A Refractory Case of Rapidly Progressive Glomerulonephritis Due to Microscopic Polyangiitis.

A 75-year-old woman, with hypertension and atrial fibrillation but no prior renal history, presented to the hospital for chest discomfort and dyspnea. She was found to be in acute renal failure, with a serum creatinine of 5.1, increased from a baseline of 0.9, and urine analysis revealing proteinuria and hematuria with dysmorphic red blood cells. Subsequent work up was significant for positive perinuclear antineutrophil cytoplasmic antibody (p-ANCA) and myeloperoxidase antibodies. She underwent a renal biopsy, which revealed necrotizing crescents in 12 of 14 glomeruli, and she was diagnosed with rapidly progressive glomerulonephritis due to microscopic polyangiitis. Despite aggressive treatment with plasmapheresis, high-dose prednisone, and rituximab infusions, renal function worsened, and she required initiation of hemodialysis. She was ultimately discharged after a three-week admission, with plans to continue rituximab infusions and three times weekly hemodialysis in the outpatient setting. Due to her poor response to traditional therapies, initiation of a new targeted immunomodulator known as avacopan, a complement 5a receptor antagonist, was considered. Such targeted immunomodulators are also of particular interest as possible ways to reduce the risk of severe infection associated with current broad immunosuppressive modalities. In addition, when used in place of steroids, they reduce the morbidity associated with cumulative glucocorticoid toxicity. For patients with ANCA-associated vasculitis refractory to standard therapies, targeted immunomodulators such as avacopan should be considered as alternative or adjunct therapy.

Super-Resolution Imaging of Voltages in the Interior of Individual, Vital Mitochondria.

We present super-resolution microscopy of isolated functional mitochondria, enabling real-time studies of structure and function (voltages) in response to pharmacological manipulation. Changes in mitochondrial membrane potential as a function of time and position can be imaged in different metabolic states (not possible in whole cells), created by the addition of substrates and inhibitors of the electron transport chain, enabled by the isolation of vital mitochondria. By careful analysis of structure dyes and voltage dyes (lipophilic cations), we demonstrate that most of the fluorescent signal seen from voltage dyes is due to membrane bound dyes, and develop a model for the membrane potential dependence of the fluorescence contrast for the case of super-resolution imaging, and how it relates to membrane potential. This permits direct analysis of mitochondrial structure and function (voltage) of isolated, individual mitochondria as well as submitochondrial structures in the functional, intact state, a major advance in super-resolution studies of living organelles.

Regional associations between inspiratory tongue dilatory movement and genioglossus activity during wakefulness in people with obstructive sleep apnoea.

Inspiratory tongue dilatory movement is believed to be mediated via changes in neural drive to genioglossus. However, this has not been studied during quiet breathing in humans. Therefore, this study investigated this relationship and its potential role in obstructive sleep apnoea (OSA). During awake supine quiet nasal breathing, inspiratory tongue dilatory movement, quantified with tagged magnetic resonance imaging, and inspiratory phasic genioglossus EMG normalised to maximum EMG were measured in nine controls [apnoea-hypopnea index (AHI) ≤5 events/h] and 37 people with untreated OSA (AHI >5 events/h). Measurements were obtained for 156 neuromuscular compartments (85%). Analysis was adjusted for nadir epiglottic pressure during inspiration. Only for 106 compartments (68%) was a larger anterior (dilatory) movement associated with a higher phasic EMG [mixed linear regression, beta = 0.089, 95% CI [0.000, 0.178], t(99) = 1.995, P = 0.049, hereafter EMG↗/mvt↗]. For the remaining 50 (32%) compartments, a larger dilatory movement was associated with a lower phasic EMG [mixed linear regression, beta = -0.123, 95% CI [-0.224, -0.022], t(43) = -2.458, P = 0.018, hereafter EMG↘/mvt↗]. OSA participants had a higher odds of having at least one decoupled EMG↘/mvt↗ compartment (binary logistic regression, odds ratio [95% CI]: 7.53 [1.19, 47.47] (P = 0.032). Dilatory tongue movement was minimal (>1 mm) in nearly all participants with only EMG↗/mvt↗ compartments (86%, 18/21). These results demonstrate that upper airway dilatory mechanics cannot be predicted from genioglossus EMG, particularly in people with OSA. Tongue movement associated with minimal genioglossus activity suggests co-activation of other airway dilator muscles. KEY POINTS: Inspiratory tongue movement is thought to be mediated through changes in genioglossus activity. However, it is unknown if this relationship is altered by obstructive sleep apnoea (OSA). During awake supine quiet nasal breathing, inspiratory tongue movement, quantified with tagged magnetic resonance imaging (MRI), and inspiratory phasic genioglossus EMG normalised to maximum EMG were measured in four tongue compartments of people with and without OSA. Larger tongue anterior (dilatory) movement was associated with higher phasic genioglossus EMG for 68% of compartments. OSA participants had an ∼7-times higher odds of having at least one compartment for which a larger anterior tongue movement was not associated with a higher phasic EMG than controls. Therefore, higher genioglossus phasic EMG does not consistently translate into tongue dilatory movement, particularly in people with OSA. Large dilatory tongue movements can occur despite minimal genioglossus inspiratory activity, suggesting co-activation of other pharyngeal muscles.

Applying the Theoretical Domains Framework to identify police, fire, and paramedic preferences for accessing mental health care in a First Responder Operational Stress Injury Clinic: a qualitative study. / Application du cadre Theoretical Domains Framework pour cerner les préférences des policiers, des pompiers et des ambulanciers en matière d'accès aux soins de santé mentale dans une clinique de traitement des blessures de stress opérationnel pour les premiers répondants : une étude qualitative.

INTRODUCTION: First responders and other public safety personnel (PSP; e.g. correctional workers, firefighters, paramedics, police, public safety communicators) are often exposed to events that have the potential to be psychologically traumatizing. Such exposures may contribute to poor mental health outcomes and a greater need to seek mental health care. However, a theoretically driven, structured qualitative study of barriers and facilitators of help-seeking behaviours has not yet been undertaken in this population. This study used the Theoretical Domains Framework (TDF) to identify and better understand critical barriers and facilitators of help-seeking and accessing mental health care for a planned First Responder Operational Stress Injury (OSI) clinic. METHODS: We conducted face-to-face, one-on-one semistructured interviews with 24 first responders (11 firefighters, five paramedics, and eight police officers), recruited using purposive and snowball sampling. Interviews were analyzed using deductive content analysis. The TDF guided study design, interview content, data collection, and analysis. RESULTS: The most reported barriers included concerns regarding confidentiality, lack of trust, cultural competency of clinicians, lack of clarity about the availability and accessibility of services, and stigma within first responder organizations. Key themes influencing help-seeking were classified into six of the TDF's 14 theoretical domains: environmental context and resources; knowledge; social influences; social/professional role and identity; emotion; and beliefs about consequences. CONCLUSION: The results identified key actions that can be utilized to tailor interventions to encourage attendance at a First Responder OSI Clinic. Such approaches include providing transparency around confidentiality, policies to ensure greater cultural competency in all clinic staff, and clear descriptions of how to access care; routinely involving families; and addressing stigma.

Direct optogenetic activation of upper airway muscles in an acute model of upper airway hypotonia mimicking sleep onset.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA), where the upper airway collapses repeatedly during sleep due to inadequate dilator muscle tone, is challenging to treat as current therapies are poorly tolerated or have variable and unpredictable efficacy. We propose a novel, optogenetics-based therapy, that stimulates upper airway dilator muscle contractions in response to light. To determine the feasibility of a novel optogenetics-based OSA therapy, we developed a rodent model of human sleep-related upper airway muscle atonia. Using this model, we evaluated intralingual delivery of candidate optogenetic constructs, notably a muscle-targeted approach that will likely have a favorable safety profile. METHODS: rAAV serotype 9 viral vectors expressing a channelrhodopsin-2 variant, driven by a muscle-specific or nonspecific promoter were injected into rat tongues to compare strength and specificity of opsin expression. Light-evoked electromyographic responses were recorded in an acute, rodent model of OSA. Airway dilation was captured with ultrasound. RESULTS: The muscle-specific promoter produced sufficient opsin expression for light stimulation to restore and/or enhance electromyographic signals (linear mixed model, F = 140.0, p < 0.001) and induce visible tongue contraction and airway dilation. The muscle-specific promoter induced stronger (RM-ANOVA, F(1,8) = 10.0, p = 0.013) and more specific opsin expression than the nonspecific promoter in an otherwise equivalent construct. Viral DNA and RNA were robust in the tongue, but low or absent in all other tissues. CONCLUSIONS: Significant functional responses to direct optogenetic muscle activation were achieved following muscle-specific promoter-driven rAAV-mediated transduction, providing proof-of-concept for an optogenetic therapy for patients with inadequate dilator muscle activity during sleep.

Nanowire biosensors with olfactory proteins: towards a genuine electronic nose with single molecule sensitivity and high selectivity.

We describe the concept and roadmap of an engineered electronic nose with specificity towards analytes that differ by as little as one carbon atom, and sensitivity of being able to electrically register a single molecule of analyte. The analyte could be anything that natural noses can detect, e.g. trinitrotoluene (TNT), cocaine, aromatics, volatile organic compounds etc. The strategy envisioned is to genetically engineer a fused olfactory odorant receptor (odorant receptor (OR), a membrane-bound G-protein coupled receptor (GPCR) with high selectivity) to an ion channel protein, which opens in response to binding of the ligand to the OR. The lipid bilayer supporting the fused sensing protein would be intimately attached to a nanowire or nanotube network (either via a covalent tether or a non-covalent physisorption process), which would electrically detect the opening of the ion channel, and hence the binding of a single ligand to a single OR protein domain. Three man-made technological advances: (1) fused GPCR to ion channel protein, (2) nanowire sensing of single ion channel activity, and (3) lipid bilayer to nanotube/nanowire tethering chemistry and on natural technology (sensitivity and selectivity of OR domains to specific analytes) each have been demonstrated and/or studied independently. The combination of these three technological advances and the result of millions of years of evolution of OR proteins would enable the goal of single molecule sensing with specificity towards analytes that differ by as little as one carbon atom. This is both a review of the past and a vision of the future.

Assessment of Risk Factors Correlated with Outcomes of Traumatic Lower Extremity Soft Tissue Reconstruction.

Identifying risk factors for traumatic lower extremity reconstruction outcomes has been limited by sample size. We evaluated patient and procedural characteristics associated with reconstruction outcomes using data from almost four million patients. Methods: The National Trauma Data Bank (2015-2018) was queried for lower extremity reconstructions. Univariable and multivariable analyses determined associations with inpatient outcomes. Results: There were 4675 patients with lower extremity reconstructions: local flaps (77%), free flaps (19.2%), or both (3.8%). Flaps were most commonly local fasciocutaneous (55.1%). Major injuries in reconstructed extremities were fractures (56.2%), vascular injuries (11.8%), and mangled limbs (2.9%). Ipsilateral procedures prereconstruction included vascular interventions (6%), amputations (5.6%), and fasciotomies (4.3%). Postoperative surgical site infection and amputation occurred in 2% and 2.6%, respectively. Among survivors (99%), mean total length of stay (LOS) was 23.2 ± 21.1 days and 46.8% were discharged to rehab. On multivariable analysis, vascular interventions prereconstruction were associated with increased infection [odds ratio (OR) 1.99, 95% confidence interval (CI) 1.05-3.79, P = 0.04], amputation (OR 4.38, 95% CI 2.56-7.47, P < 0.001), prolonged LOS (OR 1.59, 95% CI 1.14-2.22, P = 0.01), and discharge to rehab (OR 1.49, 95% CI 1.07-2.07, P = 0.02). Free flaps were associated with prolonged LOS (OR 2.08, 95% CI 1.74-2.49, P < 0.001). Conclusions: Prereconstruction vascular interventions were associated with higher incidences of adverse outcomes. Free flaps correlated with longer LOS, but otherwise similar outcomes. Investigating reasons for increased complication and healthcare utilization likelihood among these subgroups is warranted.

Application of creatinine height index in patients with trauma for the evaluation of psoas muscle mass: A clinical validation study.

BACKGROUND: The creatinine height index (CHI) is an estimate of lean body mass. We hypothesize that a modified CHI estimate using serum creatinine (sCr) levels in patients with normal renal function when performed soon after injury would reflect preinjury protein nutrition status. METHODS: The urine CHI (uCHI) was calculated using the 24-h urine sample. The serum-derived estimated CHI (sCHI) was calculated using the sCr on admission. Correlation between abdominal computed tomography images at specific lumbar vertebral levels and total body fat and muscle content was used for comparison as an independent measurement of nutrition status unlikely to be substantially altered by trauma. RESULTS: A total of 45 patients were enrolled, all with a significant injury burden (median injury severity score [ISS] = 25; interquartile range, 17-35). The calculated sCHI on admission was 71.0% (SD = 26.9%) and likely underestimates the CHI when compared with uCHI (mean = 112.5%, SD = 32.6%). Stratifying by degree of stress demonstrated that in a group of 23 moderately and severely stressed patients, uCHI (mean = 112.7%, SD = 5.7%) and sCHI (mean = 60.8%, SD = 1.9%) were significantly different and without correlation (r = -0.26, P = 0.91). In patients without stress, there was a significant negative correlation between sCHI and psoas muscle area (r = -0.869, P = 0.03), and in patients with severe stress there was a significant positive correlation between uCHI and psoas muscle area (r = 0.733, P = 0.016). CONCLUSION: The CHI calculated from the initial sCr is not an appropriate estimate of uCHI in critically ill trauma patients and is not a valid measure of psoas muscle mass in this setting.

A Drosophila chemical screen reveals synergistic effect of MEK and DGKα inhibition in Ras-driven cancer.

Elevated Ras signalling is highly prevalent in human cancer; however, targeting Ras-driven cancers with Ras pathway inhibitors often leads to undesirable side effects and to drug resistance. Thus, identifying compounds that synergise with Ras pathway inhibitors would enable lower doses of the Ras pathway inhibitors to be used and also decrease the acquisition of drug resistance. Here, in a specialised chemical screen using a Drosophila model of Ras-driven cancer, we have identified compounds that reduce tumour size by synergising with sub-therapeutic doses of the Ras pathway inhibitor trametinib, which targets MEK, the mitogen-activated protein kinase kinase, in this pathway. Analysis of one of the hits, ritanserin, and related compounds revealed that diacyl glycerol kinase α (DGKα, Dgk in Drosophila) was the critical target required for synergism with trametinib. Human epithelial cells harbouring the H-RAS oncogene and knockdown of the cell polarity gene SCRIB were also sensitive to treatment with trametinib and DGKα inhibitors. Mechanistically, DGKα inhibition synergises with trametinib by increasing the P38 stress-response signalling pathway in H-RASG12V SCRIBRNAi cells, which could lead to cell quiescence. Our results reveal that targeting Ras-driven human cancers with Ras pathway and DGKα inhibitors should be an effective combination drug therapy.

The Role of the US Trauma Centers in Older Adult Fall Prevention: A National Survey.

INTRODUCTION: Approximately 27.5% of adults 65 and older fall each year, over 3 million are treated in an emergency department, and 32 000 die. The American College of Surgeons and its Committee on Trauma (ACSCOT) have urged trauma centers (TCs) to screen for fall risk, but information on the role of TC in this opportunity for prevention is largely unknown. METHODS: A 29-item survey was developed by an ACSCOT Injury Prevention and Control Committee, Older Adult Falls workgroup, and emailed to 1000 trauma directors of the National Trauma Data Bank using Qualtrics. US TCs were surveyed regarding fall prevention, screening, intervention, and hospital discharge practices. Data collected and analyzed included respondent's role, location, population density, state designation or American College of Surgeons (ACS) level, if teaching facility, and patient population. RESULTS: Of the 266 (27%) respondents, 71% of TCs include fall prevention as part of their mission, but only 16% of TCs use fall risk screening tools. There was no significant difference between geographic location or ACS level. The number of prevention resources (F = 31.58, P < .0001) followed by the presence of a formal screening tool (F = 21.47, P < .0001) best predicted the presence of a fall prevention program. CONCLUSION: Older adult falls remain a major injury risk and injury prevention opportunity. The majority of TCs surveyed include prevention of older adult falls as part of their mission, but few incorporate the components of a fall prevention program. Development of best practices and requiring TCs to screen and offer interventions may prevent falls.

Descending pathways from the superior colliculus mediating autonomic and respiratory effects associated with orienting behaviour.

The ability to discriminate competing external stimuli and initiate contextually appropriate behaviours is a key brain function. Neurons in the deep superior colliculus (dSC) integrate multisensory inputs and activate descending projections to premotor pathways responsible for orienting, attention and defence, behaviours which involve adjustments to respiratory and cardiovascular parameters. However, the neural pathways that subserve the physiological components of orienting are poorly understood. We report that orienting responses to optogenetic dSC stimulation are accompanied by short-latency autonomic, respiratory and electroencephalographic effects in awake rats, closely mimicking those evoked by naturalistic alerting stimuli. Physiological responses were not accompanied by detectable aversion or fear, and persisted under urethane anaesthesia, indicating independence from emotional stress. Anterograde and trans-synaptic viral tracing identified a monosynaptic pathway that links the dSC to spinally projecting neurons in the medullary gigantocellular reticular nucleus (GiA), a key hub for the coordination of orienting and locomotor behaviours. In urethane-anaesthetized animals, sympathoexcitatory and cardiovascular, but not respiratory, responses to dSC stimulation were replicated by optogenetic stimulation of the dSC-GiA terminals, suggesting a likely role for this pathway in mediating the autonomic components of dSC-mediated responses. Similarly, extracellular recordings from putative GiA sympathetic premotor neurons confirmed short-latency excitatory inputs from the dSC. This pathway represents a likely substrate for autonomic components of orienting responses that are mediated by dSC neurons and suggests a mechanism through which physiological and motor components of orienting behaviours may be integrated without the involvement of higher centres that mediate affective components of defensive responses. KEY POINTS: Neurons in the deep superior colliculus (dSC) integrate multimodal sensory signals to elicit context-dependent innate behaviours that are accompanied by stereotypical cardiovascular and respiratory activities. The pathways responsible for mediating the physiological components of colliculus-mediated orienting behaviours are unknown. We show that optogenetic dSC stimulation evokes transient orienting, respiratory and autonomic effects in awake rats which persist under urethane anaesthesia. Anterograde tracing from the dSC identified projections to spinally projecting neurons in the medullary gigantocellular reticular nucleus (GiA). Stimulation of this pathway recapitulated autonomic effects evoked by stimulation of dSC neurons. Electrophysiological recordings from putative GiA sympathetic premotor neurons confirmed short latency excitatory input from dSC neurons. This disynaptic dSC-GiA-spinal sympathoexcitatory pathway may underlie autonomic adjustments to salient environmental cues independent of input from higher centres.

Upregulated Angiotensin Ia Receptors in the Hypothalamic Paraventricular Nucleus Sensitize Neuroendocrine Vasopressin Release and Blood Pressure in a Rodent Model of Polycystic Kidney Disease.

INTRODUCTION: Angiotensin (Ang) II signalling in the hypothalamic paraventricular nucleus (PVN) via Ang type-1a receptors (AT1R) regulates vasopressin release and sympathetic nerve activity - two effectors of blood pressure regulation. We determined the cellular expression and function of AT1R in the PVN of a rodent model of polycystic kidney disease (PKD), the Lewis polycystic kidney (LPK) rat, to evaluate its contribution to blood pressure regulation and augmented vasopressin release in PKD. METHODS: PVN AT1R gene expression was quantified with fluorescent in situ hybridization in LPK and control rats. PVN AT1R function was assessed with pharmacology under urethane anaesthesia in LPK and control rats instrumented to record arterial pressure and sympathetic nerve activity. RESULTS: AT1R gene expression was upregulated in the PVN, particularly in corticotrophin-releasing hormone neurons, of LPK versus control rats. PVN microinjection of Ang II produced larger increases in systolic blood pressure in LPK versus control rats (36 ± 5 vs. 17 ± 2 mm Hg; p < 0.01). Unexpectedly, Ang II produced regionally heterogeneous sympathoinhibition (renal: -33%; splanchnic: -12%; lumbar: no change) in LPK and no change in controls. PVN pre-treatment with losartan, a competitive AT1R antagonist, blocked the Ang II-mediated renal sympathoinhibition and attenuated the pressor response observed in LPK rats. The Ang II pressor effect was also blocked by systemic OPC-21268, a competitive V1A receptor antagonist, but unaffected by hexamethonium, a sympathetic ganglionic blocker. DISCUSSION/CONCLUSION: Collectively, our data suggest that upregulated AT1R expression in PVN sensitizes neuroendocrine release of vasopressin in the LPK, identifying a central mechanism for the elevated vasopressin levels present in PKD.

Resuscitation of an exsanguinated obstetrics patient with HBOC-201: A case report.

BACKGROUND: Hemorrhagic shock is a clinically challenging disease process with high mortality. When conventional blood products are unable to be administered, oxygen-carrying blood alternatives are sometimes utilized. The international experience with this scenario is limited. We aim to add to this body of literature. STUDY DESIGN AND METHODS: This is a case report of the administration of bovine hemoglobin-based oxygen-carrying red blood cell (RBC) substitute HBOC-201 (HemoPure®) to a patient with post-partum bleeding and hemorrhagic shock because the patient declined RBC transfusion. HBOC-201 was administered with consent under a one-time Emergency Investigational New Drug (eIND) approval from the Food and Drug Administration with appropriate notification of the Institutional Review Board. RESULTS: The patient was successfully resuscitated with HBOC-201 from hemorrhagic shock. She was weaned off of vasopressor support and extubated with the recovery of her baseline mental status within 4 h. However, approximately 36 h after this, the patient developed multi-organ system dysfunction, volume overload, right heart failure and ultimately expired early on post-partum day 4. DISCUSSION: Resuscitation from hemorrhagic shock with HBOC-201 as an RBC alternative is feasible, but significant challenges remain with the management of sequelae resulting from prolonged low-flow, ischemic states as well as the significant colloid pressure and volume overload experienced after massive transfusion with an acellular colloid oxygen carrier.

Regional genioglossus reflex responses to negative pressure pulses in people with obstructive sleep apnea.

Tongue and upper airway dilator muscle movement patterns during quiet breathing vary in people with obstructive sleep apnea (OSA). Many patients have inadequate or counterproductive responses to inspiratory negative airway pressure that likely contributes to their OSA. This may be due, at least in part, to inadequate or nonhomogeneous reflex drive to different regions of the largest upper airway dilator, genioglossus. To investigate potential regional heterogeneity of genioglossus reflex responses in OSA, brief suction pulses were applied via a nasal breathing mask and an electromyogram (EMG) was recorded in four regions (anterior oblique, anterior horizontal, posterior oblique, and posterior horizontal) using intramuscular fine wire electrodes in 15 people with OSA. Genioglossus short-latency reflex excitation amplitude had regional heterogeneity (horizontal vs. oblique regions) when expressed in absolute units but homogeneity when normalized as a percentage of the immediate (100 ms) prestimulus EMG. Regional variability in reflex morphology (excitation and inhibition) was present in one-third of the participants. The minimum cross-sectional area (CSA) of the pharyngeal airway was quantified using MRI and may be related to the amplitude of the short-latency reflex response to negative pressure as we found that people with a smaller CSA tended to have a greater reflex amplitude (e.g., horizontal region r2 = 0.41, P = 0.01). These findings highlight the complexity of genioglossus reflex control, the potential for regional heterogeneity, and the functional importance of upper airway anatomy in mediating genioglossus reflex responses to rapid changes in negative pressure in OSA.NEW & NOTEWORTHY Our findings indicate that 30% of participants had regional heterogeneity in reflex morphology (excitation/inhibition) to brief pulses of negative upper-airway pressure across anterior oblique, anterior horizontal, posterior oblique, and posterior horizontal regions of the genioglossus muscle. Reflex excitation amplitude was proportional to prestimulus drive, with increased activation in oblique compared with horizontal regions of the posterior tongue. People with narrower upper-airway anatomy tended to have increased genioglossus reflex amplitude to negative pressure pulses during wakefulness.

A Three-Dimensional Printed Inertial Microfluidic Platform for Isolation of Minute Quantities of Vital Mitochondria.

We demonstrate a fast and easy-to-use three-dimensional printed microfluidic platform for mitochondria isolation from cell and tissue lysates based on inertial microfluidics. We present and quantify the quality of the isolated mitochondria by measuring the respiration rate under various conditions. We demonstrate that the technology produces vital mitochondria of equal quality to traditional, but more burdensome, differential centrifugation. We anticipate that the availability of improved tools for studies of bioenergetics to the broader biological community will enable these and other links to be explored in more meaningful ways, leading to further understanding of the links between energy, health, and disease.

The relationship between mandibular advancement, tongue movement, and treatment outcome in obstructive sleep apnea.

STUDY OBJECTIVES: To characterize how mandibular advancement enlarges the upper airway via posterior tongue advancement in people with obstructive sleep apnea (OSA) and whether this is associated with mandibular advancement splint (MAS) treatment outcome. METHODS: One-hundred and one untreated people with OSA underwent a 3T magnetic resonance (MRI) scan. Dynamic mid-sagittal posterior tongue and mandible movements during passive jaw advancement were measured with tagged MRI. Upper airway cross-sectional areas were measured with the mandible in a neutral position and advanced to 70% of maximum advancement. Treatment outcome was determined after a minimum of 9 weeks of therapy. RESULTS: Seventy-one participants completed the study: 33 were responders (AHI<5 or AHI≤10 events/hr with >50% AHI reduction), 11 were partial responders (>50% AHI reduction but AHI>10 events/hr), and 27 nonresponders (AHI reduction<50% and AHI≥10 events/hr). Responders had the greatest naso- and oropharyngeal tongue anterior movement (0.40 ± 0.08 and 0.47 ± 0.13 mm, respectively) and oropharyngeal cross-sectional area enlargement (6.41 ± 2.12%) per millimeter of mandibular advancement. A multivariate model that included tongue movement and percentage of airway enlargement per millimeter of mandibular advancement along with baseline AHI correctly classified 69.2% (5-fold cross-validated 62.5%, n = 39) of participants in response categories when the jaw was advanced in the range that would usually be regarded as sufficient for clinical efficacy (> 4 mm). In comparison, a model using only baseline AHI correctly classified 50.0% of patients (5-fold cross-validated 52.5%, n = 40). CONCLUSIONS: Tongue advancement and upper airway enlargement with mandibular advancement in conjunction with baseline AHI improve treatment response categorization to a satisfactory level (69.2%, 5-fold cross-validated 62.5%).

Task-dependent neural control of regions within human genioglossus.

Anatomical and imaging evidence suggests neural control of oblique and horizontal compartments of the genioglossus differs. However, neurophysiological evidence for differential control remains elusive. This study aimed to determine whether there are differences in neural drive to the oblique and horizontal regions of the genioglossus during swallowing and tongue protrusion. Adult participants (n = 63; 48 M) were recruited from a sleep clinic; 41 had obstructive sleep apnea (OSA: 34 M, 8 F). Electromyographic (EMG) was recorded at rest (awake, supine) using four intramuscular fine-wire electrodes inserted percutaneously into the anterior oblique, posterior oblique, anterior horizontal, and posterior horizontal genioglossus. Epiglottic pressure and nasal airflow were also measured. During swallowing, two distinct EMG patterns were observed - a monophasic response (single EMG peak) and a biphasic response (2 bursts of EMG). Peak EMG and timing of the peak relative to epiglottic pressure were significantly different between patterns (linear mixed models, P < 0.001). Monophasic activation was more likely in the horizontal than oblique region during swallowing (OR = 6.83, CI = 3.46-13.53, P < 0.001). In contrast, during tongue protrusion, activation patterns and EMG magnitude were not different between regions. There were no systematic differences in EMG patterns during swallowing or tongue protrusion between OSA and non-OSA groups. These findings provide evidence for functional differences in the motoneuronal output to the oblique and horizontal compartments, enabling differential task-specific drive. Given this, it is important to identify the compartment from which EMG is acquired. We propose that the EMG patterns during swallowing may be used to identify the compartment where a recording electrode is located.NEW & NOTEWORTHY During swallowing, we observed two distinct, stereotyped muscle activation patterns that define the horizontal (monophasic, maximal EMG) and oblique (biphasic, submaximal EMG) neuromuscular compartments of genioglossus. In contrast, volitional tongue protrusions produced uniform activation across compartments. This provides evidence for task-dependent, functionally discrete neuromuscular control of the oblique and horizontal compartments of genioglossus. The magnitude and temporal patterning of genioglossus EMG during swallowing may help guide electrode placement in tongue EMG studies.

Do catecholaminergic TrkC DRG neurons represent a class of cardiovascular enteroceptor?

In a recent issue of Cell Reports, Morelli et al. (2021) identify a subpopulation of mechanosensitive peripheral sensory neurons that coexpress tyrosine hydroxylase (TH) and tropomyosin receptor kinase C (TrkC) and innervate cutaneous arterioles. They show that activation of TrkC sensory neurons causes cutaneous vasoconstriction and, most remarkably, that their lesion is associated with sudden death of an undetermined cause, preceded by a progressive drop in blood pressure, and conclude that TrkC+ TH+ neurons represent a baroreceptor class of homeostatic enteroceptor. This represents a radical departure from current consensus models for the central control of blood pressure. Here, we offer an alternative perspective on their findings and suggest priorities for further investigation. This Matters Arising paper is in response to Morelli et al. (2021), published in Cell Reports. See also the response by Heppenstall et al. (2022), published in this issue.