Effect of Telemedicine Support for Intraoperative Anaesthesia Care on Postoperative Outcomes: The TECTONICS Randomised Clinical Trial.

Background: Novel applications of telemedicine can improve care quality and patient outcomes. Telemedicine for intraoperative decision support has not been rigorously studied. Methods: This single centre randomised clinical trial ( clinicaltrials.gov NCT03923699 ) of unselected adult surgical patients was conducted between July 1, 2019 and January 31, 2023. Patients received usual care or decision support from a telemedicine service, the Anesthesiology Control Tower (ACT). The ACT provided real-time recommendations to intraoperative anaesthesia clinicians based on case reviews, machine-learning forecasting, and physiologic alerts. ORs were randomised 1:1. Co-primary outcomes of 30-day all-cause mortality, respiratory failure, acute kidney injury (AKI), and delirium were analysed as intention-to-treat. Results: The trial completed planned enrolment with 71927 surgeries (35956 ACT; 35971 usual care). After multiple testing correction, there was no significant effect of the ACT vs. usual care on 30-day mortality [641/35956 (1.8%) vs 638/35971 (1.8%), risk difference 0.0% (95% CI -0.2% to 0.3%), p=0.96], respiratory failure [1089/34613 (3.1%) vs 1112/34619 (3.2%), risk difference -0.1% (95% CI -0.4% to 0.3%), p=0.96], AKI [2357/33897 (7%) vs 2391/33795 (7.1%), risk difference -0.1% (-0.6% to 0.4%), p=0.96], or delirium [1283/3928 (32.7%) vs 1279/3989 (32.1%), risk difference 0.6% (-2.0% to 3.2%), p=0.96]. There were no significant differences in secondary outcomes or in sensitivity analyses. Conclusions: In this large RCT of a novel application of telemedicine-based remote monitoring and decision support using real-time alerts and case reviews, we found no significant differences in postoperative outcomes. Large-scale intraoperative telemedicine is feasible, and we suggest future avenues where it may be impactful.

The Antitumoral Effect In Ovo of a New Inclusion Complex from Dimethoxycurcumin with Magnesium and Beta-Cyclodextrin.

Breast cancer is one of the leading causes of death in the female population because of the resistance of cancer cells to many anticancer drugs used. Curcumin has cytotoxic activities against breast cancer cells, although it has limited use due to its poor bioavailability and rapid metabolic elimination. The synthesis of metal complexes of curcumin and curcuminoids is a relevant topic in the search for more active and selective derivatives of these molecular scaffolds. However, solubility and bioavailability are concomitant disadvantages of these types of molecules. To overcome such drawbacks, the preparation of inclusion complexes offers a chemical and pharmacologically safe option for improving the aqueous solubility of organic molecules. Herein, we describe the preparation of the inclusion complex of dimethoxycurcumin magnesium complex (DiMeOC-Mg, (4)) with beta-cyclodextrin (DiMeOC-Mg-BCD, (5)) in the stoichiometric relationship 1:1. This new inclusion complex's solubility in aqueous media phosphate buffer saline (PBS) was improved by a factor of 6x over the free metal complex (4). Furthermore, 5 affects cell metabolic rate, cell morphology, cell migration, induced apoptosis, and downregulation of the matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), and signal transducer and activator of transcription-3 (STAT3) expression levels on MD Anderson metastasis breast-231 cancer (MDA-MB-231) cell lines. Results of an antitumor assay in an in ovo model showed up to 30% inhibition of tumor growth for breast cancer (MDA-MB-231) when using (5) (0.650 mg/kg dose) and 17.29% inhibition with the free homoleptic metal complex (1.5 mg/kg dose, (4)). While the formulation of inclusion complexes from metal complexes of curcuminoids demonstrates its usefulness in improving the solubility and bioavailability of these metallodrugs, the new compound (5) exhibits excellent potential for use as a therapeutic agent in the battle against breast cancer.

PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer.

MCL1 is a member of the BCL2 family of apoptosis regulators, which play a critical role in promoting cancer survival and drug resistance. We previously described PRT1419, a potent, MCL1 inhibitor with anti-tumor efficacy in various solid and hematologic malignancies. To identify novel biomarkers that predict sensitivity to MCL1 inhibition, we conducted a gene essentiality analysis using gene dependency data generated from CRISPR/Cas9 cell viability screens. We observed that clear cell renal cancer (ccRCC) cell lines with damaging PBRM1 mutations displayed a strong dependency on MCL1. PBRM1 (BAF180), is a chromatin-targeting subunit of mammalian pBAF complexes. PBRM1 is frequently altered in various cancers particularly ccRCC with ~40% of tumors harboring damaging PBRM1 alterations. We observed potent inhibition of tumor growth and induction of apoptosis by PRT1419 in various preclinical models of PBRM1-mutant ccRCC but not PBRM1-WT. Depletion of PBRM1 in PBRM1-WT ccRCC cell lines induced sensitivity to PRT1419. Mechanistically, PBRM1 depletion coincided with increased expression of pro-apoptotic factors, priming cells for caspase-mediated apoptosis following MCL1 inhibition. Increased MCL1 activity has been described as a resistance mechanism to Sunitinib and Everolimus, two approved agents for ccRCC. PRT1419 synergized with both agents to potently inhibit tumor growth in PBRM1-loss ccRCC. PRT2527, a potent CDK9 inhibitor which depletes MCL1, was similarly efficacious in monotherapy and in combination with Sunitinib in PBRM1-loss cells. Taken together, these findings suggest PBRM1 loss is associated with MCL1i sensitivity in ccRCC and provide rationale for the evaluation of PRT1419 and PRT2527 for the treatment for PBRM1-deficient ccRCC.

Effects of the tetravanadate [V4O12]4- anion on the structural, magnetic, and biological properties of copper/phenanthroline complexes.

The aim to access linked tetravanadate [V4O12]4- anion with mixed copper(II) complexes, using α-amino acids and phenanthroline-derived ligands, resulted in the formation of four copper(II) complexes [Cu(dmb)(Gly)(OH2)]2[Cu(dmb)(Gly)]2[V4O12]·9H2O (1) [Cu(dmb)(Lys)]2[V4O12]·8H2O (2), [Cu(dmp)2][V4O12]·C2H5OH·11H2O (3), and [Cu(dmp)(Gly)Cl]·2H2O (4), where dmb = 4,4'-dimethioxy-2,2'-bipyridine; Gly = glycine; Lys = lysine; and dmp = 2,9-dimethyl-1,10-phenanthroline. The [V4O12]4- anion is functionalized with mixed copper(II) units in 1 and 2; while in 3, it acts as a counterion of two [Cu(dmp)]2+ units. Compound 4 crystallized as a unit that did not incorporate the vanadium cluster. All compounds present magnetic couplings arising from Cu⋯O/Cu⋯Cu bridges. Stability studies of water-soluble 3 and 4 by UV-Vis spectroscopy in cell culture medium confirmed the robustness of 3, while 4 appears to undergo ligand scrambling over time, resulting partially in the stable species [Cu(dmp)2]+ that was also identified by electrospray ionization mass spectrometry at m/z = 479. The in vitro cytotoxicity activity of 3 and 4 was determined in six cancer cell lines; the healthy cell line COS-7 was also included for comparative purposes. MCF-7 cells were more sensitive to compound 3 with an IC50 value of 12 ± 1.2 nmol. The tested compounds did not show lipid peroxidation in the TBARS assay, ruling out a mechanism of action via reactive oxygen species formation. Both compounds inhibited cell migration at 5 µM in wound-healing assays using MCF-7, PC-3, and SKLU-1 cell lines, opening a new window to study the anti-metastatic effect of mixed vanadium-copper(II) systems.

An Intraoperative Telemedicine Program to Improve Perioperative Quality Measures: The ACTFAST-3 Randomized Clinical Trial.

Importance: Telemedicine for clinical decision support has been adopted in many health care settings, but its utility in improving intraoperative care has not been assessed. Objective: To pilot the implementation of a real-time intraoperative telemedicine decision support program and evaluate whether it reduces postoperative hypothermia and hyperglycemia as well as other quality of care measures. Design, Setting, and Participants: This single-center pilot randomized clinical trial (Anesthesiology Control Tower-Feedback Alerts to Supplement Treatments [ACTFAST-3]) was conducted from April 3, 2017, to June 30, 2019, at a large academic medical center in the US. A total of 26 254 adult surgical patients were randomized to receive either usual intraoperative care (control group; n = 12 980) or usual care augmented by telemedicine decision support (intervention group; n = 13 274). Data were initially analyzed from April 22 to May 19, 2021, with updates in November 2022 and February 2023. Intervention: Patients received either usual care (medical direction from the anesthesia care team) or intraoperative anesthesia care monitored and augmented by decision support from the Anesthesiology Control Tower (ACT), a real-time, live telemedicine intervention. The ACT incorporated remote monitoring of operating rooms by a team of anesthesia clinicians with customized analysis software. The ACT reviewed alerts and electronic health record data to inform recommendations to operating room clinicians. Main Outcomes and Measures: The primary outcomes were avoidance of postoperative hypothermia (defined as the proportion of patients with a final recorded intraoperative core temperature >36 °C) and hyperglycemia (defined as the proportion of patients with diabetes who had a blood glucose level ≤180 mg/dL on arrival to the postanesthesia recovery area). Secondary outcomes included intraoperative hypotension, temperature monitoring, timely antibiotic redosing, intraoperative glucose evaluation and management, neuromuscular blockade documentation, ventilator management, and volatile anesthetic overuse. Results: Among 26 254 participants, 13 393 (51.0%) were female and 20 169 (76.8%) were White, with a median (IQR) age of 60 (47-69) years. There was no treatment effect on avoidance of hyperglycemia (7445 of 8676 patients [85.8%] in the intervention group vs 7559 of 8815 [85.8%] in the control group; rate ratio [RR], 1.00; 95% CI, 0.99-1.01) or hypothermia (7602 of 11 447 patients [66.4%] in the intervention group vs 7783 of 11 672 [66.7.%] in the control group; RR, 1.00; 95% CI, 0.97-1.02). Intraoperative glucose measurement was more common among patients with diabetes in the intervention group (RR, 1.07; 95% CI, 1.01-1.15), but other secondary outcomes were not significantly different. Conclusions and Relevance: In this randomized clinical trial, anesthesia care quality measures did not differ between groups, with high confidence in the findings. These results suggest that the intervention did not affect the targeted care practices. Further streamlining of clinical decision support and workflows may help the intraoperative telemedicine program achieve improvement in targeted clinical measures. Trial Registration: ClinicalTrials.gov Identifier: NCT02830126.

Improving Small-Volume Antibiotic Administration for Surgical Prophylaxis: A Quality Improvement Project.

No clear policy on administration methods for small-volume intravenous antibiotic bags (≤ 100 mL) for surgical prophylaxis lead to wide variation in anesthesia provider practice at a large academic medical center. Administration via secondary tubing is the recommended practice to minimize significant medication losses from dead volumes. An observation of current practice and measurements of dead volumes was followed by an educational intervention on best practices for administration of small-volume antibiotics. Three postintervention cycles were conducted to evaluate change in practice and reductions in dead volumes over a 6-week period. Mean dead volume losses were evaluated using one-way ANOVA. Statistically significant (P = .0012) decreases in dead volume losses were observed postintervention, from 8.48 mL (SD 6.80) to 0.93 mL (SD 1.46). The most common pre- and postintervention tubing sets used were primary tubing (pre) and secondary tubing (post). Mean dead volume losses for these respective tubing sets were 13.45 mL (SD 4.74) and 0.79 mL (SD 1.40) (P < .0001). Preintervention administration methods resulted in incomplete antibiotic administration. Overall, there was a significant reduction in dead volumes of antibiotic by changing practice to secondary tubing. With strong provider acceptance and sustained reduction in medication wastage, this intervention has shown to be a beneficial new practice moving forward.

[Effect of prebiotics, probiotics, and symbiotics on molecular markers of inflammation in obesity.] / Efecto de los prebióticos, probióticos y simbióticos sobre marcadores moleculares de inflamación en la obesidad.

OBJECTIVE: Obesity is an inflammatory disease that is widely distributed in the world's population and is related to the leading causes of death. The use of prebiotics and probiotics can be an alternative treatment against obesity. Although there have been found physiological and biochemical effects of its use, the molecular mechanism remains unclear. The present review analyzed articles that suggested the activation of pathways related to the metabolism of the fatty acids, as well as the impact on anti-inflammatory mechanisms, as part of the mechanism of action of prebiotics and probiotics, to know therefore the possible pathways activated by the prebiotics and probiotics. METHODS: Exhaustive research was made on articles included in the period 2005-2021 related to the effect of prebiotics and probiotics in obesity, inflammatory diseases, and metabolic diseases. Identifying an effect on anti-inflammatory cytokines and PPAR modulation, with a consequent decrease in inflammation and fat degradation. RESULTS: A total of sixty-three articles were obtained, which were classified as basic information on molecular markers of obesity, the effect of prebiotics and probiotics in obesity, and articles related to anti-inflammatory effects and fatty acid metabolism observed in obesity and other inflammatory diseases. CONCLUSIONS: The effect of prebiotics and probiotics in obesity can be linked to the anti-inflammatory mechanism produced, and this effect leads to an increase in the expression of genes related to fatty acid metabolism.

OBJETIVO: La obesidad es una enfermedad ampliamente distribuida en el mundo y resulta una de las principales causas de mortalidad. El uso de prebióticos y probióticos promete una alternativa en el tratamiento de la obesidad, a pesar de los efectos fisiológicos y bioquímicos encontrados, aunque no está aún esclarecido el mecanismo molecular. Por lo que, en la presente revisión, se analizaron artículos que sugerían la activación de vías relacionadas al metabolismo de grasas y azúcares, así como el impacto en los mecanismos antinflamatorios, como parte del mecanismo de acción de los prebióticos y probióticos, con la finalidad de conocer las posibles vías de acción por las cuales se puede obtener el efecto observado. METODOS: Fue realizada una búsqueda exhaustiva de artículos comprendidos en el periodo 2005-2021 relacionados con el efecto de los prebióticos y probióticos en la obesidad y las enfermedades tanto inflamatorias como metabólicas. RESULTADOS: Fueron obtenidos un total de sesenta y tres artículos, los cuales fueron clasificados en: información básica de marcadores moleculares de obesidad; efecto de prebióticos y probióticos en la obesidad; artículos de relación efectos antinflamatorios y metabolismo de grasas observados en la obesidad y otras enfermedades inflamatorias. Se identificó un efecto sobre las citoquinas antinflamatorias y la modulación de los PPAR, con consecuente disminución de la inflamación y degradación de grasas. CONCLUSIONES: El efecto de los prebióticos y probióticos en la obesidad se sugiere está ligado al mecanismo antinflamatorio que producen, lo que a su vez conlleva a un aumento en la expresión de genes relacionados con el metabolismo de grasas.

Efecto de los prebióticos, probióticos y simbióticos sobre marcadores moleculares de inflamación en la obesidad / Effect of prebiotics, probiotics, and symbiotics on molecular markers of inflammation in obesity

FUNDAMENTOS: La obesidad es una enfermedad ampliamente distribuida en el mundo y resulta una de las principales causas de mortalidad. El uso de prebióticos y probióticos promete una alternativa en el tratamiento de la obesidad, a pesar de los efectos fisiológicos y bioquímicos encontrados, aunque no está aún esclarecido el mecanismo molecular. Por lo que, en la presente revisión, se analizaron artículos que sugerían la activación de vías relacionadas al metabolismo de grasas y azúcares, así como el impacto en los mecanismos antinflamatorios, como parte del mecanismo de acción de los prebióticos y probióticos, con la finalidad de conocer las posibles vías de acción por las cuales se puede obtener el efecto observado. MÉTODOS: Fue realizada una búsqueda exhaustiva de artículos comprendidos en el periodo 2005-2021 relacionados con el efecto de los prebióticos y probióticos en la obesidad y las enfermedades tanto inflamatorias como metabólicas. RESULTADOS: Fueron obtenidos un total de sesenta y tres artículos, los cuales fueron clasificados en: información básica de marcadores moleculares de obesidad; efecto de prebióticos y probióticos en la obesidad; artículos de relación efectos antinflamatorios y metabolismo de grasas observados en la obesidad y otras enfermedades inflamatorias. Se identificó un efecto sobre las citoquinas antinflamatorias y la modulación de los PPAR, con consecuente disminución de la inflamación y degradación de grasas. CONCLUSIONES: El efecto de los prebióticos y probióticos en la obesidad se sugiere está ligado al mecanismo antinflamatorio que producen, lo que a su vez conlleva a un aumento en la expresión de genes relacionados con el metabolismo de grasas.(AU)

BACKGROUND: Obesity is an inflammatory disease that is widely distributed in the world’s population and is related to the leading causes of death. The use of prebiotics and probiotics can be an alternative treatment against obesity. Although there have been found physiological and biochemical effects of its use, the molecular mechanism remains unclear. The present review analyzed articles that suggested the activation of pathways related to the metabolism of the fatty acids, as well as the impact on anti-inflammatory mechanisms, as part of the mechanism of action of prebiotics and probiotics, to know therefore the possible pathways activated by the prebiotics and probiotics. METHODS: Exhaustive research was made on articles included in the period 2005-2021 related to the effect of prebiotics and probiotics in obesity, inflammatory diseases, and metabolic diseases. Identifying an effect on anti-inflammatory cytokines and PPAR modulation, with a consequent decrease in inflammation and fat degradation. RESULTS: A total of sixty-three articles were obtained, which were classified as basic information on molecular markers of obesity, the effect of prebiotics and probiotics in obesity, and articles related to anti-inflammatory effects and fatty acid metabolism observed in obesity and other inflammatory diseases. CONCLUSIONS: The effect of prebiotics and probiotics in obesity can be linked to the anti-inflammatory mechanism produced, and this effect leads to an increase in the expression of genes related to fatty acid metabolism.(AU)

The Symbiosis Between Lactobacillus acidophilus and Inulin: Metabolic Benefits in an Obese Murine Model.

Obesity is defined as having an excess of adipose tissue and is associated with the development of diabetes, hypertension, and atherosclerosis, which are the main causes of death worldwide. Research shows that probiotics and prebiotics reduce the metabolic alterations caused by high-fat diets. Therefore, this work evaluated the effect of the incorporation of Lactobacillus acidophilus (probiotic) and inulin (prebiotic) in the diet through obesity markers (biochemical, anthropometric, and molecular markers) in an obese murine model. Four treatments were administered: (1) hypocaloric diet (HD), (2) HD + L. acidophilus, (3) HD + inulin, and (4) DH supplemented with L. acidophilus + inulin for 8 weeks. After treatment, glucose, triglycerides, total cholesterol, HDL-C, and LDL-C in plasma were determined. In addition, the total body weight and adipose tissue were taken to calculate the body mass index. Following RNA extraction from adipose tissue, the expression of PPAR gamma, PPAR alpha, and transforming growth factor beta 1 (TGF1ß) was evaluated by semiquantitative PCR. All treatments showed an improvement in biochemical markers compared to the values of the obese model (p < 0.05). Optimal values for blood glucose (133.2 ± 14.3 mg/dL), triglycerides (71 ± 4.6 mg/dL), total cholesterol (48.9 ± 6 mg/dL), HDL-C (40.9 ± 4.8 mg/dL), and LDL-C (8.4 ± 1.7 mg/dL) were obtained in the mixed treatment. Regarding fat mass index (FMI), prebiotic treatment caused the greatest reduction. On the other hand, mixed treatment increased the gene expression of PPARα and TGF1ß in adipose tissue with DH with L. acidophilus and inulin treatment. This work demonstrates that the use of L. acidophilus and inulin as a complementary treatment is a viable alternative for prevention and action as a complementary treatment for obesity given the reduction in biochemical parameters and anthropometric indices; these reductions were greater than those found in the classic treatment of obesity due to the induction of the expression of genes related to lipid metabolism and anti-inflammatory cytokines, which contribute to reducing the high levels of glucose, triglycerides, and cholesterol caused by obesity.

Effect of electroencephalogram-guided anaesthesia administration on 1-yr mortality: follow-up of a randomised clinical trial.

BACKGROUND: Intraoperative EEG suppression duration has been associated with postoperative delirium and mortality. In a clinical trial testing anaesthesia titration to avoid EEG suppression, the intervention did not decrease the incidence of postoperative delirium, but was associated with reduced 30-day mortality. The present study evaluated whether the EEG-guided anaesthesia intervention was also associated with reduced 1-yr mortality. METHODS: This manuscript reports 1 yr follow-up of subjects from a single-centre RCT, including a post hoc secondary outcome (1-yr mortality) in addition to pre-specified secondary outcomes. The trial included subjects aged 60 yr or older undergoing surgery with general anaesthesia between January 2015 and May 2018. Patients were randomised to receive EEG-guided anaesthesia or usual care. The previously reported primary outcome was postoperative delirium. The outcome of the current study was all-cause 1-yr mortality. RESULTS: Of the 1232 subjects enrolled, 614 subjects were randomised to EEG-guided anaesthesia and 618 subjects to usual care. One-year mortality was 57/591 (9.6%) in the guided group and 62/601 (10.3%) in the usual-care group. No significant difference in mortality was observed (adjusted absolute risk difference, -0.7%; 99.5% confidence interval, -5.8% to 4.3%; P=0.68). CONCLUSIONS: An EEG-guided anaesthesia intervention aiming to decrease duration of EEG suppression during surgery did not significantly decrease 1-yr mortality. These findings, in the context of other studies, do not provide supportive evidence for EEG-guided anaesthesia to prevent intermediate term postoperative death. CLINICAL TRIAL REGISTRATION: NCT02241655.

Preoperative Cognitive Abnormality, Intraoperative Electroencephalogram Suppression, and Postoperative Delirium: A Mediation Analysis.

BACKGROUND: Postoperative delirium is a common complication that hinders recovery after surgery. Intraoperative electroencephalogram suppression has been linked to postoperative delirium, but it is unknown if this relationship is causal or if electroencephalogram suppression is merely a marker of underlying cognitive abnormalities. The hypothesis of this study was that intraoperative electroencephalogram suppression mediates a nonzero portion of the effect between preoperative abnormal cognition and postoperative delirium. METHODS: This is a prespecified secondary analysis of the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized trial, which enrolled patients age 60 yr or older undergoing surgery with general anesthesia at a single academic medical center between January 2015 and May 2018. Patients were randomized to electroencephalogram-guided anesthesia or usual care. Preoperative abnormal cognition was defined as a composite of previous delirium, Short Blessed Test cognitive score greater than 4 points, or Eight Item Interview to Differentiate Aging and Dementia score greater than 1 point. Duration of intraoperative electroencephalogram suppression was defined as number of minutes with suppression ratio greater than 1%. Postoperative delirium was detected via Confusion Assessment Method or chart review on postoperative days 1 to 5. RESULTS: Among 1,113 patients, 430 patients showed evidence of preoperative abnormal cognition. These patients had an increased incidence of postoperative delirium (151 of 430 [35%] vs.123 of 683 [18%], P < 0.001). Of this 17.2% total effect size (99.5% CI, 9.3 to 25.1%), an absolute 2.4% (99.5% CI, 0.6 to 4.8%) was an indirect effect mediated by electroencephalogram suppression, while an absolute 14.8% (99.5% CI, 7.2 to 22.5%) was a direct effect of preoperative abnormal cognition. Randomization to electroencephalogram-guided anesthesia did not change the mediated effect size (P = 0.078 for moderation). CONCLUSIONS: A small portion of the total effect of preoperative abnormal cognition on postoperative delirium was mediated by electroencephalogram suppression. Study precision was too low to determine if the intervention changed the mediated effect.

Human indole(ethyl)amine-N-methyltransferase (hINMT) catalyzed methylation of tryptamine, dimethylsulfide and dimethylselenide is enhanced under reducing conditions - A comparison between 254C and 254F, two common hINMT variants.

Phenylalanine and cysteine comprise common miss-sense variants (i.e., single nucleotide polymorphisms [SNPs]) at amino acid position 254 of the human indole(ethyl)amine-N-methyltransferase (hINMT). The phenylalanine variant, which occurs in linkage disequilibrium with two 3' UTR SNPs, has been reported to associate with elevated urine levels of trimethylselenonium (TMSe), the Se-methylated product of volatile dimethylselenide. hINMT allozymes expressing either cysteine (254C) or phenylalanine (254F) at position 254 were compared for enzyme activity (i.e., Km and Vmax) towards the INMT substrates tryptamine, dimethylsulfide (DMS) and dimethylselenide (DMSe) in vitro. The SNP 254C had a higher Vmax for DMS and tryptamine in the presence of reducing agent than in its absence. Conversely, Vmax for 254F was insensitive to the presence or absence of reducing agent for these substrates. SNP 254F showed a lower Km for tryptamine in the absence of reducing agent than 254C. No statistically significant difference in Vmax or Km was observed between 254C and 254F allozymes in the presence of reducing agent for DMSe, The Km values for DMSe methylation were about 10-fold (254C) or 6-fold (254F) more favorable than for tryptamine methylation with reducing agent present. These findings indicated that: 1) That phenylalanine at position 254 renders hINMT methylation of substrates DMS and tryptamine insensitive to a non reducing environment. 2) That human INMT harbors significant thioether-S-methyltransferase (TEMT) activity with a higher affinity for DMSe than tryptamine, 3) The reduction of a 44C/254C disulfide bond in hINMT that increases Vmax is proposed.

Effect of Electroencephalography-Guided Anesthetic Administration on Postoperative Delirium Among Older Adults Undergoing Major Surgery: The ENGAGES Randomized Clinical Trial.

Importance: Intraoperative electroencephalogram (EEG) waveform suppression, often suggesting excessive general anesthesia, has been associated with postoperative delirium. Objective: To assess whether EEG-guided anesthetic administration decreases the incidence of postoperative delirium. Design, Setting, and Participants: Randomized clinical trial of 1232 adults aged 60 years and older undergoing major surgery and receiving general anesthesia at Barnes-Jewish Hospital in St Louis. Recruitment was from January 2015 to May 2018, with follow-up until July 2018. Interventions: Patients were randomized 1:1 (stratified by cardiac vs noncardiac surgery and positive vs negative recent fall history) to receive EEG-guided anesthetic administration (n = 614) or usual anesthetic care (n = 618). Main Outcomes and Measures: The primary outcome was incident delirium during postoperative days 1 through 5. Intraoperative measures included anesthetic concentration, EEG suppression, and hypotension. Adverse events included undesirable intraoperative movement, intraoperative awareness with recall, postoperative nausea and vomiting, medical complications, and death. Results: Of the 1232 randomized patients (median age, 69 years [range, 60 to 95]; 563 women [45.7%]), 1213 (98.5%) were assessed for the primary outcome. Delirium during postoperative days 1 to 5 occurred in 157 of 604 patients (26.0%) in the guided group and 140 of 609 patients (23.0%) in the usual care group (difference, 3.0% [95% CI, -2.0% to 8.0%]; P = .22). Median end-tidal volatile anesthetic concentration was significantly lower in the guided group than the usual care group (0.69 vs 0.80 minimum alveolar concentration; difference, -0.11 [95% CI, -0.13 to -0.10), and median cumulative time with EEG suppression was significantly less (7 vs 13 minutes; difference, -6.0 [95% CI, -9.9 to -2.1]). There was no significant difference between groups in the median cumulative time with mean arterial pressure below 60 mm Hg (7 vs 7 minutes; difference, 0.0 [95% CI, -1.7 to 1.7]). Undesirable movement occurred in 137 patients (22.3%) in the guided and 95 (15.4%) in the usual care group. No patients reported intraoperative awareness. Postoperative nausea and vomiting was reported in 48 patients (7.8%) in the guided and 55 patients (8.9%) in the usual care group. Serious adverse events were reported in 124 patients (20.2%) in the guided and 130 (21.0%) in the usual care group. Within 30 days of surgery, 4 patients (0.65%) in the guided group and 19 (3.07%) in the usual care group died. Conclusions and Relevance: Among older adults undergoing major surgery, EEG-guided anesthetic administration, compared with usual care, did not decrease the incidence of postoperative delirium. This finding does not support the use of EEG-guided anesthetic administration for this indication. Trial Registration: ClinicalTrials.gov Identifier: NCT02241655.

Protocol for the Effectiveness of an Anesthesiology Control Tower System in Improving Perioperative Quality Metrics and Clinical Outcomes: the TECTONICS randomized, pragmatic trial.

Introduction: Perioperative morbidity is a public health priority, and surgical volume is increasing rapidly. With advances in technology, there is an opportunity to research the utility of a telemedicine-based control center for anesthesia clinicians that assess risk, diagnoses negative patient trajectories, and implements evidence-based practices. Objectives: The primary objective of this trial is to determine whether an anesthesiology control tower (ACT) prevents clinically relevant adverse postoperative outcomes including 30-day mortality, delirium, respiratory failure, and acute kidney injury. Secondary objectives are to determine whether the ACT improves perioperative quality of care metrics including management of temperature, mean arterial pressure, mean airway pressure with mechanical ventilation, blood glucose, anesthetic concentration, antibiotic redosing, and efficient fresh gas flow. Methods and analysis: We are conducting a single center, randomized, controlled, phase 3 pragmatic clinical trial. A total of 58 operating rooms are randomized daily to receive support from the ACT or not. All adults (eighteen years and older) undergoing surgical procedures in these operating rooms are included and followed until 30 days after their surgery. Clinicians in operating rooms randomized to ACT support receive decision support from clinicians in the ACT. In operating rooms randomized to no intervention, the current standard of anesthesia care is delivered. The intention-to-treat principle will be followed for all analyses. Differences between groups will be presented with 99% confidence intervals; p-values <0.005 will be reported as providing compelling evidence, and p-values between 0.05 and 0.005 will be reported as providing suggestive evidence. Registration: TECTONICS is registered on ClinicalTrials.gov, NCT03923699; registered on 23 April 2019.

Achieving Milestones as a Prerequisite for Proceeding With a Clinical Trial.

BACKGROUND: Although the National Institutes of Health (NIH) invests $30 billion in research annually, many funded studies fail to generate results that can inform practice. The National Institutes of Health introduced a phased funding mechanism as one potential solution. Study-specific milestones are established for an initial pilot phase. We assess the utility of this phased approach through the ongoing Electroencephalography (EEG) Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) pragmatic clinical trial. The hypothesis of the trial is that EEG guidance of general anesthesia, through prevention of EEG suppression, can decrease postoperative delirium and its downstream negative sequelae. METHODS: In collaboration with study stakeholders, we identified critical milestones for the ENGAGES study, with themes common to many clinical trials. These themes include: regulatory tasks; enrollment targets; feasibility and impact of study intervention; primary outcome incidence; measurement reliability of primary outcome; and follow-up. Progress in achieving the milestones was assessed at regular intervals during the pilot phase by ENGAGES investigators, a National Institute on Aging program officer, and a nonpartisan research organization (Westat). RESULTS: Regulatory tasks, including institutional review board approval, infrastructure establishment, and trial registration, were completed on schedule. A total of 117 patients were randomized, exceeding the target by 51. The EEG-guided protocol was successfully implemented, and a relevant effect on anesthetic practice was demonstrated (decrease in median age-adjusted minimum alveolar anesthetic concentration from 0.93 to 0.78 [P < .001] and increase in median proportion of zero EEG suppression time from 87% to 94% [P < .01]). Nearly all patients (115 of 117, 98.3%) were assessed for delirium using the Confusion Assessment Method, and the delirium incidence was similar (28.1%; 95% CI, 20%-37%) to the estimate (25%) used for the sample size calculation. Good interrater reliability of delirium assessment was demonstrated (κ = 0.94 [95% CI, 0.86-1]). Finally, 1-month follow-up vital status data were obtained for 96.9% of patients, with 85.7% of patients completing at least 1 survey. CONCLUSIONS: With the ENGAGES trial, we demonstrated that key milestones can be identified and progressively assessed during a pilot phase. Success in attaining appropriate milestones hypothetically predicts meaningful completion of a study, and can provide justification for proceeding beyond a pilot phase. The impact of this phased approach on return on investment and scientific yield requires additional study.

Draft Whole-Genome Assemblies of Drug-Resistant Clinical Isolates of Klebsiella pneumoniae from the Philippines.

Here, we report the draft assemblies of 11 clinical isolates of Klebsiella pneumoniae that are resistant to cephalosporins, carbapenems, and/or colistin. The assemblies ranged from 5.37 Mbp to 5.70 Mbp in size. Several plasmid sequences were present, and resistance genes spanning multiple classes of antibiotics were predicted.

The Sigma-1 Receptor-A Therapeutic Target for the Treatment of ALS?

The membrane bound 223 amino acid Sigma-1 Receptor (S1R) serves as a molecular chaperone and functional regulator of many signaling proteins. Spinal cord motor neuron activation occurs, in part, via large ventral horn cholinergic synapses called C-boutons/C-terminals. Chronic excitation of motor neurons and alterations in C-terminals has been associated with Amyotrophic Lateral Sclerosis (ALS ). The S1R has an important role in regulating motor neuron function. High levels of the S1R are localized in postsynaptic endoplasmic reticulum (ER) subsurface cisternae within 10-20 nm of the plasma membrane that contain muscarinic type 2 acetylcholine receptors (M2AChR), calcium activated potassium channels (Kv2.1) and slow potassium (SK) channels. An increase in action potentials in the S1R KO mouse motor neurons indicates a critical role for the S1R as a "brake" on motor neuron function possibly via calcium dependent hyperpolarization mechanisms involving the aforementioned potassium channels. The longevity of SOD-1/S1R KO ALS mice is significantly reduced compared to SOD-1/WT ALS controls. The S1R colocalizes in C-terminals with Indole(ethyl)amine-N-methyl transferase (INMT ), the enzyme that produces the S1R agonist , N,N'- dimethyltryptamine (DMT). INMT methylation can additionally neutralize endogenous toxic sulfur and selenium derivatives thus providing functional synergism with DMT to reduce oxidative stress in motor neurons . Small molecule activation of the S1R and INMT thus provides a possible therapeutic strategy to treat ALS .

Emergence of Klebsiella pneumoniae ST273 Carrying blaNDM-7 and ST656 Carrying blaNDM-1 in Manila, Philippines.

We sought to determine the epidemiology of carbapenem-resistant Enterobacteriaceae and to investigate the emergence of carbapenem-resistant Klebsiella pneumoniae in two teaching hospitals in Manila, Philippines. We screened 364 Enterobacteriaceae for carbapenem resistance between 2012 and 2013 and detected four carbapenem-resistant K. pneumoniae isolates from three different patients. We used whole genome sequencing to determine the antibiotic resistance profiles and confirmed the presence of carbapenemase genes by multiplex PCR. We used multilocus sequence typing and PCR-based replicon typing to genetically characterize the carbapenem-resistant isolates. The carbapenemase gene blaNDM was detected in K. pneumoniae isolates from two patients. The first patient had ventilator-associated pneumonia and lumbar shunt infection from K. pneumoniae ST273 carrying blaNDM-7. The second patient had asymptomatic genitourinary colonization with K. pneumoniae ST656 carrying blaNDM-1. The third patient had a gluteal abscess with K. pneumoniae ST1 that did not carry a carbapenemase gene, but did carry blaDHA-1, blaOXA-1, and blaSHV-1. In this study, we report the first cases of blaNDM-carrying pathogens in the Philippines and add to the growing evidence of the worldwide spread of ST273 and NDM-7, a more efficient carbapenem hydrolyzer than NDM-1.

Hybrid Vibrio cholerae El Tor lacking SXT identified as the cause of a cholera outbreak in the Philippines.

UNLABELLED: Cholera continues to be a global threat, with high rates of morbidity and mortality. In 2011, a cholera outbreak occurred in Palawan, Philippines, affecting more than 500 people, and 20 individuals died. Vibrio cholerae O1 was confirmed as the etiological agent. Source attribution is critical in cholera outbreaks for proper management of the disease, as well as to control spread. In this study, three V. cholerae O1 isolates from a Philippines cholera outbreak were sequenced and their genomes analyzed to determine phylogenetic relatedness to V. cholerae O1 isolates from recent outbreaks of cholera elsewhere. The Philippines V. cholerae O1 isolates were determined to be V. cholerae O1 hybrid El Tor belonging to the seventh-pandemic clade. They clustered tightly, forming a monophyletic clade closely related to V. cholerae O1 hybrid El Tor from Asia and Africa. The isolates possess a unique multilocus variable-number tandem repeat analysis (MLVA) genotype (12-7-9-18-25 and 12-7-10-14-21) and lack SXT. In addition, they possess a novel 15-kb genomic island (GI-119) containing a predicted type I restriction-modification system. The CTXΦ-RS1 array of the Philippines isolates was similar to that of V. cholerae O1 MG116926, a hybrid El Tor strain isolated in Bangladesh in 1991. Overall, the data indicate that the Philippines V. cholerae O1 isolates are unique, differing from recent V. cholerae O1 isolates from Asia, Africa, and Haiti. Furthermore, the results of this study support the hypothesis that the Philippines isolates of V. cholerae O1 are indigenous and exist locally in the aquatic ecosystem of the Philippines. IMPORTANCE: Genetic characterization and phylogenomics analysis of outbreak strains have proven to be critical for probing clonal relatedness to strains isolated in different geographical regions and over time. Recently, extensive genetic analyses of V. cholerae O1 strains isolated in different countries have been done. However, genome sequences of V. cholerae O1 isolates from the Philippines have not been available for epidemiological investigation. In this study, molecular typing and phylogenetic analysis of Vibrio cholerae isolated from both clinical and environmental samples in 2011 confirmed unique genetic features of the Philippines isolates, which are helpful to understand the global epidemiology of cholera.

Postoperative delirium in a substudy of cardiothoracic surgical patients in the BAG-RECALL clinical trial.

BACKGROUND: Postoperative delirium in the intensive care unit (ICU) is a frequent complication after cardiac or thoracic surgery and is associated with increased morbidity and mortality. METHODS: In this single-center substudy of the BAG-RECALL trial (NCT00682825), we screened patients after cardiac or thoracic surgery in the ICU twice daily for delirium using the Confusion Assessment Method for the ICU. The primary outcome was the incidence of delirium in patients who had been randomized to intraoperative Bispectral Index (BIS)-guided and end-tidal anesthetic concentration-guided depth of anesthesia protocols. As a secondary analysis, a Bayesian stochastic search variable selection strategy was used to rank a field of candidate risk factors for delirium, followed by binary logistic regression. RESULTS: Of 310 patients assessed, 28 of 149 (18.8%) in the BIS group and 45 of 161 (28.0%) in the end-tidal anesthetic concentration group developed postoperative delirium in the ICU (odds ratio 0.60, 95% confidence interval, 0.35-1.02, P= 0.058). Low average volatile anesthetic dose, intraoperative transfusion, ASA physical status, and European System for Cardiac Operative Risk Evaluation were identified as independent predictors of delirium. CONCLUSIONS: A larger randomized study should determine whether brain monitoring with BIS or an alternative method decreases delirium after cardiac or thoracic surgery. The association between low anesthetic concentration and delirium is a surprising finding and could reflect that patients with poor health are both more sensitive to the effects of volatile anesthetic drugs and are also more likely to develop postoperative delirium. Investigation of candidate methods to prevent delirium should be prioritized in view of the established association between postoperative delirium and adverse patient outcomes.