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Background The North Carolina Community Research Partnership developed, implemented, and tested weCare, a 12-month bilingual mHealth social media intervention designed to reduce missed HIV care appointments and increase viral suppression among racially/ethnically diverse gay, bisexual, and other men who have sex with men (GBMSM) and transgender women living with HIV by harnessing established social media platforms (i.e., Facebook, texting, and dating apps). Methods We randomized 198 GBMSM and transgender women (mean age = 26) living with HIV to the weCare intervention ( n = 100) or usual-care ( n = 98) group. Inclusion criteria included being newly diagnosed or not in care. Participants completed structured assessments at baseline and 6-month postintervention follow-up (18 months after baseline data collection). HIV care appointment and viral load data were abstracted from each participant’s electronic health record at baseline and follow-up. Follow-up retention was 85.5%. Results Among participants, 94% self-identified as cisgender men, 6% as transgender, 64% as African American/Black, and 13% as Latine. Participants in both groups significantly reduced missed HIV care appointments and increased viral suppression at follow-up compared with baseline. However, there were no significant differences between weCare and usual-care participants for either outcome at follow-up. Conclusions An intervention effect was not identified for our two primary outcomes. Several factors may have influenced the lack of significant differences between weCare and usual-care participants at follow-up, including intervention implementation (e.g., staffing changes and lack of fidelity to the intervention as originally designed by the partnership), data collection (e.g., data collection time points and retention strategies), and clinical (e.g., contamination) factors.

With increasingly complicated patients and faster throughput, time for thorough critical thinking and thoughtful clinical documentation is limited, especially in the training environment. Advocating for the value of clinical documentation as a robust opportunity for critical thinking, we describe the implementation and evaluation of a clinical reasoning and documentation curriculum for internal medicine residents. Our curriculum employed facilitated discussion, practical application, and a resident-as-teacher model. Resident surveys showed improved perceptions of the clinical and educational value of clinical documentation. Residents reported increased feedback to interns about their documentation and more appreciation of documentation as a venue for critical thinking.The online version contains supplementary material available at 10.1007/s40670-022-01570-5.

Radiolucent lesions with gingival swelling found in the premolar and intercanine region can elicit a different clinical diagnosis than one confirmed by histologic findings. The purpose of the study is to identify and present the frequency of the unexpected microscopic diagnosis of odontogenic keratocyst (OKC) in a location preoperatively favoring a lateral periodontal cyst (LPC) with similar clinical and radiographic appearance.A retrospective analysis of biopsies received from 2011 and 2019 was performed, and the number of LPC and OKC cases was assessed. The alignment of clinical and radiographic diagnosis to histologic findings and anatomic location was analyzed, and the number of OKC cases preoperatively misdiagnosed as LPCs was identified.A total of 79,257 biopsies were received. Of those, 184 were diagnosed as LPCs and 742 as OKCs. For all preoperatively diagnosed LPCs, the clinical and histologic diagnosis aligned; however, 182 of 742 OKCs were submitted with a clinical misdiagnosis of LPCs. The location of these lesions with the unanticipated diagnosis overlapped with those for LPCs, specifically the maxillary and mandibular anterior and premolar regions.Radiolucent lesions with gingival swelling in the premolar and intercanine region are frequently clinically and radiographically misdiagnosed. A biopsy should be considered in all cases to establish the correct pathologic diagnosis and treatment course.

Fast cholinergic neurotransmission is mediated by acetylcholine-gated ion channels; in particular, excitatory nicotinic acetylcholine receptors play well established roles in virtually all nervous systems. Acetylcholine-gated inhibitory channels have also been identified in some invertebrate phyla, yet their roles in the nervous system are less well understood. We report the existence of multiple new inhibitory ion channels with diverse ligand activation properties inCaenorhabditis elegans. We identify three channels, LGC-40, LGC-57, and LGC-58, whose primary ligand is choline rather than acetylcholine, as well as the first evidence of a truly polymodal channel, LGC-39, which is activated by both cholinergic and aminergic ligands. Using our new ligand–receptor pairs we uncover the surprising extent to which single neurons in the hermaphrodite nervous system express both excitatory and inhibitory channels, not only for acetylcholine but also for the other major neurotransmitters. The results presented in this study offer new insight into the potential evolutionary benefit of a vast and diverse repertoire of ligand-gated ion channels to generate complexity in an anatomically compact nervous system.SIGNIFICANCE STATEMENTHere we describe the diversity of cholinergic signaling in the nematodeCaenorhabditis elegans. We identify and characterize a novel family of ligand-gated ion channels and show that they are preferentially gated by choline rather than acetylcholine and expressed broadly in the nervous system. Interestingly, we also identify one channel gated by chemically diverse ligands including acetylcholine and aminergic ligands. By using our new knowledge of these ligand-gated ion channels, we built a model to predict the synaptic polarity in theC. elegansconnectome. This model can be used for generating hypotheses on neural circuit function.

Natural killer (NK) cell–based immunotherapy is being explored for treating infectious diseases, including viral infections. Here, we discuss evidence of NK cell responses to different viruses, ongoing clinical efforts to treat such infections with NK cell products, and review platforms to generate NK cell products.

SummaryNeuropeptides are ancient, widespread signaling molecules that underpin almost all brain functions. They constitute a broad ligand-receptor network, mainly by binding to G protein-coupled receptors (GPCRs). However, the organization of the peptidergic network and roles of many neuropeptides remain elusive, as our insight into neuropeptide-receptor interactions is limited and many peptide GPCRs in animal models and humans are still orphan receptors. Here we report a genome-wide neuropeptide-GPCR interaction map inC. elegans. By reverse pharmacology screening of over 55,384 possible interactions, we identify 461 cognate peptide-GPCR couples that uncover a broad signaling network with specific and complex combinatorial interactions encoded across and within single peptidergic genes. These interactions provide insights into neuropeptide functions and evolution. Combining our dataset with phylogenetic analysis supports peptide-receptor co-evolution and conservation of at least 14 bilaterian peptidergic systems inC. elegans. This resource lays a foundation for system-wide analysis of the peptidergic network.HighlightsSystem-wide reverse pharmacology deorphanizes 68C. eleganspeptide GPCRsDiscovery of 461 peptide-GPCR pairs and additional ligands for characterized GPCRsNeuropeptides show specific and complex combinatorial receptor interactionsPeptide-GPCR pairs support long-range conservation and expansion of peptide systems

SummaryEfforts are currently ongoing to map synaptic wiring diagrams or connectomes in order to understand the neural basis of brain function. However, chemical synapses represent only one type of functionally important neuronal connection; in particular, extrasynaptic, “wireless” signaling by neuropeptides is widespread and plays essential roles in all nervous systems. By integrating single-cell anatomical and gene expression datasets with a biochemical analysis of receptor-ligand interactions, we have generated a draft connectome of neuropeptide signaling in theC. elegansnervous system. This connectome is characterized by a high connection density, extended signaling cascades, autocrine foci, and a decentralized topology, with a large, highly interconnected core containing three constituent communities sharing similar patterns of input connectivity. Intriguingly, several of the most important nodes in this connectome are little-studied neurons that are specialized for peptidergic neuromodulation. We anticipate that theC. elegansneuropeptidergic connectome will serve as a prototype to understand basic organizational principles of neuroendocrine signaling networks.

Sexual dimorphism occurs where different sexes of the same species display differences in characteristics not limited to reproduction. For the nematode Caenorhabditis elegans, in which the complete neuroanatomy has been solved for both hermaphrodites and males, sexually dimorphic features have been observed both in terms of the number of neurons and in synaptic connectivity. In addition, male behaviours, such as food-leaving to prioritise searching for mates, have been attributed to neuropeptides released from sex-shared or sex-specific neurons. In this study, we show that the lury-1 neuropeptide gene shows a sexually dimorphic expression pattern; being expressed in pharyngeal neurons in both sexes but displaying additional expression in tail neurons only in the male. We also show that lury-1 mutant animals show sex differences in feeding behaviours, with pharyngeal pumping elevated in hermaphrodites but reduced in males. LURY-1 also modulates male mating efficiency, influencing motor events during contact with a hermaphrodite. Our findings indicate sex-specific roles of this peptide in feeding and reproduction in C. elegans, providing further insight into neuromodulatory control of sexually dimorphic behaviours.

The DEG/ENaC family of ion channels was defined based on the sequence similarity between degenerins (DEG) from the nematode Caenorhabditis elegans and subunits of the mammalian epithelial sodium channel (ENaC), and also includes a diverse array of non-voltage-gated cation channels from across animal phyla, including the mammalian acid-sensing ion channels (ASICs) and Drosophila pickpockets. ENaCs and ASICs have wide ranging medical importance; for example, ENaCs play an important role in respiratory and renal function, and ASICs in ischaemia and inflammatory pain, as well as being implicated in memory and learning. Electrophysiological approaches, both in vitro and in vivo, have played an essential role in establishing the physiological properties of this diverse family, identifying an array of modulators and implicating them in an extensive range of cellular functions, including mechanosensation, acid sensation and synaptic modulation. Likewise, genetic studies in both invertebrates and vertebrates have played an important role in linking our understanding of channel properties to function at the cellular and whole animal/behavioural level. Drawing together genetic and physiological evidence is essential to furthering our understanding of the precise cellular roles of DEG/ENaC channels, with the diversity among family members allowing comparative physiological studies to dissect the molecular basis of these diverse functions. ispartof: JOURNAL OF PHYSIOLOGY-LONDON vol:601 issue:9 pages:1521-1542 ispartof: location:England status: published

Acid sensing ion channels (ASICs) are members of the diverse family of degenerin/epithelial sodium channels (DEG/ENaCs). They perform a wide range of physiological roles in healthy organisms, including in gut function and synaptic transmission, but also play important roles in disease, as acidosis is a hallmark of painful inflammatory and ischaemic conditions. We performed a screen for acid-sensitivity on all 30 subunits of the C. elegans DEG/ENaC family using Two-Electrode Voltage Clamp (TEVC) in Xenopus oocytes. We found two groups of acid-sensing DEG/ENaCs characterised by being inhibited or activated by increasing proton concentrations. Three of these acid-sensitive C. elegans DEG/ENaCs were activated by acidic pH, making them functionally similar to the vertebrate ASICs. We also identified four new members of the acid-inhibited DEG/ENaC group, giving a total of seven additional acid-sensitive channels. We observed sensitivity to the anti-hypertensive drug amiloride as well as modulation by the trace element zinc. Acid-sensitive DEG/ENaCs were found to be expressed in both neurons and non-neuronal tissue, highlighting the likely functional diversity of these channels. Our findings provide a framework to exploit the C. elegans channels as models to study the function of these acid-sensing channels in vivo, as well as to study them as potential targets for anti-helminthic drugs.

Young gay, bisexual, and other men who have sex with men and transgender women with HIV, particularly those who are racial or ethnic minorities, often have poor health outcomes. They also utilize a wide array of social media. Accordingly, we developed and implemented weCare, an mHealth (mobile health) intervention where cyberhealth educators utilize established social media platforms (e.g., Facebook, texting, and GPS-based mobile applications [“apps”]) designed for social and sexual networking) to improve HIV-related care engagement and health outcomes. As part of the process evaluation of weCare, we conducted 32 interviews with intervention participants ( n = 18) and HIV clinic providers and staff ( n = 14). This article highlights three key intervention characteristics that promoted care engagement, including that weCare is (1) targeted (e.g., using existing social media platforms, similarity between intervention participants and cyberhealth educator, and implementation within a supportive clinical environment), (2) tailored (e.g., bidirectional messaging and trusting relationship between participants and cyberhealth educators to direct interactions), and (3) personalized (e.g., addressing unique care needs through messaging content and flexibility in engagement with intervention). In addition, interviewees’ recommendations for improving weCare focused on logistics, content, and the ways in which the intervention could be adapted to reach a larger audience. Quality improvement efforts to ensure that mHealth interventions are relevant for young gay, bisexual, and other men who have sex with men and transgender women are critical to ensure care engagement and support health outcomes.

Sexual dimorphism occurs where different sexes of the same species display differences in characteristics not limited to reproduction. For the nematode

Sexual dimorphism occurs where different sexes of the same species display differences in characteristics not limited to reproduction. For the nematode Caenorhabditis elegans, in which the complete neuroanatomy has been solved for both hermaphrodites and males, sexually dimorphic features have been observed both in terms of the number of neurons and in synaptic connectivity. In addition, male behaviours, such as food-leaving to prioritise searching for mates, have been attributed to neuropeptides released from sex-shared or sex-specific neurons.In this study, we show that the lury-1 neuropeptide gene shows a sexually dimorphic expression pattern; being expressed in pharyngeal neurons in both sexes but displaying additional expression in tail neurons only in the male. We also show that lury-1 mutant animals show sex differences in feeding behaviours, with pharyngeal pumping elevated in hermaphrodites but reduced in males. LURY-1 also modulates male mating efficiency, influencing motor events during contact with a hermaphrodite. Our findings indicate sex-specific roles of this peptide in feeding and reproduction in C. elegans, providing further insight into neuromodulatory control of sexually dimorphic behaviours.

Biological clocks are fundamental to an organism's health, controlling periodicity of behaviour and metabolism. Here, we identify two acid-sensing ion channels, with very different proton sensing properties, and describe their role in an ultradian clock, the defecation motor program (DMP) of the nematodeBiological clocks regulate a myriad of processes that occur periodically, from sleeping and waking to how cells use nutrients and energy. One such clock is the one that controls intestinal movements and defecation in the nematode worm

Biological clocks are fundamental to an organism’s health, controlling periodicity of behavior and metabolism. Here, we identify two acid-sensing ion channels, with very different proton sensing properties, and describe their role in an ultradian clock, the defecation motor program (DMP) of the nematode Caenorhabditis elegans. An ACD-5-containing channel, on the apical membrane of the intestinal epithelium, is essential for maintenance of luminal acidity, and thus the rhythmic oscillations in lumen pH. In contrast, the second channel, composed of FLR-1, ACD-3 and/or DEL-5, located on the basolateral membrane, controls the intracellular Ca2+ wave and forms a core component of the master oscillator that controls timing and rhythmicity of the DMP. flr-1 and acd-3/del-5 mutants show severe developmental and metabolic defects. We thus directly link the proton-sensing properties of these channels to their physiological roles in pH regulation and Ca2+ signaling, the generation of an ultradian oscillator, and its metabolic consequences.One-Sentence SummaryTwo acid-sensing DEG/ENaC channels play distinct roles in controlling different aspects of rhythmic proton and Ca2+ oscillations in the C. elegans intestine.

Trimethyl glycine, or betaine, is an amino acid derivative found in diverse organisms, from bacteria to plants and animals. It can function as an osmolyte to protect cells against osmotic stress, and building evidence suggests betaine may also play important functional roles in the nervous system. However, despite growing interest in betaine’s roles in the nervous system, few molecular mechanisms have been elucidated. Here we identify the expression of betaine synthesis pathway genes in the nervous system of the nematode worm, C. elegans. We show that betaine, produced in a single pair of interneurons, the RIMs, can control complex behavioural states. Moreover, we also identify and characterise a new betaine-gated inhibitory ligand gated ion channel, LGC-41, which is required for betaine related behavioural changes. Intriguingly we observed expression of LGC-41 in punctate structures across several sensory and interneurons, including those synaptically connected to the RIMs. Our data presents a neuronal molecular mechanism for the action of betaine, via a specific receptor, in the control of complex behaviour within the nervous system of C. elegans. This may suggest a much broader role for betaine in the regulation of animal nervous systems than previously recognised.

A pediatric ED program sought to promote injury prevention through distribution of child restraint systems. Program funds are paid for child passenger safety technician certification of all personnel. Pediatric emergency nurses distributed child restraint systems at hospital discharge and dedicated technicians at fitting stations. Researchers described program characteristics, developed a baseline understanding of program outreach using geographic information systems, and evaluated adherence to manufacturer guidelines with a sensitivity analysis.This retrospective cross-sectional study used distribution forms linked to hospital records from 2013 to 2016. Testing for differences used nonparametric methods. Median values and interquartile ranges for weight and height of children were compared with manufacturer guidelines. Geographic information systems visualized recipients' street addresses and motor vehicle crashes on an underlying base map.There were 312 child restraint systems distributed: of which 179 (57.4%) at the hospital, 126 (40.4%) at fitting stations, and 7 (2.2%) missing a location. Among those on Medicaid, 64.4% received a child restraint system at the hospital compared with 35.6% at fitting stations (χDespite the workplace pressures of clinical care, pediatric emergency nurses delivered educational information and demonstrated hands-on installation at similar rates to dedicated technicians. Distribution of child restraint systems through the hospital reached a uniquely underserved population. Further research should investigate methods to improve fitting station outreach among Medicaid recipients.

Pentameric ligand-gated ion channels (LGICs) play conserved, critical roles in both excitatory and inhibitory synaptic transmission and can be activated by diverse neurochemical ligands. We have performed a characterization of orphan channels from the nematode C. elegans, identifying five new monoamine-gated LGICs with diverse functional properties and expression postsynaptic to aminergic neurons. These include polymodal anion channels activated by both dopamine and tyramine, which may mediate inhibitory transmission by both molecules in vivo. Intriguingly, we also find that a novel serotonin-gated cation channel, LGC-50, is essential for aversive olfactory learning of pathogenic bacteria, a process known to depend on serotonergic neurotransmission. Remarkably, the redistribution of LGC-50 to neuronal processes is modulated by olfactory conditioning, and lgc-50 point mutations that cause misregulation of receptor membrane expression interfere with olfactory learning. Thus, the intracellular trafficking and localization of these receptors at synapses may represent a molecular cornerstone of the learning mechanism. ispartof: CURRENT BIOLOGY vol:31 issue:19 pages:4282-+ ispartof: location:England status: published

Summary Mechanotransduction channels have been proposed as force sensors in various physiological processes, such as hearing and touch. In particular, TMC1 has been shown to constitute the pore of hair cell mechanotransduction channels, but little is known about how force is sensed by TMC channels. Here, we identify UNC-44/ankyrin as an essential component of the TMC-1 mechanotransduction channel complex in the sensory cilia of Caenorhabditis elegans mechanoreceptor neurons. Ankyrin binds indirectly to TMC-1 via evolutionarily conserved CIB proteins, which are required for TMC-1-mediated mechanosensation in C. elegans OLQ neurons and body wall muscles. Mechanosensory activity conferred by ectopically expressed TMCs in mechanoinsensitive neurons depends on both ankyrin and CIB proteins, indicating that the ankyrin-CIB subcomplex is required for TMC mechanosensitivity. Our work indicates that ankyrin is a long-sought intracellular tether that transmits force to TMC mechanotransduction channels., Graphical Abstract, Highlights • TMC-1 functions as a mechanosensor in C. elegans neurons and muscles • UNC-44/ankyrin binds indirectly to TMC-1 via CALM-1 • CALM-1 and ankyrin are required for TMC-1-mediated mechanosensation • Ankyrin acts as an intracellular tether to confer mechanosensitivity to TMC channels, TMC channels are important for sensory transduction, notably as key components of the hair cell mechanotransducer. In this issue of Neuron, Tang et al. show that the mechanosensory activity of C. elegans TMCs requires the intracellular tether ankyrin, which interacts with TMC-1 through the adaptor protein CALM-1.

When faced with an uncertain clinical pathosis in the oral cavity, identifying the color of the mucosal lesion helps to narrow down a differential diagnosis. Although less common than red and white lesions, yellow lesions encompass a small group of distinct mucosal pathologic entities. Adipose tissue, lymphoid tissue, and sebaceous glands are naturally occurring yellow constituents of the oral cavity and become apparent with associated developmental or neoplastic lesions. Reactive and inflammatory lesions can create a yellow hue due to purulence, necrosis, and calcification. Some systemic diseases are known to deposit yellow bi-products such as amyloid or bilirubin into the oral mucosa of an affected person, and while not always yellow, unusual entities like verruciform xanthoma and granular cell tumor fall under the umbrella of yellow lesions given their occasional propensity to demonstration the color. This chapter aims to explore the unique group that is yellow lesions presenting in the oral mucosa.

Sleep, a state of quiescence associated with growth and restorative processes, is conserved across species. Invertebrates including the nematodeCaenorhabditis elegansexhibit sleep-like states during development, satiety, and stress. Here, we describe behavior and neural activity during sleep and awake states in adultC. eleganshermaphrodites using new microfluidic methods. We observed effects of fluid flow, oxygen, feeding, odors, and genetic perturbations on long-term sleep behavior over 12 h. We developed a closed-loop sleep detection system to automatically deliver chemical stimuli to assess sleep-dependent changes to evoked neural responses in individual animals. Sleep increased the arousal threshold to aversive stimulation, yet the associated sensory neuron and first-layer interneuron responses were unchanged. This localizes adult sleep-dependent neuromodulation within interneurons presynaptic to the premotor interneurons, rather than afferent sensory circuits. However, sleep prolonged responses in appetitive chemosensory neurons, suggesting that sleep modulates responsiveness specifically across sensory systems rather than broadly damping global circuit activity.SIGNIFICANCE STATEMENTMuch is known about molecular mechanisms that facilitate sleep control. However, it is unclear how these pathways modulate neural circuit-level sensory processing or how misregulation of neural activity contributes to sleep disorders. The nematodeCaenorhabditis elegansprovides the ability to study neural circuitry with single-neuron resolution, and recent studies examined sleep states between developmental stages and when stressed. Here, we examine an additional form of spontaneous sleep in adultC. elegansat the behavioral and neural activity levels. Using a closed-loop system, we show that delayed behavioral responses to aversive chemical stimulation during sleep arise from sleep-dependent sensorimotor modulation localized presynaptic to the premotor circuit, rather than early sensory circuits.

Social support (SS) predicts health outcomes among patients living with HIV. Systematic assessment of SS in routine HIV care is rare. We administered a brief, validated measure of SS, the Multifactoral Assessment of Perceived Social Support, within a patient-reported outcomes assessment of several health domains in routine HIV care at 4 U.S. clinics in English and Spanish (n=708). In univariate analysis, low SS was associated with poorer engagement in care, antiretroviral adherence, and health-related quality of life (HRQL); current methamphetamine/crystal use, depression, anxiety, and HIV stigma (all p

SummaryPentameric ligand-gated ion channels (LGCs) play conserved, critical roles in fast synaptic transmission, and changes in LGC expression and localisation are thought to underlie many forms of learning and memory. TheC. elegansgenome encodes a large number of LGCs without a known ligand or function. Here, we deorphanize five members of a family of Cys-loop LGCs by characterizing their diverse functional properties that are activated by biogenic amine neurotransmitters. To analyse the neuronal function of these LGCs, we show that a novel serotonin-gated cation channel, LGC-50, is essential for aversive olfactory learning.lgc-50mutants show a specific defect in learned olfactory avoidance of pathogenic bacteria, a process known to depend on serotonergic neurotransmission. Remarkably, the expression of LGC-50 in neuronal processes is enhanced by olfactory conditioning; thus, the regulated expression of these receptors at synapses appears to represent a molecular cornerstone of the learning mechanism.

Background The impact of clinician specialty on cardiovascular disease risk factor outcomes among persons with HIV (PWH) is unclear. Methods PWH receiving care at 3 Southeastern US academic HIV clinics between January 2014 and December 2016 were retrospectively stratified into 5 groups based on the specialty of the clinician managing their hypertension or hyperlipidemia. Patients were followed until first atherosclerotic cardiovascular disease event, death, or end of study. Outcomes of interest were meeting 8th Joint National Commission (JNC-8) blood pressure (BP) goals and National Lipid Association (NLA) non–high-density lipoprotein (HDL) goals for hypertension and hyperlipidemia, respectively. Point estimates for associated risk factors were generated using modified Poisson regression with robust error variance. Results Of 1667 PWH in the analysis, 965 had hypertension, 205 had hyperlipidemia, and 497 had both diagnoses. At study start, the median patient age was 52 years, 66% were Black, and 65% identified as male. Among persons with hypertension, 24% were managed by an infectious diseases (ID) clinician alone, and 5% were co-managed by an ID clinician and a primary care clinician (PCC). Persons managed by an ID clinician were less likely to meet JNC-8 hypertension targets at the end of observation than the rest of the cohort (relative risk [RR], 0.84; 95% CI, 0.75–0.95), but when mean study blood pressure was considered, there was no difference between persons managed by ID and the rest of the cohort (RR, 0.96; 95% CI, 0.88–1.05). There was no significant association between the ID clinician managing hyperlipidemia and meeting NLA non-HDL goals (RR, 0.89; 95% CI, 0.68–1.15). Conclusions Clinician specialty may play a role in suboptimal hypertension outcomes in persons with HIV., In this retrospective study of HIV outpatient data from three large academic centers in the Southeastern United States, clinician specialty may play a role in how often evidence-based cardiovascular disease risk factor targets are met among persons living with HIV.