Citations

Abstract Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep disruption enhances pain, but the underlying mechanisms remain unknown. Chronic pain engages brain stress circuits and increases secretion of dynorphin, an endogenous ligand of the kappa opioid receptor (KOR). We therefore hypothesized that hypothalamic dynorphin/KOR signalling may be a previously unknown mechanism that is recruited in pathological conditions requiring increased vigilance. We investigated the role of KOR in wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in freely moving naïve mice and in mice with neuropathic pain induced by partial sciatic nerve ligation using EEG/EMG recordings. Systemic continuous administration of U69,593, a KOR agonist, over 5 days through an osmotic minipump decreased the amount of NREM and REM sleep and increased sleep fragmentation in naïve mice throughout the light-dark sleep cycle. We used KORcre mice to selectively express a Gi-coupled designer receptor activated by designer drugs (Gi-DREADD) in KORcre neurons of the hypothalamic paraventricular nucleus, a key node of the hypothalamic-pituitary-adrenal stress response. Sustained activation of Gi-DREADD with clozapine-N-oxide delivered in drinking water over 4 days, disrupted sleep in these mice in a similar way as systemic U69,593. Mice with chronic neuropathic pain also showed disrupted NREM and total sleep that was normalized by systemic administration of two structurally different KOR antagonists, norbinaltorphimine and NMRA-140, currently in phase II clinical development, or by CRISPR/Cas9 editing of paraventricular nucleus KOR, consistent with endogenous KOR activation disrupting sleep in chronic pain. Unexpectedly, REM sleep was diminished by either systemic KOR antagonist or by CRISPR/Cas9 editing of paraventricular nucleus KOR in sham-operated mice. Our findings reveal previously unknown physiological and pathophysiological roles of dynorphin/KOR in eliciting arousal. Physiologically, dynorphin/KOR signalling affects transitions between sleep stages that promote REM sleep. Furthermore, while KOR antagonists do not promote somnolence in the absence of pain, they normalized disrupted sleep in chronic pain, revealing a pathophysiological role of KOR signalling that is selectively recruited to promote vigilance, increasing chances of survival. Notably, while this mechanism is likely beneficial in the short-term, disruption of the homeostatic need for sleep over longer periods may become maladaptive resulting in sustained pain chronicity. A novel approach for treatment of chronic pain may thus result from normalization of chronic pain-related sleep disruption by KOR antagonism.

AbstractIntroductionAlthough letters of reference (LORs) are required for postgraduate year one (PGY1) residency applications and used to distinguish between candidates, an evaluation of residency program director (RPD) perceptions and values surrounding LORs has not been described.ObjectiveThe aim of the study was to describe PGY1 RPDs' processes, values, and perceptions surrounding LORs.MethodsThis was a cross‐sectional descriptive survey. After assessing content validity, the Education and Training Practice and Research Network (PRN) taskforce sent a 25‐item electronic survey to 1266 PGY1 RPDs. Survey questions captured program demographics, LOR requirements, processes for LOR review, and perceptions about the value of LORs. Two open‐ended questions solicited suggestions for LORs and the existing standardized form; responses were evaluated via thematic analysis.ResultsA total of 291 (24%) programs completed the survey. LORs were rated as extremely or quite valuable by 82% of respondents and moderately valuable by 16% of respondents. Scoring rubrics for LOR evaluation were used by 79% of programs, and performance ratings were reported to impact interview consideration by a majority of programs. Accuracy, detailed comments, and inclusion of specific candidate strengths and areas for improvement were rated as extremely or quite important characteristics by 90% or more of respondents. Specific strengths were reported to be present in LORs more than half of the time by 81% of programs; however, accuracy, detailed comments, and inclusion of specific areas for improvement were only reported to be present about half the time or less by 41%, 63%, and 63% of respondents. Among 207 suggestions submitted to improve LOR utility, common themes included a desire for LOR authors to have candid discussions with candidates prior to letter writing, to contextualize their relationship with the candidate, and provide honest and specific assessments.ConclusionLORs remain highly valued by PGY1 RPDs during application review. Several notable findings were observed, resulting in recommendations for LOR authors, residency applicants, and the standardized LOR form.

Purpose: This study aimed to determine whether onset–offset N1–P2 auditory evoked responses differ in amplitude, latency, and offset-to-onset trough-to-peak N1–P2 amplitude ratios (OOAR) between normal hearing (NH) sensitivity and moderate high-frequency sensorineural hearing loss (HFSNHL) groups when stimuli target regions of peripheral hearing sensitivity where the groups are in the normal range (i.e., 500 Hz) versus where they differ regarding presence of hearing loss (i.e., 4000 Hz). Method: Onset–offset N1–P2 auditory evoked responses were measured from 10 participants with normal hearing sensitivity and seven participants with moderate HFSNHL using 500-Hz and 4000-Hz narrowband noise (NBN) stimuli. Stimuli were 2000 ms with 40-ms rise-fall times presented at 50 dB SL referenced to stimulus behavioral thresholds. Amplitudes and latencies were analyzed for N1 and P2 onset and offset components via repeated measures analysis of variance (ANOVA). OOARs were compared between groups using one-way ANOVA and across stimuli per group using paired samples t tests. Results: Despite dB SPL stimulus presentation differences between groups, there were no significant differences in individual/absolute amplitude and latency waveform components between groups for either stimulus. Derived comparative calculations of OOAR for 4000-Hz NBN were significantly larger ( p < .025; NH: .39; HFSNHL: .62) for the group with HFSNHL than the group with NH sensitivity; 500-Hz NBN OOAR did not reach significance. OOARs revealed no significant difference between stimuli for the group with normal hearing sensitivity, with .38 OOAR for both stimuli ( p = .961). OOAR comparisons for the HFSNHL group across stimuli were significant ( p = .012), with the 4000-Hz NBN OOAR being nearly double the size of the 500-Hz NBN OOAR. Conclusions: OOARs may provide insight to the balance of excitatory and inhibitory neural firing in the central auditory nervous system (CANS). Larger OOARs may be a biomarker of reduced CANS inhibition, perhaps indicative of a homeostatic central auditory gain mechanism.

AbstractProsthetic valve endocarditis (PVE) remains a serious condition with a high mortality rate. Precise identification of the PVE-associated pathogen/s and their virulence is essential for successful therapy and patient survival. The commonly described PVE-associated pathogens are staphylococci, streptococci, and enterococci, with Staphylococcus aureus being the most frequently diagnosed species. Furthermore, multi-drug resistance pathogens are increasing in prevalence and continue to pose new challenges mandating a personalized approach. Blood cultures in combination with echocardiography are the most common methods to diagnose PVE, often being the only indication, it exists. In many cases, the diagnostic strategy recommended in the clinical guidelines does not identify the precise microbial agent, and frequently, false-negative blood cultures are reported. Despite the fact that blood culture findings are not always a good indicator of the actual PVE agent in the valve tissue, only a minority of re-operated prostheses are subjected to microbiological diagnostic evaluation. In this review, we focus on the diversity and the complete spectrum of PVE-associated bacterial, fungal, and viral pathogens in blood and prosthetic heart valve, their possible virulence potential, and their challenges in making a microbial diagnosis. We are curious to understand if the unacceptable high mortality of PVE is associated with the high number of negative microbial findings in connection with a possible PVE. Herein, we discuss the possibilities and limits of the diagnostic methods conventionally used and make recommendations for enhanced pathogen identification. We also show possible virulence factors of the most common PVE-associated pathogens and their clinical effects. Based on blood culture, molecular biological diagnostics, and specific valve examination, better derivations for the antibiotic therapy as well as possible preventive intervention can be established in the future.

Abstract Background Neuromodulators have proven efficacy in reducing facial rhytides and have also been reported to improve jawline contour and the appearance of platysmal bands. Lifting effects of the tail of the eyebrow are expected outcomes when targeting the lateral periorbital region, underscoring the versatility of neuromodulator treatments. Objectives The aim of this study was to analyze the clinical effectiveness of a novel neuromodulator-based injection algorithm with regards to its ability to reposition the middle and lower facial soft tissues. Methods Seventy-five study participants (8 males, 67 females) with a mean [standard deviation] age of 37.5 [8.5] years were injected with neuromodulators in the subdermal plane of the mandibular soft tissues following a standardized algorithm. Live rating of clinical appearance was performed, as well as volume change and skin vector displacement measured by 3-dimensional imaging at baseline, Day 14, and Day 30. Results Three-dimensional volume analysis revealed an increase in midfacial volume by 0.46 mL, and a decrease of the lower facial volume by 0.30 mL compared with baseline. Additionally, an improvement of midfacial fullness (by 0.13) and jawline contour (by 0.44) was reported on clinical rating scales at Day 30 compared with baseline. Conclusions Facial soft tissues can be repositioned during the 30-day follow-up period following a neuromodulator treatment; this was reflected through an increase in midfacial volume as well as through a decrease in lower facial volume. The novel injection algorithm presented can provide a safe and effective option for patients desiring improvement of midfacial fullness and jawline contour with neuromodulator treatment alone. Level of Evidence: 4

AbstractBackgroundPatients with gastroparesis (GP) and functional dyspepsia (FD) have similar symptoms, but the pathophysiology of postprandial symptoms remains uncertain.AimsTo compare symptoms and gastric myoelectrical activity (GMA) after liquid and solid test meals in patients with GP and FD.MethodsPatients enrolled in the Gastroparesis Clinical Research Consortium Registry were studied. Clinical characteristics were measured with standard questionnaires. GP was determined by 4‐h solid‐phase gastric scintigraphy. GMA was measured using electrogastrography before and after ingestion of a water load or nutrient bar on separate days. Symptoms were measured on visual analog scales. GMA responses to the water load for individual patients were also determined.Results284 patients with GP and 113 with FD were identified who ingested both test meals. Patients with GP and FD had similar maximal tolerated volumes of water [mean (SD) 378 (218) ml vs. 402 (226) ml,p = 0.23] and reported similar intensity of fullness, nausea, bloating, and abdominal discomfort after the test meals. Twenty‐six percent and 19% of the patients with GP and FD, respectively, ingested subthreshold (<238 ml) volumes of water (p = 0.15). Gastric dysrhythmias were recorded in 66% of the GP and 65% of the FD patients after the water load. Symptoms and GMA were similar in both groups after ingestion of the nutrient bar.ConclusionThe similarity in GMA responses and symptoms after ingestion of solid or liquid test meals suggests GP and FD are closely related gastric neuromuscular disorders.

AbstractIntroductionVentricular tachycardia (VT) in structurally normal hearts or nonischemic cardiomyopathy can originate from the aortic sinuses of Valsalva (SoV). It is unknown whether VT can originate from the SoVs in patients with prior myocardial infarction (MI).ObjectiveTo evaluate the prevalence, arrhythmogenic substrate, and ablation outcomes of postinfarction VT originating from the SoVs.MethodsAmong 217 consecutive patients with postinfarction VT undergoing ablation, we identified 13 (6%) patients who had ≥1 VT mapped in a SoV. Control groups of 13 patients with idiopathic SoV VT and 13 postinfarction patients without SoV VT were included.ResultsIn the study group, 17 VTs were mapped in a SoV (right n = 5, left‐right commissure n = 6, left n = 6). SoV VT target sites had low bipolar voltage during sinus rhythm [median 0.42 (IQR: 0.16–0.53) mV] which was significantly lower than target sites in patients with idiopathic SoV VTs [median 1.02 (IQR: 0.89–1.52) mV; p < .001]. An area of endocardial low voltage was found below the aortic valve in all patients with postinfarction SoV VTs compared to 9 (69%) of the patients in the postinfarction control group without SoV VT (p = .02). Morphology characteristics of postinfarction SoV VTs differed from idiopathic SoV VTs. None of the postinfarction SoV VTs were inducible after ablation and none recurred after a median follow‐up of 14 months.ConclusionIn patients with prior MI, VT can be targeted in an aortic SoV. The SoVs should be routinely investigated in postinfarction patients with inferior axis VT and an area of low voltage below the aortic valve.

Background: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. Methods: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome—a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status—was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. Results: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P =0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P =0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P =0.004). Conclusions: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.

AbstractMigraine headache results from activation of meningeal nociceptors, however, the hypothalamus is activated many hours before the emergence of pain. How hypothalamic neural mechanisms may influence trigeminal nociceptor function remains unknown. Stress is a common migraine trigger that engages hypothalamic dynorphin/kappa opioid receptor (KOR) signalling and increases circulating prolactin. Prolactin acts at both long and short prolactin receptor isoforms that are expressed in trigeminal afferents. Following downregulation of the prolactin receptor long isoform, prolactin signalling at the prolactin receptor short isoform sensitizes nociceptors selectively in females. We hypothesized that stress may activate the kappa opioid receptor on tuberoinfundibular dopaminergic neurons to increase circulating prolactin leading to female-selective sensitization of trigeminal nociceptors through dysregulation of prolactin receptor isoforms.A mouse two-hit hyperalgesic priming model of migraine was used. Repeated restraint stress promoted vulnerability (i.e. first-hit priming) to a subsequent subthreshold (i.e. second-hit) stimulus from inhalational umbellulone, a TRPA1 agonist. Periorbital cutaneous allodynia served as a surrogate of migraine-like pain. Female and male KORCre; R26lsl-Sun1-GFP mice showed a high percentage of KORCre labelled neurons co-localized in tyrosine hydroxylase-positive cells in the hypothalamic arcuate nucleus. Restraint stress increased circulating prolactin to a greater degree in females. Stress-primed, but not control, mice of both sexes developed periorbital allodynia following inhalational umbellulone. Gi-DREADD activation (i.e. inhibition through Gi-coupled signalling) in KORCre neurons in the arcuate nucleus also increased circulating prolactin and repeated chemogenetic manipulation of these neurons primed mice of both sexes to umbellulone. Clustered regularly interspaced short palindromic repeats–Cas9 deletion of the arcuate nucleus KOR prevented restraint stress-induced prolactin release in female mice and priming from repeated stress episodes in both sexes. Inhibition of circulating prolactin occurred with systemic cabergoline, a dopamine D2 receptor agonist, blocked priming selectively in females. Repeated restraint stress downregulated the prolactin receptor long isoform in the trigeminal ganglia of female mice. Deletion of prolactin receptor in trigeminal ganglia by nasal clustered regularly interspaced short palindromic repeats–Cas9 targeting both prolactin receptor isoforms prevented stress-induced priming in female mice.Stress-induced activation of hypothalamic KOR increases circulating prolactin resulting in trigeminal downregulation of prolactin receptor long and pain responses to a normally innocuous TRPA1 stimulus. These are the first data that provide a mechanistic link between stress-induced hypothalamic activation and the trigeminal nociceptor effectors that produce trigeminal sensitization and migraine-like pain. This sexually dimorphic mechanism may help to explain female prevalence of migraine. KOR antagonists, currently in phase II clinical trials, may be useful as migraine preventives in both sexes, while dopamine agonists and prolactin/ prolactin receptor antibodies may improve therapy for migraine, and other stress-related neurological disorders, in females.