Dual-responsive supramolecular photodynamic nanomedicine with activatable immunomodulation for enhanced antitumor therapy

A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8+ T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

A Prospective Study of Acute Spinal Blockade Complications Occurring in 24 hours at Labasa Divisional Hospital – from November 2019 to November 2020

Objective@#To determine the incidence of acute spinal blockade complications and the association of frequent spinal blockade complications and acute spinal blockade complications.@*Methodology@#A prospective, qualitative survey of 685 adults at Labasa Hospital was done from November 2019 to November 2020 to determine the incidence of having spinal blockade complications in 24 hours. Cross tabulation was used to determine the strength of association between frequent spinal blockade complications and the incidence of acute post spinal blockade complications.@*Results@#The incidence of acute post spinal complications was 18%. 685 participants were entered into analysis. 17% of patients thereby had frequent spinals during the study period. The Odds Ratio of frequent spinal blockade complications to acute post spinal complications was found to be 2.56 (Confidence Interval: 1.62-4.02).@*Conclusion@#The study describes the cohort getting spinal blockades in Labasa Hospital. In addition, this audit highlights the incidence of acute post spinal blockade complications. The strong association of acute post spinal blockade complications and frequent spinal blockades is confirmed. The author believes that this lays groundwork for studies showing the validity of doing post anaesthesia visits and increasing research into the dangers of having frequent spinal blockades.

Evaluation on the blocking effect of hepatitis B vaccine on mother-to-infant transmission in 302 cases and analysis of influencing factors / 公共卫生与预防医学

Objective To evaluate the effect of the current immunization strategy for hepatitis B virus (Hepatitis B) in blocking mother-to-infant transmission in Hubei Province, and to explore the mechanism and possible influencing factors of failure of mother-to-infant blockade. Methods A multi-stage random sampling method was used to select 2 counties or districts in Hubei Province. Through maternity hospital health handbook, neonatal health record or hospital medical record system, hepatitis B virus (HBV) surface antigen (HBsAg)-positive pregnant women in 2012-2018 years were included to retrospectively investigate their delivery status and the HBV infection status of their children. Results Among the 302 newborns, 32 were positive for HBsAg, and the success rate of blockade of mother-to-infant transmission of hepatitis B was 89.45%. Further analysis showed that 68.21% (206 / 302) of newborns were delivered in township hospitals, 66.23% (200 / 302) were delivered by caesarean section and 41.72% (126 / 302) were breastfed, while 16.89% (51/302) were positive for hepatitis B virus e antigen (HBeAg), and 41.06% (124/302) were positive for anti-HBe. The vaccination rate of hepatitis B immunoglobulin (HBIG) during pregnancy was 3.31% (10/302), and the newborn HBIG vaccination rate was 94.37% (285/302). There were 84.11% (254/302) of pregnant women taking protective measures in daily life. Logistic regression analysis showed that township hospitals (OR=2.82, P<0.05), HBeAg positivity during pregnancy (OR=8.68, P<0.05), and HBIG vaccination during pregnancy (OR=12.62 , P<0.05) were risk factors for failure of mother-to-infant blockade, while anti-HBe positivity during pregnancy (OR=0.22, P<0.05), vaccination of newborns with HBIG (OR=0.20, P<0.05), and protective measures taken in daily life (OR=0.28, P<0.05) were protective factors for mother-to-infant interruption. Conclusion Deliveries in township hospitals and HBeAg-positivity during pregnancy are more likely to fail in blocking of mother-to-infant transmission of hepatitis B. HBIG vaccination during pregnancy does not reduce the risk of blockade failure. Neonatal HBIG vaccination, anti-HBe positivity during pregnancy, and protective measures in daily life can reduce the risk of blockade failure of mother-to-infant transmission of hepatitis B.

Comparison of analgesic efficacy and postoperative recovery between multi-point and single-point fascia iliaca compartment block in patients with hip fracture: a randomized controlled trial / 中华全科医师杂志

Objective:To compare the analgesic effect and postoperative recovery between multi-point and single-point ultrasound-guided fascia iliaca compartment block (FCIB) in elderly patients with hip fracture.Methods:From June 2019 to April 2020, 96 patients aged (71.1±5.4) years undergoing elective surgery for hip fracture in Renji Hospital were randomly assigned in multi-point block group or single-point block group, and the multi-point or single-point ultrasound-guided FCIB was performed for the two groups, respectively. The primary outcomes were the success rate for block of femoral nerve, lateral femoral cutaneous nerve and obturator nerve, and the 24 hours postoperative pain visual analog scale (VAS) score at rest and passive movement. The secondary outcomes were the onset time of sensory blocks of the above three nerves, complications of FICB, the satisfaction score of pain control during 48 hours after surgery and postoperative recovery of patients.Results:The success rate for block of lateral femoral cutaneous nerve in multi-point block group was 97.9% (47/48), which was significantly higher than that in single-point block group (83.3%(40/48)) ( P=0.031). The success rate for block of obturator nerve in multi-point block group was 95.8% (46/48), which was significantly higher than that in single-point block group which was 81.3% (39/48) ( P=0.025). The success rate of femoral nerve block in both groups was 97.9% (47/48) ( P=1.000). The 24 hours postoperative VAS scores at rest and passive movement in the multi-point block group were significantly lower than those in the single-point block group ( P<0.05). The onset time for block of lateral femoral cutaneous nerve and obturator nerve in multi-point block group was shorter than that in single-point block group ( P=0.025 and P<0.01). There was no significant difference in the onset time for block of femoral nerve between the two groups ( P=0.343). The satisfaction score of patients at 48 hours after surgery in multipoint block group was higher than that in single point block group ( P=0.024). The length of hospital stay in the multi-point block group was shorter than that in the single-point block group ( P=0.042), the proportion of intravenous analgesic drugs used after surgery was lower than that in the single-point block group ( P=0.041), and the complication rate within 30 days after surgery was also lower than that in the single point block group ( P=0.026). Conclusion:Compared with single-point block, ultrasound-guided multi-point block in iliac fascia space has advantages of increasing analgesic efficacy and promoting postoperative recovery in elderly patients with hip fracture.

Efficacy of ultrasound guided intercostal nerve pulse radiofrequency combined with nerve block in the treatment of post-herpetic neuralgia / 中国基层医药

Objective:To analyze the efficacy and safety of ultrasound-guided intercostal nerve pulse radiofrequency combined with nerve block in the treatment of post-herpetic neuralgia.Methods:The clinical data of 62 patients with post-herpetic neuralgia who received treatment in The Affiliated Hospital of Southwest Medical University from May 2017 to May 2021 were retrospectively analyzed. These patients underwent nerve block (NB group, n = 30) or pulsed radiofrequency plus nerve block (PRF + NB group, n = 32). Before and after treatment, The Numerical Rating Scale (NRS) score and Pittsburgh Sleep Quality Index (PSQI) score were compared between the two groups. After treatment, the occurrence of complications including pneumothorax, infection, and skin numbness was evaluated in each group. Results:Before treatment, there were no significant differences in NRS and PSQI scores between the two groups (all P > 0.05). Immediately, 1 week and 1 month after treatment, there was no significant difference in PSQI score between the two groups (all P > 0.05). At 3 and 6 months after treatment, the NRS score in the NB +PRF group was (1.71 ± 0.35) points and (1.68 ± 0.36) points, which were significantly lower than (2.72 ± 0.68) points and (3.26 ± 0.76) points in the NB group ( t = 54.40, 78.18, both P < 0.05). There were no treatment-related complications such as pneumothorax, infection, nerve numbness, or muscle weakness in the two groups. Conclusion:Ultrasound-guided pulsed radiofrequency combined with nerve block has a definite curative effect on post-herpetic neuralgia and is highly safe. The medium- and long-term efficacy of the combined therapy is superior to that of nerve block alone.

Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator

The use of checkpoint-blockade antibodies is still restricted in several malignancies due to the modest efficacy, despite considerable success in anti-tumor immunotherapy. The poor response of cancer cells to immune destruction is an essential contributor to the failure of checkpoint therapy. We hypothesized that combining checkpoint therapy with natural-product chemosensitizer could enhance immune response. Herein, a targeted diterpenoid derivative was integrated with the checkpoint blockade (anti-CTLA-4) to improve immunotherapy using thermosensitive liposomes as carriers. In vivo, the liposomes enabled the co-delivery of the two drug payloads into the tumor. Consequently, the regulatory T cell proliferation was restrained, the cytotoxic T cell infiltration was enhanced, and the profound immunotherapeutic effect was achieved. In addition, the immunotherapeutic effect of another clinically used checkpoint antibody, anti-PD-1, also benefited from the diterpenoid derivative. Of note, our mechanism study revealed that the targeted diterpenoid derivative increased the sensitivity of cancer cells to immune attack via THBS1 downregulation and the resultant destruction of THBS1-CD47 interaction. Collectively, co-delivering THBS1 inhibitor and checkpoint blockade is promising to boost cancer immunotherapy. We first time discovered that THBS1 suppression could strengthen checkpoint therapy.

Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms and strategies / 医学前沿

Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

Liver-directed treatment is associated with improved survival and increased response to immune checkpoint blockade in metastatic uveal melanoma: results from a retrospective multicenter trial / 医学前沿

Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.

Research progress of a new immune checkpoint inhibitor T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain in anti-tumor immunotherapy / 中国热带医学

@#The T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an inhibitory receptor mainly expressed on active T-cells, or natural killer cells (NK cells) that activate negative stimulus signals in immune cells by combining with multiple ligands on the surface of target cells including tumor cells and infected cells. TIGIT plays an important regulatory role in the immune pathogenesis of tumors, viral infections and various autoimmune diseases by inhibiting the over activation of cells and the over secretion of proinflammatory cytokines. Recent researches show that TIGIT is highly expressed in T cells and NK cells of cancer patients, and is related to disease progression and poor clinical prognosis. Researchers try to enhance the activity of T cells or NK cells by blocking the binding of TIGIT and its ligand for therapeutic intervention. At present, there have been many reports about the use of anti-TIGIT monoclonal antibody treatment in different mouse tumor models leading to tumor regression, TIGIT has received extensive attention in cancer immunotherapy as a promising target for next generation cancer immunotherapy. Several clinical trials are currently evaluating the efficacy of anti-TIGIT monoclonal antibodies (mAbs) in patients with several cancers. The most advanced candidate, tiragolumab, has exhibited remarkable efficacy in programmed cell death ligand 1 (PD-L1)-positive non-small cell lung carcinoma (NSCLC) patients in phase Ⅱ clinical trials, in combination with PD-L1 blockade. However, the specific mechanism of TIGIT blockade remains to be fully elucidated.

Cancer-cell-intrinsic mechanisms shaping the immunosuppressive landscape of prostate cancer / 亚洲男科学杂志(英文版)

Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types, only a subset of patients shows meaningful clinical responses. In particular, advanced prostate cancer exhibits overwhelming de novo resistance to immune checkpoint blockade therapy. This is primarily due to the immunosuppressive tumor microenvironment of prostate cancer. Therefore, it is paramount to understand how prostate cancer cell-intrinsic mechanisms promote immune evasion and foster an immunosuppressive microenvironment. Here, we review recent findings that reveal the roles of the genetic alterations, androgen receptor signaling, cancer cell plasticity, and oncogenic pathways in shaping the immunosuppressive microenvironment and thereby driving immunotherapy resistance. Based on preclinical and clinical observations, a variety of therapeutic strategies are being developed that may illuminate new paths to enhance immunotherapy efficacy in prostate cancer.

Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA

Mevalonate metabolism plays an important role in regulating tumor growth and progression; however, its role in immune evasion and immune checkpoint modulation remains unclear. Here, we found that non-small cell lung cancer (NSCLC) patients with higher plasma mevalonate response better to anti-PD-(L)1 therapy, as indicated by prolonged progression-free survival and overall survival. Plasma mevalonate levels were positively correlated with programmed death ligand-1 (PD-L1) expression in tumor tissues. In NSCLC cell lines and patient-derived cells, supplementation of mevalonate significantly up-regulated the expression of PD-L1, whereas deprivation of mevalonate reduced PD-L1 expression. Mevalonate increased CD274 mRNA level but did not affect CD274 transcription. Further, we confirmed that mevalonate improved CD274 mRNA stability. Mevalonate promoted the affinity of the AU-rich element-binding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA. By in vivo study, we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1, increased the infiltration of CD8+ T cells, and improved cytotoxic function of T cells. Collectively, our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody, and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.

Comparison of onset of neuromuscular blockade with electromyographic and acceleromyographic monitoring: a prospective clinical trial

Abstract Background Reliable devices that quantitatively monitor the level of neuromuscular blockade after neuromuscular blocking agents' administration are crucial. Electromyography and acceleromyography are two monitoring modalities commonly used in clinical practice. The primary outcome of this study is to compare the onset of neuromuscular blockade, defined as a Train-Of-Four Count (TOFC) equal to 0, as measured by an electromyography-based device (TetraGraph) and an acceleromyography-based device (TOFscan). The secondary outcome was to compare intubating conditions when one of these two devices reached a TOFC equal to 0. Methods One hundred adult patients scheduled for elective surgery requiring neuromuscular blockade were enrolled. Prior to induction of anesthesia, TetraGraph electrodes were placed over the forearm of patients' dominant/non-dominant hand based on randomization and TOFscan electrodes placed on the contralateral forearm. Intraoperative neuromuscular blocking agent dose was standardized to 0.5 mg.kg−1 of rocuronium. After baseline values were obtained, objective measurements were recorded every 20 seconds and intubation was performed using video laryngoscopy once either device displayed a TOFC = 0. The anesthesia provider was then surveyed about intubating conditions. Results Baseline TetraGraph train-of-four ratios were higher than those obtained with TOFscan (Median: 1.02 [0.88, 1.20] vs. 1.00 [0.64, 1.01], respectively, p < 0.001). The time to reach a TOFC = 0 was significantly longer when measured with TetraGraph compared to TOFscan (Median: 160 [40, 900] vs. 120 [60, 300] seconds, respectively, p < 0.001). There was no significant difference in intubating conditions when either device was used to determine the timing of endotracheal intubation. Conclusions The onset of neuromuscular blockade was longer when measured with TetraGraph than TOFscan, and a train-of-four count of zero in either device was a useful indicator for adequate intubating conditions. Clinical trial number and registry URL NCT05120999, https://clinicaltrials.gov/ct2/show/NCT05120999.

Tratamiento con bloqueo esfenopalatino de la cefalea refractaria por trombosis del seno cavernoso / Treatment with sphenopalatine blockade against refractory headache due to thrombosis of the cavernous sinus

Introducción: Entre las cefaleas secundarias se encuentra la atribuida a flebotrombosis cerebral producida por trombosis séptica del seno cavernoso. El ganglio esfenopalatino interviene en la génesis y mantenimiento de cefaleas unilaterales; pues envía conexiones a la cavidad nasofaríngea y meninges, así desempeña una función importante en la modulación neuronal; el bloqueo de dicho ganglio es un método fácil, seguro, económico y efectivo de tratamiento del dolor irruptivo de algunos tipos de cefalea. Objetivo: Presentar los resultados del bloqueo GEFP en el tratamiento de la cefalea grave refractaria secundaria a trombosis séptica del seno cavernoso. Presentación de caso: Paciente de 71 años de edad, al que se realizó de forma exitosa bloqueo transnasal del ganglio esfenopalatino, para tratamiento de cefalea grave refractaria secundaria a trombosis séptica del seno cavernoso, consiguiéndose analgesia efectiva con disminución progresiva de la cefalea y control total de la misma a las 72 h de tratamiento. Conclusiones: El bloqueo podría constituir una opción en la terapéutica de este tipo de cefalea(AU)

Introduction: Among secondary headaches, one is attributed to cerebral phlebothrombosis produced by septic thrombosis of the cavernous sinus. The sphenopalatine ganglion (SPG) is involved in the genesis and maintenance of unilateral headaches, since it sends connections to the nasopharyngeal cavity and meninges, playing thus an important role in neuronal modulation; therefore; the blockade of this ganglion is an easy, safe, economic and effective method for treating breakthrough pain in some types of headache. Objective: To present the results of SPG blockade in the treatment of refractory severe headache produced by septic thrombosis of the cavernous sinus. Case presentation: A 71-year-old male patient is presented, who was successfully performed a transnasal SPG blockade, as a treatment for refractory severe headache caused by septic thrombosis of the cavernous sinus. Effective analgesia is achieved, together with progressive decrease of headache until it was totally controlled at 72 hours. Conclusions: Blockade was an option in the therapy of this type of headache(AU)

Efecto del óxido nítrico inhalado en la mecánica ventilatoria y oxigenación de pacientes con hipoxemia grave refractaria a prono prolongado y bloqueo neuromuscular secundario a infección por SARS-CoV-2 / Effect of inhaled nitric oxide on ventilatory mechanics and oxygenation of patients with severe hypoxemia refractory to prolonged prone and neuromuscular blockade secondary to SARS-CoV-2 / Efeito do óxido nítrico inalado na mecânica ventilatória e oxigenação de pacientes com hipoxemia grave refratária a pronação prolongada e bloqueio neuromuscular secundário à infecção por SARS-CoV-2

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Abstract: Introduction: Among the patients infected with SARS-CoV-2, 14.6% were admitted to intensive care unit. this 29 to 75% required invasive mechanical ventilation with an associated mortality of 12 to 81%. Acute respiratory distress syndrome (ARDS) is the most serious form of presentation. The pathophysiology of ARDS secondary to SARS-CoV-2 differs from conventional causes. It presents dysregulation in hypoxic pulmonary vasoconstriction, secondary acute pulmonary hypertension and microthrombotic phenomena. The development of refractory severe hypoxemia (PaO2 < 60 mmHg or PaO2/FiO2 < 100 mmHg, with FiO2 80 to 100%, with PEEP > 10 to 20 cmH2O for at least 10 to 12 hours) constitutes the scenario of maximum severity with an associated mortality of 71 to 94%. The use of rescue strategies that impact on the specific pathophysiology of this entity such as the use of inhaled nitric oxide, neuromuscular blockade and prone ventilation have emerged as therapeutic targets of interest. Protective mechanical ventilation (plateau pressure [Pplat] < 27 cmH2O and driving pressure [DP] < 15 cmH2O) continues to be the cornerstone of the management. Objectives: To determine whether there is an association between the use of inhaled nitric oxide and prone ventilation with ventilatory mechanics in patients with severe refractory hypoxemia secondary to SARS-CoV-2 infection. Material and methods: A historical, retrospective, descriptive, comparative and retrolective cohort study was carried out. Data from the records of patients admitted to the Respiratory ICU of the ABC Medical Center with a diagnosis of ARDS secondary to SARS-CoV-2 infection who required iNO and mechanical ventilation in prone from April 1 to December 31, 2020 were analyzed. A univariate analysis was performed, the statistical analysis was performed in SPSS v 21, measures of trend, dispersion were analyzed as well as the analysis of risk factors with Student's t test and χ2. Results: A total of 108 patients were analyzed, of which 54 received iNO, neuromuscular blockade and prone and 54 only neuromuscular blockade and prone ventilation. 81.5% (n = 88) were men. The most common comorbidity was diabetes mellitus in 51.9% (n = 56). The increase in oxygenation (delta PaO2/FiO2) was with a median of 31.9 ± 15.2 mmHg in the iNO group and 52.9 ± 16.74 mmHg in the control group (p = 0.001). The postintervention Pplat in the iNO group was 26.3 ± 3 and 34.5 ± 1.9 cmH2O in the control group (p = 0.792). The preintervention DP in the iNO group was 17.2 ± 3.9 and 13.4 ± 2.8 cmH2O in control group vs 13.1 ± 1.29 and 12 ± 1.92 cmH2O after the intervention (p = 0.001). Conclusions: The use of iNO in patients with severe hypoxemia refractory to prone ventilation and neuromuscular blockade did not produce a statistically significant improvement in oxygenation, however it allowed to reprogram the ventilatory support to keep the patient in goals of alveolar protection.

Resumo: Introdução: 14.6% dos pacientes infectados com SARS-CoV-2 são internados em terapia intensiva. Destes, 29 a 75% necessitam de ventilação mecânica invasiva com mortalidade associada de 12 a 81%. A síndrome do desconforto respiratório agudo (SDRA) é a forma mais grave de apresentação. A fisiopatologia da SDRA secundária ao SARS-CoV-2 difere das causas convencionais. Apresenta desregulação na vasoconstrição pulmonar hipóxica, hipertensão pulmonar aguda secundária e fenômenos microtrombóticos. O desenvolvimento de hipoxemia grave refratária (PaO2 < 60 mmHg ou PaO2/FiO2 < 100 mmHg, com FiO2 de 80 a 100%, PEEP > 10 a 20 cmH2O por pelo menos 10 a 12 horas) constitui o cenário mais grave com mortalidade associada de 71 a 94%. O uso de estratégias de resgate que impactam na fisiopatologia específica dessa entidade, como o uso de óxido nítrico inalatório (NOi), bloqueio neuromuscular e ventilação prona, surgiram como alvos terapêuticos de interesse. A ventilação mecânica protetora (Pressão de Platô [PPLAT] < 27 cmH2O e Pressão de Condução [CP] < 15 cmH2O) continua sendo a base de seu manejo. Objetivo: Determinar se existe associação entre o uso de óxido nítrico inalatório e ventilação prona prolongada com mecânica ventilatória em pacientes com hipoxemia refratária grave secundária à infecção por SARS-CoV-2. Material e métodos: Realizou-se um estudo de coorte histórico, retrospectivo, descritivo, comparativo e retroletivo. Analisaram-se dados dos prontuários de pacientes internados na UTI Respiratória do Centro Médico ABC com diagnóstico de SDRA secundária à infecção por SARS-CoV-2 que necessitaram de óxido nítrico inalatório e ventilação mecânica prona no período de 1o de abril a 31 de dezembro de 2020. Realizou-se uma análise univariada , a análise estatística foi realizada no SPSS v 21, foram analisadas as medidas de tendência e dispersão, assim como a análise dos fatores de risco com teste t de Student e χ2. Resultados: Analisaram-se 108 pacientes, dos quais 54 receberam NOi, bloqueio neuromuscular e prono e 54 apenas bloqueio neuromuscular e ventilação prona. 81.5% (n = 88) eram homens. A comorbidade mais comum foi diabetes mellitus em 51.9% (n = 56). O aumento da oxigenação (Delta PaO2/FiO2) foi com mediana de 31.9 ± 15.2 mmHg no grupo NOi e 52.9 ± 16.74 mmHg no grupo controle (p = 0.001). A PPLAT após a intervenção no grupo NOi foi de 26.3 ± 3 e 34.5 ± 1.9 cmH2O no grupo controle (p = 0.792). A PC antes da intervenção no grupo NOi foi de 17.2 ± 3.9 e 13.4 ± 2.8 cmH2O no grupo controle vs 13.1 ± 1.29 e 12 ± 1.92 cmH2O após a intervenção (p = 0.001). Conclusões: O uso de NOi em pacientes com hipoxemia grave refratária à ventilação em pronação e bloqueio neuromuscular não produziu melhora estatisticamente significativa na oxigenação, porém permitiu que o suporte ventilatório fosse reprogramado para manter as metas de proteção alveolar do paciente.

Continuous erector spinae block for postoperative analgesia in a partial colectomy by subcostal incision / Bloqueo continuo de los erectores espinales para la analgesia postoperatoria en una colectomía parcial por incisión subcostal

Abstract: Erector spinae plane block is an ultrasound-guided technique who has seen a growing role as a perioperative analgesic technique due to its safety profile and versatility. We describe a case of an elderly female with a history of ischemic heart disease and atrial fibrillation, who underwent segmental colectomy by left subcostal laparotomy under general anesthesia, for removal of a colon tumor. An erector spinae plane catheter was placed at the T7 level under ultrasound guidance, and then used for postoperative analgesia. Ropivacaine 0.2% (initial bolus + infusion at 8 mL/h) was used through the catheter, together with intravenous paracetamol and metamizol. This analgesic regimen was maintained for 72 hours, with excellent pain control, after which the catheter was removed. The patient's pain remained controlled and rescue analgesia was not required until her discharge at seven days postoperative. Continuous ESP block was an effective technique for postoperative analgesia in this case, allowing excellent pain control with a low risk of complications and avoiding the use of opioids.

Resumen: El bloqueo del plano del músculo erector espinal es una técnica ecoguiada que ha ganado popularidad como técnica analgésica perioperatoria debido a su perfil de seguridad y versatilidad. Se describe el caso de una anciana con cardiopatía isquémica y fibrilación auricular, a la que se le realizó colectomía segmentaria mediante laparotomía subcostal izquierda bajo anestesia general, para la escisión de un tumor de colon. Se colocó un catéter en el plano del músculo erector espinal al nivel T7 bajo guía ultrasónica y luego se utilizó para analgesia postoperatoria (ropivacaína 0.2% bolo + infusión a 8 mL/h) junto con paracetamol intravenoso y metamizol. Este régimen analgésico se mantuvo durante 72 horas, con excelente control del dolor, tras lo cual se retiró el catéter. La paciente permaneció con adecuada analgesia sin opioides de rescate hasta su alta a los siete días del postoperatorio. El bloqueo del plano del erector espinal torácico continuo fue una técnica eficaz para la analgesia postoperatoria en cirugía abdominal abierta, con bajo riesgo de complicaciones y evitando el uso de opioides.

Effects of ultrasound-guided erector spinae plane block on analgesic dosage, lumbar function and pain in patients undergoing percutaneous kyphoplasty / 中国基层医药

Objective:To investigate the effects of ultrasound-guided erector spinae plane block on analgesic dosage, lumbar function and pain in patients undergoing percutaneous kyphoplasty.Methods:A total of 100 patients who underwent percutaneous kyphoplasty in Hangzhou Cancer Hospital from November 2018 to October 2021 were included in this study. They were randomly assigned to undergo either local infiltration anesthesia (control group, n = 50) or ultrasound-guided erector spinae plane block (observation group, n = 50). Analgesic dosages, pain status at different phases (Visual Analogue Scale score) and lumbar function (Oswestry Disability Index score), intraoperative and postoperative conditions (operative time, time to get out of bed, time to first exhaust), and the incidence of adverse reactions were compared between the two groups. Results:At 24 and 48 hours after surgery, the amount of analgesics infused in the observation group was (24.54 ± 2.52) mL and (55.68 ± 5.61) mL, respectively, and the number of analgesic pump pressings was (1.01 ± 0.26) times and (3.15 ± 1.02) times, which were significantly lower than those in the control group [amount of analgesics infused at 24 and 48 hours after surgery: (32.78 ± 3.31) mL, (62.57 ± 6.42) mL; the number of analgesic pump pressings at 24 and 48 hours after surgery: (6.42 ± 1.53) times, (10.78 ± 2.45) times, t = 14.00, 5.71, 24.65, 20.33, all P < 0.001]. Visual Analogue Scale score at the time at which the balloon was pressurized and expanded in the observation group was significantly lower than that in the control group [(4.10 ± 0.87) points vs. (4.65 ± 1.01) points, t = 2.92, P < 0.05]. At 1 day and 1 month after surgery, Oswestry Disability Index score in the observation group was (18.37 ± 2.78) points and (12.15 ± 2.02) points, respectively, which were lower than (23.56 ± 3.42) points and (17.53 ± 2.34) points in the control group ( t = 8.33, 12.31, both P < 0.05). The time to get out of bed and the time to first exhaust in the observation group were (9.12 ± 2.54) days and (23.56 ± 4.56) hours, respectively, which were significantly shorter than those in the control group [(11.64 ± 3.12) days, (28.14 ± 5.12) hours, t = 4.43, 4.72, both P < 0.001). There was no significant difference in the incidence of adverse reactions between the two groups ( P > 0.05). Conclusion:Ultrasound-guided erector spinae plane block for percutaneous kyphoplasty can effectively ameliorate lumbar spine function, reduce postoperative pain, and facilitate postoperative recovery, without affecting the dosage of narcotics and analgesics. The method is safe and effective.

Analgesic effects of ultrasound-guided rectus sheath block in open gastrectomy / 中国基层医药

Objective:To investigate the analgesic effects of ultrasound-guided rectus abdominis sheath block (RSB) in open gastrectomy.Methods:Forty-one patients with gastric cancer who underwent open gastrectomy in Binzhou Hospital of Traditional Chinese Medicine from December 2019 to December 2020 were included in this study. They were randomly assigned to undergo either RSB with 40 mL of 0.375% ropivacaine (group A, n = 21) or RSB with 40 mL of 0.9% sodium chloride injection (group B, n = 20) based on total intravenous anesthesia. After skin sutures, patient-controlled analgesia (PCA) was performed. Intraoperative dose of remifentanil and postoperative dose of PCA drug were compared between the two groups. Results:Intraoperative dose of remifentanil was significantly lower in the group A than that in the group B [(1 021.4 ± 172.0) μg vs. (1 415.0 ± 330.6) μg, t = -4.04, P = 0.001]. Postoperative doses of PCA drug used by 1 and 2 hours after surgery were (1.14 ± 0.90) mL and (0.85 ± 0.70) mL respectively in group A, which were significantly lower than (1.85 ± 0.70) mL and (1.45 ± 1.00) mL in the group B ( t = -5.96, -2.75, P < 0.001, P = 0.009). There were no significant differences in postoperative doses of PCA drug used by 3, 6, 12, 24, 48 and 72 hours after surgery between the two groups (both P > 0.05). Conclusion:RSB with 40 mL of ropivacaine applied to both sides of the incision before open gastrectomy can reduce the dose of remifentanil used during surgery and the dose of PCA drug used within 2 hours after surgery.

Appropriate degree of neuromuscular block for monitoring abnormal muscle response during microvascular decompression / 中华麻醉学杂志

Objective:To determine the appropriate degree of neuromuscular block (NMB) for abnormal muscle response (AMR) monitoring during microvascular decompression.Methods:Fifty American Society of Anesthesiologists physical status Ⅰ or Ⅱ patients of both sexes, aged 20-64 yr, with body mass index≤30 kg/m 2, who were diagnosed with facial spasm before surgery, scheduled for elective microvascular decompression, were selected.Anesthesia was induced with midazolam 0.05-0.10 mg/kg, sufentanil 0.3-0.5 μg/kg and propofol 1.5-2.5 mg/kg. After patients lost consciousness, electrophysiological monitoring was performed, the zygomatic branch of the facial nerve was stimulated, and the baseline of AMR was recorded in the mental muscle.NMB was monitored with TOF-Watch SX monitor.After rocuronium 0.6 mg/kg was intravenously injected, the amplitude and latency of AMR were measured at different degrees of NMB (100%, 75%, 50% and 25%). The amplitude reservation ratio (the ratio of the amplitude of AMR monitored to the baseline value) was calculated.Linear correlation of the amplitude reservation ratio or latency of AMR with the degree of NMB was analyzed.The criteria for determining the appropriate degree of NMB in AMR monitoring were: 1.amplitude reservation ratio of AMR≥50%; 2.no body movement during electrical stimulatation of facial nerve. Results:No patients had any body movement during electrical stimulation performed at different degrees of NMB.The amplitude reservation ratio ( Y) was negatively correlated with the degree of NMB ( X) ( r=-0.943, t=-42.73, P<0.001), the linear regression equation of the interaction between the degree of NMB ( X) and the amplitude reservation ratio (Y) was Y=90.36-0.894 7 X, and the coefficient of determination R2 was 0.8804 ( F=1825.41, P<0.001). The amplitude reservation ratio ( Y) was positively correlated with the degree of NMB ( X) ( r=0.879, t=28.67, P<0.001) in the latency period, the linear regression equation of the interaction between the degree of NMB ( X) and the latency ( Y) was Y=10.77+ 0.074 3 X, and the coefficient of determination R2 was 0.7681 ( F=821.30, P<0.001). The estimated appropriate degree of NMB for AMR monitoring during microvascular decompression was 25%-45%. Conclusions:The appropriate degree of NMB for AMR monitoring during microvascular decompression was 25%-45%.

Stimuli-responsive nano vehicle enhances cancer immunotherapy by coordinating mitochondria-targeted immunogenic cell death and PD-L1 blockade

Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin (DOX) massively amplified ICD via substantial generation of reactive oxygen species (ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways: (1) ROS elevated endoplasmic reticulum (ER) stress, leading to surface exposure of calreticulin; (2) ROS promoted release of various mitochondria-associated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback, we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.

Non-alcoholic Fatty Liver Disease Affect Efficacy of Immune Checkpoint Inhibitors for Patients with Hepatocellular Carcinoma: Manifestations and Mechanisms / 肿瘤防治研究

The number of patients with the combination of non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) is gradually increasing. In recent years, the immunotherapy has become a new effective way to treat unresectable HCC. The clinical research revealed that the NAFLD could affect the efficacy of immunotherapy treating the HCC. But the mechanism is complicated. The major routes are CD8+PD-1+T cells increasing in NAFLD cause the deficiency in cell proliferation ability; Zn64 activates the anti-tumor immune response of the CSF1; PCSK9 downregulates the LDLR level to suppress the immune response of the CD8+T cells in tumor microenvironment; loss of the immune response induces the liver damage. Researches had indicated that the combination of lenvatinib, PKCa inhibitor, PCSK9 protein inhibition, ferroptosis inducer, and HIF2a small molecule inhibitor can improve the efficacy of immune checkpoint inhibitors for NAFLD-associated hepatocellular carcinoma. This review focuses on the impact of NAFLD on tumor microenvironment and how the NAFLD affect the immune check-point inhibitor effect and to discover the exact mechanism.