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The dorsal funiculus in the spinal cord relays somatosensory information to the brain. It is made of T-shaped bifurcation of dorsal root ganglion (DRG) sensory axons. Our previous study has shown that Slit signaling is required for proper guidance during bifurcation, but loss of Slit does not affect all DRG axons. Here, we examined the role of the extracellular molecule Netrin-1 (Ntn1). Using wholemount staining with tissue clearing, we showed that mice lacking Ntn1 had axons escaping from the dorsal funiculus at the time of bifurcation. Genetic labeling confirmed that these misprojecting axons come from DRG neurons. Single axon analysis showed that loss of Ntn1 did not affect bifurcation but rather altered turning angles. To distinguish their guidance functions, we examined mice with triple deletion of Ntn1, Slit1, and Slit2 and found a completely disorganized dorsal funiculus. Comparing mice with different genotypes using immunolabeling and single axon tracing revealed additive guidance errors, demonstrating the independent roles of Ntn1 and Slit. Moreover, the same defects were observed in embryos lacking their cognate receptors. These in vivo studies thus demonstrate the presence of multi-factorial guidance mechanisms that ensure proper formation of a common branched axonal structure during spinal cord development.

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OBJECTIVE: To examine the relationship between the penetration (or reach) of a national program aiming to integrate mental health clinicians into all primary care clinics (PC-MHI) and rates of guideline-concordant follow-up and treatment among clinic patients newly identified with depression in the Veterans Health Administration (VA). DATA SOURCES/STUDY SETTING: 15,155 screen-positive patients 607,730 patients with 2-item Patient Health Questionnaire scores in 82 primary care clinics, 2015-2019. STUDY DESIGN: In this retrospective cohort study, we used established depression care quality measures to assess primary care patients who (a) newly screened positive (score ≥3) and (b) were identified with depression by clinicians via diagnosis and/or medication (n = 15,155; 15,650 patient-years). Timely follow-up included ≥3 mental health, ≥3 psychotherapy, or ≥3 primary care visits for depression. Minimally appropriate treatment included ≥4 mental health visits, ≥3 psychotherapy, or ≥60 days of medication. In multivariate regressions, we examined whether higher rates of PC-MHI penetration in clinic (proportion of total primary care patients in a clinic who saw any PC-MHI clinician) were associated with greater depression care quality among cohort patients, adjusting for year, healthcare system, and patient and clinic characteristics. DATA COLLECTION/EXTRACTION METHODS: Electronic health record data from 82 VA clinics across three states. PRINCIPAL FINDINGS: A median of 9% of all primary care patients were seen by any PC-MHI clinician annually. In fully adjusted models, greater PC-MHI penetration was associated with timely depression follow-up within 84 days (∆P = 0.5; SE = 0.1; p < 0.001) and 180 days (∆P = 0.3; SE = 0.1; p = 0.01) of a positive depression screen. Completion of at least minimal treatment within 12 months was high (77%), on average, and not associated with PC-MHI penetration. CONCLUSIONS: Greater PC-MHI program penetration was associated with early depression treatment engagement at 84-/180-days among clinic patients newly identified with depression, with no effect on already high rates of completion of minimally sufficient treatment within the year.

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The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum set of variant alleles (tier 1) and an extended list of variant alleles (tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. The goal of this Working Group is to promote standardization of PGx testing across clinical laboratories. This document will focus on clinical DPYD PGx testing that may be applied to all dihydropyrimidine dehydrogenase-related medications. These recommendations are not to be interpreted as prescriptive but to provide a reference guide.

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Purpose: To explore the enabling factors, barriers, and strategies to improve retention in HIV care and adherence to antiretroviral therapy (ART) among adults (18 years and above) living with HIV in Dar es Salaam, Tanzania. Methods: We conducted a descriptive qualitative study to better understand and explore enablers, barriers, and strategies to improve retention in HIV care and adherence to antiretroviral therapy (ART) among PLHIV in Dar es Salaam, Tanzania. Focus group discussions (FGD) were conducted with a semi-structured discussion guide between December 2021 and June 2022. A non-random purposive sampling technique was used to select PLHIV and people involved in provision of healthcare and socioeconomic support to PLHIV. Thematic analysis was used to identify and interpret the themes. Results: Three major themes with 10 sub-themes emerged. Participants indicated that family and partner support, peer-support group/adherence clubs, and healthcare provider counselling on medication adherence facilitated retention and adherence to ART. In contrast, stigma and discrimination, financial constraints, disease outbreaks such as the COVID-19 pandemic, myths and misconceptions about HIV, and side effects of antiretrovirals were mentioned as barriers. Strengthening community and patient education about HIV and ART through peer support groups and financial support for poor PLHIV were the proposed mitigation. Conclusion: Addressing the challenges to ART adherence may require a more holistic approach. We recommend the implementation of peer support groups and financial support through small microfinance groups as interventions to increase retention in HIV care and adherence to ART in the study area.

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The DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), which is involved in the catalysis of uracil and thymine, as well as 5-fluorouracil (5-FU), which is used to treat solid tumors. Patients with decreased DPD activity are at risk of serious, sometimes fatal, adverse drug reactions to this important cancer drug. Pharmacogenetic testing for DPYD is increasingly provided by clinical and research laboratories; however, only a limited number of quality control and reference materials are currently available for clinical DPYD testing. To address this need, the Division of Laboratory Systems, Centers for Disease Control and Prevention-based Genetic Testing Reference Materials Coordination Program, in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Institute for Medical Research, has characterized 33 DNA samples derived from Coriell cell lines for DPYD. Samples were distributed to four volunteer laboratories for genetic testing using a variety of commercially available and laboratory-developed tests. Sanger sequencing was used by one laboratory and publicly available whole-genome sequence data from the 1000 Genomes Project were used by another to inform genotype. Thirty-three distinct DPYD variants were identified among the 33 samples characterized. These publicly available and well-characterized materials can be used to support the quality assurance and quality control programs of clinical laboratories performing clinical pharmacogenetic testing.

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Changes in the density and organization of fibrous biological tissues often accompany the progression of serious diseases ranging from fibrosis to neurodegenerative diseases, heart disease and cancer. However, challenges in cost, complexity, or precision faced by existing imaging methodologies pose barriers to elucidating the role of tissue microstructure in disease. Here, we leverage the intrinsic optical anisotropy of the Morpho butterfly wing and introduce Morpho-Enhanced Polarized Light Microscopy (MorE-PoL), a stain- and contact-free imaging platform which enhances and quantifies the birefringent material properties of fibrous biological tissues. We develop a mathematical model, based on Jones calculus, which quantifies fibrous tissue density and organization. As a representative example, we analyze collagen-dense and collagen-sparse human breast cancer tissue sections and leverage our technique to assess the microstructural properties of distinct regions of interest. We compare our results with conventional Hematoxylin and Eosin (H&E) staining procedures and second harmonic generation (SHG) microscopy for fibrillar collagen detection. Our findings demonstrate that our MorE-PoL technique provides a robust, quantitative, and accessible route toward analyzing biological tissue microstructures, with great potential for application to a broad range of biological materials.

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Functional assessment in neurocognitive evaluation is often provided via informant reports. These subjective reports can vary based on the characteristics of informants and their relationships with participants, such as informant sex. However, whether informant sex intersects with participant sex to impact subjective ratings of participants' daily functioning, and whether such effects mirror observed patterns in neuropsychological performance, has not been adequately examined with ethnoracially diverse samples. We examined differences among participant-informant sex-based dyads on subjective informant reports of participants' daily functioning (assessed via the Functional Activities Questionnaire [FAQ]), and whether any observed differences on reported functioning corresponded to differences in objective participant performance on neuropsychological performance, among middle-aged and older Hispanic/Latino (n = 543), non-Hispanic Black (NHB; n = 1030), and non-Hispanic White (NHW; n = 5356) adults in the National Alzheimer's Coordinating Center cohort (n = 6929). Analysis of covariance (ANCOVA) tests revealed significant dyad differences on FAQ scores in the NHB (p<.001) and NHW subsamples (p<.05), but not in the Hispanic/Latino subsample (p>.05). For the Hispanic/Latino and NHB subsamples, ANCOVA tests revealed no significant effects of dyad on neuropsychological performance (ps>.01), whereas for the NHW subsample, ANCOVA tests revealed significant dyad differences on performance in multiple cognitive domains (ps<.01). Nevertheless, the pattern of dyad differences on neuropsychological performance did not mirror the pattern of observed differences on FAQ scores in the NHW subsample. Findings and their implications, including potential contributions of other informant characteristics on observed dyad differences on reported functioning, are discussed.

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As the proportion of women diagnosed with invasive breast cancer increases, the role of imaging for staging and surveillance purposes should be determined based on evidence-based guidelines. It is important to understand the indications for extent of disease evaluation and staging, as unnecessary imaging can delay care and even result in adverse outcomes. In asymptomatic patients that received treatment for curative intent, there is no role for imaging to screen for distant recurrence. Routine surveillance with an annual 2-D mammogram and/or tomosynthesis is recommended to detect an in-breast recurrence or a new primary breast cancer in women with a history of breast cancer, and MRI is increasingly used as an additional screening tool in this population, especially in women with dense breasts. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

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An assurance calculation is a Bayesian alternative to a power calculation. One may be performed to aid the planning of a clinical trial, specifically setting the sample size or to support decisions about whether or not to perform a study. Immuno-oncology is a rapidly evolving area in the development of anticancer drugs. A common phenomenon that arises in trials of such drugs is one of delayed treatment effects, that is, there is a delay in the separation of the survival curves. To calculate assurance for a trial in which a delayed treatment effect is likely to be present, uncertainty about key parameters needs to be considered. If uncertainty is not considered, the number of patients recruited may not be enough to ensure we have adequate statistical power to detect a clinically relevant treatment effect and the risk of an unsuccessful trial is increased. We present a new elicitation technique for when a delayed treatment effect is likely and show how to compute assurance using these elicited prior distributions. We provide an example to illustrate how this can be used in practice and develop open-source software to implement our methods. Our methodology has the potential to improve the success rate and efficiency of Phase III trials in immuno-oncology and for other treatments where a delayed treatment effect is expected to occur.

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PURPOSE OF REVIEW: Up to 60% of breast cancer patients continue to experience pain three months or more after surgery, with 15 to 25% reporting moderate to severe pain. Post-mastectomy pain syndrome (PMPS) places a high burden on patients. We reviewed recent studies on perioperative interventions to prevent PMPS incidence and severity. RECENT FINDINGS: Recent studies on pharmacologic and regional anesthetic interventions were reviewed. Only nine of the twenty-three studies included reported a significant improvement in PMPS incidence and/or severity, sometimes with mixed results for similar interventions. Evidence for prevention of PMPS is mixed. Further investigation of impact of variations in dosing is warranted. In addition, promising newer interventions for prevention of PMPS such as cryoneurolysis of intercostal nerves and stellate ganglion block need confirmatory studies.

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Many glial biologists consider glia the neglected cells of the nervous system. Among all the glia of the central and peripheral nervous system, satellite glia may be the most often overlooked. Satellite glial cells (SGCs) are located in ganglia of the cranial nerves and the peripheral nervous system. These small cells surround the cell bodies of neurons in the trigeminal ganglia (TG), spiral ganglia, nodose and petrosal ganglia, sympathetic ganglia, and dorsal root ganglia (DRG). Essential SGC features include their intimate connections with the associated neurons, their small size, and their derivation from neural crest cells. Yet SGCs also exhibit tissue-specific properties and can change rapidly, particularly in response to injury. To illustrate the range of SGC functions, we will focus on three types: those of the spiral, sympathetic, and DRG, and consider both their shared features and those that differ based on location.

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Background/Objective: Pudendal neuralgia is a distressing condition that presents with pain in the perineum. While a positive anesthetic pudendal nerve block is one of the essential criteria for diagnosing this condition, this block can also provide a therapeutic effect for those afflicted with pudendal neuralgia. There are multiple ways in which a pudendal nerve block can be performed. The objective of this study is to share our results and follow-up of fluoroscopy-guided transgluteal pudendal nerve blocks. Methods: This is a retrospective case series. Included were 101 patients who met four out of the five Nantes criteria (pain in the anatomical territory of the pudendal nerve, pain worsened by sitting, pain that does not wake the patient up at night, and no objective sensory loss on clinical examination) who did not respond to conservative treatment and subsequently underwent a fluoroscopy-guided transgluteal pudendal nerve block. Therapeutic success was defined as a 30% or greater reduction in pain. Success rates were calculated, and the duration over which that success was sustained was recorded. Results: For achieving at least 30% relief of pain, using worst-case analysis, the success rate at two weeks was 49.4% (95% CI: 38.5%, 60.3%). In addition to pain relief, patients experienced other therapeutic benefits, such as reductions in medication use and improvements in activities of daily living. Conclusions: Fluoroscopy-guided transgluteal pudendal nerve block appears to be effective in patients who have pudendal neuralgia that is resistant to conservative therapy, with good short-term success.

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Anti-T-lymphocyte globulin (ATLG) is used in hematopoietic stem cell transplantation (HSCT) to prevent graft-versus-host disease (GVHD) and graft failure. To date, insight in ATLG pharmacokinetics and -dynamics (PK/PD) is limited, and population PK (POPPK) models are lacking. In this prospective study, we describe ATLG POPPK using NONMEM® and the impact of ATLG exposure on clinical outcome and immune reconstitution in a homogeneous cohort of pediatric acute lymphoblastic leukemia (ALL) patients transplanted with a matched unrelated donor and receiving uniform ATLG dosing. Based on 121 patients and 812 samples for POPPK analysis, a two-compartmental model with parallel linear and non-linear clearance and bodyweight as covariate, best described the ATLG concentration-time data. The level of ATLG exposure (day active ATLG <1 AU/mL, median 16 days post-HSCT) was strongly associated with aGVHD grade II-IV, with a lower incidence in patients with prolonged active ATLG exposure (≤day 16 50% vs. >day 16 8.2%; P<0.001). When stratified for remission state, patients transplanted in complete remission (CR) 2 or 3 with prolonged ATLG exposure had a higher relapse risk, while this effect was not seen in CR1 patients (P=0.010). High level ATLG exposure was associated with delayed CD4 T-cell recovery at 4 and 8 weeks post-HSCT, but not at 12 weeks, and overall and relapse-free survival were not influenced by CD4 recovery at 12 weeks post-HSCT. This study underlines the importance of individualized ATLG exposure with the use of model-informed precision dosing in order to optimize the HSCT outcome in pediatric ALL.

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Introduction: We investigated cognitive profiles among diverse, middle-aged and older Hispanic/Latino adults in the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) cohort using a cross-sectional observational study design. Methods: Based on weighted descriptive statistics, the average baseline age of the target population was 56.4 years, slightly more than half were women (54.6%), and 38.4% reported less than a high school education. We used latent profile analysis of demographically adjusted z scores on SOL-INCA neurocognitive tests spanning domains of verbal memory, language, processing speed, and executive function. Results: Statistical fit assessment indices combined with clinical interpretation suggested five profiles: (1) a Higher Global group performing in the average-to-high-average range across all cognitive and instrumental activity of daily living (IADL) tests (13.8%); (2) a Higher Memory group with relatively high performance on memory tests but average performance across all other cognitive/IADL tests (24.6%); (3) a Lower Memory group with relatively low performance on memory tests but average performance across all other cognitive/IADL tests (32.8%); (4) a Lower Executive Function group with relatively low performance on executive function and processing speed tests but average-to-low-average performance across all other cognitive/IADL tests (16.6%); and (5) a Lower Global group performing low-average-to-mildly impaired across all cognitive/IADL tests (12.1%). Discussion: Our results provide evidence of heterogeneity in the cognitive profiles of a representative, community-dwelling sample of diverse Hispanic/Latino adults. Our analyses yielded cognitive profiles that may assist efforts to better understand the early cognitive changes that may portend Alzheimer's disease and related dementias among diverse Hispanics/Latinos. Highlights: The present study characterized cognitive profiles among diverse middle-aged and older Hispanic/Latino adults.Latent profile analysis of neurocognitive test scores was the primary analysis conducted.The target population consists of middle-aged and older Hispanic/Latino adults enrolled in the Hispanic Community Health Study/Study of Latinos and ancillary Study of Latinos - Investigation of Neurocognitive Aging.

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INTRODUCTION: Executive functioning and processing speed are crucial elements of neuropsychological assessment. To meet the needs of the Hispanic/Latino population, we aimed to provide normative data for the Digit Symbol Substitution (DSS) test. METHODS: The target population for the Study of Latinos-Investigation of Neurocognitive Aging included six heritage backgrounds (n = 6177). Average age was 63.4 ± 8.3 years, 54.5% were female, and mean education was 11.0 ± 4.7 years. Participants were administered the DSS as part of a larger battery. Heritage-adjusted DSS scores, and percentile cut-points were created using survey-adjusted regression and quantile regression models. RESULTS: Age, education, sex, heritage, and language preference were associated with DSS scores. DISCUSSION: Significant correlates of DSS performance should be considered when evaluating cognitive performance. Representative DSS norms for Hispanics/Latinos will advance assessment and accuracy of neurocognitive disorder diagnosis in clinical practice. To facilitate interpretation, we provide norms to reduce test biases and developed an online dashboard. Highlights: Normative data for the Digit Symbol Substitution (DSS) for diverse Hispanic/Latino adults: Results from the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) This study is the first to develop norms for the DSS test across four regions of the United States.Factors such as age, education, sex, and Hispanic/Latino heritage and language preference are associated with differences in executive functioning and information processing speed.We created norms and an online dashboard (https://solincalab.shinyapps.io/dsst_shiny/) providing an easily accessible tool to evaluate processing speed and executive functioning in Hispanic/Latino adults.

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Introduction: Beginning in 2019, the Department of Veterans Affairs (VA) prioritized improving access to care nationally to deliver virtual care and implemented 18 regionally based Clinical Resource Hubs (CRHs) to meet this priority. This observational study describes the quantity and types of care delivered by CRH Mental Health teams, and the professions of those hired to deliver it. Methods: A retrospective cohort study, based on national VA CRH mental health care utilization data and CRH staffing data for CRH's first 3 years, was conducted. Results: CRH Mental Health teams primarily used Telemental Health (TMH) to provide care (98.1% of all CRH MH encounters). The most common disorders treated included depression, post-traumatic stress disorder, and anxiety disorders. The amount of care delivered overtime steadily increased as did the racial and ethnic diversity of Veterans served. Psychologists accounted for the largest share of CRH staffing, followed by psychiatrists. Conclusions: CRH TMH delivered from a regional hub appears to be a feasible and acceptable visit modality, based on the continuously increasing CRH TMH visit rates. Our results showed that CRH TMH was predominantly used to address common mental health diagnoses, rather than serious mental illnesses. Traditionally marginalized patient populations increased over the 3-year window, suggesting that CRH TMH resources were accessible to many of these patients. Future research should assess barriers and facilitators for accessing CRH TMH, especially for difficult-to-service patient populations, and should consider whether similar results to ours occur when regional TMH is delivered to non-VA patient populations.

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Coincidence detection is a common neural computation that identifies co-occurring stimuli by integration of inputs. In the auditory system, octopus cells act as coincidence detectors for complex sounds that include both synchronous and sequenced combinations of frequencies. Octopus cells must detect coincidence on both the millisecond and submillisecond time scale, unlike the average neuron, which integrates inputs over time on the order of tens of milliseconds. Here, we show that octopus cell computations in the cell body are shaped by inhibition in the dendrites, which adjusts the strength and timing of incoming signals to achieve submillisecond acuity. This mechanism is crucial for the fundamental process of integrating the synchronized frequencies of natural auditory signals over time.

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Vibrations are ubiquitous in nature, shaping behavior across the animal kingdom. For mammals, mechanical vibrations acting on the body are detected by mechanoreceptors of the skin and deep tissues and processed by the somatosensory system, while sound waves traveling through air are captured by the cochlea and encoded in the auditory system. Here, we report that mechanical vibrations detected by the body's Pacinian corpuscle neurons, which are unique in their ability to entrain to high frequency (40-1000 Hz) environmental vibrations, are prominently encoded by neurons in the lateral cortex of the inferior colliculus (LCIC) of the midbrain. Remarkably, most LCIC neurons receive convergent Pacinian and auditory input and respond more strongly to coincident tactile-auditory stimulation than to either modality alone. Moreover, the LCIC is required for behavioral responses to high frequency mechanical vibrations. Thus, environmental vibrations captured by Pacinian corpuscles are encoded in the auditory midbrain to mediate behavior.

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