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BACKGROUND: High levels of catecholamines are cardiotoxic and associated with stress-induced cardiomyopathies. Using a septic shock model that reproduces the reversible cardiomyopathy seen over 10 days associated with human septic shock, we investigated the effects of catecholamines on microcirculatory perfusion and cardiac dysfunction. METHODS AND RESULTS: Purpose-bred beagles received intrabronchial Staphylococcus aureus (n=30) or saline (n=6). The septic animals were than randomized to epinephrine (1 µg/kg per minute, n=15) or saline (n=15) infusions from 4 to 44 hours. Serial cardiac magnetic resonance imaging, catecholamine levels, and troponins were collected over 92 hours. Serial adenosine-stress perfusion cardiac magnetic resonance imaging was performed on septic animals randomized to receive saline (n=8 out of 15) or epinephrine (n=8 out of 15). High-dose sedation was given to suppress endogenous catecholamine release. Despite catecholamine levels largely remaining within the normal range throughout, by 48 hours, septic animals receiving saline versus nonseptic animals still developed significant worsening of left ventricular ejection fraction, circumferential strain, and ventricular-aortic coupling. In septic animals that received epinephrine versus saline infusions, plasma epinephrine levels increased 800-fold, but epinephrine produced no significant further worsening of left ventricular ejection fraction, circumferential strain, or ventricular-aortic coupling. Septic animals receiving saline had a significant increase in microcirculatory reserve without troponin elevations. Septic animals receiving epinephrine had decreased edema, blunted microcirculatory perfusion, and elevated troponin levels that persisted for hours after the epinephrine infusion stopped. CONCLUSIONS: Cardiac dysfunction during sepsis is not primarily due to elevated endogenous or exogenous catecholamines nor due to decreased microvascular perfusion-induced ischemia. However, epinephrine itself has potentially harmful long-lasting ischemic effects during sepsis including impaired cardiac microvascular perfusion that persists after stopping the infusion.
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Cardiomiopatías , Modelos Animales de Enfermedad , Epinefrina , Microcirculación , Choque Séptico , Animales , Perros , Choque Séptico/fisiopatología , Choque Séptico/complicaciones , Choque Séptico/sangre , Epinefrina/sangre , Microcirculación/efectos de los fármacos , Cardiomiopatías/fisiopatología , Cardiomiopatías/sangre , Cardiomiopatías/etiología , Volumen Sistólico/efectos de los fármacos , Circulación Coronaria/efectos de los fármacos , Isquemia Miocárdica/fisiopatología , Isquemia Miocárdica/sangre , Isquemia Miocárdica/complicaciones , Función Ventricular Izquierda/efectos de los fármacos , Catecolaminas/sangre , Troponina/sangre , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/complicaciones , Infecciones Estafilocócicas/fisiopatología , Factores de Tiempo , Imagen de Perfusión Miocárdica/métodos , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Septic shock is associated with increases in end-diastolic volume (EDV) and decreases in ejection fraction that reverse within 10 days. Nonsurvivors do not develop EDV increases. The mechanism is unknown. METHODS AND RESULTS: Purpose-bred beagles (n=33) were randomized to receive intrabronchial Staphylococcus aureus or saline. Over 96 hours, cardiac magnetic resonance imaging and echocardiograms were performed. Tissue was obtained at 66 hours. From 0 to 96 hours after bacterial challenge, septic animals versus controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%). On histology, the major finding was nonocclusive microvascular injury with edema in myocytes, the interstitium, and endothelial cells. Edema was associated with significant worsening of biventricular ejection fractions, ventricular-arterial coupling, and circumferential strain. Early during sepsis, (0-24 hours), the EDV decreased; significantly more in nonsurvivors (ie, greater diastolic dysfunction). From 24 to 48 hours, septic animals' biventricular chamber sizes increased; in survivors significantly greater than baseline and nonsurvivors, whose EDVs were not different from baseline. Preload, afterload, or heart rate differences did not explain these differential changes. CONCLUSIONS: The cardiac dysfunction of sepsis is associated with wall edema. In nonsurvivors, at 0 to 24 hours, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part, explain the EDV increases from 24 to 48 hours because of a potentially reparative process removing damaged wall tissue. Septic cardiomyopathy is most consistent with a nonocclusive microvascular injury resulting in edema causing reversible systolic and diastolic dysfunction with more severe diastolic dysfunction being associated with a decreased EDV and death.
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Modelos Animales de Enfermedad , Choque Séptico , Volumen Sistólico , Animales , Perros , Choque Séptico/fisiopatología , Choque Séptico/complicaciones , Imagen por Resonancia Magnética , Edema Cardíaco/fisiopatología , Edema Cardíaco/patología , Edema Cardíaco/diagnóstico por imagen , Función Ventricular Izquierda , Factores de Tiempo , Humanos , Infecciones Estafilocócicas/complicaciones , Infecciones Estafilocócicas/fisiopatología , Ecocardiografía , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiología , MasculinoRESUMEN
BACKGROUND/AIMS: In people with opioid use disorder (OUD), buprenorphine is a vital treatment to decrease opioid use and overdose. The US Food and Drug Administration's prescribing information for buprenorphine advises dosing up to 24 mg/day; however, doses of buprenorphine up to 32 mg have been shown to be safe and effective. We compared outcomes associated increased dosing from 24 to 32 mg/day. DESIGN: Prospective cohort investigation. SETTING: Low-barrier buprenorphine clinic in Washington, District of Columbia, USA. PARTICIPANTS: Participants in the ANCHOR study (people with hepatitis C virus (HCV), OUD, and active opioid misuse who were treated for HCV and offered buprenorphine) who received buprenorphine at doses of 24 and/or 32 mg/day. 72 participants were included in the analysis: 24 (33%) patients stabilized on 24 mg, and 48 (67%) patients stabilized on 32 mg. Patients were predominantly male (78%), Black (96%), unstably housed (57%), and used opioids by injection (93%). MEASUREMENTS: Patient-reported drug use, use frequency, triggers for use, and urine drug screens were collected at each visit. For analysis, the cohort was divided into individuals stabilized on 24 mg (24 mg cohort) or 32 mg (32 mg cohort). Drug use outcomes were assessed between cohorts at 24 mg dosing and at respective maximum dosing. Within the 32 mg cohort, outcomes were compared at 24 mg versus 32 mg dosing. FINDINGS: Within the 32 mg cohort, increased dosing from 24 to 32 mg was associated with a decline in opioid use (68.5% [5.2%] at 24 mg vs 59.5% [5.6%] at 32 mg; P = 0.02), frequency of use per week (1.58 [0.19] at 24 mg vs. 1.15 [0.16] at 32 mg; P = 0.0002) and physiologic triggers for use (38.2% [6.0%] at 24 mg vs 7.0% [1.9%] at 32 mg; P < 0.0001). At the end of the study period, there were significantly more patients retained in the 32 mg cohort (78.7%) compared with the 24 mg cohort (50.0%, P = 0.02). CONCLUSION: Higher buprenorphine dosing (32 mg/day) appears to improve outcomes in people with opioid use disorder, even in the absence of abstinence.
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Collective studies have demonstrated that transcranial ultrasound stimulation (TUS) can elicit activation in hemodynamics, implying its potential in treating cerebral or peripheral vessel-related malfunction. The theory for hemodynamic response to TUS is neurovascular coupling (NVC) following the ultrasound-induced cellular (de)polarization. However, it was not conclusive due to the co-existence of the pathway of direct ultrasound-vessel interactions. This study thus aims to investigate and provide direct evidence for NVC pathway in a rodent model of TUS by inhibiting neural activity with sodium valproate (VPA), a GABAergic agent. Twenty Sprague-Dawley rats were randomly assigned to VPA and Saline groups. Microelectrode and optical imaging were utilized to record local field potential and relative cerebral blood flow (rCBF) during baseline, before, and after TUS periods. We found the attenuated neural activity was associated with reduced rCBF responses. These results provided direct evidence for the presence of NVC pathway in hemodynamic modulation by TUS.
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Background: A prior single-center, retrospective cohort study identified baseline lung allograft dysfunction (BLAD) as a risk factor for death in bilateral lung transplant recipients. In this multicenter prospective cohort study, we test the association of BLAD with death in bilateral lung transplant recipients, identify clinical risk factors for BLAD, and assess its association with allograft injury on the molecular level. Methods: This multicenter, prospective cohort study included 173 bilateral lung transplant recipients that underwent serial pulmonary function testing and plasma collection for donor-derived cell-free DNA at prespecified time points. BLAD was defined as failure to achieve ≥80% predicted for both forced expiratory volume in 1 s and forced vital capacity after lung transplant, on 2 consecutive measurements at least 3 mo apart. Results: BLAD was associated with increased risk of death (hazard ratio, 1.97; 95% confidence interval [CI], 1.05-3.69; Pâ =â 0.03) but not chronic lung allograft dysfunction alone (hazard ratio, 1.60; 95% CI, 0.87-2.95; P = 0.13). Recipient obesity (odds ratio, 1.69; 95% CI, 1.15-2.80; Pâ =â 0.04) and donor age (odds ratio, 1.03; 95% CI, 1.02-1.05; Pâ =â 0.004) increased the risk of developing BLAD. Patients with BLAD did not demonstrate higher log10(donor-derived cell-free DNA) levels compared with no BLAD (slope [SE]: -0.0095 [0.0007] versus -0.0109 [0.0007]; Pâ =â 0.15). Conclusions: BLAD is associated with an increased risk of death following lung transplantation, representing an important posttransplant outcome with valuable prognostic significance; however, early allograft specific injury on the molecular level does not increase the risk of BLAD, supporting further mechanistic insight into disease pathophysiology.
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BACKGROUND: Abnormalities in cortical excitability and plasticity have been considered to underlie the pathophysiology of schizophrenia. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) can provide a direct evaluation of cortical responses to TMS. Here, we employed TMS-EEG to investigate cortical responses to orbitofrontal cortex (OFC) stimulation in schizophrenia. METHODS: In total, we recruited 92 drug-naïve patients with first-episode schizophrenia and 51 age- and sex-matched healthy individuals. For each participant, one session of 1-Hz repetitive TMS (rTMS) was delivered to the right OFC, and TMS-EEG data were obtained to explore the change in cortical-evoked activities before and immediately after rTMS during the eyes-closed state. The MATRICS Consensus Cognitive Battery was used to assess neurocognitive performance. RESULTS: The cortical responses indexed by global mean field amplitudes (i.e., P30, N45, and P60) were larger in patients with schizophrenia than in healthy control participants at baseline. Furthermore, after one session of 1-Hz rTMS over the right OFC, the N100 amplitude was significantly reduced in the healthy control group but not in the schizophrenia group. In the healthy control participants, there was a significant correlation between modulation of P60 amplitude by rTMS and working memory; however, this correlation was absent in patients with schizophrenia. CONCLUSIONS: Aberrant global cortical responses following right OFC stimulation were found in patients with drug-naïve first-episode schizophrenia, supporting its significance in the primary pathophysiology of schizophrenia.
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Electroencefalografía , Corteza Prefrontal , Esquizofrenia , Estimulación Magnética Transcraneal , Humanos , Estimulación Magnética Transcraneal/métodos , Esquizofrenia/fisiopatología , Esquizofrenia/terapia , Femenino , Masculino , Corteza Prefrontal/fisiopatología , Adulto , Adulto Joven , Potenciales Evocados/fisiologíaRESUMEN
Background: Septic shock, in humans and in our well-established animal model, is associated with increases in biventricular end diastolic volume (EDV) and decreases in ejection fraction (EF). These abnormalities occur over 2 days and reverse within 10 days. Septic non-survivors do not develop an increase in EDV. The mechanism for this cardiac dysfunction and EDV differences is unknown. Methods: Purpose-bred beagles randomized to receive intrabronchial Staphylococcus aureus (n=27) or saline (n=6) were provided standard ICU care including sedation, mechanical ventilation, and fluid resuscitation to a pulmonary arterial occlusion pressure of over 10mmHg. No catecholamines were administered. Over 96h, cardiac magnetic resonance imaging, echocardiograms, and invasive hemodynamics were serially performed, and laboratory data was collected. Tissue was obtained at 66h from six septic animals. Results: From 0-96h after bacterial challenge, septic animals vs. controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%) which was more pronounced at 48h in non-survivors than survivors. On histology, edema was located predominantly in myocytes, the interstitium, and endothelial cells. Edema was associated with significantly worse biventricular function (lower EFs), ventricular-arterial coupling, and circumferential strain. In septic animals, from 0-24h, the EDV decreased from baseline and, despite cardiac filling pressures being similar, decreased significantly more in non-survivors. From 24-48h, all septic animals had increases in biventricular chamber sizes. Survivors biventricular EDVs were significantly greater than baseline and in non-survivors, where biventricular EDVs were not different from baseline. Preload, afterload, or HR differences did not explain these differential serial changes in chamber size. Conclusion: Systolic and diastolic cardiac dysfunction during sepsis is associated with ventricular wall edema. Rather than differences in preload, afterload, or heart rate, structural alterations to the ventricular wall best account for the volume changes associated with outcome during sepsis. In non-survivors, from 0-24h, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part explain, the EDV increases from 24-48h. However, these changes continued and even accelerated into the recovery phase consistent with a reparative process rather than ongoing injury.
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Enfermedades Cardiovasculares , Transfusión de Eritrocitos , Humanos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/terapia , Transfusión de Eritrocitos/efectos adversos , Factores de Riesgo , Medición de Riesgo , Resultado del Tratamiento , Hemorragia/terapia , Toma de Decisiones ClínicasRESUMEN
Visual selective attention studies generally tend to apply cuing paradigms to instructively direct observers' attention to certain locations, features or objects. However, in real situations, attention in humans often flows spontaneously without any specific instructions. Recently, a concept named "willed attention" was raised in visuospatial attention, in which participants are free to make volitional attention decisions. Several ERP components during willed attention were found, along with a perspective that ongoing alpha activity may bias the subsequent attentional choice. However, it remains unclear whether similar neural mechanisms exist in feature- or object-based willed attention. Here, we included choice cues and instruct cues in a feature-based selective attention paradigm, allowing participants to freely choose or to be instructed to attend a color for the subsequent target detection task. Pre-cue ongoing alpha oscillations, cue-evoked potentials and target-related steady-state visual evoked potentials (SSVEPs) were simultaneously measured as markers of attentional processing. As expected, SSVEP responses were similarly modulated by attention between choice and instruct cue trials. Similar to the case of spatial attention, a willed-attention component (Willed Attention Component, WAC) was isolated during the cue-related choice period by comparing choice and instruct cues. However, pre-cue ongoing alpha oscillations did not predict the color choice (yellow vs blue), as indicated by the chance level decoding accuracy (50%). Overall, our results revealed both similarities and differences between spatial and feature-based willed attention, and thus extended the understanding toward the neural mechanisms of volitional attention.
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Electroencefalografía , Potenciales Evocados Visuales , Humanos , Potenciales Evocados/fisiología , Señales (Psicología) , Estimulación Luminosa , Percepción Visual/fisiologíaRESUMEN
Photoperiod is an important environmental factor that influences seasonal reproduction behavior in birds. Birds translate photoperiodic information into neuroendocrine signals through deep brain photoreceptors (DBPs). OPN5 has been considered candidate DBPs involved in regulating seasonal reproduction in birds. We found that OPN5 could mediate light to regulate the follicle development in ducks. In this study, we further verified the effect of OPN5 on follicular development in Shan Partridge ducks by immunizing against the extracellular domain (ECD) of OPN5. We investigated the specific regulatory mechanism of photoperiod mediated by OPN5 on the reproductive activity of ducks. The trial randomly divided 120 Shan Partridge ducks into 3 groups with different treatments: the immunization of OPN5 group was done at d0, d15, d30, and d40 with 1 mL of vaccine containing OPN5 protein (thus containing 1, 1, 0.5, and 0.5 mg of OPN5-KLH protein), and the control group (CS and CL groups) was injected at the same time with the same dose of OPN5-uncontained blank vaccine. The group of CS (900 lux), OPN5 (600 lux), and CL (600 lux) lasted for 40 d in 12 L:12 D photoperiods, respectively. Then, the groups of CS, OPN5, and CL subsequently received 12 L:12 D, 12 L:12 D, and 17 L:7 D light treatments for 33 d, respectively. The ducks were caged in 3 constant rooms with the same feeding conditions for each group, free water, and limited feeding (150 g per duck each day). Duck serum and tissue samples were collected at d 40, d 62, and d 73 (n = 12). It was found that before prolonged light, the group of immunization (group OPN5) and the group of strong light intensity (group CS) were higher than the group of CL in egg production. Subsequent to prolonged light, the group CL in egg production rose about the same as the group immunization, while the strong light group (group CS) was lower. Group OPN5 increased the ovarian index of ducks, and both the immunization of group OPN5 and group CL (extended light) increased the thickness of the granular layer and promoted the secretion of E2, P4, LH, and PRL hormones. Compared with group CS, group CL and OPN5 increased the mRNA level and protein expression of OPN5 in the hypothalamus on d 62 and d 73 (P < 0.05). The gene or protein expression patterns of GnRH, TRH, TSHß, DIO2, THRß, VIP, and PRL were positively correlated with OPN5, whereas the gene expression patterns of GnIH and DIO3 were negatively correlated with OPN5. The results showed that immunization against OPN5 could activate the corresponding transmembrane receptors to promote the expression of OPN5, up-regulate the expression of TSHß and DIO2, and then regulate the HPG axis-related genes to facilitate the follicular development of Shan Partridge ducks. In addition, in this experiment, prolonging the photoperiod or enhancing the light intensity could also enhance follicle development, but the effect was not as significant as immunizing against OPN5. Our results will offer beneficial data and more supportive shreds of evidence in favor of elucidating the role of OPN5 in relation to photoperiods and reproduction.
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Fotoperiodo , Vacunas , Animales , Patos/fisiología , Pollos , Reproducción , Inmunización/veterinariaRESUMEN
ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) is a promising technology to reduce chronic pain. Investigating the mechanisms of rTMS analgesia holds the potential to improve treatment efficacy. Using a double-blind and placebo-controlled design at both stimulation and pharmacologic ends, this study investigated the opioidergic mechanisms of rTMS analgesia by abolishing and recovering analgesia in 2 separate stages across brain regions and TMS doses. A group of 45 healthy participants were equally randomized to the primary motor cortex (M1), the dorsolateral prefrontal cortex (DLPFC), and the Sham group. In each session, participants received an intravenous infusion of naloxone or saline before the first rTMS session. Participants then received a second dose of rTMS session after the drugs were metabolized at 90 minutes. M1-rTMS-induced analgesia was abolished by naloxone compared with saline and was recovered by the second rTMS run when naloxone was metabolized. In the DLPFC, double but not the first TMS session induced significant pain reduction in the saline condition, resulting in less pain compared with the naloxone condition. In addition, TMS over the M1 or DLPFC selectively increased plasma concentrations of ß-endorphin or encephalin, respectively. Overall, we present causal evidence that opioidergic mechanisms are involved in both M1-induced and DLPFC-rTMS-induced analgesia; however, these are shaped by rTMS dosage and the release of different endogenous opioids.
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OBJECTIVES: COVID-19 pandemic surges strained hospitals globally. We performed a systematic review to examine measures of pandemic caseload surge and its impact on mortality of hospitalized patients. DATA SOURCES: PubMed, Embase, and Web of Science. STUDY SELECTION: English-language studies published between December 1, 2019, and November 22, 2023, which reported the association between pandemic "surge"-related measures and mortality in hospitalized patients. DATA EXTRACTION: Three authors independently screened studies, extracted data, and assessed individual study risk of bias. We assessed measures of surge qualitatively across included studies. Given multidomain heterogeneity, we semiquantitatively aggregated surge-mortality associations. DATA SYNTHESIS: Of 17,831 citations, we included 39 studies, 17 of which specifically described surge effects in ICU settings. The majority of studies were from high-income countries ( n = 35 studies) and included patients with COVID-19 ( n = 31). There were 37 different surge metrics which were mapped into four broad themes, incorporating caseloads either directly as unadjusted counts ( n = 11), nested in occupancy ( n = 14), including additional factors (e.g., resource needs, speed of occupancy; n = 10), or using indirect proxies (e.g., altered staffing ratios, alternative care settings; n = 4). Notwithstanding metric heterogeneity, 32 of 39 studies (82%) reported detrimental adjusted odds/hazard ratio for caseload surge-mortality outcomes, reporting point estimates of up to four-fold increased risk of mortality. This signal persisted among study subgroups categorized by publication year, patient types, clinical settings, and country income status. CONCLUSIONS: Pandemic caseload surge was associated with lower survival across most studies regardless of jurisdiction, timing, and population. Markedly variable surge strain measures precluded meta-analysis and findings have uncertain generalizability to lower-middle-income countries (LMICs). These findings underscore the need for establishing a consensus surge metric that is sensitive to capturing harms in everyday fluctuations and future pandemics and is scalable to LMICs.
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COVID-19 , COVID-19/epidemiología , Humanos , Mortalidad Hospitalaria , Pandemias , Capacidad de Reacción , Unidades de Cuidados Intensivos/estadística & datos numéricos , Unidades de Cuidados Intensivos/organización & administración , SARS-CoV-2 , Carga de Trabajo/estadística & datos numéricosRESUMEN
Dynamic functional connectivity (FC) analyses have provided ample information on the disturbances of global functional brain organization in patients with schizophrenia. However, our understanding about the dynamics of local FC in never-treated first episode schizophrenia (FES) patients is still rudimentary. Dynamic Regional Phase Synchrony (DRePS), a newly developed dynamic local FC analysis method that could quantify the instantaneous phase synchronization in local spatial scale, overcomes the limitations of commonly used sliding-window methods. The current study performed a comprehensive examination on both the static and dynamic local FC alterations in FES patients (N = 74) from healthy controls (HCs, N = 41) with resting-state functional magnetic resonance imaging using DRePS, and compared the static local FC metrics derived from DRePS with those calculated from two commonly used regional homogeneity (ReHo) analysis methods that are defined based on Kendall's coefficient of concordance (KCC-ReHo) and frequency coherence (Cohe-ReHo). Symptom severities of FES patients were assessed with a set of clinical scales. Cognitive functions of FES patients and HCs were assessed with the MATRICS consensus cognitive battery. Group-level analysis revealed that compared with HCs, FES patients exhibited increased static local FC in right superior, middle temporal gyri, hippocampus, parahippocampal gyrus, putamen, and bilateral caudate nucleus. Nonetheless, the dynamic local FC metrics did not show any significant differences between the two groups. The associations between all local FC metrics and clinical characteristics manifested scores were explored using a relevance vector machine. Results showed that the Global Assessment of Functioning score highest in past year and the Brief Visuospatial Memory Test-Revised task score were statistically significantly predicted by a combination of all static and dynamic features. The diagnostic abilities of different local FC metrics and their combinations were compared by the classification performance of linear support vector machine classifiers. Results showed that the inclusion of zero crossing ratio of DRePS, one of the dynamic local FC metrics, alongside static local FC metrics improved the classification accuracy compared to using static metrics alone. These results enrich our understanding of the neurocognitive mechanisms underlying schizophrenia, and demonstrate the potential of developing diagnostic biomarker for schizophrenia based on DRePS.
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Imagen por Resonancia Magnética , Esquizofrenia , Humanos , Esquizofrenia/diagnóstico por imagen , Benchmarking , Encéfalo/diagnóstico por imagen , CogniciónRESUMEN
Importance: Transferring patients to other hospitals because of inpatient saturation or need for higher levels of care was often challenging during the early waves of the COVID-19 pandemic. Understanding how transfer patterns evolved over time and amid hospital overcrowding could inform future care delivery and load balancing efforts. Objective: To evaluate trends in outgoing transfers at overall and caseload-strained hospitals during the COVID-19 pandemic vs prepandemic times. Design, Setting, and Participants: This retrospective cohort study used data for adult patients at continuously reporting US hospitals in the PINC-AI Healthcare Database. Data analysis was performed from February to July 2023. Exposures: Pandemic wave, defined as wave 1 (March 1, 2020, to May 31, 2020), wave 2 (June 1, 2020, to September 30, 2020), wave 3 (October 1, 2020, to June 19, 2021), Delta (June 20, 2021, to December 18, 2021), and Omicron (December 19, 2021, to February 28, 2022). Main Outcomes and Measures: Weekly trends in cumulative mean daily acute care transfers from all hospitals were assessed by COVID-19 status, hospital urbanicity, and census index (calculated as daily inpatient census divided by nominal bed capacity). At each hospital, the mean difference in transfer counts was calculated using pairwise comparisons of pandemic (vs prepandemic) weeks in the same census index decile and averaged across decile hospitals in each wave. For top decile (ie, high-surge) hospitals, fold changes (and 95% CI) in transfers were adjusted for hospital-level factors and seasonality. Results: At 681 hospitals (205 rural [30.1%] and 476 urban [69.9%]; 360 [52.9%] small with <200 beds and 321 [47.1%] large with ≥200 beds), the mean (SD) weekly outgoing transfers per hospital remained lower than the prepandemic mean of 12.1 (10.4) transfers per week for most of the pandemic, ranging from 8.5 (8.3) transfers per week during wave 1 to 11.9 (10.7) transfers per week during the Delta wave. Despite more COVID-19 transfers, overall transfers at study hospitals cumulatively decreased during each high national surge period. At 99 high-surge hospitals, compared with a prepandemic baseline, outgoing acute care transfers decreased in wave 1 (fold change -15.0%; 95% CI, -22.3% to -7.0%; P < .001), returned to baseline during wave 2 (2.2%; 95% CI, -4.3% to 9.2%; P = .52), and displayed a sustained increase in subsequent waves: 19.8% (95% CI, 14.3% to 25.4%; P < .001) in wave 3, 19.2% (95% CI, 13.4% to 25.4%; P < .001) in the Delta wave, and 15.4% (95% CI, 7.8% to 23.5%; P < .001) in the Omicron wave. Observed increases were predominantly limited to small urban hospitals, where transfers peaked (48.0%; 95% CI, 36.3% to 60.8%; P < .001) in wave 3, whereas large urban and small rural hospitals displayed little to no increases in transfers from baseline throughout the pandemic. Conclusions and Relevance: Throughout the COVID-19 pandemic, study hospitals reported paradoxical decreases in overall patient transfers during each high-surge period. Caseload-strained rural (vs urban) hospitals with fewer than 200 beds were unable to proportionally increase transfers. Prevailing vulnerabilities in flexing transfer capabilities for care or capacity reasons warrant urgent attention.
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COVID-19 , Esguinces y Distensiones , Adulto , Humanos , COVID-19/epidemiología , Pandemias , Transferencia de Pacientes , Estudios Retrospectivos , Hospitales UrbanosRESUMEN
As an intrinsic cellular mechanism responsible for the internalization of extracellular ligands and membrane components, caveolae-mediated endocytosis (CavME) is also exploited by certain pathogens for endocytic entry [e.g., Newcastle disease virus (NDV) of paramyxovirus]. However, the molecular mechanisms of NDV-induced CavME remain poorly understood. Herein, we demonstrate that sialic acid-containing gangliosides, rather than glycoproteins, were utilized by NDV as receptors to initiate the endocytic entry of NDV into HD11 cells. The binding of NDV to gangliosides induced the activation of a non-receptor tyrosine kinase, Src, leading to the phosphorylation of caveolin-1 (Cav1) and dynamin-2 (Dyn2), which contributed to the endocytic entry of NDV. Moreover, an inoculation of cells with NDV-induced actin cytoskeletal rearrangement through Src to facilitate NDV entry via endocytosis and direct fusion with the plasma membrane. Subsequently, unique members of the Rho GTPases family, RhoA and Cdc42, were activated by NDV in a Src-dependent manner. Further analyses revealed that RhoA and Cdc42 regulated the activities of specific effectors, cofilin and myosin regulatory light chain 2, responsible for actin cytoskeleton rearrangement, through diverse intracellular signaling cascades. Taken together, our results suggest that an inoculation of NDV-induced Src-mediated cellular activation by binding to ganglioside receptors. This process orchestrated NDV endocytic entry by modulating the activities of caveolae-associated Cav1 and Dyn2, as well as specific Rho GTPases and downstream effectors. IMPORTANCE: In general, it is known that the paramyxovirus gains access to host cells through direct penetration at the plasma membrane; however, emerging evidence suggests more complex entry mechanisms for paramyxoviruses. The endocytic entry of Newcastle disease virus (NDV), a representative member of the paramyxovirus family, into multiple types of cells has been recently reported. Herein, we demonstrate the binding of NDV to induce ganglioside-activated Src signaling, which is responsible for the endocytic entry of NDV through caveolae-mediated endocytosis. This process involved Src-dependent activation of the caveolae-associated Cav1 and Dyn2, as well as specific Rho GTPase and downstream effectors, thereby orchestrating the endocytic entry process of NDV. Our findings uncover a novel molecular mechanism of endocytic entry of NDV into host cells and provide novel insight into paramyxovirus mechanisms of entry.
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Macrófagos , Enfermedad de Newcastle , Virus de la Enfermedad de Newcastle , Transducción de Señal , Internalización del Virus , Animales , Endocitosis , Gangliósidos/metabolismo , Macrófagos/metabolismo , Macrófagos/virología , Enfermedad de Newcastle/virología , Virus de la Enfermedad de Newcastle/fisiología , Proteínas de Unión al GTP rho/metabolismoRESUMEN
BACKGROUND: Low-intensity focused ultrasound stimulation (LIFUS) has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents. However, the cellular and molecular mechanisms of neurological repair and remodelling after LIFUS in ischaemic stroke are unclear. METHODS: Ultrasound stimulation was treated in adult male mice 7 days after transient middle cerebral artery occlusion. Angiogenesis was measured by laser speckle imaging and histological analyses. Electromyography and fibre photometry records were used for synaptogenesis. Brain atrophy volume and neurobehaviour were assessed 0-14 days after ischaemia. iTRAQ proteomic analysis was performed to explore the differentially expressed protein. scRNA-seq was used for subcluster analysis of astrocytes. Fluorescence in situ hybridisation and Western blot detected the expression of HMGB1 and CAMK2N1. RESULTS: Optimal ultrasound stimulation increased cerebral blood flow, and improved neurobehavioural outcomes in ischaemic mice (p<0.05). iTRAQ proteomic analysis revealed that the expression of HMGB1 increased and CAMK2N1 decreased in the ipsilateral hemisphere of the brain at 14 days after focal cerebral ischaemia with ultrasound treatment (p<0.05). scRNA-seq revealed that this expression pattern belonged to a subcluster of astrocytes after LIFUS in the ischaemic brain. LIFUS upregulated HMGB1 expression, accompanied by VEGFA elevation compared with the control group (p<0.05). Inhibition of HMGB1 expression in astrocytes decreased microvessels counts and cerebral blood flow (p<0.05). LIFUS reduced CAMK2N1 expression level, accompanied by increased extracellular calcium ions and glutamatergic synapses (p<0.05). CAMK2N1 overexpression in astrocytes decreased dendritic spines, and aggravated neurobehavioural outcomes (p<0.05). CONCLUSION: Our results demonstrated that LIFUS promoted angiogenesis and synaptogenesis after focal cerebral ischaemia by upregulating HMGB1 and downregulating CAMK2N1 in a subcluster of astrocytes, suggesting that LIFUS activated specific astrocyte subcluster could be a key target for ischaemic brain therapy.
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Low-intensity ultrasound stimulation (LIUS) is an emerging neuro- and vascular-modulation technique. Studies on humans and animals have shown that LIUS could induce changes in neuronal oscillations or blood flow. However, it is still inconclusive whether the hemodynamic response to LIUS is due to neurovascular coupling (NVC), direct ultrasound-vessel interactions, or both. This study aims to detect the direct effect of LIUS on vessels using optical imaging. Fluorescence images with indocyanine green (ICG) were used to identify and quantify the morphological change in the auricle vessels of rats. Diameters of vessels were measured before, during, and post LIUS. The results indicated that LIUS could significantly increase the vessel diameters (p = 0.031). Further exploratory analysis showed that vessel dilation occurred among the majority of randomly selected vessels (i.e., 21/30 animals (70%), dilation: 6.84±1.95µm, 95% CI: [3.02,10.66]), with a significant confounding effect of the vessel size. The results provided indirect evidence for two distinct pathways in LIUS-based neurovascular modulation, i.e., the NVC and the direct ultrasound-vessel interactions.
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Neuronas , Humanos , Ratas , Animales , UltrasonografíaRESUMEN
Repetitive transcranial magnetic stimulation (rTMS) has been used in the treatment of patients with schizophrenia. The conventional targets of rTMS treatment are the dorsolateral prefrontal cortex (DLPFC) and temporoparietal cortex (TPC). However, the efficacy of these two treatment strategies was quite heterogeneous. Structural and functional abnormalities of the orbitofrontal cortex (OFC) in schizophrenia are closely related to negative symptoms. We sought to determine whether 1 Hz rTMS over the right OFC is effective in treating patients with first-episode schizophrenia. In this study, eighty-nine patients with drug-naïve, first-episode schizophrenia were randomly divided into the rTMS (n = 47) or sham stimulation (n = 42) groups, with both groups receiving twenty sessions of 1 Hz rTMS treatment. The PANSS was assessed at baseline, day 10, and day 20, and MATRICS Consensus Cognitive Battery (MCCB) was implemented to assess the cognitive impairment at baseline and day 20. Results showed that patients in the active rTMS group had more improvement in clinical symptoms and cognitive deficits than patients in sham group at day 20. In conclusion, 1 Hz rTMS over OFC can improve psychotic symptoms and cognitive functions in schizophrenic patients. Our study provides a new alternative for the treatment of negative symptoms and cognitive deficits in schizophrenia.
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Disfunción Cognitiva , Esquizofrenia , Humanos , Esquizofrenia/diagnóstico , Estimulación Magnética Transcraneal/métodos , Resultado del Tratamiento , Corteza Prefrontal , Método Doble CiegoRESUMEN
OBJECTIVE: Intermittent theta burst stimulation (iTBS) is based on the phase-amplitude coupling (PAC) pattern. We aimed to investigate the effect of iTBS on PAC in resting electroencephalography (EEG), which may provide insight into the underlying mechanism. METHODS: Twenty-one healthy volunteers were recruited and received both active and sham neuroimaging-guided iTBS on two separate days, which was precisely delivered to the right superior temporal gyrus. On each experimental day, resting EEG was recorded before and after stimulation for each participant. PACs across electrodes and frequency bands were calculated and compared to investigate the effect of iTBS. RESULTS: Theta (4-6 Hz) -low gamma (45-55 Hz) PAC over the stimulation site had a significant interaction effect, which increased after the active iTBS but did not differ after the sham iTBS. No significant interaction effect occurred in other cross-frequency couplings such as delta-low gamma, alpha-low gamma, delta-high gamma, theta-high gamma, or alpha-high gamma PAC in the region of interest. CONCLUSION: iTBS selectively modulated theta-low gamma PAC at the stimulation area, which exhibited both region- and frequency- specificity. This suggests that PAC may be a bridge connecting external neuromodulation to internal neuroplasticity.
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Ritmo Teta , Estimulación Magnética Transcraneal , Humanos , Ritmo Teta/fisiología , Electroencefalografía , Plasticidad Neuronal/fisiología , Voluntarios SanosRESUMEN
Electroencephalography alpha-band (8-13 Hz) activity during visual spatial attention declines in normal aging. We recently reported the impacts of pre-cue baseline alpha and cueing strategy on post-cue anticipatory alpha activity and target processing in visual spatial attention (Wang et al., Cerebral Cortex, 2023). However, whether these factors affected aging effects remains unaddressed. We investigated this issue in two independent experiments (n = 114) with different cueing strategies (instructional vs. probabilistic). When median-splitting young adults (YA) by their pre-cue alpha power, we found that older adults exhibited similar pre-cue and post-cue alpha activity as YA with lower pre-cue alpha, and only YA with higher pre-cue alpha showed significant post-cue alpha activity, suggesting that diminished anticipatory alpha activity was not specific to aging but likely due to a general decrease with baseline alpha. Moreover, we found that the aging effects on cue-related event-related potentials were dependent on cueing strategy but were relatively independent of pre-cue alpha. However, age-related deficits in target-related N1 attentional modulation might depend on both pre-cue alpha and cueing strategy. By considering the impacts of pre-cue alpha and cueing strategy, our findings offer new insights into age-related deficits in anticipatory alpha activity and target processing during visual spatial attention.