Comparative efficacy and tolerability of targeted and immunotherapy combined with chemotherapy as first-line treatment for advanced gastric cancer: a Bayesian network meta-analysis.

The use of target agents and immune checkpoint inhibitors have changed the treatment landscape for AGC in the first-line setting. However, the crosswise comparison between each regimen is rare. Therefore, we estimated the efficacy and safety of targeted therapy or immunotherapy with chemotherapy in AGC patients as the first-line treatment. Included studies were divided into "average" or "specific positivity" group according to whether the patients were selected by a certain pathological expression. We conducted a Bayesian network meta-analysis for all regimens in both groups. In average group, no regimen showed significant improvements in overall survival (OS) and progression free survival (PFS), while pembrolizumab and nivolumab combined with chemotherapy were ranked first and second respectively without an obvious safety difference. In specific positivity group, zolbetuximab plus chemotherapy significantly prolonged OS (HR 0.53, 95% CI 0.36-0.79) and PFS (HR 0.45, 95% CI 0.25-0.81). The top three regimens were zolbetuximab-chemotherapy, trastuzumab plus pertuzuma-chemotherapy and nivolumab-chemotherapy respectively, with no significant safety risk. For average patients, immune checkpoint inhibitor PD-1 plus chemotherapy will be the promising regimen. For patients with overexpression of CLDN18.2, zolbetuximab combined with chemotherapy comes with greater survival benefits, while for patients who have PD-L1 expression with no HER-2 or CLDN18.2 positivity, additional immune checkpoint inhibitor of PD-1 will be a good considered option.

Astrocytes in CA1 modulate schema establishment in the hippocampal-cortical neuron network.

BACKGROUND: Schema, a concept from cognitive psychology used to explain how new information is integrated with previous experience, is a framework of acquired knowledge within associative network structures as biological correlate, which allows new relevant information to be quickly assimilated by parallel cortical encoding in the hippocampus (HPC) and cortex. Previous work demonstrated that myelin generation in the anterior cingulate cortex (ACC) plays a critical role for dynamic paired association (PA) learning and consolidation, while astrocytes in ACC play a vital role in cognitive decision-making. However, circuit components and mechanism involving HPC-anterior cingulate cortex (ACC) during schema formation remain uncertain. Moreover, the correlation between HPC-ACC circuit and HPC astrocytic activity is unclear. RESULTS: Utilizing a paired association (PA) behavioral paradigm, we dynamically recorded calcium signals of CA1-ACC projection neurons and ACC neurons during schema formation. Depending on the characteristics of the calcium signals, three distinct stages of schema establishment process were identified. The recruitment of CA1-ACC network was investigated in each stage under CA1 astrocytes Gi pathway chemogenetic activation. Results showed that CA1-ACC projecting neurons excitation gradually decreased along with schema development, while ACC neurons revealed an excitation peak in the middle stage. CA1 astrocytic Gi pathway activation will disrupt memory schema development by reducing CA1-ACC projection neuron recruitment in the initial stage and prevent both CA1-ACC projection neurons and ACC neuron excitation in the middle stage. CA1 astrocytes Gi markedly suppress new PA assimilation into the established memory schema. CONCLUSIONS: These results not only reveal the dynamic feature of CA1-ACC network during schema establishment, but also suggest CA1 astrocyte contribution in different stages of schema establishment.

Comparison of analgesic modalities for patients undergoing midline laparotomy: a systematic review and network meta-analysis.

BACKGROUND: Midline laparotomy is associated with severe pain. Epidural analgesia has been the established standard, but multiple alternative regional anesthesia modalities are now available. We aimed to compare continuous and single-shot regional anesthesia techniques in this systematic review and network meta-analysis. METHODS: We included randomized controlled trials on adults who were scheduled for laparotomy with solely a midline incision under general anesthesia and received neuraxial or regional anesthesia for pain. Network meta-analysis was performed with a frequentist method, and continuous and dichotomous outcomes were presented as mean differences and odds ratios, respectively, with 95% confidence intervals. The quality of evidence was rated with the  grading of recommendations, assessment, development, and evaluation system. RESULTS: Overall, 36 trials with 2,056 patients were included. None of the trials assessed erector spinae plane or quadratus lumborum block, and rectus sheath blocks and transversus abdominis plane blocks were combined into abdominal wall blocks (AWB). For the co-primary outcome of pain score at rest at 24 hr, with a minimal clinically important difference (MCID) of 1, epidural was clinically superior to control and single-shot AWB; epidural was statistically but not clinically superior to continuous wound infiltration (WI); and no statistical or clinical difference was found between control and single-shot AWB. For the co-primary outcome of cumulative morphine consumption at 24 hr, with a MCID of 10 mg, epidural and continuous AWB were clinically superior to control; epidural was clinically superior to continuous WI, single-shot AWB, single-shot WI, and spinal; and continuous AWB was clinically superior to single-shot AWB. The quality of evidence was low in view of serious limitations and imprecision. Other results of importance included: single-shot AWB did not provide clinically relevant analgesic benefit beyond two hr; continuous WI was clinically superior to single-shot WI by 8-12 hr; and clinical equivalence was found between epidural, continuous AWB, and continuous WI for the pain score at rest, and epidural and continuous WI for the cumulative morphine consumption at 48 hr. CONCLUSIONS: Single-shot AWB were only clinically effective for analgesia in the early postoperative period. Continuous regional anesthesia modalities increased the duration of analgesia relative to their single-shot counterparts. Epidural analgesia remained clinically superior to alternative continuous regional anesthesia techniques for the first 24 hr, but reached equivalence, at least with respect to static pain, with continuous AWB and WI by 48 hr. TRIAL REGISTRATION: PROSPERO (CRD42021238916); registered 25 February 2021.

RéSUMé: CONTEXTE: La laparotomie médiane est associée à une douleur sévère. L'analgésie péridurale est la norme de soins établie, mais plusieurs modalités alternatives d'anesthésie régionale sont aujourd'hui disponibles. Dans cette revue systématique et méta-analyse en réseau, nous avons cherché à comparer les techniques d'anesthésie régionale continue et par injection unique. MéTHODE: Nous avons inclus les études randomisées contrôlées portant sur des adultes devant bénéficier d'une laparotomie avec une simple incision médiane sous anesthésie générale et qui ont reçu une anesthésie neuraxiale ou régionale pour la douleur. Une méta-analyse en réseau a été réalisée avec une méthode fréquentiste, et les résultats continus et dichotomiques ont été présentés sous forme de différences moyennes et de rapports de cotes, respectivement, avec des intervalles de confiance à 95 %. La qualité des données probantes a été évaluée avec le système GRADE (Grading of Recommendations Assessment, Development and Evaluation). RéSULTATS: Au total, 36 études portant sur 2056 patients ont été incluses. Aucune des études n'a évalué le bloc du plan des muscles érecteurs du rachis ou du carré des lombes. Les blocs de la gaine des grands droits et du plan des muscles transverses de l'abdomen ont été combinés en blocs de la paroi abdominale (BPA). Concernant le critère d'évaluation principal de score de douleur au repos à 24 heures, avec une différence minimale cliniquement pertinente (DMCP) de 1, l'analgésie péridurale était cliniquement supérieure au BPA de contrôle et par injection unique; l'analgésie péridurale était statistiquement mais non cliniquement supérieure à l'infiltration continue de la plaie; et aucune différence statistique ou clinique n'a été constatée entre le BPA de contrôle et par injection unique. Pour le deuxième critère d'évaluation principal portant sur la consommation cumulative de morphine à 24 heures, avec une DMCP de 10 mg, la péridurale et le BPA continu étaient cliniquement supérieurs au groupe contrôle; la péridurale était cliniquement supérieure à l'infusion continue de la plaie, au BPA par injection unique, à l'infiltration par injection unique de la plaie et à la rachianesthésie; et le BPA continu était cliniquement supérieur au BPA par injection unique. La qualité des données probantes était faible compte tenu d'importantes limites et d'imprécisions. De plus, le BPA par injection unique n'a fourni aucun avantage analgésique cliniquement pertinent au-delà de deux heures; l'infiltration continue de la plaie était cliniquement supérieure de 8 à 12 heures à l'infiltration de la plaie en injection unique; et une équivalence clinique a été observée entre la péridurale, le BPA continu et l'infiltration continue de la plaie en ce qui avait trait au score de douleur au repos, et entre la péridurale et l'infiltration continue de la plaie en ce qui touchait à la consommation cumulative de morphine à 48 heures. CONCLUSION: Les BPA par injection unique n'étaient cliniquement efficaces pour procurer une analgésie qu'au début de la période postopératoire. Les modalités d'anesthésie régionale continue ont augmenté la durée de l'analgésie par rapport aux modalités équivalentes par injection unique. L'analgésie péridurale est demeurée cliniquement supérieure aux techniques alternatives d'anesthésie régionale continue pendant les 24 premières heures, mais a atteint l'équivalence, au moins en ce qui concerne la douleur statique, avec les BPA et les infiltrations de lésions continus à 48 heures. Enregistrement de l'étude : PROSPERO (CRD42021238916); enregistrée le 25 février 2021.

Developing a simulation programme to train airway management during the COVID-19 pandemic in a tertiary-level hospital.

Tracheal intubation of a patient with COVID-19 is a high-risk procedure for not only the patient, but all healthcare workers involved, leading to an understandable degree of staff anxiety. We used simulation to help train airway managers to intubate patients with COVID-19. Based on action cards developed by our department, we designed a series of scenarios to simulate airway management during the COVID-19 pandemic. Teams were asked to perform a rapid sequence induction with tracheal intubation. We designed in situ scenarios with low-fidelity manikins that could be set up in operating theatres across multiple sites. Over a period of 4 weeks, 101 consultant anaesthetists, 58 anaesthetic trainees and 30 operating department practitioners received intubation training. These members made up the airway response team of our hospital. 30 emergency department doctors also received training in anticipation of further COVID-19 surges leading to the possibility of overwhelmed services. Simulation-based training was an invaluable tool for our hospital to rapidly upskill medical professionals during the first wave of the COVID-19 pandemic. We have used feedback and additional guidelines to improve our scenarios to retrain staff during subsequent waves.

Suppression of Pain in the Late Phase of Chronic Trigeminal Neuropathic Pain Failed to Rescue the Decision-Making Deficits in Rats.

Trigeminal neuropathic pain (TNP) led to vital cognitive functional deficits such as impaired decision-making abilities in a rat gambling task. Chronic TNP caused hypomyelination in the anterior cingulate cortex (ACC) associated with decreased synchronization between ACC spikes and basal lateral amygdala (BLA) theta oscillations. The aim of this study was to investigate the effect of pain suppression on cognitive impairment in the early or late phases of TNP. Blocking afferent signals with a tetrodotoxin (TTX)-ELVAX implanted immediately following nerve lesion suppressed the allodynia and rescued decision-making deficits. In contrast, the TTX used at a later phase could not suppress the allodynia nor rescue decision-making deficits. Intra-ACC administration of riluzole reduced the ACC neural sensitization but failed to restore ACC-BLA spike-field phase synchrony during the late stages of chronic neuropathic pain. Riluzole suppressed allodynia but failed to rescue the decision-making deficits during the late phase of TNP, suggesting that early pain relief is important for recovering from pain-related cognitive impairments. The functional disturbances in ACC neural circuitry may be relevant causes for the deficits in decision making in the chronic TNP state.

Comparison of local and regional anesthesia modalities in breast surgery: A systematic review and network meta-analysis.

STUDY OBJECTIVE: Moderate to severe postoperative pain occurs in up to 60% of women following breast operations. Our aim was to perform a network meta-analysis and systematic review to compare the efficacy and side effects of different analgesic strategies in breast surgery. DESIGN: Systematic review and network meta-analysis. SETTING: Operating room, postoperative recovery room and ward. PATIENTS: Patients scheduled for breast surgery under general anesthesia. INTERVENTIONS: Following an extensive search of electronic databases, those who received any of the following interventions, control, local anesthetic (LA) infiltration, erector spinae plane (ESP) block, pectoralis nerve (PECS) block, paravertebral block (PVB) or serratus plane block (SPB), were included. Exclusion criteria were met if the regional anesthesia modality was not ultrasound-guided. Network plots were constructed and network league tables were produced. MEASUREMENTS: Co-primary outcomes were the pain at rest at 0-2 h and 8-12 h. Secondary outcomes were those related to analgesia, side effects and functional status. MAIN RESULTS: In all, 66 trials met our inclusion criteria. No differences were demonstrated between control and LA infiltration in regard to the co-primary outcomes, pain at rest at 0-2 and 8-12 h. The quality of evidence was moderate in view of the serious imprecision. With respect to pain at rest at 8-12 h, ESP block, PECS block and PVB were found to be superior to control or LA infiltration. No differences were revealed between control and LA infiltration for outcomes related to analgesia and side effects, and few differences were shown between the various regional anesthesia techniques. CONCLUSIONS: In breast surgery, regional anesthesia modalities were preferable from an analgesic perspective to control or LA infiltration, with a clinically significant decrease in pain score and cumulative opioid consumption, and limited differences were present between regional anesthetic techniques themselves.