Cellular Metabolism of Substance P Produces Neurokinin-1 Receptor Peptide Agonists with diminished cyclic AMP Signaling.

Substance P (SP) is released from sensory nerves in arteries and heart. It activates neurokinin-1 receptors (NK1R) causing vasodilation, immune modulation, and adverse cardiac remodeling. The hypothesis was tested that SP and SP metabolites activate different second messenger signaling pathways. Macrophages, endothelial cells and fibroblasts metabolized SP to N- and C-terminal metabolites to varying extents. SP 5-11 was the most abundant metabolite followed by SP 1-4, SP 7-11, SP 6-11, SP 3-11 and SP 8-11. In NK1R expressing HEK293 cells, SP and some C-terminal SP metabolites stimulate the NK1R promoting dissociation of several Ga proteins including Gas and Gaq from their bg subunits. SP increases intracellular calcium concentrations ([Ca]i) and cyclic AMP (cAMP) accumulation with similar -log EC50 values of 8.5±0.3 and 7.8±0.1 M, respectively. N-Terminal metabolism of SP by up to 5 amino acids and C-terminal deamidation of SP produce peptides that retain activity to increase [Ca]i but not to increase cAMP. C-Terminal metabolism results in loss of both activities. Thus, [Ca]i and cAMP signaling are differentially affected by SP metabolism. To assess the role of N-terminal metabolism, SP and SP 6-11 were compared on cAMP-mediated activities in NK1R expressing 3T3 fibroblasts. SP inhibits NFkB activity, cell proliferation and wound healing and stimulates collagen production. SP 6-11 had little or no activity. COX-2 expression is increased by SP but not SP 6-11. Thus, metabolism may select the cellular response to SP by inhibiting or re-directing the second messenger signaling pathway activated by the NK1R.

Using Arterial Recoil for Large Bore Access Closure After Impella Assist Device Removal.

The use of Impella assist device for high-risk percutaneous coronary interventions and cardiogenic shock has increased in the last decade and requires a large bore arterial access (LBA). However, LBA closure following Impella removal is associated with significant complications. Herein, we describe the safety and efficacy of a novel method of LBA closure using arterial recoil following Impella removal. We performed a retrospective review of electronic medical records of patients who underwent LBA closure using this method from July 1, 2018 to June 30, 2022. The procedure involves controlled downsizing of the arterial sheath from 12 French (Fr) to 6 Fr catheters with intermittent compression to allow patent hemostasis facilitated by arterial recoil. Baseline characteristics and outcomes including closure success, immediate/delayed bleeding, and access site complications were included. Of 103 patients with Impella placement, 20 (19%) underwent LBA closure with this method. Patients were predominantly male (80%) and White (55%) with a mean age of 65 ± 16 years. After downsizing of the femoral sheath to 6 Fr, 14 patients underwent manual compression, 3 patients had a 6 Fr catheter left in place to maintain access, and 3 patients underwent placement of a Perclose or Vascade device. Successful LBA closure was performed in all patients with no immediate or delayed bleeding complications. Five patients (25%) died inpatient; the deaths were unrelated to complications of Impella removal. In conclusion, LBA closure post-Impella removal with this novel method was safe and effective. Further prospective studies are needed to ascertain its comparative efficacy.

Ayahuasca in the treatment of posttraumatic stress disorder: Mixed-methods case series evaluation in military combat veterans.

OBJECTIVE: Although ayahuasca-a plant-based psychedelic-is discussed as promising in the treatment of posttraumatic stress disorder (PTSD), evidence so far remains limited to retrospective case reports and qualitative surveys. No study to date has examined whether ayahuasca results in prospective and clinically meaningful changes in trauma symptoms across individuals with PTSD symptoms. METHOD: To address this gap, we conducted a convergent mixed-methods case series study on eight military veterans with PTSD who participated in a 3-day ayahuasca intervention in Central America. Clinically meaningful changes from pre- to posttreatment and at a 3-month follow-up were assessed in three ways using: (a) PTSD checklist-5 (PCL-5); (b) experience sampling measurement of momentary PTSD and mood symptoms; and (c) an open-ended survey on perceived benefits. RESULTS: The majority (87.5%; 7/8) of participants demonstrated reliable and/or clinically significant changes in PCL-5 symptoms by posttreatment, which were maintained by 70% (5/7) of veterans by the 3-month follow-up. On average, veterans also reported significant improvements in momentary PTSD symptoms, as well as negative and positive affect in daily life posttreatment, with 63% (5/8) reporting moderate-to-large improvements in these domains. Broad themes characterizing the perceived benefits of ayahuasca included deep positive emotions, decentering/acceptance, and purpose in life; adverse acute experiences were, however, reported. CONCLUSIONS: This study provides preliminary support for the clinically meaningful and lasting benefits of a brief ayahuasca intervention on PTSD/mood symptoms in military veterans. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Provision of Patient Care Services and Goals for Expansion in Community and Ambulatory Care Pharmacies in Southeastern North Carolina.

In February 2022, the North Carolina legislature expanded pharmacist dispensing authority without a prescription. We conducted a cross-sectional interview of currently licensed pharmacy managers of outpatient pharmacies located in five counties in southeastern North Carolina. Pharmacy managers were eligible to participate if their pharmacy was either a community pharmacy, clinic-based pharmacy, or outpatient health system pharmacy. Forty-four of 116 eligible pharmacy managers participated (38% response rate). The most common services offered by pharmacies included medication synchronization services (93.2%), on-site immunizations (90.9%), and refill reminders (88.6%). The least common services offered include INR screens (0%), A1c screens (7%), and 'incident-to' billing services associated with CPT codes: annual wellness visits (0%), chronic care management (0%), transitional care management (0%), and remote patient monitoring (2.4%). The services that pharmacy managers wanted to learn more about through continuing education included: oral/transdermal contraceptives (60.5%), administration of long-acting injectables (LAIs) (36.8%), and dispensing of HIV post-exposure prophylaxis (PEP) (23.7%).

The multi-mode acoustic gravitational wave experiment: MAGE.

The Multi-mode Acoustic Gravitational wave Experiment (MAGE) is a high frequency gravitational wave detection experiment. In its first stage, the experiment features two near-identical quartz bulk acoustic wave resonators that act as strain antennas with spectral sensitivity as low as 6.6 × 10-21 [strain]/[Formula: see text] in multiple narrow bands across MHz frequencies. MAGE is the successor to the initial path-finding experiments; GEN 1 and GEN 2. These precursor runs demonstrated the successful use of the technology, employing a single quartz gravitational wave detector that found significantly strong and rare transient features. As the next step to this initial experiment, MAGE will employ further systematic rejection strategies by adding an additional quartz detector such that localised strains incident on just a single detector can be identified. The primary goals of MAGE will be to target signatures arising from objects and/or particles beyond that of the standard model, as well as identifying the source of the rare events seen in the predecessor experiment. The experimental set-up, current status and future directions for MAGE are discussed. Calibration procedures of the detector and signal amplification chain are presented. The sensitivity of MAGE to gravitational waves is estimated from knowledge of the quartz resonators. Finally, MAGE is assembled and tested in order to determine the thermal state of its new components.

Respiratory Syncytial Virus Infection Among Hospitalized Infants in Four Middle-Income Countries.

BACKGROUND: Understanding respiratory syncytial virus (RSV) global epidemiology is important to inform future prevention strategies. METHODS: Hospitalized infants <1-year-old with acute illness were enrolled prospectively in Albania, Jordan, Nicaragua, and Philippines during respiratory seasons in 2015-2017. Medical chart review, parental interview, and post-discharge follow up were conducted. Respiratory specimens were tested using real-time RT-PCR for RSV. Infant characteristics associated with very severe illness (intensive care unit [ICU] admission or receipt of supplemental oxygen) were assessed using logistic regression to adjust for potential confounders (age, sex, study site, and preterm birth). RESULTS: Of 3634 enrolled hospitalized infants, 1129 (31%) tested positive for RSV. The median age of RSV-positive infants was 2.7 (IQR: 1.4-6.1) months and 665 (59%) were male. Very severe illness in 583 (52%) RSV-positive infants was associated with younger age (aOR 4.1, 95% CI: 2.6-6.5 for 0-2 compared to 9-11-months; P < .01), low weight-for-age z-score (aOR 1.9, 95% CI: 1.2-2.8; P < .01), ICU care after birth (aOR 1.6, 95% CI: 1.0-2.5; P = .048), and cesarean delivery (aOR 1.4, 95% CI: 1.0-1.8; P = .03). RSV subgroups A and B co-circulated at all sites with alternating predominance by year; subgroup was not associated with severity (aOR 1.0, 95% CI: 0.8-1.4). Nine (0.8%) RSV-positive infants died during admission or within ≤30 days of discharge, of which 7 (78%) were <6-months-old. CONCLUSIONS: RSV was associated with nearly a third of infant acute illness hospitalizations in four middle-income countries during the respiratory season, where, in addition to young age, factors including low weight-for-age might be important predictors of severity. RSV prevention strategies targeting young infants could substantially reduce RSV-associated hospitalizations in middle-income countries.

Ruptured Penetrating Atherosclerotic Ulcer Repaired With an Amplatzer Atrial Septal Occluder.

Ascending aortic pseudoaneurysms are an infrequent but life-threatening complication of cardiac and aortic surgery. Although rare, these pseudoaneurysms can form as a complication of penetrating atherosclerotic ulcers. We report a case of a ruptured penetrating atherosclerotic ulcer repaired percutaneously with an Amplatzer Atrial Septal Occluder (Abbott, Plymouth, MN, USA).

Crosslinked Polyethylene (XLPE) Recycling via Foams.

Efficient recycling of crosslinked polyethylene has been challenging due to manufacturing difficulties caused by chemical crosslinking. This study focuses on simple processing via solid waste powder generation and particle fining for the subsequent crosslinked polyethylene inclusion and dispersion in rigid polyurethane foam. In addition, the concentration effects of crosslinked polyethylene in polyurethane were studied, showing a well-controlled foam microstructure with uniform pores, retained strength, better thermal degradation resistance, and, more importantly, increased thermal capabilities. Thus, the simple mechanical processing of crosslinked polyethylene and chemical urethane foaming showed the massive potential of recycling large amounts of crosslinked polyethylene in foams for broad applications in food packaging, house insulation, and sound reduction.

Development of a novel tau propagation mouse model endogenously expressing 3 and 4 repeat tau isoforms.

The phenomenon of 'prion-like propagation' in which aggregates of abnormal amyloid-fibrilized protein propagate between neurons and spread pathology, is attracting attention as a new mechanism in neurodegenerative diseases. There is a strong correlation between the accumulation or spread of abnormal tau aggregates and the clinical symptoms of tauopathies. Microtubule-associated protein tau (MAPT) contains a microtubule-binding domain that consists of three or four repeats (3R/4R) due to alternative mRNA splicing of transcripts for the MAPT gene. Although a number of models for tau propagation have been reported, most use 4R human tau transgenic mice or adult wild-type mice expressing only endogenous 4R tau and these models have not been able to reproduce the pathology of Alzheimer's disease in which 3R and 4R tau accumulate simultaneously, or that of Pick's disease in which only 3R tau is aggregated. These deficiencies may reflect differences between human and rodent tau isoforms in the brain. To overcome this problem, we used genome editing techniques to generate mice that express an equal ratio of endogenous 3R and 4R tau, even after they become adults. We injected these mice with sarkosyl-insoluble fractions derived from the brains of human tauopathy patients such as those afflicted with Alzheimer's disease (3R and 4R tauopathy), corticobasal degeneration (4R tauopathy) or Pick's disease (3R tauopathy). At 8-9 months following intracerebral injection of mice, histopathological and biochemical analyses revealed that the abnormal accumulation of tau was seed-dependent, with 3R and 4R tau in Alzheimer's disease-injected brains, 4R tau only in corticobasal degeneration-injected brains and 3R tau only in Pick disease-injected brains, all of which contained isoforms related to those found in the injected seeds. The injected abnormal tau was seeded, and accumulated at the site of injection and at neural connections, predominantly within the same site. The abnormal tau newly accumulated was found to be endogenous in these mice and to have crossed the species barrier. Of particular importance, Pick's body-like inclusions were observed in Pick's disease-injected mice, and accumulations characteristic of Pick's disease were reproduced, suggesting that we have developed the first model that recapitulates the pathology of Pick's disease. These models are not only useful for elucidating the mechanism of propagation of tau pathology involving both 3R and 4R isoforms, but can also reproduce the pathology of tauopathies, which should lead to the discovery of new therapeutic agents.

Macrophage 12(S)-HETE Enhances Angiotensin II-Induced Contraction by a BLT2 (Leukotriene B4 Type-2 Receptor) and TP (Thromboxane Receptor)-Mediated Mechanism in Murine Arteries.

12/15-LO (12/15-lipoxygenase), encoded by Alox15 gene, metabolizes arachidonic acid to 12(S)-HETE (12-hydroxyeicosatetraenoic acid). Macrophages are the major source of 12/15-LO among immune cells, and 12/15-LO plays a crucial role in development of hypertension. Global Alox15- or macrophage-deficient mice are resistant to Ang II (angiotensin II)-induced hypertension. This study tests the hypothesis that macrophage 12(S)-HETE contributes to Ang II-mediated arterial constriction and thus to development of Ang II-induced hypertension. Ang II constricted isolated abdominal aortic and mesenteric arterial rings. 12(S)-HETE (100 nmol/L) alone was without effect; however, it significantly enhanced Ang II-induced constriction. The presence of wild-type macrophages also enhanced the Ang II-induced constriction, while Alox15-/- macrophages did not. Using this model, pretreatment of aortic rings with inhibitors, receptor agonists/antagonists, or removal of the endothelium, systematically uncovered an endothelium-mediated, Ang II receptor-2-mediated and superoxide-mediated enhancing effect of 12(S)-HETE on Ang II constrictions. The role of superoxide was confirmed using aortas from p47phox-/- mice where 12(S)-HETE failed to enhance constriction to Ang II. In cultured arterial endothelial cells, 12(S)-HETE increased the production of superoxide, and 12(S)-HETE or Ang II increased the production of an isothromboxane-like metabolite. A TP (thromboxane receptor) antagonist inhibited 12(S)-HETE enhancement of Ang II constriction. Both Ang II-induced hypertension and the enhancing effect of 12(S)-HETE on Ang II contractions were eliminated by a BLT2 (leukotriene B4 receptor-2) antagonist. These results outline a mechanism where the macrophage 12/15-LO pathway enhances the action of Ang II. 12(S)-HETE, acting on the BLT2, contributes to the hypertensive action of Ang II in part by promoting endothelial synthesis of a superoxide-derived TP agonist.

Rare Events Detected with a Bulk Acoustic Wave High Frequency Gravitational Wave Antenna.

This work describes the operation of a high frequency gravitational wave detector based on a cryogenic bulk acoustic wave cavity and reports observation of rare events during 153 days of operation over two separate experimental runs (run 1 and run 2). In both run 1 and run 2, two modes were simultaneously monitored. Across both runs, the third overtone of the fast shear mode (3B) operating at 5.506 MHz was monitored; whereas in run 1, the second mode was chosen to be the fifth overtone of the slow shear mode (5C) operating at 8.392 MHz. However, in run 2, the second mode was selected to be closer in frequency to the first mode; and it was chosen to be the third overtone of the slow shear mode (3C) operating at 4.993 MHz. Two strong events were observed as transients responding to energy deposition within acoustic modes of the cavity. The first event occurred during run 1 on 12 May 2019 (UTC), and it was observed in the 5.506 MHz mode; whereas the second mode at 8.392 MHz observed no event. During run 2, a second event occurred on 27 November 2019 (UTC) and was observed by both modes. Timings of the events were checked against available environmental observations as well as data from other detectors. Various possibilities explaining the origins of the events are discussed.

Acute Macular Neuroretinopathy Related to Alcoholic Hepatitis.

A 33-year-old woman admitted for acute alcoholic hepatitis was referred to the ophthalmology department with an acute onset paracentral scotoma of the left eye. On examination, best-corrected visual acuity was Snellen 6/4 in the right eye and 6/9 in the left eye. Dilated left fundus examination revealed wedge-shaped changes at the macula. Spectral-domain ocular coherence tomography (SD-OCT) initially revealed a small cuff of subfoveal fluid and band-like hyperreflectivity extending outwards from the outer plexiform layer consistent with acute macular neuroretinopathy (AMN). Four days later, repeat SD-OCT was performed and it demonstrated resolution of the subfoveal fluid and disruption of the outer retinal layers. At the 6-week follow-up, the patient had no improvement in her symptoms and OCT angiography demonstrated coarsening and microvascular changes in both the deep vascular plexus and the choriocapillaris. To our knowledge, this is the first case of AMN in association with acute hepatitis. Although the exact pathophysiology of AMN remains obscure, this case highlights the benefits of multimodal retinal imaging and aims to bring attention to the possible association of AMN with alcoholic hepatitis.

Searching for Scalar Dark Matter via Coupling to Fundamental Constants with Photonic, Atomic, and Mechanical Oscillators.

We present a way to search for light scalar dark matter (DM), seeking to exploit putative coupling between dark matter scalar fields and fundamental constants, by searching for frequency modulations in direct comparisons between frequency stable oscillators. Specifically we compare a cryogenic sapphire oscillator (CSO), hydrogen maser (HM) atomic oscillator, and a bulk acoustic wave quartz oscillator (OCXO). This work includes the first calculation of the dependence of acoustic oscillators on variations of the fundamental constants, and demonstration that they can be a sensitive tool for scalar DM experiments. Results are presented based on 16 days of data in comparisons between the HM and OCXO, and 2 days of comparison between the OCXO and CSO. No evidence of oscillating fundamental constants consistent with a coupling to scalar dark matter is found, and instead limits on the strength of these couplings as a function of the dark matter mass are determined. We constrain the dimensionless coupling constant d_{e} and combination |d_{m_{e}}-d_{g}| across the mass band 4.4×10^{-19}≲m_{φ}≲6.8×10^{-14} eV c^{-2}, with most sensitive limits d_{e}≳1.59×10^{-1}, |d_{m_{e}}-dg|≳6.97×10^{-1}. Notably, these limits do not rely on maximum reach analysis (MRA), instead employing the more general coefficient separation technique. This experiment paves the way for future, highly sensitive experiments based on state-of-the-art acoustic oscillators, and we show that these limits can be competitive with the best current MRA-based exclusion limits.

Cystic Adventitial Disease Presenting as Occlusion of the External Iliac Artery: A Rare Manifestation.

Cystic adventitial disease (CAD) is a rare, non-atherosclerotic cause of peripheral arterial disease characterized by mucinous cyst formation in the adventitial layer of arteries; with approximately 80% to 90% of cases involving the popliteal artery. We describe a case of CAD presenting in a female with left external iliac artery occlusion and intermittent claudication, for whom an intra-operative diagnosis of CAD of the ilio-femoral segment was made. A 37-year-old mother-of-two was referred to a Vascular Surgeon with a 3 to 4-year history of progressive intermittent claudication. A computed tomography (CT) angiogram demonstrated a left external iliac artery occlusion. Given the location of the lesion, the absence of cardiovascular risk factors and the patient's history of cycling, a diagnosis of left external iliac artery occlusion secondary to arterial endofibrosis or spontaneous arterial dissection was thought to be likely. A left Rutherford-Morrison incision was made and an extraperitoneal approach used to expose the left iliac system. A cyst was opened and marsupialized along the superior aspect of the external iliac artery, releasing gelatinous material. A provisional intra-operative diagnosis of CAD was made. The patient was systemically heparinized and an external iliac to common femoral artery bypass was performed using reversed ipsilateral greater saphenous vein. CAD primarily involves the popliteal artery. Under 40 cases of CAD with iliofemoral involvement have been reported. Our case is unusual given the location of CAD, as well as its occurrence in a female. Management options for similar cases have been described in the literature ranging from cyst excision and arterial patching, to interposition bypass and even exclusion bypass, in the case of longer segment occlusions. In our case, an exclusion bypass was deemed the most appropriate treatment given the extensive length and complete occlusion of the external iliac artery.

Combat-Sustained Peripheral Nerve Injuries in the United States Military.

PURPOSE: Combat-sustained peripheral nerve injuries (CSPNIs) are often the result of high-energy blast mechanisms and are increasing in frequency and severity among US forces engaged in contemporary warfare. The purpose of this study was to describe CSPNIs and report outcomes after evaluation in a military multidisciplinary peripheral nerve clinic. We hypothesized that a shorter time to evaluation by a multidisciplinary peripheral nerve team would improve outcomes. METHODS: The Peripheral Nerve Consortium (PNC) maintains an electronic database of all active duty service members who sustained a peripheral nerve injury (PNI) and were treated by the PNC between 2004 and 2009. This database was queried for service member demographic information, injury characteristics, wounding patterns, CSPNI description, surgical procedures, and Medical Research Council final motor and sensory outcome. RESULTS: Among the 104 service members treated by the PNC in the 6-year period reviewed, there were 138 PNIs. Average age was 27 years, time to initial evaluation by the PNC was 4 (±7) months, and average follow-up was 18 (±18) months. Associated injuries included fractures (31.1%), multiple PNIs (76.8%), vascular injury (30.4%), and traumatic brain injury (34.1%). There was no association between Sunderland classification and time to evaluation, mechanism of injury, or nerve injured. However, Sunderland classification was correlated with final motor and final sensory scores. Service members with better final sensory score (S1 or S2) had shorter time to initial evaluation than did patients with a final sensory score of S0 (<0.05). This did not hold true for final motor score. CONCLUSIONS: Service members with more severe initial injuries had worse final outcomes. Although timely referral does not occur for most CSPNIs, a shorter time to presentation also led to improved sensory recovery. Complex combat-sustained PNIs may be best understood and treated within a multidisciplinary team. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

The Histamine 3 Receptor Is Expressed in the Heart and Its Activation Opposes Adverse Cardiac Remodeling in the Angiotensin II Mouse Model.

Histamine is a basic amine stored in mast cells, with its release capable of activating one of four histamine receptors. The histamine 3 receptor (H3R) is known to be cardioprotective during acute ischemia by acting to limit norepinephrine release. However, a recent study reported that myofibroblasts isolated from the infarct zone of rat hearts responded to H3R activation by up-regulating collagen production. Thus, it is necessary to clarify the potential role of the H3R in relation to fibrosis in the heart. We identified that the mouse left ventricle (LV) expresses the H3R. Isolation of mouse cardiac fibroblasts determined that while angiotensin II (Ang II) increased levels of the H3R, these cells did not produce excess collagen in response to H3R activation. Using the Ang II mouse model of adverse cardiac remodeling, we found that while H3R blockade had little effect on cardiac fibrosis, activation of the H3R reduced cardiac fibrosis and macrophage infiltration. These findings suggest that when activated, the H3R is anti-inflammatory and anti-fibrotic in the mouse heart and may be a promising target for protecting against cardiac fibrosis.