Striatal Dopamine Contributions to Skilled Motor Learning.

Coordinated multijoint limb and digit movements-"manual dexterity"-underlie both specialized skills (e.g., playing the piano) and more mundane tasks (e.g., tying shoelaces). Impairments in dexterous skill cause significant disability, as occurs with motor cortical injury, Parkinson's disease, and a range of other pathologies. Clinical observations, as well as basic investigations, suggest that corticostriatal circuits play a critical role in learning and performing dexterous skills. Furthermore, dopaminergic signaling in these regions is implicated in synaptic plasticity and motor learning. Nonetheless, the role of striatal dopamine signaling in skilled motor learning remains poorly understood. Here, we use fiber photometry paired with a genetically encoded dopamine sensor to investigate striatal dopamine release in both male and female mice as they learn and perform a skilled reaching task. Dopamine rapidly increases during a skilled reach and peaks near pellet consumption. In the dorsolateral striatum, dopamine dynamics are faster than in the dorsomedial and ventral striatum. Across training, as reaching performance improves, dopamine signaling shifts from pellet consumption to cues that predict pellet availability, particularly in medial and ventral areas of the striatum. Furthermore, performance prediction errors are present across the striatum, with reduced dopamine release after an unsuccessful reach. These findings show that dopamine dynamics during skilled motor behaviors change with learning and are differentially regulated across striatal subregions.

Consumption of a smoothie or cereal-based breakfast: impact on thirst, hunger, appetite and subsequent dietary intake.

Smoothies are a popular breakfast option. However, liquids may evoke weaker satiation than nutritionally comparable semi-solid and solid foods. This study examined consumption of cereal and milk (CM) or a nutritionally comparable fruit smoothie (FS) for breakfast on subsequent dietary behaviours, in a controlled laboratory setting. Twenty-five participants (age 25 ± 6 y) completed three trials, receiving either CM or FS for breakfast. Afterwards, participants remained isolated for 4 h with ad libitum access to foods/beverages. A repeat trial (CM or FS) allowed exploration of normal variability. Post-breakfast energy intake (EI) (CM = 1465(2436) vs. FS = 1787(3190) kJ, Median (IQR), p = 0.099), time to intake of next food/fluid (meal latency) (CM = 146(97) vs. FS = 180(100) min, p = 0.127), and subjective hunger, desire to eat, fullness and thirst ratings were similar between conditions (p's > 0.05). The mean coefficient of variation for EI and meal latency were 41% and 21%, respectively. Consumption of a FS does not negatively impact acute EI and meal latency.

Striatal dopamine contributions to skilled motor learning.

Coordinated multi-joint limb and digit movements - "manual dexterity" - underlie both specialized skills (e.g., playing the piano) and more mundane tasks (e.g., tying shoelaces). Impairments in dexterous skill cause significant disability, as occurs with motor cortical injury, Parkinson's Disease, and a range of other pathologies. Clinical observations, as well as basic investigations, suggest that cortico-striatal circuits play a critical role in learning and performing dexterous skills. Furthermore, dopaminergic signaling in these regions is implicated in synaptic plasticity and motor learning. Nonetheless, the role of striatal dopamine signaling in skilled motor learning remains poorly understood. Here, we use fiber photometry paired with a genetically encoded dopamine sensor to investigate striatal dopamine release as mice learn and perform a skilled reaching task. Dopamine rapidly increases during a skilled reach and peaks near pellet consumption. In dorsolateral striatum, dopamine dynamics are faster than in dorsomedial and ventral striatum. Across training, as reaching performance improves, dopamine signaling shifts from pellet consumption to cues that predict pellet availability, particularly in medial and ventral areas of striatum. Furthermore, performance prediction errors are present across the striatum, with reduced dopamine release after an unsuccessful reach. These findings show that dopamine dynamics during skilled motor behaviors change with learning and are differentially regulated across striatal subregions.

Methenamine for urinary tract infection prophylaxis: A systematic review.

Urinary tract infections (UTIs) commonly affect many patient populations. Recurrent UTIs (rUTIs) can be particularly problematic and lead to potential hospitalizations, multiple antibiotic courses, and have a potential negative impact on quality of life. To prevent UTIs, antibiotics are frequently used for prophylaxis; however, antibiotic prophylaxis has notable untoward consequences including but not limited to potential adverse effects and development of antibiotic resistance. Methenamine, an antiseptic agent initially available in 1967, has re-emerged as a potential option for UTI prophylaxis in various populations, including older adults and renal transplant recipients. The objective of this systematic review was to evaluate the clinical effectiveness and safety of methenamine for UTI prophylaxis. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance was performed. A PubMed, Embase, and Cochrane library search was conducted to identify relevant English-language studies evaluating methenamine for UTI prophylaxis including randomized controlled trials, case-control studies, and meta-analyses through June 2023. Articles were excluded if the studies did not primarily describe or evaluate methenamine for UTI prophylaxis, were commentaries/viewpoints articles, point prevalence studies, review articles, studies that evaluated methenamine used with another agent, and any duplicate publications from searched databases. A total of 11 articles were identified for inclusion. This systematic review suggests methenamine generally appears to be an effective and well-tolerated antibiotic-sparing option for UTI prophylaxis. Furthermore, the pharmacology, dosage and formulation, warnings, precautions, and safety considerations of methenamine that provide potential clinical considerations regarding its use for UTI prophylaxis are described. Further studies are needed to evaluate the clinical utility of methenamine for UTI prophylaxis.

"Who am I going to stay with? Who will accept me?": family-level domains influencing HIV care engagement among disengaged adolescents in Kenya.

INTRODUCTION: Adolescents living with HIV (ALHIV, ages 10-19) have developmentally specific needs in care, and have lower retention compared to other age groups. Family-level contexts may be critical to adolescent HIV outcomes, but have often been overlooked. We investigated family-level factors underlying disengagement and supporting re-engagement among adolescents disengaged from HIV care. METHODS: Semi-structured interviews were performed with 42 disengaged ALHIV, 32 of their caregivers and 28 healthcare workers (HCW) in the Academic Model Providing Access to Healthcare (AMPATH) program in western Kenya, from 2018 to 2020. Disengaged ALHIV had ≥1 visit within the 18 months prior to data collection at one of two sites and nonattendance ≥60 days following their last scheduled appointment. HCW were recruited from 10 clinics. Transcripts were analysed through thematic analysis. A conceptual model for family-level domains influencing adolescent HIV care engagement was developed from these themes. RESULTS: Family-level factors emerged as central to disengagement. ALHIV-particularly those orphaned by the loss of one or both parents-experienced challenges when new caregivers or unstable living situations limited support for HIV care. These challenges were compounded by anticipated stigma; resultant non-disclosure of HIV status to household members; enacted stigma in the household, with overwhelming effects on adolescents; or experiences of multiple forms of trauma, which undermined HIV care engagement. Some caregivers lacked finances or social support to facilitate care. Others did not feel equipped to support adolescent engagement or adherence. Regarding facilitators to re-engagement, participants described roles for household disclosure; and solidarity from caregivers, especially those also living with HIV. Family-level domains influencing HIV care engagement were conceptualized as follows: (1) adolescent living situation and contexts; (2) household material resources or poverty; (3) caregiver capacities and skills to support adolescent HIV care; and (4) HIV stigma or solidarity at the household level. CONCLUSIONS: Family-level factors are integral to retention in care for ALHIV. The conceptual model developed in this study for family-level influences on care engagement may inform holistic approaches to promote healthy outcomes for ALHIV. Developmentally appropriate interventions targeting household relationships, disclosure, HIV stigma reduction, HIV care skills and resources, and economic empowerment may promote adolescent engagement in HIV care.