigated the impact of ETI therapy on liver stiffness and bile acid metabolism in a cohort of children and young adults with CF. METHODS: A prospective observational study (NCT05576324) was conducted from September 2020 to November 2021 enrolling CF patients naive to ETI. Standard laboratory chemistry, sweat test, lung function, share wave velocity (SWV) derived by acoustic radiation force impulse imaging (ARFI) and serum bile acid profiles were assessed before and 6 months after induction of ETI therapy. RESULTS: A total of 20 patients (10 aged <20 years) completed the study. While lung function and BMI improved after ETI therapy, ARFI SWV increased in CF patients <20 years of age (from 1.27 to 1.43 m/s, p = 0.023). Bile acid (BA) profiles revealed a decrease in unconjugated (5.75 vs 1.46, p = 0.007) and increase in glycine-conjugated derivatives (GCDCA) (4.79 vs 6.64 p = 0.016). There was a positive correlation between ARFI SWV values and GCDCA (r = 0.80, p < 0.0001). Glycine-conjugated BA provided high diagnostic accuracy to predict increased ARFI measurements (AUC 0.90) and clinical (Colombo) CFLD grading (AUC 0.97). CONCLUSIONS: ARFI SWV and bile acid profiles provide evidence for early increase in liver stiffness and altered bile acid metabolism in young CF patients after initiation of ETI and may serve as synergistic measures for detection of hepatic complications during ETI therapy.

Detailed clinical phenotyping and generalisability in prognostic models of functioning in at-risk populations.

Personalised prediction of functional outcomes is a promising approach for targeted early intervention in psychiatry. However, generalisability and resource efficiency of such prognostic models represent challenges. In the PRONIA study (German Clinical Trials Register: DRKS00005042), we demonstrate excellent generalisability of prognostic models in individuals at clinical high-risk for psychosis or with recent-onset depression, and substantial contributions of detailed clinical phenotyping, particularly to the prediction of role functioning. These results indicate that it is possible that functioning prediction models based only on clinical data could be effectively applied in diverse healthcare settings, so that neuroimaging data may not be needed at early assessment stages.

Mapping Solanum chacoense mediated Colorado potato beetle (Leptinotarsa decemlineata) resistance in a self-compatible F2 diploid population.

KEY MESSAGE: A major QTL on chromosome 2 associated with leptine biosynthesis and Colorado potato beetle resistance was identified in a diploid S. chacoense F2 population using linkage mapping and bulk-segregant analysis. We examined the genetic features underlying leptine glycoalkaloid mediated Colorado potato beetle (Leptinotarsa decemlineata) host plant resistance in a diploid F2 mapping population of 233 individuals derived from Solanum chacoense lines USDA8380-1 and M6. The presence of foliar leptine glycoalkaloids in this population segregated as a single dominant gene and displayed continuous distribution of accumulated quantity in those individuals producing the compound. Using biparental linkage mapping, a major overlapping QTL region with partial dominance effects was identified on chromosome 2 explaining 49.3% and 34.1% of the variance in Colorado potato beetle field resistance and leptine accumulation, respectively. Association of this putative resistance region on chromosome 2 was further studied in an expanded F2 population in a subsequent field season. Loci significantly associated with leptine synthesis colocalized to chromosome 2. Significant correlation between increased leptine content and decreased Colorado potato beetle defoliation suggests a single QTL on chromosome 2. Additionally, a minor QTL with overdominance effects explaining 6.2% associated with Colorado potato beetle resistance donated by susceptible parent M6 was identified on chromosome 7. Bulk segregant whole genome sequencing of the same F2 population detected QTL associated with Colorado potato beetle resistance on chromosomes 2, 4, 6, 7, and 12. Weighted gene co-expression network analysis of parental lines and resistant and susceptible F2 individuals identified a tetratricopeptide repeat containing protein with a putative regulatory function and a previously uncharacterized acetyltransferase within the QTL region on chromosome 2, possibly under the control of a regulatory Tap46 subunit within the minor QTL on chromosome 12.

What Are Strategies to Advance Policies Supporting Family Caregivers? Promising Approaches From a Statewide Task Force.

Family caregivers are the cornerstone of the long-term supports and services infrastructure in the United States, yet they often contend with many challenges related to this role. Public policy has been slow to change, leaving many caregivers vulnerable to health and economic consequences. Using models of policy making, we identify barriers to advancing policies that support family caregivers and overcome policy drift. We draw on discussions from the California Task Force on Family Caregiving as it prepares state policy recommendations. Identified strategies include identification of caregivers in health care and workplace settings to promote political consciousness raising, collecting and reporting on data that frame caregiving as a policy problem, borrowing policies and language from overlapping fields to emulate their policy successes, and presenting supportive caregiver policies as solutions to other policy problems. By presenting specific strategic approaches to advance caregiving policies, we provide tools to address the growing gap between caregiver needs and policy responses.

Skin conductance levels may reflect emotional blunting in behavioral variant frontotemporal dementia.

Emotional blunting is a core diagnostic feature of behavioral variant frontotemporal dementia (bvFTD). The authors evaluated skin conductance as a measure of emotional blunting among 10 patients with bvFTD compared with 10 with Alzheimer's disease and 14 healthy control subjects. Despite responses to an auditory startle stimulus, skin conductance levels (SCLs) were lower in the patients with bvFTD compared with the other groups. The low SCLs significantly correlated with ratings of emotional blunting. The authors conclude that low SCLs in bvFTD indicate a low resting sympathetic state and low emotional arousal. The measurement of SCLs may be a useful noninvasive diagnostic test for bvFTD.

Differences in anxiety among patients with early- versus late-onset Alzheimer's disease.

The authors sought to evaluate the incidence and correlates of anxiety in early-onset Alzheimer's disease (EOAD) versus the more typical late-onset AD (LOAD). A group of 23 EOAD and 22 LOAD patients were compared by the Neuropsychiatric Inventory Anxiety subscale. Demographic and disease-related relationships with anxiety were evaluated, as well as types of anxiety symptoms that were endorsed. EOAD patients had significantly more anxiety symptoms than LOAD patients. Among those with EOAD, anxiety was associated with male gender, higher Mini-Mental State Exam score, and separation from caregivers. Among LOAD patients, anxiety was associated with psychotic and activating psychiatric symptoms. These results have implications for the management and alleviation of anxiety in AD.

Suicidal behavior and loss of the future self in semantic dementia.

Semantic dementia impairs semantic autobiographical memory, but tends to spare its episodic components that are critical for the sense of self. Investigators have recently discovered disturbances in the "future self" in semantic dementia. We report a 63-year-old man with semantic dementia who was hospitalized after suicide attempts that he attributed to his loss of a sense of future self. He complained of a decreased sense of being human, because he could not imagine doing things in the future that he had done in the past. Suicidal thinking and inability to place himself in future tasks persisted despite resolution of depression. Clinical assessment revealed a crossmodal loss of semantic knowledge, and neuroimaging showed bilateral anterior temporal atrophy and hypometabolism. On specific tests of autobiographical memory, identity, attribute knowledge, and future projection, the patient could return to the past and visualize himself in familiar scenarios, but he could not visualize himself even passively in these scenarios in the future. His future self was impaired not from seeing himself disabled; it was from an absence of semantic details of potential experiences, associated with impaired semantic autobiographical memory. His self-representations were concrete and specific rather than abstract and generalizable. This patient and recent publications indicate that semantic dementia impairs the ability to imagine oneself as capable in the future, leading some patients to suicidal behavior. We discuss possible mechanisms for these findings, including the potential role of abstract construals for future thinking.

Elexacaftor - Tezacaftor - Ivacaftor treatment improves systemic infection parameters and Pseudomonas aeruginosa colonization rate in patients with cystic fibrosis a monocentric observational study.

Background & aims: The CFTR-modulating therapy Elexaftor - Tezacaftor - Ivacaftor (ETI) has been widely prescribed since its approval in 2020 in the European Union. The aim of this study was to methodically evaluate the effects of an ETI treatment on clinical, biochemical data and Pseudomonas colonization in order to demonstrate its efficacy. Methods: This prospective monocentric study comprised 69 patients diagnosed with cystic fibrosis aged at least 12 years and treated with ETI between September 2020 and November 2021. Clinical and laboratory data of each patient and study visit were collected before and after 24 weeks of ETI treatment. Follow-up status of Pseudomonas aeruginosa (PsA) colonization was assessed after one year of therapy by regularly determined sputum or throat swab samples. Results: Marked improvements biochemical markers of systemic inflammation as white blood cell count, levels of immunoglobulins A, G and M and albumin within 24 weeks of therapy were observed. ETI treatment proved to be effective as seen by amelioration of lung function and sweat chloride concentration. Assessment of PsA colonization status revealed a conversion from a positive to negative detection in 36% of the cases after one year of therapy. Conclusions: ETI treatment effectively improves systemic inflammation parameters and shows promising results in PsA status conversion.

Phased, chromosome-scale genome assemblies of tetraploid potato reveal a complex genome, transcriptome, and predicted proteome landscape underpinning genetic diversity.

Cultivated potato is a clonally propagated autotetraploid species with a highly heterogeneous genome. Phased assemblies of six cultivars including two chromosome-scale phased genome assemblies revealed extensive allelic diversity, including altered coding and transcript sequences, preferential allele expression, and structural variation that collectively result in a highly complex transcriptome and predicted proteome, which are distributed across the homologous chromosomes. Wild species contribute to the extensive allelic diversity in tetraploid cultivars, demonstrating ancestral introgressions predating modern breeding efforts. As a clonally propagated autotetraploid that undergoes limited meiosis, dysfunctional and deleterious alleles are not purged in tetraploid potato. Nearly a quarter of the loci bore mutations are predicted to have a high negative impact on protein function, complicating breeder's efforts to reduce genetic load. The StCDF1 locus controls maturity, and analysis of six tetraploid genomes revealed that 12 allelic variants of StCDF1 are correlated with maturity in a dosage-dependent manner. Knowledge of the complexity of the tetraploid potato genome with its rampant structural variation and embedded deleterious and dysfunctional alleles will be key not only to implementing precision breeding of tetraploid cultivars but also to the construction of homozygous, diploid potato germplasm containing favorable alleles to capitalize on heterosis in F1 hybrids.

Observation of social behavior in frontotemporal dementia.

BACKGROUND: The most characteristic manifestations of behavioral variant frontotemporal dementia (bvFTD) are abnormalities in social behavior. However, distinguishing bvFTD based on social behavior can be difficult in structured clinical settings. METHODS: Using a Social Observation Inventory, 10 patients with bvFTD and 10 patients with Alzheimer's disease (AD) were compared to their caregiver interlocutors on 1-hour mealtime, in-home videotaped segments. RESULTS: Compared to caregivers and patients with AD, patients with bvFTD were significantly disturbed in social behavior. In contrast, patients with AD were indistinguishable from their caregivers. The lack of "you" comments and decreased tact and manners distinguished 92.6% of the patients with bvFTD from patients with AD and caregivers. The Social Observation Inventory scores correlated with scores on frontal-executive tests and socioemotional scales. CONCLUSIONS: The systematic observation of social behavior during routine activities may be one of the best ways to distinguish patients with bvFTD from normal individuals and from patients with other dementias.

A scale of socioemotional dysfunction in frontotemporal dementia.

Early social dysfunction is a hallmark symptom of behavioral variant frontotemporal dementia (bvFTD); however, validated measures for assessing social deficits in dementia are needed. The purpose of the current study was to examine the utility of a novel informant-based measure of social impairment, the Socioemotional Dysfunction Scale (SDS) in early-onset dementia. Sixteen bvFTD and 18 early-onset Alzheimer's disease (EOAD) participants received standard clinical neuropsychological measures and neuroimaging. Caregiver informants were administered the SDS. Individuals with bvFTD exhibited greater social dysfunction on the SDS compared with the EOAD group; t(32) = 6.32, p < .001. The scale demonstrated preliminary evidence for discriminating these frequently misdiagnosed groups (area under the curve = 0.920, p = <.001) and internal consistency α = 0.977. The SDS demonstrated initial evidence as an effective measure for detecting abnormal social behavior and discriminating bvFTD from EOAD. Future validation is recommended in larger and more diverse patient groups.

What dementia reveals about proverb interpretation and its neuroanatomical correlates.

OBJECTIVE: Neuropsychologists frequently include proverb interpretation as a measure of executive abilities. A concrete interpretation of proverbs, however, may reflect semantic impairments from anterior temporal lobes, rather than executive dysfunction from frontal lobes. The investigation of proverb interpretation among patients with different dementias with varying degrees of temporal and frontal dysfunction may clarify the underlying brain-behavior mechanisms for abstraction from proverbs. We propose that patients with behavioral variant frontotemporal dementia (bvFTD), who are characteristically more impaired on proverb interpretation than those with Alzheimer's disease (AD), are disproportionately impaired because of anterior temporal-mediated semantic deficits. METHODS: Eleven patients with bvFTD and 10 with AD completed the Delis-Kaplan Executive Function System (D-KEFS) Proverbs Test and a series of neuropsychological measures of executive and semantic functions. The analysis included both raw and age-adjusted normed data for multiple choice responses on the D-KEFS Proverbs Test using independent samples t-tests. Tensor-based morphometry (TBM) applied to 3D T1-weighted MRI scans mapped the association between regional brain volume and proverb performance. Computations of mean Jacobian values within select regions of interest provided a numeric summary of regional volume, and voxel-wise regression yielded 3D statistical maps of the association between tissue volume and proverb scores. RESULTS: The patients with bvFTD were significantly worse than those with AD in proverb interpretation. The worse performance of the bvFTD patients involved a greater number of concrete responses to common, familiar proverbs, but not to uncommon, unfamiliar ones. These concrete responses to common proverbs correlated with semantic measures, whereas concrete responses to uncommon proverbs correlated with executive functions. After controlling for dementia diagnosis, TBM analyses indicated significant correlations between impaired proverb interpretation and the anterior temporal lobe region (left>right). CONCLUSIONS: Among two dementia groups, those with bvFTD, demonstrated a greater number of concrete responses to common proverbs compared to those with AD, and this performance correlated with semantic deficits and the volume of the left anterior lobe, the hub of semantic knowledge. The findings of this study suggest that common proverb interpretation is greatly influenced by semantic dysfunction and that the use of proverbs for testing executive functions needs to include the interpretation of unfamiliar proverbs.

Neuropsychological and neuroimaging markers in early versus late-onset Alzheimer's disease.

BACKGROUND: Early-onset Alzheimer's disease (EOAD) has been overshadowed by the more common late-onset AD (LOAD). Yet, the literature indicates EOAD may have less hippocampal-memory presentations and more focal neocortical localization early in the disease. OBJECTIVE: To evaluate these proposed differences between these 2 forms of AD and to explore what they inform about differences in AD pathophysiology. METHODS: In all, 21 patients with EOAD and 24 patients with LOAD matched for disease progression and severity were compared on neurocognitive measures and resting state fluorodeoxy-glucose positron-emission tomography (FDG-PET). RESULTS: Patients with EOAD had worse executive functions with greater hypometabolism in the parietal regions; whereas patients with LOAD had worse confrontation naming and verbal recognition memory with greater hypometabolism in inferior frontotemporal regions. CONCLUSIONS: In addition to highlighting significant differences between EOAD and LOAD, these results reveal dissociation between executive deficits in AD and frontal hypometabolism, suggesting early disturbances of the parietal-frontal network in EOAD.

Toward a cancer-specific model of psychological distress: population data from the 2003-2005 National Health Interview Surveys.

INTRODUCTION: Population-based estimates of emotional distress in cancer survivors are lacking, and little is known about specific correlates of clinically meaningful distress. METHODS: Combined 2003-2005 National Health Interview Surveys (NHIS) data were analyzed to evaluate differences in non-somatic distress (measured using the Kessler 6) for those with a history of cancer, those with other chronic health conditions, and healthy adults. RESULTS: The prevalence of clinically meaningful distress was higher in cancer survivors (5.7%) than those with other health conditions (4.3%) or healthy adults (0.7%). In multivariate models, the strongest correlates of serious distress were younger age, lower educational attainment, lack of health insurance coverage, being unmarried, and having pain, fair/poor health status, or other comorbid conditions. While predictors of distress overlapped considerably between those with cancer and other chronic health conditions, having a history of cancer significantly magnified the effects of age, number of children and elders in the household, and access to health insurance on distress. DISCUSSIONS/CONCLUSIONS: The impact of psychological distress is more severe in those with cancer than those living with other chronic health conditions. Those at greatest risk appear to be those with fewer resources to manage their illness. IMPLICATIONS FOR CANCER SURVIVORS: Identifying and understanding correlates of clinically meaningful distress may improve efforts to prevent, identify, and treat significant distress in cancer survivors.