Structural Learning in Autistic and Non-Autistic Children: A Replication and Extension.

The hippocampus is involved in many cognitive domains which are difficult for autistic individuals. Our previous study using a Structural Learning task that has been shown to depend on hippocampal functioning found that structural learning is diminished in autistic adults (Ring et al., 2017). The aim of the present study was to examine whether those results can be replicated in and extended to a sample of autistic and non-autistic children. We tested 43 autistic children and 38 non-autistic children with a subsample of 25 autistic and 28 non-autistic children who were well-matched on IQ. The children took part in a Simple Discrimination task which a simpler form of compound learning, and a Structural Learning task. We expected both groups to perform similarly in Simple Discrimination but reduced performance by the autism group on the Structural Learning task, which is what we found in both the well-matched and the non-matched sample. However, contrary to our prediction and the findings from autistic adults in our previous study, autistic children demonstrated a capacity for Structural Learning and showed an overall better performance in the tasks than was seen in earlier studies. We discuss developmental differences in autism as well as the role of executive functions that may have contributed to better than predicted task performance in this study.

Sleep and Alcohol Use Among Veterans Living With Long COVID.

OBJECTIVES: Study objectives were to: (1) better understand sleep experiences and unhealthy alcohol use among Veterans with long COVID and (2) explore providers' perceptions of barriers and facilitators to delivering evidence-based care for sleep problems and unhealthy alcohol use in patients with long COVID. METHODS: VA electronic health records were used to conduct chart reviews (n = 57) of patients evaluated in a VA COVID-19 Recovery Clinic during 1 calendar year; semi-structured interviews were completed with Veterans (n = 5) and clinicians (n = 7) recruited from the clinic. Veteran participants also completed quantitative, self-report measures assessing sleep- and alcohol-related experiences and behaviors. RESULTS: Data from chart reviews and interviews suggested that Veterans with long COVID often had pre-existing sleep problems that were exacerbated during long COVID. Patients and providers agreed that sleep interventions would be beneficial and acceptable in the COVID-19 Recovery clinic. Conversely, few Veterans with long COVID had a pre-existing alcohol use disorder (AUD) diagnosis; alcohol use occurred less frequently and was less often discussed between patients and providers. Providers had mixed viewpoints on delivering alcohol-related care in the clinic; some were highly amenable, others were unsure whether patients would be receptive. CONCLUSIONS: This study is among the first to take a mixed-method approach to understanding experiences of sleep-wake behaviors and unhealthy alcohol use in Veterans with long COVID. Characterizing sleep and alcohol-related experiences, examining associations with functioning, and exploring perspectives on treatment approaches is critical to support efforts to refine, personalize, and optimize evidence-based sleep and alcohol care for Veterans living with long COVID.

Participation of Veterans Affairs Medical Centers in veteran-centric community-based service navigation networks: A mixed methods study.

OBJECTIVE: To understand the determinants and benefits of cross-sector partnerships between Veterans Affairs Medical Centers (VAMCs) and geographically affiliated AmericaServes Network coordination centers that address Veteran health-related social needs. DATA SOURCES AND SETTING: Semi-structured interviews were conducted with AmericaServes and VAMC staff across seven regional networks. We matched administrative data to calculate the percentage of AmericaServes referrals that were successfully resolved (i.e., requested support was provided) in each network overall and stratified by whether clients were also VAMC patients. STUDY DESIGN: Convergent parallel mixed-methods study guided by Himmelman's Developmental Continuum of Change Strategies (DCCS) for interorganizational collaboration. DATA COLLECTION: Fourteen AmericaServes staff and 17 VAMC staff across seven networks were recruited using snowball sampling and interviewed between October 2021 and April 2022. Rapid qualitative analysis methods were used to characterize the extent and determinants of VAMC participation in networks. PRINCIPAL FINDINGS: On the DCCS continuum of participation, three networks were classified as networking, two as coordinating, one as cooperating, and one as collaborating. Barriers to moving from networking to collaborating included bureaucratic resistance to change, VAMC leadership buy-in, and not having VAMCs staff use the shared technology platform. Facilitators included ongoing communication, a shared mission of serving Veterans, and having designated points-of-contact between organizations. The percentage of referrals that were successfully resolved was lowest in networks engaged in networking (65.3%) and highest in cooperating (85.6%) and collaborating (83.1%) networks. For coordinating, cooperating, and collaborating networks, successfully resolved referrals were more likely among Veterans who were also VAMC patients than among Veterans served only by AmericaServes. CONCLUSIONS: VAMCs participate in AmericaServes Networks at varying levels. When partnerships are more advanced, successful resolution of referrals is more likely, especially among Veterans who are dually served by both organizations. Although challenges to establishing partnerships exist, this study highlights effective strategies to overcome them.

Microbial ecosystem assessment and hydrogen oxidation potential of newly discovered vent systems from the Central and South-East Indian Ridge.

In order to expand the knowledge of microbial ecosystems from deep-sea hydrothermal vent systems located on the Central and South-East Indian Ridge, we sampled hydrothermal fluids, massive sulfides, ambient water and sediments of six distinct vent fields. Most of these vent sites were only recently discovered in the course of the German exploration program for massive sulfide deposits and no previous studies of the respective microbial communities exist. Apart from typically vent-associated chemosynthetic members of the orders Campylobacterales, Mariprofundales, and Thiomicrospirales, high numbers of uncultured and unspecified Bacteria were identified via 16S rRNA gene analyses in hydrothermal fluid and massive sulfide samples. The sampled sediments however, were characterized by an overall lack of chemosynthetic Bacteria and the presence of high proportions of low abundant bacterial groups. The archaeal communities were generally less diverse and mostly dominated by members of Nitrosopumilales and Woesearchaeales, partly exhibiting high proportions of unassigned Archaea. Correlations with environmental parameters were primarily observed for sediment communities and for microbial species (associated with the nitrogen cycle) in samples from a recently identified vent field, which was geochemically distinct from all other sampled sites. Enrichment cultures of diffuse fluids demonstrated a great potential for hydrogen oxidation coupled to the reduction of various electron-acceptors with high abundances of Hydrogenovibrio and Sulfurimonas species. Overall, given the large number of currently uncultured and unspecified microorganisms identified in the vent communities, their respective metabolic traits, ecosystem functions and mediated biogeochemical processes have still to be resolved for estimating consequences of potential environmental disturbances by future mining activities.

An anchor-tether 'hindered' HCN1 inhibitor is antihyperalgesic in a rat spared nerve injury neuropathic pain model.

BACKGROUND: Neuropathic pain impairs quality of life, is widely prevalent, and incurs significant costs. Current pharmacological therapies have poor/no efficacy and significant adverse effects; safe and effective alternatives are needed. Hyperpolarisation-activated cyclic nucleotide-regulated (HCN) channels are causally implicated in some forms of peripherally mediated neuropathic pain. Whilst 2,6-substituted phenols, such as 2,6-di-tert-butylphenol (26DTB-P), selectively inhibit HCN1 gating and are antihyperalgesic, the development of therapeutically tolerable, HCN-selective antihyperalgesics based on their inverse agonist activity requires that such drugs spare the cardiac isoforms and do not cross the blood-brain barrier. METHODS: In silico molecular dynamics simulation, in vitro electrophysiology, and in vivo rat spared nerve injury methods were used to test whether 'hindered' variants of 26DTB-P (wherein a hydrophilic 'anchor' is attached in the para-position of 26DTB-P via an acyl chain 'tether') had the desired properties. RESULTS: Molecular dynamics simulation showed that membrane penetration of hindered 26DTB-Ps is controlled by a tethered diol anchor without elimination of head group rotational freedom. In vitro and in vivo analysis showed that BP4L-18:1:1, a variant wherein a diol anchor is attached to 26DTB-P via an 18-carbon tether, is an HCN1 inverse agonist and an orally available antihyperalgesic. With a CNS multiparameter optimisation score of 2.25, a >100-fold lower drug load in the brain vs blood, and an absence of adverse cardiovascular or CNS effects, BP4L-18:1:1 was shown to be poorly CNS penetrant and cardiac sparing. CONCLUSIONS: These findings provide a proof-of-concept demonstration that anchor-tethered drugs are a new chemotype for treatment of disorders involving membrane targets.

Improving suicide prevention for women veterans: Recommendations from VHA suicide prevention coordinators.

OBJECTIVE: Women are a minority veteran subpopulation experiencing particular risk for suicide and facing distinct challenges in accessing Veterans Health Administration (VHA) care. As part of efforts to enhance suicide prevention, the VHA established Suicide Prevention Coordinators (SPC) as clinicians who work exclusively to connect high-risk veterans to the scope of VHA's services. To understand the experiences of women veterans with suicide risk who access care, this study presents findings from qualitative interviews with SPCs regarding the care needs, preferences, and concerns of women veterans who utilize VHA for enhanced suicide-related care. METHODS: We conducted qualitative interviews with 20 SPCs from 13 VAMCs around the United States. We specifically asked SPCs to share perspectives on women veterans' barriers to accessing care and their recommendations to improve suicide prevention for this subpopulation. We conducted a thematic content analysis to extract key themes. RESULTS: SPCs revealed that women veterans opt to avoid VHA due to prior negative experiences, often related to provider sensitivity to women's issues. Safety was another key concern, specifically related to feeling unwelcome or intimidated in the male dominated veteran community. Key provider recommendations include increasing the availability of gender-sensitive providers and making changes to the physical spaces of the VHA to better facilitate women veterans' access to care. CONCLUSIONS: SPCs underscored the importance of comfort and relatability between women patients and providers, especially in relation to enhanced care for suicide risk. This study presents important evidence in support of enhancing suicide prevention by better engaging women veterans in care that is more inclusive and more sensitive to their experiences and identity, in and outside VHA.

Activity-Based Screening of Metagenomic Fosmid Libraries for Hydrogen-Uptake Enzymes.

Here, we outline how to identify hydrogenase enzymes from metagenomic fosmid libraries through an activity-based screening approach. A metagenomic fosmid library is constructed in E. coli and the fosmids are transferred into a hydrogenase deletion mutant of Shewanella oneidensis MR-1 (ΔhyaB) via triparental mating. If a fosmid clone exhibits hydrogen-uptake activity, S. oneidensis' phenotype is restored and hydrogenase activity is indicated by a color change of the medium from yellow to colorless. The screen enables screening of 48 metagenomic fosmid clones in parallel.

Impact of high Fe-concentrations on microbial community structure and dissolved organics in hydrothermal plumes: an experimental study.

Iron (Fe) is an essential trace element for life. In the ocean, Fe can be exceptionally scarce and thus biolimiting or extremely enriched causing microbial stress. The ability of hydrothermal plume microbes to counteract unfavorable Fe-concentrations up to 10 mM is investigated through experiments. While Campylobacterota (Sulfurimonas) are prominent in a diverse community at low to intermediate Fe-concentrations, the highest 10 mM Fe-level is phylogenetically less diverse and dominated by the SUP05 clade (Gammaproteobacteria), a species known to be genetically well equipped to strive in high-Fe environments. In all incubations, Fe-binding ligands were produced in excess of the corresponding Fe-concentration level, possibly facilitating biological Fe-uptake in low-Fe incubations and detoxification in high-Fe incubations. The diversity of Fe-containing formulae among dissolved organics (SPE-DOM) decreased with increasing Fe-concentration, which may reflect toxic conditions of the high-Fe treatments. A DOM-derived degradation index (IDEG) points to a degradation magnitude (microbial activity) that decreases with Fe and/or selective Fe-DOM coagulation. Our results show that some hydrothermal microbes (especially Gammaproteobacteria) have the capacity to thrive even at unfavorably high Fe-concentrations. These ligand-producing microbes could hence play a key role in keeping Fe in solution, particularly in environments, where Fe precipitation dominates and toxic conditions prevail.

Effects of an integrated mindfulness intervention for veterans with diabetes distress: a randomized controlled trial.

INTRODUCTION: US military veterans have disproportionately high rates of diabetes and diabetes-related morbidity in addition to being at risk of comorbid stress-related conditions. This study aimed to examine the effects of a technology-supported mindfulness intervention integrated into usual diabetes care and education on psychological and biobehavioral outcomes. RESEARCH DESIGN AND METHODS: Veterans (N=132) with type 1 or 2 diabetes participated in this two-arm randomized controlled efficacy trial. The intervention arm received a one-session mindfulness intervention integrated into a pre-existing program of diabetes self-management education and support (DSMES) plus one booster session and 24 weeks of home practice supported by a mobile application. The control arm received one 3-hour comprehensive DSMES group session. The primary outcome was change in diabetes distress (DD). The secondary outcomes were diabetes self-care behaviors, diabetes self-efficacy, post-traumatic stress disorder (PTSD), depression, mindfulness, hemoglobin A1C (HbA1C), body weight, and blood pressure. Assessments were conducted at baseline, 12 weeks, and 24 weeks. Participant satisfaction and engagement in home practice were assessed in the intervention group at 12 and 24 weeks. RESULTS: Intention-to-treat group by time analyses showed a statistically significant improvement in DD in both arms without significant intervention effect from baseline to 24 weeks. Examination of distal effects on DD between weeks 12 and 24 showed significantly greater improvement in the intervention arm. Improvement in DD was greater when baseline HbA1C was <8.5%. A significant intervention effect was also shown for general dietary behaviors. The secondary outcomes diabetes self-efficacy, PTSD, depression, and HbA1C significantly improved in both arms without significant intervention effects. Mindfulness and body weight were unchanged in either group. CONCLUSIONS: A technology-supported mindfulness intervention integrated with DSMES showed stronger distal effects on DD compared with DSMES control. Examination of longer-term outcomes, underlying mechanisms, and the feasibility of virtual delivery is warranted. TRIAL REGISTRATION NUMBER: NCT02928952.

Environmental changes affect the microbial release of hydrogen sulfide and methane from sediments at Boknis Eck (SW Baltic Sea).

Anthropogenic activities are modifying the oceanic environment rapidly and are causing ocean warming and deoxygenation, affecting biodiversity, productivity, and biogeochemical cycling. In coastal sediments, anaerobic organic matter degradation essentially fuels the production of hydrogen sulfide and methane. The release of these compounds from sediments is detrimental for the (local) environment and entails socio-economic consequences. Therefore, it is vital to understand which microbes catalyze the re-oxidation of these compounds under environmental dynamics, thereby mitigating their release to the water column. Here we use the seasonally dynamic Boknis Eck study site (SW Baltic Sea), where bottom waters annually fall hypoxic or anoxic after the summer months, to extrapolate how the microbial community and its activity reflects rising temperatures and deoxygenation. During October 2018, hallmarked by warmer bottom water and following a hypoxic event, modeled sulfide and methane production and consumption rates are higher than in March at lower temperatures and under fully oxic bottom water conditions. The microbial populations catalyzing sulfide and methane metabolisms are found in shallower sediment zones in October 2018 than in March 2019. DNA-and RNA profiling of sediments indicate a shift from primarily organotrophic to (autotrophic) sulfide oxidizing Bacteria, respectively. Previous studies using data collected over decades demonstrate rising temperatures, decreasing eutrophication, lower primary production and thus less fresh organic matter transported to the Boknis Eck sediments. Elevated temperatures are known to stimulate methanogenesis, anaerobic oxidation of methane, sulfate reduction and essentially microbial sulfide consumption, likely explaining the shift to a phylogenetically more diverse sulfide oxidizing community based on RNA.

Veterans' Experiences With Diabetes: A Qualitative Analysis.

PURPOSE: The purpose of the study was to explore an understanding of the psychosocial-behavioral impact of diabetes self-management among veterans with diabetes. METHODS: Twenty-six veterans participated in 1 of 9 focus groups that were conducted following a group diabetes self-management education class and prior to a mindfulness intervention as part of a feasibility pilot study. Discussions were guided by open-ended questions that addressed the overarching research question, "How do attitudes and experiences with diabetes inform psychosocial-educational approaches to diabetes self-management education and care for veterans?" Focus groups were audio-recorded and transcribed. The data was then independently coded and thematically analyzed by 2 coders. RESULTS: Five main themes that reflect veterans' perceptions of their experiences with diabetes and diabetes self-management were identified: (1) distress and negative emotions, (2) social isolation, (3) perceived lack of control, (4) attitudes toward diabetes support, and (5) desire for information about stress, diabetes, health, and behavior. CONCLUSIONS: Veterans experience emotional distress and have unmet psychosocial needs related to diabetes self-management. Insight gained from these veteran perspectives suggests a framework for integrating psycho-educational interventions like mindfulness into diabetes care that emphasize stress reduction, person-centered communication, and opportunities for peer support.

Brain-behaviour correlates of habitual motivation in chronic back pain.

Chronic pain may sap the motivation for positive events and stimuli. This may lead to a negative behavioural cycle reducing the establishment of appetitive habitual engagement. One potential mechanism for this might be biased learning. In our experiment, chronic back pain patients and healthy controls completed an appetitive Pavlovian-instrumental transfer procedure. We examined participants` behaviour and brain activity and reported pain, depression and anxiety. Patients showed reduced habitual behaviour and increased responses in the hippocampus than controls. This behavioural bias was related to motivational value and reflected in the updating of brain activity in prefrontal-striatal-limbic circuits. Moreover, this was influenced by pain symptom duration, depression and anxiety (explained variance: up to 50.7%). Together, findings identify brain-behaviour pathways for maladaptive habitual learning and motivation in chronic back pain, which helps explaining why chronic pain can be resistant to change, and where clinical characteristics are significant modulators.

Volumetric brain correlates of approach-avoidance behavior and their relation to chronic back pain.

Avoiding any harm, such as painful experiences, is an important ability for our physical and mental health. This avoidance behavior might be overactive under chronic pain, and the cortical and subcortical brain volumetry, which also often changes in chronic pain states, might be a significant correlate of this behavior. In the present study, we thus investigated the association between volumetric brain differences using 3 T structural magnetic resonance imaging and pain- versus pleasure-related approach-avoidance behavior using an Approach Avoidance Task in the laboratory in chronic back pain (N = 42; mean age: 51.34 years; 23 female) and healthy individuals (N = 43; mean age: 45.21 years; 15 female). We found significant differences in hippocampal, amygdala and accumbens volumes in patients compared to controls. The patients` hippocampal volume was significantly positively related to pain avoidance, the amygdala volume to positive approach, and the accumbens volume negatively to a bias to pain avoidance over positive approach. These associations were significantly moderated by pain symptom duration. Cortical structure may thus contribute to an overacting pain avoidance system in chronic back pain, and could, together with a reduction in approaching positive stimuli, be related to maladaptive choice and decision-making processes in chronic pain.

Alkylphenol inverse agonists of HCN1 gating: H-bond propensity, ring saturation and adduct geometry differentially determine efficacy and potency.

BACKGROUND AND PURPOSE: In models of neuropathic pain, inhibition of HCN1 is anti-hyperalgesic. 2,6-di-iso-propyl phenol (propofol) and its non-anesthetic congener, 2,6-di-tert-butyl phenol, inhibit HCN1 channels by stabilizing closed state(s). EXPERIMENTAL APPROACH: Using in vitro electrophysiology and kinetic modeling, we systematically explore the contribution of ligand architecture to alkylphenol-channel coupling. KEY RESULTS: When corrected for changes in hydrophobicity (and propensity for intra-membrane partitioning), the decrease in potency upon 1-position substitution (NCO∼OH >> SH >>> F) mirrors the ligands' H-bond acceptor (NCO > OH > SH >>> F) but not donor profile (OH > SH >>> NCO∼F). H-bond elimination (OH to F) corresponds to a ΔΔG of ∼4.5 kCal mol-1 loss of potency with little or no disruption of efficacy. Substitution of compact alkyl groups (iso-propyl, tert-butyl) with shorter (ethyl, methyl) or more extended (sec-butyl) adducts disrupts both potency and efficacy. Ring saturation (with the obligate loss of both planarity and π electrons) primarily disrupts efficacy. CONCLUSIONS AND IMPLICATIONS: A hydrophobicity-independent decrement in potency at higher volumes suggests the alkylbenzene site has a volume of ≥800 Å3. Within this, a relatively static (with respect to ligand) H-bond donor contributes to initial binding with little involvement in generation of coupling energy. The influence of π electrons/ring planarity and alkyl adducts on efficacy reveals these aspects of the ligand present towards a face of the channel that undergoes structural changes during opening. The site's characteristics suggest it is "druggable"; introduction of other adducts on the ring may generate higher potency inverse agonists.

The association between California Verbal Learning Test performance and fibre impairment in multiple sclerosis: evidence from diffusion tensor imaging.

The California Verbal Learning Test (CVLT) is recognized as a standard clinical tool for assessing episodic memory difficulties in multiple sclerosis (MS), but its neural correlates have not yet been examined in detail in this patient population. We combined neuropsychological examination and diffusion tensor imaging (DTI) analysis in a group of MS patients (N = 50) and demographically matched healthy participants (N = 20). We investigated the degree of impairment of the uncinate fascicle (UF), the superior longitudinal fascicle (SLF), the fornix (FX) and the cingulum (CG). The patients were impaired on all CVLT parameters and the DTI parameters correlated moderately with disease-related variables. Regression analyses in the complete study sample showed that CVLT learning scores correlated with impairment of the right UF. This association reached marginal significance in the patient sample. In contrast to other studies claiming retrieval deficits, our results suggest that encoding and consolidation deficits may play a major role in verbal memory impairments in MS. The findings also provide evidence for an association between degree of myelination of prefrontal fibre pathways and encoding efficiency. Finally, DTI-derived measurements appear to reflect disease progression in MS. The results are discussed in light of functional MRI studies investigating compensatory brain activity during cognitive processing in MS.