Predictors of National Institute on Alcohol Abuse and Alcoholism (NIAAA) Alcohol Recovery among Individuals in Alcohol Treatment: Implications for Social Work.

The National Institute on Alcohol Abuse and Alcoholism's (NIAAA) definition of alcohol use disorder (AUD) recovery stipulates two criteria: remission from DSM-5 AUD and cessation of heavy drinking. Importantly, these criteria allow for consideration of nonabstinent alcohol treatment outcomes. However, researchers have yet to assess potential predictors of the NIAAA recovery outcome. The current study examined associations between mental health and coping predictors of NIAAA recovery status in an AUD treatment sample. At baseline (BL) and end-of-treatment (EOT) research interviews in a clinical trial, participants (N = 118) completed questionnaires assessing alcohol dependence, mental health, and confidence levels in reducing heavy drinking, as well as alcohol use and DSM-5 AUD symptom endorsement. Logistic regression models tested the associations between chosen predictors and the odds of achieving NIAAA recovery. Twenty-four percent of individuals (n = 28) met both criteria for NIAAA recovery at EOT. Higher levels of BL state anxiety and anxiety sensitivity predicted lower odds of achieving NIAAA recovery, while greater confidence to reduce heavy drinking predicted increased odds of NIAAA recovery. Social workers are encouraged to continue assessing and addressing mental health in AUD treatment to help individuals with alcohol problems achieve their AUD recovery goals.

Socioeconomic Disadvantage, Neighborhood Belonging, and Inflammation Among Adolescents.

OBJECTIVE: Childhood socioeconomic disadvantage is associated with a host of adverse health outcomes across the lifespan. However, there is increasing interest in identifying factors that may promote resilience to disadvantage's effects on health. One promising candidate in this regard is a sense of neighborhood belonging, which could offset health risks by providing a sense of connection to others, as well as a sense of belonging to a community larger than oneself. METHODS: In a sample of 245 adolescents (age: M = 15.98 years, SD = 0.54; sex: 64.1% female; race: 41.6% White, 37.6% Black/African American, 9.8% Other; ethnicity: 68.6% non-Hispanic), we examined neighborhood belonging as a moderator of the relationship between socioeconomic disadvantage (measured on a 0-5-point scale, M = 1.21; SD = 1.36) and low-grade inflammation (measured via a composite of circulating inflammatory biomarkers including IL-6, IL-8, IL-10, TNF-a, CRP, and suPAR). Covariates included age, sex, race/ethnicity, and pubertal status. RESULTS: Neighborhood belonging buffered the relationship between socioeconomic disadvantage and low-grade inflammation, a key mechanistic pathway to multiple chronic diseases. Specifically, there was a positive relationship between socioeconomic disadvantage and low-grade inflammation among individuals with low neighborhood belonging, but not among individuals with high neighborhood belonging. CONCLUSIONS: These findings suggest that neighborhood belonging is one type of social connection factor that can mitigate the relationship between socioeconomic disadvantage and low-grade inflammation in youth.

The Evolving Role of Genetic Testing in Monogenic Kidney Stone Disease: Spotlight on Primary Hyperoxaluria.

PURPOSE: Multiple factors are thought to give rise to common, recurrent kidney stone disease, but for monogenic stone disorders a firm diagnosis is possible through genetic testing. The autosomal recessive primary hyperoxalurias (PH) are rare forms of monogenic kidney stone disease. All 3 types of PH are caused by inborn errors of glyoxylate metabolism in the liver, leading to hepatic oxalate overproduction and excessive renal urinary oxalate excretion. These conditions are characterized by kidney stones, nephrocalcinosis, progressive chronic kidney disease, and kidney failure. Systemic oxalosis, the extra-renal deposition of oxalate resulting in severe morbidity and mortality, occurs in chronic kidney disease when oxalate clearance by the kidneys declines. Novel small interfering RNA-based therapeutics targeting the liver to reduce urinary oxalate excretion have been approved, introducing precision medicine to treat primary hyperoxaluria type 1. The goal of this narrative review is to address the benefits and practicalities of genetic testing for suspected monogenic kidney stone disease and the critical roles of a multidisciplinary team. MATERIALS AND METHODS: We collated our procedures, education, training, and workflows to help other clinicians integrate genetic assessment into their diagnostic routines. RESULTS: In our experience, increased access to genetic testing facilitates early detection of PH and other monogenic causes of kidney stone disease so that individualized care can be instituted promptly. CONCLUSIONS: Alongside biochemical assessments, more widespread genetic testing may ensure more timely diagnoses so that patients with suspected monogenic kidney stone disease gain access to an expanded range of services and enrollment in clinical trials and registries.

Cross-modal Transfer Learning Based on an Improved CycleGAN Model for Accurate Kidney Segmentation in Ultrasound Images.

OBJECTIVE: Deep-learning algorithms have been widely applied in the field of automatic kidney ultrasound (US) image segmentation. However, obtaining a large number of accurate kidney labels clinically is very difficult and time-consuming. To solve this problem, we have proposed an efficient cross-modal transfer learning method to improve the performance of the segmentation network on a limited labeled kidney US dataset. METHODS: We aim to implement an improved image-to-image translation network called Seg-CycleGAN to generate accurate annotated kidney US data from labeled abdomen computed tomography images. The Seg-CycleGAN framework primarily consists of two structures: (i) a standard CycleGAN network to visually simulate kidney US from a publicly available labeled abdomen computed tomography dataset; (ii) and a segmentation network to ensure accurate kidney anatomical structures in US images. Based on the large number of simulated kidney US images and small number of real annotated kidney US images, we then aimed to employ a fine-tuning strategy to obtain better segmentation results. RESULTS: To validate the effectiveness of the proposed method, we tested this method on both normal and abnormal kidney US images. The experimental results showed that the proposed method achieved a segmentation accuracy of 0.8548 in dice similarity coefficient on all testing datasets and 0.7622 on the abnormal testing dataset. CONCLUSIONS: Compared with existing data augmentation and transfer learning methods, the proposed method improved the accuracy and generalization of the kidney US image segmentation network on a limited number of training datasets. It therefore has the potential to significantly reduce annotation costs in clinical settings.

Age-associated temporal decline in butyrate-producing bacteria plays a key pathogenic role in the onset and progression of neuropathology and memory deficits in 3×Tg-AD mice.

Alterations in the gut-microbiome-brain axis are increasingly being recognized to be involved in Alzheimer's disease (AD) pathogenesis. However, the functional consequences of enteric dysbiosis linking gut microbiota and brain pathology in AD progression remain largely undetermined. The present work investigated the causal role of age-associated temporal decline in butyrate-producing bacteria and butyrate in the etiopathogenesis of AD. Longitudinal metagenomics, neuropathological, and memory analyses were performed in the 3×Tg-AD mouse model. Metataxonomic analyses showed a significant temporal decline in the alpha diversity marked by a decrease in butyrate-producing bacterial communities and a concurrent reduction in cecal butyrate production. Inferred metagenomics analysis identified the bacterial acetyl-CoA pathway as the main butyrate synthesis pathway impacted. Concomitantly, there was an age-associated decline in the transcriptionally permissive acetylation of histone 3 at lysines 9 and 14 (H3K9/K14-Ac) in hippocampal neurons. Importantly, these microbiome-gut-brain changes preceded AD-related neuropathology, including oxidative stress, tau hyperphosphorylation, memory deficits, and neuromuscular dysfunction, which manifest by 17-18 months. Initiation of oral administration of tributyrin, a butyrate prodrug, at 6 months of age mitigated the age-related decline in butyrate-producing bacteria, protected the H3K9/K14-Ac status, and attenuated the development of neuropathological and cognitive changes associated with AD pathogenesis. These data causally implicate age-associated decline in butyrate-producing bacteria as a key pathogenic feature of the microbiome-gut-brain axis affecting the onset and progression of AD. Importantly, the regulation of butyrate-producing bacteria and consequent butyrate synthesis could be a significant therapeutic strategy in the prevention and treatment of AD.

Development and Validation of Electronic Health Record Measures of Safety Planning Practices as Part of Zero Suicide Implementation.

OBJECTIVE: Safety planning for suicide prevention is an important quality metric for Zero Suicide implementation. We describe the development, validation, and application of electronic health record (EHR) programs to measure uptake of safety planning practices across six integrated healthcare systems as part of a Zero Suicide evaluation study. METHODS: Safety planning was documented in narrative notes and structured EHR templates using the Stanley Brown Safety Planning Intervention (SBSPI) in response to a high-risk cutoff score on the Columbia Suicide Severity Rating Scale (CSSRS). Natural Language Processing (NLP) metrics were developed and validated using chart review to characterize practices documented in narrative notes. We applied NLP to measure frequency of documentation in the narrative text and standard programming methods to examine structured SBSPI templates from 2010-2022. RESULTS: Chart reviews found three safety planning practices documented in narrative notes that were delivered to at least half of patients at risk: professional contacts, lethal means counseling for firearms, and lethal means counseling for medication access/storage. NLP methods were developed to identify these practices in clinical text with high levels of accuracy (Sensitivity, Specificity, & PPV ≥ 82%). Among visits with a high-risk CSSRS, 40% (Range 2-73% by health system) had an SBSPI template within 1 year of implementation. CONCLUSIONS: This is one of the first reports describing development of measures that leverage electronic health records to track use of suicide prevention safety plans. There are opportunities to use the methods developed here in future evaluations of safety planning.

Measuring safety planning delivery in real-world systems to understand quality of suicide prevention care is challenging.Natural Language Processing (NLP) methods effectively identified some safety planning practices in electronic health records (EHR) from all notes ensuring a comprehensive measurement, but NLP will require updates/testing for local documentation practices.Structured safety planning templates in the EHR using the Stanley Brown Safety Planning Intervention improve ease and accuracy of measurement but may be less comprehensive than NLP for capturing all instances of safety planning documentation.

Voluntary co-contraction of ankle muscles alters motor unit discharge characteristics and reduces estimates of persistent inward currents.

Motoneuronal persistent inward currents (PICs) are facilitated by neuromodulatory inputs but are highly sensitive to local inhibitory circuits. Estimates of PICs are reduced by group Ia reciprocal inhibition, and increased with the diffuse actions of neuromodulators released during remote muscle contraction. However, it remains unknown how motoneurons function in the presence of simultaneous excitatory and inhibitory commands. To probe this topic, we investigated motor unit discharge patterns and estimated PICs during voluntary co-contraction of ankle muscles, which simultaneously demands the contraction of agonist-antagonist pairs. Twenty participants performed triangular ramps of both co-contraction (simultaneous dorsiflexion and plantar flexion) and isometric dorsiflexion to a peak of 30% of their maximum muscle activity from a maximal voluntary contraction. Motor unit spike trains were decomposed from high-density surface EMG activity recorded from tibialis anterior using blind source separation algorithms. Voluntary co-contraction altered motor unit discharge rate characteristics. Discharge rate at recruitment and peak discharge rate were modestly reduced (∼6% change; P < 0.001; d = 0.22) and increased (∼2% change; P = 0.001, d = -0.19), respectively, in the entire dataset but no changes were observed when motor units were tracked across conditions. The largest effects during co-contraction were that estimates of PICs (ΔF) were reduced by ∼20% (4.47 vs. 5.57 pulses per second during isometric dorsiflexion; P < 0.001, d = 0.641). These findings suggest that, during voluntary co-contraction, the inhibitory input from the antagonist muscle overcomes the additional excitatory and neuromodulatory drive that may occur due to the co-contraction of the antagonist muscle, which constrains PIC behaviour. KEY POINTS: Voluntary co-contraction is a unique motor behaviour that concurrently provides excitatory and inhibitory synaptic input to motoneurons. Co-contraction of agonist-antagonist pairs alters agonist motor unit discharge characteristics, consistent with reductions in persistent inward current magnitude.

Protocol for monitoring fatty acid trafficking from lipid droplets to mitochondria in cultured cells.

Intracellular trafficking of fatty acids (FAs) between organelles is critical for cells to adjust their metabolism in response to stimuli such as exercise, fasting, and cold exposure. Here, we describe a protocol to monitor trafficking of FAs from lipid droplets to mitochondria. We describe the labeling of organelles in cultured C2C12 myoblasts with transfection and dyes. We detail a pulse-chase labeling paradigm using a fluorescent FA analog, live-cell imaging to visualize trafficking of FAs, and steps to quantify FA trafficking. For complete details on the use and execution of this protocol, please refer to Miner et al.1.

Synthesis and in vitro evaluation of novel amino-phenylmethylene-imidazolone 5-HT2A receptor antagonists.

Many drugs target the serotonin 2A (5-HT2A) receptor, including psychedelics, antidepressants, and antipsychotics. This study investigates the 5-HT2A receptor-binding properties of a series of novel compounds with an amino-phenylmethylene-imidazolone (APMI) core structure. Two compounds (2a and 2c) demonstrated significant 5-HT2A receptor-binding affinity without agonistic activity, instead displaying antagonistic effects. Structurally, these compounds differ from previously reported phenethylamine-based antagonists. This work introduces APMIs as a novel pharmacophore for 5-HT2A receptor interaction and provides a foundation for developing new 5-HT2A receptor-targeting therapeutic agents.

Dynamic retrieval of events and associations from memory: An integrated account of item and associative recognition.

Memory theories distinguish between item and associative information, which are engaged by different tasks: item recognition uses item information to decide whether an event occurred in a particular context; associative recognition uses associative information to decide whether two events occurred together. Associative recognition is slower and less accurate than item recognition, suggesting that item and associative information may be represented in different forms and retrieved using different processes. Instead, I show how a dynamic model (Cox & Criss, 2020; Cox & Shiffrin, 2017) accounts for accuracy and response time distributions in both item and associative recognition with the same set of representations and processes. Item and associative information are both represented as vectors of features. Item and associative recognition both depend on comparing traces in memory with probes of memory in which item and associative features gradually accumulate. Associative features are slower to accumulate, but largely because they emerge from conjunctions of already-accumulated item features. I apply the model to data from 453 participants, each of whom performed an item and performed associative recognition following identical study conditions (Cox et al., 2018). Comparisons among restricted versions of the model show that its account of associative feature formation, coupled with limits on the rate at which features accumulate from multiple items, explains how and why the dynamics of associative recognition differ from those of item recognition even while both tasks rely on the same underlying representations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Contrast and Complexity in the Low-Temperature Kinetics of CN(v = 1) with O2 and NO: Simultaneous Kinetics and Ringdown in a Uniform Supersonic Flow.

Bimolecular rate coefficients were determined for the reaction CN(v = 1) + NO and O2 using continuous wave cavity ringdown spectroscopy in a uniform supersonic flow (UF-CRDS). The well-matched time scales for ringdown and reaction under pseudo-first-order conditions allow for the use of the SKaR method (simultaneous kinetics and ringdown) in which the full kinetic trace is obtained on each ringdown. The reactions offer an interesting contrast in that the CN(v = 1) + NO system is nonreactive and proceeds by complex-mediated vibrational relaxation, while the CN(v = 1) + O2 reaction is primarily reactive. The measured rate coefficients at 70 K are (2.49 ± 0.08) × 10-11 and (10.49 ± 0.22) × 10-11 cm3 molecule-1 s-1 for the reaction with O2 and NO, respectively. The rate for reaction with O2 is a factor 2 lower than previously reported for v = 0 in the same temperature range, a surprising result, while that for NO is consistent with extrapolation of previous high-temperature measurements to 70 K. The latter is also discussed in light of theoretical calculations and measurements of the rate constants for the association reaction in the high-pressure limit. The measurements are complicated by the presence of a metastable population of high-J CN formed by photolysis of the precursor BrCN, and a kinetic model is developed to treat the competing relaxation and reaction. It is particularly problematic for reactions at low temperatures where the rotational relaxation and reaction have similar rates, precluding a reliable determination of the rate coefficients at 30 K. Also presented are important modifications to the data acquisition and control for the instrument that have yielded considerably enhanced stability and throughput.

Pilot study comparing sleep logs to a commercial wearable device in describing the sleep patterns of physicians-in-training.

With the increasing burden of professional burnout in physicians, attention is being paid to optimizing sleep health, starting in training. The multiple dimensions of physicians' sleep are not well described due to obstacles to easily and reliably measuring sleep. This pilot study tested the feasibility of using commercial wearable devices and completing manual sleep logs to describe sleep patterns of medical students and residents. Prospective pilot study of 50 resident physicians and medical students during a single year of training. Participants completed a manual sleep log while concurrently wearing the Fitbit Inspire device for 14-consecutive days over three clinical rotations of varying work schedules: light, medium, and heavy clinical rotations. Study completion was achieved in 24/50 (48%) participants. Overall correlation coefficients between the sleep log and Fitbit were statistically low; however, the discrepancies were acceptable, i.e., Fitbit underestimated time in bed and total sleep time by 4.3 and 2.7 minutes, respectively. Sleep onset time and waketime were within 8 minutes, with good agreement. Treatment of sleep episodes during the day led to variance in the data. Average missingness of collected data did not vary between medical students or residents or by rotation type. When comparing the light to heavy rotations, hours slept went from 7.7 (±0.64) to 6.7 (±0.88), quality-of-life and sleep health decreased and stress, burnout, and medical errors increased. Burnout was significantly associated with worse sleep health, hours worked, and quality-of-life. Prospective data collection of sleep patterns using both sleep logs and commercial wearable devices is burdensome for physicians-in-training. Using commercial wearable devices may increase study success as long as attention is paid to daytime sleep. In future studies investigating the sleep of physicians, the timing of data collection should account for rotation type.

Acute intermittent hypoxia increases maximal motor unit discharge rates in people with chronic incomplete spinal cord injury.

Acute intermittent hypoxia (AIH) is an emerging technique for enhancing neuroplasticity and motor function in respiratory and limb musculature. Thus far, AIH-induced improvements in strength have been reported for upper and lower limb muscles after chronic incomplete cervical spinal cord injury (iSCI), but the underlying mechanisms have been elusive. We used high-density surface EMG (HDsEMG) to determine if motor unit discharge behaviour is altered after 15 × 60 s exposures to 9% inspired oxygen, interspersed with 21% inspired oxygen (AIH), compared to breathing only 21% air (SHAM). We recorded HDsEMG from the biceps and triceps brachii of seven individuals with iSCI during maximal elbow flexion and extension contractions, and motor unit spike trains were identified using convolutive blind source separation. After AIH, elbow flexion and extension torque increased by 54% and 59% from baseline (P = 0.003), respectively, whereas there was no change after SHAM. Across muscles, motor unit discharge rates increased by ∼4 pulses per second (P = 0.002) during maximal efforts, from before to after AIH. These results suggest that excitability and/or activation of spinal motoneurons is augmented after AIH, providing a mechanism to explain AIH-induced increases in voluntary strength. Pending validation, AIH may be helpful in conjunction with other therapies to enhance rehabilitation outcomes after incomplete spinal cord injury, due to these enhancements in motor unit function and strength. KEY POINTS: Acute intermittent hypoxia (AIH) causes increases in muscular strength and neuroplasticity in people living with chronic incomplete spinal cord injury (SCI), but how it affects motor unit discharge rates is unknown. Motor unit spike times were identified from high-density surface electromyograms during maximal voluntary contractions and tracked from before to after AIH. Motor unit discharge rates were increased following AIH. These findings suggest that AIH can facilitate motoneuron function in people with incomplete SCI.

Single-nucleus multi-omics of Parkinson's disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks.

The genetic architecture of Parkinson's disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precision level. Using parallel single-nucleus (sn)RNA-seq and snATAC-seq analyses we simultaneously profiled the transcriptomic and chromatin accessibility landscapes in temporal cortex tissues from 12 PD compared to 12 control subjects at a granular single cell resolution. An integrative bioinformatic pipeline was developed and applied for the analyses of these snMulti-omics datasets. The results identified a subpopulation of cortical glutamatergic excitatory neurons with remarkably altered gene expression in PD, including differentially-expressed genes within PD risk loci identified in genome-wide association studies (GWAS). This was the only neuronal subtype showing significant and robust overexpression of SNCA. Further characterization of this neuronal-subpopulation showed upregulation of specific pathways related to axon guidance, neurite outgrowth and post-synaptic structure, and downregulated pathways involved in presynaptic organization and calcium response. Additionally, we characterized the roles of three molecular mechanisms in governing PD-associated cell subtype-specific dysregulation of gene expression: (1) changes in cis-regulatory element accessibility to transcriptional machinery; (2) changes in the abundance of master transcriptional regulators, including YY1, SP3, and KLF16; (3) candidate regulatory variants in high linkage disequilibrium with PD-GWAS genomic variants impacting transcription factor binding affinities. To our knowledge, this study is the first and the most comprehensive interrogation of the multi-omics landscape of PD at a cell-subtype resolution. Our findings provide new insights into a precise glutamatergic neuronal cell subtype, causal genes, and non-coding regulatory variants underlying the neuropathological progression of PD, paving the way for the development of cell- and gene-targeted therapeutics to halt disease progression as well as genetic biomarkers for early preclinical diagnosis.

Preoperative vs Postoperative Opioid Prescriptions and Prolonged Opioid Refills Among US Youths.

Importance: High-risk practices, including dispensing an opioid prescription before surgery when not recommended, remain poorly characterized among US youths and may contribute to new persistent opioid use. Objective: To characterize changes in preoperative, postoperative, and refill opioid prescriptions up to 180 days after surgery. Design, Setting, and Participants: This retrospective cohort study was performed using national claims data to determine opioid prescribing practices among a cohort of opioid-naive youths aged 11 to 20 years undergoing 22 inpatient and outpatient surgical procedures between 2015 and 2020. Statistical analysis was performed from June 2023 to April 2024. Main Outcomes and Measures: The primary outcome was the percentage of initial opioid prescriptions filled up to 14 days prior to vs 7 days after a procedure. Secondary outcomes included the likelihood of a refill up to 180 days after surgery, including refills at 91 to 180 days, as a proxy for new persistent opioid use, and the opioid quantity dispensed in the initial and refill prescriptions in morphine milligram equivalents (MME). Exposures included patient and prescriber characteristics. Multivariable logistic regression models were used to estimate the association between prescription timing and prolonged refills. Results: Among 100 026 opioid-naive youths (median [IQR] age, 16.0 [14.0-18.0] years) undergoing a surgical procedure, 46 951 (46.9%) filled an initial prescription, of which 7587 (16.2%) were dispensed 1 to 14 days before surgery. The mean quantity dispensed was 227 (95% CI, 225-229) MME; 6467 youths (13.8%) filled a second prescription (mean MME, 239 [95% CI, 231-246]) up to 30 days after surgery, and 1216 (3.0%) refilled a prescription 91 to 180 days after surgery. Preoperative prescriptions, increasing age, and procedures not typically associated with severe pain were most strongly associated with new persistent opioid use. Conclusions and Relevance: In this retrospective study of youths undergoing surgical procedures, of which, many are typically not painful enough to require opioid use, opioid dispensing declined, but approximately 1 in 6 prescriptions were filled before surgery, and 1 in 33 adolescents filled prescriptions 91 to 180 days after surgery, consistent with new persistent opioid use. These findings should be addressed by policymakers and communicated by professional societies to clinicians who prescribe opioids.