Rejected

Intracranial hypertension (IH) is a clinical condition commonly encountered in the intensive care unit, which requires immediate treatment. The maintenance of normal intracranial pressure (ICP) and cerebral perfusion pressure in order to prevent secondary brain injury (SBI) is the central focus of management. SBI can be detected through clinical examination and invasive and non-invasive ICP monitoring. Progress in monitoring and understanding the pathophysiological mechanisms of IH allows the implementation of targeted interventions in order to improve the outcome of these patients. Initially, general prophylactic measures such as patient's head elevation, fever control, adequate analgesia and sedation depth should be applied immediately to all patients with suspected IH. Based on specific indications and conditions, surgical resection of mass lesions and cerebrospinal fluid drainage should be considered as an initial treatment for lowering ICP. Hyperosmolar therapy (mannitol or hypertonic saline) represents the cornerstone of medical treatment of acute IH while hyperventilation should be limited to emergency management of life-threatening raised ICP. Therapeutic hypothermia could have a possible benefit on outcome. To control elevated ICP refractory to maximum standard medical and surgical treatment, at first, high-dose barbiturate administration and then decompressive craniectomy as a last step are recommended with unclear and probable benefit on outcomes, respectively. The therapeutic strategy should be based on a staircase approach and be individualized for each patient. Since most therapeutic interventions have an uncertain effect on neurological outcome and mortality, future research should focus on both studying the long-term benefits of current strategies and developing new ones.

Chronic insomnia is a disease which brings intense mental pain and disturbing complications to patients worldwide. The oral microbiome exhibits a mechanistic influence on human health. Therefore, it is crucial to understand the oral microbial diversity in insomnia. Tongue diagnosis has been considered a critical basic procedure in insomnia therapeutic decision-making in Traditional Chinese Medicine (TCM). Hence, it is significant to elucidate the various oral microbiome differences in chronic insomnia patients with different tongue features. In this paper, we used 16S rRNA gene sequencing and bioinformatics analysis to investigate dynamic changes in oral bacterial profile and correlations between chronic insomnia patients and healthy individuals, as well as in patients with different tongue coatings. Moreover, the relationship between the severity of insomnia and oral microbiota was explored. Our findings showed that chronic insomnia patients harbored a significantly higher diversity of oral bacteria when compared to healthy controls. More importantly, the results revealed that the diversity and relative abundance of the bacterial community was significantly altered among different tongue coatings in patients but not in healthy individuals. Oral bacteria with a relative abundance [Formula: see text]1% and [Formula: see text] among different tongue groups were considered remarkable bacteria, which included three phyla and four genera, , and . Our findings indicate that changes in oral microbiome correlate with tongue coatings in patients with chronic insomnia. Thus, the remarkable microbiome may provide inspiration for further studies on the correlation between tongue diagnosis and oral microbiome in chronic insomnia patients.

The visceral analgesic efficacy of erector spinae plane block (ESPB) is still a matter of debate. This study attempted to investigate the visceral analgesic efficacy of ESPB in clinical setting. After randomized, we performed ultrasound-guided bilateral rectus sheath block (RSB), which was aimed to prevent postoperative somatic pain on all patients who underwent laparoscopic cholecystectomy (LC). Ultrasound-guided bilateral ESPB at T7 level was performed only to the intervention group to provide the visceral analgesic block. The intraoperative requirement for remifentanil (P = 0.021) and the cumulative fentanyl consumption at postoperative 24-hours was significantly lower in the ESPB group (206.5 ± 82.8 μg vs.283.7 ± 102.4 μg, respectively; P = 0.004) compared to non-ESPB group. The ESPB group consistently showed lower accumulated analgesic consumption compared with those in the non-ESPB group at all observed time-points (all P < 0.05) after 2 hours and the degree of the accumulated analgesic consumption reduction was greater (P = 0.04) during the 24-hour postoperative period. Pain severity was lower in the ESPB group at 6-hours postoperatively. The significantly reduced opioid consumption in ESPB group may imply that while preliminary and in need of confirmation, ESPB has potential visceral analgesic effect. Therefore, performing ESPB solely may be feasible in inducing both somatic and visceral analgesia.

Chronic renal failure patients with arteriovenous hemodialysis access may exhibit pain and neurological complaints due to local nerve compression by the access conduit vessels of autogenous arteriovenous fistulas or the prosthesis of arteriovenous grafts. In this study, we have examined the results of surgical intervention for vascular access-related nerve compression in the upper extremity.

The main factors involved in the pathogenesis of atopic dermatitis (AD) are skin barrier abnormality, allergy/immunology, and pruritus. Considering how oxidative stress influences these factors, antioxidant agents may be effective candidates in the treatment of AD. To evaluate the effect of Caffeoyl-Pro-His amide (CA-PH), an antioxidant agent, on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like phenotypes in BALB/c mice. Topical sensitization and challenge by DNCB were performed on the dorsal skin of BALB/c mice to induce AD-like cutaneous lesions, phenotypes, and immunologic response. CA-PH was applied topically for 2 weeks to assess its effects on DNCB-induced AD-like phenotypes. As a result, CA-PH relieved DNCB-induced AD-like phenotypes quantified by dermatitis severity score, scratching duration, and trans-epidermal water loss. Histopathological analysis showed that CA-PH decreased epidermal thickening, the number of mast cells, and eosinophil infiltration in dermis. Immunohistochemical staining revealed that CA-PH recovered skin barrier-related proteins: filaggrin, involucrin, and loricrin. As for the immunologic aspects, CA-PH treatment lowered mRNA or protein levels of interleukin (IL)-4, IL-6, IL-17a, IL-1b, IL-31, and IL-33 levels and thymic stromal lymphopoietin (TSLP) levels in cutaneous tissue, reducing the DNCB-induced serum IgE level elevation. In conclusion, topical CA-PH may be a therapeutic option for the treatment of AD.

To explore the mechanism of microRNA-155 (miR-155) deficiency, protecting against experimental autoimmune prostatitis (EAP) in a toll-like receptor 4 (TLR4)-dependent manner. After wild-type (WT) and miR-155 mice were injected with complete Freund's adjuvant and prostate antigen to establish EAP model, half were randomly selected for injection with lipopolysaccharide (LPS, a TLR4 ligand). The following experiments were then performed: von Frey filaments, hematoxylin-eosin (HE) staining, real time quantitative polymerase chain reaction (qRT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). And the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and the level of Malondialdehyde (MDA) were detected by corresponding kits. miR-155 mice with prostatitis exhibited the attenuated pelvic tactile allodynia/hyperalgesia and the suppressed TLR4/nuclear factor-kappa B (NF-κB) pathway as compared with the WT mice with prostatitis. In addition, LPS enhanced the upregulation of miR-155 and the activation of the TLR4/NF-κB pathway in the prostatic tissues of WT mice with EAP. Furthermore, prostatitis mice had aggravated inflammation scores accompanying the increased interleukin (IL)-1β, tumor necrosis factor-α, IL-6, interferon-γ, IL-12, and MDA in prostatic tissues with the decreased IL-10, SOD and GSH-Px, and the unaltered IL-4. Compared with the mice from the WT + EAP group and the miR-155 + EAP + LPS group, mice from the miR-155 + EAP group had decreased inflammation and oxidative stress. miR-155 deficiency ameliorated pelvic tactile allodynia/hyperalgesia in EAP mice and improved inflammation and oxidative stress in prostatic tissues in a TLR4-dependent manner involving NF-κB activation, thereby exerting a therapeutic effect in chronic prostatitis treatment.

This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempeg-a-ldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension ( = 1), hyperglycemia ( = 1), metabolic acidosis ( = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8 T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.

Sofosbuvir plus daclatasvir with or without ribavirin has demonstrated a high efficacy and an acceptable safety profile in clinical trials of patients infected with genotype 2 hepatitis Cvirus (HCV); however, there are currently no real-world data available for this regimen. To evaluate the real-life safety and efficacy of sofosbuvir/daclatasvir with or without ribavirin in genotype 2 HCV patients in the French cohort ANRS CO22 HEPATHER(NCT01953458). In this ongoing, national, multicentre, prospective, observational study, we observed patients with HCV genotype 2 infection who initiated treatment with sofosbuvir (400 mg/d) plus daclatasvir with or without ribavirin (1-1.2 g/d). Patients were divided into two treatment groups: sofosbuvir/daclatasvir with or without ribavirin (12 weeks/24 weeks). The primary end point was a sustained virological response at week 12 following the end of therapy. Overall, 88% and 91% of patients achieved a sustained virological response following 12 and 24 weeks of treatment with sofosbuvir/daclatasvir with or without ribavirin, respectively. The most common adverse events were asthenia (29%), headache (15%) and fatigue (20%), and ribavirin addition was associated with a higher rate of adverse events and treatment discontinuation. Sofosbuvir/daclatasvir with or without ribavirin was associated with lower rates of sustained virological response in the real-life setting compared with the clinical setting and demonstrated suboptimal efficacy for the treatment of patients with genotype 2 chronic HCV.

Scombroid food poisoning is caused by eating fish with a high concentration of histamine. Histamine is converted from histidine in fish of the Scombroidea family if it is not stored at a sufficiently low temperature. The clinical picture resembles an allergic reaction.

Treating chronic pain using opioids, such as morphine, is hampered by the development of opioid-induced hyperalgesia (OIH; increased pain sensitivity), antinociceptive tolerance and withdrawal which can contribute to dependence and abuse. In the central nervous system, the purine nucleoside adenosine has been implicated in beneficial and detrimental actions of morphine, but the extent of their interaction remains poorly understood. Here, we demonstrate that morphine-induced OIH and antinociceptive tolerance in rats is associated with a 2-fold increase in adenosine kinase (ADK) expression in the dorsal horn of the spinal cord (DH-SC). Blocking ADK activity in the spinal cord provided greater than 90% attenuation of OIH and antinociceptive tolerance through A adenosine receptor (AAR) signaling. Supplementing adenosine signaling with selective AAR agonists blocked OIH and antinociceptive tolerance in rodents of both sexes. Engagement of AAR in the spinal cord with an ADK inhibitor or AAR agonist was associated with reduced DH-SC expression of the NOD-like receptor pyrin domain-containing 3 (NLRP3; 60-75%), cleaved caspase 1 (40-60%), interleukin (IL)-1β (76-80%) and tumor necrosis factor (TNF; 50-60%). In contrast, the neuroinhibitory and anti-inflammatory cytokine IL-10 increased 2-fold. In mice, AAR agonists prevented the development of tolerance in a model of neuropathic pain and reduced naloxone-dependent withdrawal behaviors by greater than 50%. These findings suggest AAR-dependent adenosine signaling is compromised during sustained morphine to allow the development of morphine-induced adverse effects. These findings raise the intriguing possibility that AAR agonists may be useful adjunct to opioids to manage their unwanted effects.