Cortico-cortical feedback engages active dendrites in visual cortex.

Sensory processing in the neocortex requires both feedforward and feedback information flow between cortical areas1. In feedback processing, higher-level representations provide contextual information to lower levels, and facilitate perceptual functions such as contour integration and figure-ground segmentation2,3. However, we have limited understanding of the circuit and cellular mechanisms that mediate feedback influence. Here we use long-range all-optical connectivity mapping in mice to show that feedback influence from the lateromedial higher visual area (LM) to the primary visual cortex (V1) is spatially organized. When the source and target of feedback represent the same area of visual space, feedback is relatively suppressive. By contrast, when the source is offset from the target in visual space, feedback is relatively facilitating. Two-photon calcium imaging data show that this facilitating feedback is nonlinearly integrated in the apical tuft dendrites of V1 pyramidal neurons: retinotopically offset (surround) visual stimuli drive local dendritic calcium signals indicative of regenerative events, and two-photon optogenetic activation of LM neurons projecting to identified feedback-recipient spines in V1 can drive similar branch-specific local calcium signals. Our results show how neocortical feedback connectivity and nonlinear dendritic integration can together form a substrate to support both predictive and cooperative contextual interactions.

Impact of National Volume-Based Procurement on the Procurement Volumes and Spending for Antiviral Medications of Hepatitis B Virus.

Introduction: Although persistent inhibition of HBV replication by antiviral therapy has shown to slow disease progression, cost-related access barriers to these essential medicines are becoming salient. The national volume-based procurement (NVBP) was piloted in China and led to substantial reduction in the list price of prescription drugs. To examine the impact of NVBP on selected antiviral medication costs per defined daily dose (DDD), procurement volumes, and spending. Methods: We employed an interrupted time series design to examine changes in cost per defined daily dose (DDD), procurement volumes, and spending for NVBP bid-winning antiviral medications (tenofovir disoproxil fumarate and entecavir) in 11 pilot cities from 2017 to 2020. Procurement transaction data were obtained from 9,454 hospitals in the Chinese Hospital Pharmaceutical Audit (CHPA) database. In the secondary analysis, the control group comprised two non-NVBP drugs (adefovir and lamivudine) procured in 11 cities not exposed to the NVBP. Results: Cost per DDD of the two hepatitis B virus (HBV) antiviral medications reduced by CNY1.598 (p = 0.002) immediately following the implementation of NVBP, dropping from an average cost of CNY16.483 per DDD at baseline to CNY6.420 at the end of the observation period. NVBP implementation resulted in a substantial reduction in daily costs of antivirals and an increase in monthly procurement volumes by 6.674 million DDDs (p = 0.017), while monthly spending was reduced by CNY138.26 million (p = 0.002). In the secondary ITS analysis with a control group, the average cost per DDD of the NVBP bid-winning antivirals declined by CNY4.537 (p < 0.001), monthly procurement volumes increased by 7.209 million DDDs (p = 0.002), and monthly spending dropped by CNY138.83 million (p < 0.001). Conclusion: Volume-based procurement piloted in China may be effective for reducing price and total expenditures and improving drug utilization, which is especially important for HBV patients who need constant access to antiviral therapies.

Pharmacotherapy Management for COVID-19 and Cardiac Safety: A Data Mining Approach for Pharmacovigilance Evidence from the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Several pharmacological agents, such as chloroquine/hydroxychloroquine, have been promoted for COVID-19 treatment or pre-exposure prophylaxis. However, no comprehensive evaluation of the safety of these possible agents is available, and is urgently needed. OBJECTIVE: The purpose of this study was to investigate the risks of cardiac adverse events associated with the possible pharmacotherapies for COVID-19, including certain antimalarial, antiviral, and antibiotic drugs. PATIENTS AND METHODS: We conduced retrospective pharmacovigilance analyses of the US Food and Drug Administration Adverse Event Reporting System database. The reporting odds ratio (ROR), a data mining algorithm commonly used in pharmacovigilance assessment, was generated to quantify the detection signal of adverse events. RESULTS: Among individuals without coronavirus infection from 2015 Q1 to 2020 Q1, increased risks for cardiac disorders were found for antiviral agents such as chloroquine/hydroxychloroquine (ROR: 1.68; 95% confidence interval [CI] 1.66-1.70), lopinavir/ritonavir (ROR: 1.52; 95% CI 1.39-1.66), and antibiotics such as azithromycin (ROR: 1.37; 95% CI 1.30-1.44) and ceftriaxone (ROR: 1.92; 95% CI 1.80-2.05). Increased serious cardiac adverse events, including myocardial infarction, arrhythmia, and cardiac arrest, were also reported for these drugs. Further analyses of individuals with coronavirus infections revealed that 40% of individuals receiving chloroquine/hydroxychloroquine reported serious cardiac adverse events. Two cases resulted in QT prolongations and one case resulted in cardiac arrest. Chloroquine/hydroxychloroquine and azithromycin contributed to all the QT prolongation and cardiac arrest cases. CONCLUSIONS: The current pharmacotherapies for COVID-19 are associated with increased risks of cardiac adverse events. Variations in the cardiac safety profiles of these pharmacotherapies were also observed. Clinicians should closely monitor patients with COVID-19, especially those at high risk, using chloroquine/hydroxychloroquine and azithromycin.

Economic and clinical burdens and associated health disparities in HIV/AIDS management using big data: potentially inappropriate use and deprescribing of benzodiazepines.

This study aimed to examine factors, healthcare utilization, and medical costs associated with potentially inappropriate use of benzodiazepines in persons living with HIV (PLWH). We used big data from Medicare claims in 2017. Potentially inappropriate use of benzodiazepines was defined as having any benzodiazepine claims in individuals 65+ years or having benzodiazepine claims for more than four weeks in individuals 18-64 years. Logistic regressions, zero-inflated negative binomial regressions, and generalized linear models were used. This study included 1,211 PLWH and 235 (19.41%) had potentially inappropriate use of benzodiazepines. PLWH who were 65+ years (OR: 0.56; 95% CI: 0.33, 0.96), non-Hispanic blacks (OR: 0.29; 95% CI: 0.20, 0.41), or Hispanics (OR: 0.55; 95% CI: 0.35, 0.88) were less likely to use benzodiazepines inappropriately. PLWH who had potentially inappropriate use of benzodiazepines had more inpatient (IRR: 1.46; 95% CI: 1.10, 1.94), outpatient (IRR: 1.14; 95% CI 1.02, 1.28), and emergency room (IRR: 1.32; 95% CI: 1.03, 1.68) visits. Potentially inappropriate use of benzodiazepines was associated with higher total (ß: 0.16; 95% CI: 0.07, 0.25), Medicare (ß: 0.18; 95% CI: 0.07, 0.28), and out-of-pocket (ß: 0.21; 95% CI: 0.05, 0.36) costs. This study provides real-world evidence to support deprescribing benzodiazepines in PLWH.

Deletion of Acid-Sensing Ion Channel 3 Relieves the Late Phase of Neuropathic Pain by Preventing Neuron Degeneration and Promoting Neuron Repair.

Neuropathic pain is one type of chronic pain that occurs as a result of a lesion or disease to the somatosensory nervous system. Chronic excessive inflammatory response after nerve injury may contribute to the maintenance of persistent pain. Although the role of inflammatory mediators and cytokines in mediating allodynia and hyperalgesia has been extensively studied, the detailed mechanisms of persistent pain or whether the interactions between neurons, glia and immune cells are essential for maintenance of the chronic state have not been completely elucidated. ASIC3, a voltage-insensitive, proton-gated cation channel, is the most essential pH sensor for pain perception. ASIC3 gene expression is increased in dorsal root ganglion neurons after inflammation and nerve injury and ASIC3 is involved in macrophage maturation. ASIC currents are increased after nerve injury. However, whether prolonged hyperalgesia induced by the nerve injury requires ASIC3 and whether ASIC3 regulates neurons, immune cells or glial cells to modulate neuropathic pain remains unknown. We established a model of chronic constriction injury of the sciatic nerve (CCI) in mice. CCI mice showed long-lasting mechanical allodynia and thermal hyperalgesia. CCI also caused long-term inflammation at the sciatic nerve and primary sensory neuron degeneration as well as increased satellite glial expression and ATF3 expression. ASIC3 deficiency shortened mechanical allodynia and attenuated thermal hyperalgesia. ASIC3 gene deletion shifted ATF3 expression from large to small neurons and altered the M1/M2 macrophage ratio, thereby preventing small neuron degeneration and relieved pain.

Treating acute hypertensive cardiogenic pulmonary edema with high-dose nitroglycerin.

Acute pulmonary edema due to sympathetic surge and increased peripheral vascular resistance often present to the emergency department (ED) with markedly elevated blood pressure, severe dyspnea, and desaturation. This condition is known as "SCAPE" (sympathetic crashing acute pulmonary edema). We present three SCAPE patients who were successfully treated with high-dose nitroglycerin (NTG) and bilevel positive airway pressure (BiPAP) ventilation. All three patients presented with respiratory failure on arrival but rapidly improved after treatment and did not require endotracheal intubation or admission to the intensive care unit (ICU). SCAPE patients usually present to the ED with extreme respiratory distress associated with diaphoresis, restlessness, and high blood pressure. Emergency physicians must know how to manage SCAPE with high-dose nitrates and NIPPV (noninvasive positive pressure ventilation) because, when treated promptly, one will not only save a life but also obviate the need for endotracheal intubation and ICU admission.