Purpose
Perioperative intravenous ketamine may be a useful addition in pain management regimens. Previous systematic reviews have included all methods of ketamine administration, and heterogeneity ...between studies has been substantial. This study addresses this issue by narrowing the inclusion criteria, using a random effects model, and performing subgroup analysis to determine the specific types of patients, surgery, and clinical indications which may benefit from perioperative ketamine administration.
Source
We included published studies from 1966 to 2010 which were randomized, double-blinded, and placebo-controlled using intravenous ketamine (bolus or infusion) to decrease postoperative pain. Studies using any form of regional anesthesia were excluded. No limitation was placed on the ketamine dose, patient age, or language of publication.
Principal findings
Ninety-one comparisons in seventy studies involving 4,701 patients met the inclusion criteria (2,652 in ketamine groups and 2,049 in placebo groups). Forty-seven of these studies were appropriate for evaluation in the core meta-analysis, and the remaining 23 studies were used to corroborate the results. A reduction in total opioid consumption and an increase in the time to first analgesic were observed across all studies (
P
< 0.001). The greatest efficacy was found for thoracic, upper abdominal, and major orthopedic surgical subgroups. Despite using less opioid, 25 out of 32 treatment groups (78%) experienced less pain than the placebo groups at some point postoperatively when ketamine was efficacious. This finding implies an improved quality of pain control in addition to decreased opioid consumption. Hallucinations and nightmares were more common with ketamine but sedation was not. When ketamine was efficacious for pain, postoperative nausea and vomiting was less frequent in the ketamine group. The dose-dependent role of ketamine analgesia could not be determined.
Conclusion
Intravenous ketamine is an effective adjunct for postoperative analgesia. Particular benefit was observed in painful procedures, including upper abdominal, thoracic, and major orthopedic surgeries. The analgesic effect of ketamine was independent of the type of intraoperative opioid administered, timing of ketamine administration, and ketamine dose.
Notch1 is associated with the initiation and progression of various solid tumors. However, the exact role of Notch1 expression in head and neck squamous cell carcinoma (HNSCC) remain unclear. We ...created cells ectopically expressing notch intracellular domain (NICD) from previously established HNSCC cells and examined self-renewal capacity and stem cell markers' expression compared with control cells. In addition, we knocked Notch1 down in primary spheres obtained from HNSCC tumor tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined clinical relevance of Notch1 expression in HNSCC patients. Constitutive activation of NICD promoted the self-renewal capacity of HNSCC cells by activating sphere formation and increased the expression of stem cell markers such as Oct4, Sox2, and CD44. In contrast, Notch1 knockdown in primary HNSCC cancer stem cells (CSCs) attenuated CSC traits and augmented the chemosensitizing effects of cisplatin along with the decreased expression of almost all of ABC transporter genes. In addition, Notch1 knockdown in HNSCC CSCs inhibited tumor formation and increased survival of mice in a xenograft model. Also, Notch1 acted upstream of canonical Wnt signaling in HNSCC cells. Finally, elevated Notch1 expression is associated with poor prognosis in patients with HNSCC. In conclusion, Notch1 may be a critical regulator of stemness in HNSCC cells, and inactivation of this pathway could be a potential targeted approach for the treatment of HNSCC.
Compound K (CK), a ginsenoside with high bioavailability, is present at low levels in wild-simulated ginseng leaves (WSGL). WSGL contains the CK precursors, Rd and F2, in amounts up to 26.4 ± 0.4 and ...24.1 ± 1.9 mg/g extract, respectively. In this study, CK production in WGSL reached 25.9 ± 1.0 mg/g extract following treatment with Viscozyme, Celluclast 1.5 L, Pectinex Ultra SP-L, and their combination. The antioxidant activities indicated by oxygen radical absorbance capacity, ferric reducing antioxidant power, and ABTS- and DPPH radical scavenging activity of enzyme-treated WSGL were enhanced 1.69-, 2.51-, 2.88-, and 1.80-fold, respectively, compared to non-treated WSGL. Furthermore, the CK-enriched WSGL demonstrated a 1.94-fold decrease in SA-β-galactosidase expression in human dermal fibroblasts and a 3.8-fold enhancement of inhibition of nitric oxide release in lipopolysaccharide-induced RAW 264.7 cells relative to non-treated WSGL. Consequently, WSGL subjected to enzymatic upcycling has potential as a functional material in the food and pharmaceutical industries.
Key points
•
Food-grade commercial enzymes were used to produce compound K in wild-simulated ginseng leaves
.
•
Compound K of WSGL was produced up to 25.9 mg/g extract by enzyme treatment
.
•
CK-enriched WSGL inhibited SA-β-galactosidase expression and nitric oxide release in cells
.
Background
Postoperative vomiting (POV) in children is frequent. Dextrose-containing intravenous fluids in the perioperative period have shown improvement of POV in adults. Similar studies have not ...been done in children.
Aim
The primary purpose was to study the efficacy of intraoperative intravenous dextrose for antiemetic prophylaxis in children undergoing ambulatory surgery.
Methods
A non-inferiority randomized clinical trial of healthy children (three to nine years old) undergoing ambulatory dental surgery was conducted. The control group received dexamethasone (0.15 mg·kg
−1
iv
) and ondansetron (0.05 mg·kg
−1
iv
); the intervention group received dexamethasone (0.15 mg·kg
−1
iv
) and intravenous 5% dextrose in 0.9% normal saline according to a weight-based maintenance rate. The primary outcome was POV in the postanesthetic care unit (PACU) within two hr after surgery. Secondary outcomes included POV within 24 hr from discharge and unplanned hospital admission. A non-inferiority analysis was conducted on the primary outcome using an absolute risk difference of 7.5% as the non-inferiority margin.
Results
Data from 290 patients were analyzed. Demographics and intraoperative anesthetic management were similar between groups. Vomiting in the PACU occurred in 7.6% and 3.5% of the dextrose and ondansetron groups, respectively, with a risk difference of 4.2% (95% confidence interval CI, -1.0 to 9.5). Given that the upper limit of the 95% CI exceeded our non-inferiority margin, non-inferiority of dextrose compared with ondansetron was not shown.
Conclusion
These results do not support the use of intravenous dextrose as a satisfactory alternative to ondansetron to prevent POV in ambulatory pediatric dental surgery patients.
Trial registration
www.clinicaltrials.gov
(NCT 01912807); registered 18 July 2013.
Different clones, protocol conditions, instruments, and scoring/readout methods may pose challenges in introducing different PD-L1 assays for immunotherapy. The diagnostic accuracy of using different ...PD-L1 assays interchangeably for various purposes is unknown. The primary objective of this meta-analysis was to address PD-L1 assay interchangeability based on assay diagnostic accuracy for established clinical uses/purposes. A systematic search of the MEDLINE database using PubMed platform was conducted using "PD-L1" as a search term for 01/01/2015 to 31/08/2018, with limitations "English" and "human". 2,515 abstracts were reviewed to select for original contributions only. 57 studies on comparison of two or more PD-L1 assays were fully reviewed. 22 publications were selected for meta-analysis. Additional data were requested from authors of 20/22 studies in order to enable the meta-analysis. Modified GRADE and QUADAS-2 criteria were used for grading published evidence and designing data abstraction templates for extraction by reviewers. PRISMA was used to guide reporting of systematic review and meta-analysis and STARD 2015 for reporting diagnostic accuracy study. CLSI EP12-A2 was used to guide test comparisons. Data were pooled using random-effects model. The main outcome measure was diagnostic accuracy of various PD-L1 assays. The 22 included studies provided 376 2×2 contingency tables for analyses. Results of our study suggest that, when the testing laboratory is not able to use an Food and Drug Administration-approved companion diagnostic(s) for PD-L1 assessment for its specific clinical purpose(s), it is better to develop a properly validated laboratory developed test for the same purpose(s) as the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic, than to replace the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic with a another PD-L1 Food and Drug Administration-approved companion diagnostic that was developed for a different purpose.
The School of Medicine, University of Saskatchewan curriculum promotes self-direction as one of its learning philosophies. The authors sought to identify changes in self-directed learning (SDL) ...readiness during training.
Guglielmino's SDL Readiness Scale (SDLRS) was administered to five student cohorts (N = 375) at admission and the end of every year of training, 2006 to 2010. Scores were analyzed using repeated-measurement analysis. A focus group and interviews captured students' and instructors' perceptions of self-direction.
Overall, the mean SDLRS score was 230.6; men (n = 168) 229.5; women (n = 197) 232.3, higher than in the average adult population. However, the authors were able to follow only 275 students through later years of medical education. There were no significant effects of gender, years of premedical training, and Medical College Admission Test scores on SDLRS scores. Older students were more self-directed. There was a significant drop in scores at the end of year one for each of the cohorts (P < .001), and no significant change to these SDLRS scores as students progressed through medical school. Students and faculty defined SDL narrowly and had similar perceptions of curricular factors affecting SDL.
The initial scores indicate high self-direction. The drop in scores one year after admission, and the lack of change with increased training, show that the current educational interventions may require reexamination and alteration to ones that promote SDL. Comparison with schools using a different curricular approach may bring to light the impact of curriculum on SDL.
When a patient experiences an event other than the one of interest in the study, usually the probability of experiencing the event of interest is altered. By contrast, disease-free survival time ...analysis by standard methods, such as the Kaplan-Meier method and the standard Cox model, does not distinguish different causes in the presence of competing risks. Alternative approaches use the cumulative incidence estimator by the Cox models on cause-specific and on subdistribution hazards models. We applied cause-specific and subdistribution hazards models to a diabetes dataset with two competing risks (end-stage renal disease (ESRD) or death without ESRD) to measure the relative effects of covariates and cumulative incidence functions.
In this study, the cumulative incidence curve of the risk of ESRD by the cause-specific hazards model was revealed to be higher than the curves generated by the subdistribution hazards model. However, the cumulative incidence curves of risk of death without ESRD based on those three models were very similar.
In analysis of competing risk data, it is important to present both the results of the event of interest and the results of competing risks. We recommend using either the cause-specific hazards model or the subdistribution hazards model for a dominant risk. However, for a minor risk, we do not recommend the subdistribution hazards model and a cause-specific hazards model is more appropriate. Focusing the interpretation on one or a few causes and ignoring the other causes is always associated with a risk of overlooking important features which may influence our interpretation.
The programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assay is used to select patients for first or second-line pembrolizumab monotherapy in NSCLC. The PD-L1 IHC 22C3 pharmDx assay ...requires an Autostainer Link 48 instrument. Laboratories without this stainer have the option to develop a highly accurate 22C3 IHC laboratory-developed test (LDT) on other instruments. The Canadian 22C3 IHC LDT validation project was initiated to harmonize the quality of PD-L1 22C3 IHC LDT protocols across 20 Canadian pathology laboratories.
Centrally optimized 22C3 LDT protocols were distributed to participating laboratories. The LDT results were assessed against results using reference PD-L1 IHC 22C3 pharmDx. Analytical sensitivity and specificity were assessed using cell lines with varying PD-L1 expression levels (phase 1) and IHC critical assay performance controls (phase 2B). Diagnostic sensitivity and specificity were assessed using whole sections of 50 NSCLC cases (phase 2A) and tissue microarrays with an additional 50 NSCLC cases (phase 2C).
In phase 1, 80% of participants reached acceptance criteria for analytical performance in the first attempt with disseminated protocols. However, in phase 2A, only 40% of participants reached the desired diagnostic accuracy for both 1% and 50% tumor proportion score cutoff. In phase 2B, further protocol modifications were conducted, which increased the number of successful laboratories to 75% in phase 2C.
It is possible to harmonize highly accurate 22C3 LDTs for both 1% and 50% tumor proportion score in NSCLC across many laboratories with different platforms. However, despite a centralized approach, diagnostic validation of predictive IHC LDTs can be challenging and not always successful.
Irreversible electroporation (IRE) is an ablation technology that uses electrical energy delivered between electrodes. If the electrodes are placed atraumatically, there is little to no risk of ...collateral injury, making IRE appealing for the treatment of pancreatic tumors.
We report on 20 patients with pancreatic adenocarcinoma (PAC) who underwent 21 IRE in our center. There were 6 IRE for stage 2 PAC, 11 for stage 3 PAC, 1 for stage 4 PAC, and 2 patients treated with IRE for recurrence after pancreaticoduodenectomy. One patient had local progression 18 months after IRE and received a second IRE treatment. Using propensity score matching (age, sex, stage, tumor size, and chemotherapy), cases were matched 2 to 1 with patients from the Surveillance, Epidemiology, and End Results database.
A total of 7 cases experienced 8 complications; 4 complications were mild, and 4 were severe. Significant survival benefit was seen for patients with stage 3 PAC (27.5 vs 14.6 months for the matched group, P = 0.003); for stage 2, median survival was 15 months, and the single stage 4 patient survived 9 months after IRE treatment.
Pancreatic cancers were safely and effectively treated with image-guided IRE in our medium-sized center.
PD-L1 testing by immunohistochemistry (IHC) has presented significant challenges not only for clinical laboratories, but also for external quality assurance (EQA) entities that provide proficiency ...testing (PT) for clinical laboratories. Canadian Immunohistochemistry Quality Control (CIQC) has used educational runs to explore approaches to sample design and analysis of results that would enhance patient safety. As PT for predictive biomarkers requires modeling at every level (design of the run, assessment of the run, and reporting of "pass" or "fail") based on "fit-for-purpose" principles, CIQC has applied those principles to PD-L1 PT runs. Each laboratory received unstained slides with TMA tissue cores from 104 randomly selected primary NSCLC and tonsil tissues to test with their current PD-L1 assay. Diagnostic sensitivity and specificity were calculated against designated gold standards based on the "3D" approach (drug-disease-diagnostic assay). Depending on the selection of fit-for-purpose gold standards and also on the selection of what was considered fit-for-purpose cut-off points, great variation in the performance (accuracy) of both companion/complementary diagnostic assays and laboratory developed tests was seen. "Fit-for-purpose" in PT for PD-L1 testing entails that the purpose(s) of each PT run is declared a priori, that the PT program has selected/designated purpose-specific gold standard results for the PT challenge, and that the PT materials for the PT run are designed and constructed to enable calculations of diagnostic accuracy.
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