Formation of Alternating Surfactant-Enriched and Surfactant-Depleted Phases in the Taylor Cone of a Nanoelectrospray.

The electrospray ionization of highly conductive solutions containing Triton X-100, a nonionic surfactant, is found to induce alternating periods of surfactant enrichment and depletion when the concentration of the surfactant is near the critical micelle concentration (CMC) and when the flow rate is on the order of 10 nL/min. Analyzing the surfactant-protein mixture shows that the protein is partially denatured during the surfactant enrichment. The measurement of the phospholipid and oligosaccharide mixture prepared in the surfactant solution shows that the ion signal of the lipid is in phase with, and the hydrophilic oligosaccharide is out of phase with the surfactant signal. The results suggest that this novel phenomenon can be exploited for in situ separation of compounds in ESI-MS. Besides the ion signal, the condition of the alternating phase is also reflected in the spray current and Taylor cone's apex angle. The phase separation is likely related to the formation of a micelle in the Taylor cone and can be selectively triggered by tuning the flow rate with emitter voltage for an on-demand application.

Tuning the Internal Energy of Ions Produced by Atmospheric and High-Pressure Electrospray by Modulating the Gas Throughput into the First Vacuum Stage.

In a high-pressure environment, electrospray ionization (ESI) can be achieved without discharge between the emitter and the counter electrode, thus enabling the generation of gas-phase ions from liquid with high surface tension, such as pure water, which requires a high onset voltage for stable ESI. In this study, the ion dissociation during the transferring of ions/charged droplets from a superatmospheric pressure environment to vacuum has been systematically investigated using benzyl ammonium thermometer ions. The ion source pressure did not affect the internal energy distribution of ions, whereas the gas throughput into the first vacuum stage clearly influences the internal energy distribution of the ions. The increase in the gas throughput increased the density of molecules/atoms presented in ion transfer/focusing electrodes located in the first vacuum stage. As a result, the mean free path of ions in the first vacuum stage decreases, and the energy of ions decreases by decreasing the kinetic energy involved in each collision between ions and residue gas. The gas throughput into the first vacuum stage is found to describe the internal energy distribution of ions associated with the local conditions more quantitatively instead of using the measured pressure of the vacuum stage, which is different from the effective local pressure. This study also demonstrated the controlled dissociation of ions using the ion transfer settings of the instrument in combination with ion inlet tubes of different sizes.

NCP, a dual kappa and mu opioid receptor agonist, is a potent analgesic against inflammatory pain without reinforcing or aversive properties.

While agonists of mu (MOR) and kappa (KOR) opioid receptors have analgesic effects, they produce euphoria and dysphoria, respectively. Other side effects include respiratory depression and addiction for MOR agonists and sedation for KOR agonists. We reported that 17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6ß-{[4'-(2'-cyanopyridyl)]carboxamido}cmorphinan (NCP) displayed potent KOR full agonist and MOR partial agonist activities (58%) with 6.5x KOR-over-MOR selectivity in vitro Herein, we characterized pharmacological effects of NCP in rodents. In mice, NCP exerted analgesic effects against inflammatory pain in both the formalin test and the acetic acid writhing test, with A50 values of 47.6 and 14.4 microg/kg (s.c.), respectively. The analgesic effects in the acetic acid writhing test were mediated by the KOR. NCP at doses much higher than those effective in reducing inflammatory pain did not produce antinociception in the hot plate and tail flick tests, inhibit compound 48/80-induced scratching, cause conditioned place aversion (CPA) or preference, impair rotarod performance, inhibit locomotor activity, cause respiratory depression, or precipitate morphine withdrawal. However, NCP (10~100 microg/kg) inhibited gastrointestinal transit with a maximum of ~40% inhibition. In MOR knockout mice, NCP caused CPA, demonstrating that its lack of CPA is due to combined actions on the MOR and KOR. Following s.c. injection, NCP penetrated into the mouse brain. In rats trained to self-administer heroin, NCP (1~320 microg/kg/infusion) did not function as a reinforcer. Thus, NCP produces potent analgesic effects via KOR without side effects except constipation. Therefore, dual full KOR/partial MOR agonists with moderate KOR-over-MOR selectivity may be promising as non-addictive analgesics for inflammatory pain. Significance Statement Developing non-addictive analgesics is crucial for reducing opioid overdose deaths, minimizing drug misuse, and promoting safer pain management practices. Herein, pharmacology of a potential non-addictive analgesic, NCP, is reported. NCP has full KOR agonist / partial MOR agonist activities with a 6.5 x selectivity for KOR over MOR. Unlike MOR agonists, analgesic doses of NCP do not lead to self-administration or respiratory depression. Furthermore, NCP does not produce aversion, hypolocomotion, or motor incoordination, side effects typically associated with KOR activation.

Oenothein B from Eugenia uniflora leaves exerts pro-angiogenic effects by increasing VEGF and TNF-α levels.

Oenothein B (OeB), a dimeric ellagitannin with a macrocyclic structure, is reported to have beneficial effects, including antioxidant, antitumor, antiviral, and antimutagenic effects, on human health. Despite the remarkable properties of OeB, its role in neovascularization process has not yet been evaluated. Thus, this study aimed to evaluate the angiogenic activity of OeB using a chorioallantoic membrane (CAM) assay at different concentrations (6.25, 12.5, and 25 µg/µL), employing digital imaging and histological analysis. Furthermore, to elucidate the mechanisms by which OeB influences angiogenesis, we assessed the levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) in CAM using immunohistochemical analysis. All concentrations of OeB significantly increased (p < 0.05) the percentage of vascularization as well as the levels of all the angiogenesis-associated parameters evaluated, indicating the pronounced pro-angiogenic activity of OeB. Our results showed that inflammation was one of the most relevant phenomena observed in CAM histology along with angiogenesis. In addition, a significant increase in VEGF and TNF-α levels was observed in all the CAMs compared to the negative control (p < 0.05). We suggest that OeB may induce the presence of inflammatory cells in CAM, leading to increased VEGF and TNF-α levels that result in the induction of angiogenesis. Therefore, OeB presents a favorable profile that could be further explored for the development of drugs for pro-angiogenic and tissue repair therapies.

Pedunculagin and tellimagrandin-I stimulate inflammation and angiogenesis and upregulate vascular endothelial growth factor and tumor necrosis factor-alpha in vivo.

Pedunculagin (PD) and tellimagrandin-I (TL), isolated from Myrciaria cauliflora seeds and Eucaliptus microcorys leaves, respectively, have attracted great attention owing to their relevant biological activities, such as antitumor, antioxidant, and hepatoprotective activities. This study investigated the angiogenic potential of PD and TL using a chick embryo chorioallantoic membrane (CAM) assay. Using the CAM assay, our results showed that both PD and TL promoted a significant increase in the number and caliber of blood vessels, the thickness of the CAM, and the presence of fibroblasts and inflammatory cells. Moreover, an increase of tumor necrosis factor-α and vascular endothelial growth factor was observed in the CAM treated with PD and TL, indicating the induction of angiogenic factors. Thus, the remarkable profile of PD and TL in inducing angiogenesis opens up new perspectives for their potential utilization in different therapeutic approaches involving neovascularization.

Automated sample preparation for electrospray ionization mass spectrometry based on CLOCK-controlled autonomous centrifugal microfluidics.

We report a centrifugal microfluidic device that automatically performs sample preparation under steady-state rotation for clinical applications using mass spectrometry. The autonomous microfluidic device was designed for the control of liquid operation on centrifugal hydrokinetics (CLOCK) paradigm. The reported device was highly stable, with less than 7% variation with respect to the time of each unit operation (sample extraction, mixing, and supernatant extraction) in the preparation process. An agitation mechanism with bubbling was used to mix the sample and organic solvent in this device. We confirmed that the device effectively removed the protein aggregates from the sample, and the performance was comparable to those of conventional manual sample preparation procedures that use high-speed centrifugation. In addition, probe electrospray ionization mass spectrometry (PESI-MS) was performed to compare the device-treated and manually treated samples. The obtained PESI-MS spectra were analyzed by partial least squares discriminant analysis, and the preparation capability of the device was found to be equivalent to that of the conventional method.

The role of race/ethnicity and age in clinical trial knowledge among patients with gynecologic malignancy.

PURPOSE: To identify whether race/ethnicity plays a role in knowledge of clinical trials among patients with a gynecologic malignancy. PATIENTS AND METHODS: A cross-sectional survey was conducted at a tertiary medical center. Participants were adults (≥18 years old), with gynecologic malignancy, and literate in English, Spanish or Chinese. Participants completed a 9-item clinical trial knowledge assessment. Demographic characteristics were summarized using descriptive statistics. A multivariable model was employed to evaluate the relationship between race/ethnicity and clinical trial knowledge. RESULTS: 245 patients were approached, 25 (10.2%) declined. Among participants, 108 (50.2%) were white, and 107 (49.8%) were people of color. Significant differences were noted for age, education, birthplace, and income; no difference was observed for cancer type or stage. The median number of correct answers for the knowledge assessment was seven. 67 (62%) white vs 26 (24.3%) people of color had an above average clinical trial knowledge score (p < 0.001). Multivariable analysis showed white participants were 2.7 times more likely to have an above average clinical trial knowledge score. White participants overall utilized more resources. Elder adults (≥65 years old) had higher knowledge of clinical trials compared to non-elder adults (<65 years old); however, these findings were not significant. CONCLUSION: This study observed significant differences in clinical trial knowledge between white and people of color diagnosed with a gynecologic malignancy. White patients utilize more informational resources compared to people of color. Further studies need to develop resources and outreach mechanisms that will increase access and diversity in clinical trial participation.

Effects of anions on the electrospray ionization of proteins in strong acids.

The effect of anions on the positive electrospray ionization (ESI) of proteins in different strong acids with varying pH values from 3 to 1 is studied using high-pressure ESI. Reducing the pH from ∼2 to 1 caused a drastic shift in charge state from a high-charge-state distribution (HCSD) to a narrow low-charge-state distribution (LCSD). The shift in charge state was consistent with the circular dichroism result that showed a conformational change due to the "acid-induced folding" of proteins from an unfolding state to a compact molten globule state. Acids of different anions produced noticeable differences in the average charge for HCSD and LCSD. For HCSD, the average charge was lower than the value typically observed using formic and acetic acids. As for LCSD, the average charge was lower than the "native" charge. The high abundance of acid anion that induces the protein compaction was believed to play a role in charge reduction. The effectiveness of anions to "refold" a highly unfolded protein to a compact state and the propensity to reduce the charge of HCSD for proteins appeared to follow the selectivity series of anions towards the stationary phase in ion chromatography. However, the propensity of anions to reduce the charge for LCSD follows quite an opposite trend. The presence of ammonium salt in the acidic solution was found to increase the charge of LCSD. The simple mass spectrum with a narrow distribution of charge state obtained with perchloric acid at pH 1 was demonstrated to facilitate the counting of basic sites.

Differences in Acute Postoperative Opioid Use by English Proficiency, Race, and Ethnicity After Total Knee and Hip Arthroplasty.

BACKGROUND: There is increasing interest in documenting disparities in pain management for racial and ethnic minorities and patients with language barriers. Previous studies have found differential prescription patterns of opioids for racial and ethnic minority group and patients having limited English proficiency (LEP) after arthroplasty. However, there is a knowledge gap regarding how the intersection of these sociodemographic factors is associated with immediate postoperative pain management. This study aimed to explore language and racial-ethnic disparities in short-term opioid utilization after total hip and knee arthroplasty. METHODS: We conducted a retrospective cohort study of adult patients who underwent total hip and knee arthroplasty from 2015 to 2019 at an urban medical center. The primary predictor variables included LEP status and racial-ethnic category, and the primary outcome variables were oral morphine equivalents (OMEs) during 2 distinct postoperative periods: the first 12 hours after surgery and from the end of surgery to the end of postoperative day (POD) 1. Patient characteristics and perioperative metrics were described by language status, race, and ethnicity using nonparametric tests, as appropriate. We performed an adjusted generalized estimating equation to assess the total effect of the intersection of LEP and racial-ethnic categories on short-term postoperative opioid use in mean ratios (MRs). RESULTS: This study included a total of 4090 observations, in which 7.9% (323) patients had LEP. Patients reported various racial-ethnic categories, with 72.7% (2975) non-Hispanic White, and minority groups including non-Hispanic Asian and Pacific Islander (AAPI), Hispanic/Latinx, non-Hispanic Black/African American, and Others. Patients self-identifying as non-Hispanic AAPI received fewer OME regardless of LEP status during the first 12 hours postoperatively (MR for English proficient [EP], 0.12 [95% confidence interval, CI, 0.08-0.18]; MR for LEP, 0.22 [95% CI, 0.13-0.37]) and from end of surgery to the end of POD 1 (MR for EP, 0.24 [95% CI, 0.16-0.37]; MR for LEP, 0.42, [95% CI, 0.24-0.73]) than EP non-Hispanic White. Hispanic/Latinx patients with LEP received lower amounts of OME during the first postoperative 12 hours (MR, 0.29; 95% CI, 0.17-0.53) and from end of surgery to the end of POD 1 (MR, 0.42; 95% CI 0.23-0.79) than EP non-Hispanic White. Furthermore, within the non-Hispanic White group, those with LEP received fewer OME within the first 12 hours (MR, 0.33; 95% CI, 0.13-0.83). CONCLUSIONS: We identified an association between LEP, racial-ethnic identity, and short-term postoperative OME utilization after total knee and hip arthroplasty. The observed differences in opioid utilization imply there may be language and racial-ethnic disparities in acute pain management and perioperative care.

Evaluation of infliximab-induced genotoxicity and possible action on BCL-2 and P53 genes.

Although the last pandemic created an urgency for development of vaccines, there was a continuous and concerted effort to search for therapeutic medications among existing drugs with different indications. One of the medications of interest that underwent this change was infliximab (IFM). This drug is used as an anti-inflammatory, predominantly in patients with Crohn 's disease, colitis ulcerative, and rheumatoid arthritis. In addition to these patients, individuals infected with Coronavirus Disease (COVID-19) were administered this chimeric monoclonal antibody (IMF) to act as an immunomodulator for patients in the absence of comprehensive research. Consequently, the present study aimed to examine the genotoxic effects attributed to IFM treatment employing different assays in vivo using mouse Mus musculus. Therefore, IFM was found to induce genotoxic effects as evidenced by the comet assay but did not demonstrate genotoxic potential utilizing mouse bone marrow MN test. The results of evaluating the expression of the P53 and BCL-2 genes using RT-qPCR showed stimulation of expression of these genes at 24 hr followed by a decline at 48 hr. Although the comet assay provided positive results, it is noteworthy that based upon negative findings in the micronucleus test, the data did not demonstrate significant changes in the genetic material that might affect the therapeutic use of IFM. The stimulation of expression of P53 and BCL-2 genes at 24 hr followed by a decline at 48 hr suggest a transient, if any, effect on genetic material. However, there is still a need for more research to more comprehensively understand the genotoxic profile of this medication.

Tellimagrandin-I and camptothin a exhibit chemopreventive effects in Salmonella enterica serovar Typhimurium strains and human lymphocytes.

Tellimagrandin-I (TL) and camptothin A (CA) are ellagitannins widely found in diverse plant species. Numerous studies demonstrated their significant biological activities, which include antitumor, antioxidant, and hepatoprotective properties. Despite this protective profile, the effects of TL and CA on DNA have not been comprehensively investigated. Thus, the aim of this study was to determine the mutagenic and antimutagenic effects attributed to TL and CA exposure on Salmonella enterica serovar Typhimurium strains using the Ames test. In addition, the cytotoxic and genotoxic effects were examined on human lymphocytes, employing both trypan blue exclusion and CometChip assay. The antigenotoxic effect was determined following TL and CA exposure in the presence of co-treatment with doxorubicin (DXR). Our results from the Ames test indicated that TL or CA did not display marked mutagenic activity. However, TL or CA demonstrated an ability to protect DNA against the damaging effects of the mutagens 4-nitroquinoline-1-oxide and sodium azide, thereby exhibiting antimutagenic properties. In relation to human lymphocytes, TL or CA did not induce significant cytotoxic or genotoxic actions on these cells. Further, these ellagitannins exhibited an ability to protect DNA from damage induced by DOX during co-treatment, indicating their potential beneficial usefulness as antigenotoxic agents. In conclusion, the protective effects of TL or CA against mutagens, coupled with their absence of genotoxic and cytotoxic effects on human lymphocytes, emphasize their potential therapeutic value in chemopreventive strategies.

IL-10 Enhances the Inhibitory Effect of Adipose-Derived Stromal Cells on Insulin Resistance/Liver Gluconeogenesis by Treg Cell Induction.

The modulation of cellular phenotypes within adipose tissue provides a potential means for therapeutic intervention for diabetes. Endogenous interleukin-10 (IL-10) protects against diet-induced insulin resistance. We examined the effects and mechanisms of action of IL-10-treated adipose-derived stromal cells on diabetes-induced insulin resistance and liver gluconeogenesis. We harvested stromal vascular fractions (SVFs) from the adipose tissue of diabetic (Leprdb/db) mice and treated them with IL-10 in vitro. SVFs treated with 10 or 100 ng of IL-10 were injected into the inguinal adipose tissue of Leprdb/db mice. IL-10 treatment suppressed the mRNA expression of IL-6, IL-33, CCL2, TNF-α, and IL-1ß. Additionally, it suppressed the protein expression of IL-6, pmTOR, pJNK, and pNF-κB but enhanced Foxp3 mRNA expression in SVFs from diabetic mice. Meanwhile, IL-10 treatment repressed CCL2 and PDGFRα expression in adipose tissue macrophages (ATMs) and IL-6 expression in non-ATMs but increased the Foxp3 and IL-10 mRNA expression of ATMs from diabetic mice. Injection of IL-10-treated SVFs decreased the IL-6, IL-33, CCL2, IL-1ß, and CCL2 but enhanced the Foxp3 and IL-10 mRNA expression of adipose tissue from Leprdb/db mice. Furthermore, injection of IL-10-treated SVFs increased CD4+ regulatory T cells (Tregs) in SVFs and adipose IL-10 levels and suppressed plasma adiponectin levels and DPP4 activity in diabetic mice. Injection of IL-10-treated SVFs decreased hepatic G6PC and PCK1 mRNA expression and increased Akt activation, STAT3 phosphorylation in the liver, and glucose tolerance in diabetic mice. Our data suggest that IL-10 treatment decreases inflammation in adipose SVFs of diabetic mice. Injection of IL-10-treated SVFs into the adipose tissue decreased diabetes-induced gluconeogenesis gene expression, DPP4 activity, and insulin resistance by enhancing Treg cells in diabetic mice. These data suggest that IL-10-treated adipose stromal vascular cells could be a promising therapeutic strategy for diabetes mellitus.

Hemodynamic and Clinical Profiles of Pulmonary Arterial Hypertension Patients with GDF2 and BMPR2 Variants.

Asians have a higher carrier rate of pulmonary arterial hypertension (PAH)-related genetic variants than Caucasians do. This study aimed to identify PAH-related genetic variants using whole exome sequencing (WES) in Asian idiopathic and heritable PAH cohorts. A WES library was constructed, and candidate variants were further validated by polymerase chain reaction and Sanger sequencing in the PAH cohort. In a total of 69 patients, the highest incidence of variants was found in the BMPR2, ATP13A3, and GDF2 genes. Regarding the BMPR2 gene variants, there were two nonsense variants (c.994C>T, p. Arg332*; c.1750C>T, p. Arg584*), one missense variant (c.1478C>T, p. Thr493Ile), and one novel in-frame deletion variant (c.877_888del, p. Leu293_Ser296del). Regarding the GDF2 variants, there was one likely pathogenic nonsense variant (c.259C>T, p. Gln87*) and two missense variants (c.1207G>A, p. Val403Ile; c.38T>C, p. Leu13Pro). The BMPR2 and GDF2 variant subgroups had worse hemodynamics. Moreover, the GDF2 variant patients were younger and had a significantly lower GDF2 value (135.6 ± 36.2 pg/mL, p = 0.002) in comparison to the value in the non-BMPR2/non-GDF2 mutant group (267.8 ± 185.8 pg/mL). The BMPR2 variant carriers had worse hemodynamics compared to the patients with the non-BMPR2/non-GDF2 mutant group. Moreover, there was a significantly lower GDF2 value in the GDF2 variant carriers compared to the control group. GDF2 may be a protective or corrected modifier in certain genetic backgrounds.

Incorporating low haemoglobin into a risk prediction model for conversion in minimally invasive gynaecologic oncology surgeries.

BACKGROUND: A well-known complication of laparoscopic management of gynaecologic masses and cancers is the need to perform an intraoperative conversion to laparotomy. The purpose of this study was to identify novel patient risk factors for conversion from minimally invasive to open surgeries for gynaecologic oncology operations. METHODS: This was a retrospective cohort study of 1356 patients ≥18 years of age who underwent surgeries for gynaecologic masses or malignancies between February 2015 and May 2020 at a single academic medical centre. Multivariable logistic regression was used to study the effects of older age, higher body mass index (BMI), higher American Society of Anaesthesiologist (ASA) physical status, and lower preoperative haemoglobin (Hb) on odds of converting from minimally invasive to open surgery. Receiver operating characteristic (ROC) curve analysis assessed the discriminatory ability of a risk prediction model for conversion. RESULTS: A total of 704 planned minimally invasive surgeries were included with an overall conversion rate of 6.1% (43/704). Preoperative Hb was lowest for conversion cases, compared to minimally invasive and open cases (11.6 ± 1.9 vs 12.8 ± 1.5 vs 11.8 ± 1.9 g/dL, p<.001). Patients with preoperative Hb <10 g/dL had an adjusted odds ratio (OR) of 3.94 (CI: 1.65-9.41, p=.002) for conversion while patients with BMI ≥30 kg/m2 had an adjusted OR of 2.86 (CI: 1.50-5.46, p=.001) for conversion. ROC curve analysis using predictive variables of age >50 years, BMI ≥30 kg/m2, ASA physical status >2, and preoperative haemoglobin <10 g/dL resulted in an area under the ROC curve of 0.71. Patients with 2 or more risk factors were at highest risk of requiring an intraoperative conversion (12.0%). CONCLUSIONS: Lower preoperative haemoglobin is a novel risk factor for conversion from minimally invasive to open gynaecologic oncology surgeries and stratifying patients based on conversion risk may be helpful for preoperative planning.

Minimally invasive surgery for management of gynaecologic masses (masses that affect the female reproductive organs) is often preferred over more invasive surgery, because it involves smaller surgical incisions and can have overall better recovery time. However, one unwanted complication of minimally invasive surgery is the need to unexpectedly convert the surgery to an open surgery, which entails a larger incision and is a higher risk procedure. In our study, we aimed to find patient characteristics that are associated with higher risk of converting a minimally invasive surgery to an open surgery. Our study identified that lower levels of preoperative haemoglobin, the protein that carries oxygen within red blood cells, is correlated with higher risk for conversion. This new risk factor was used with other known risk factors, including having higher age, higher body mass index, and higher baseline medical complexity to create a model to help surgical teams identify high risk patients for conversion. This model may be useful for surgical planning before and during the operation to improve patient outcomes.

Performance of Prehospital ECG and Impact on Prehospital Service Time: Comparison between EMT-II and EMT-P Teams.

Background: Prehospital electrocardiogram (PHECG) shortens door-to-balloon time in patients with ST-elevation myocardial infarction. However, it may increase the prehospital service time, thus offsetting the benefits gained. The performance of PHECG could be influenced by the proficiency of the emergency medical technicians (EMTs). Objectives: To investigate whether there are differences in the performance of PHECG between EMT-II and EMT-paramedics (EMT-P). Methods: This prospectively designed, retrospectively analyzed study of PHECG was conducted in Taipei from February 2019 to April 2021. Comparisons were made between EMT-II and EMT-P teams. The primary outcomes were the acceptance of PHECG suggestions and prehospital service time. The secondary outcomes were gender disparities in the primary outcomes. Results: A total of 2,991 patients were included, of whom 2,617 received PHECG. For the primary outcomes, the acceptance of PHECG was higher in those approached by EMT-P (99.6% vs. 71.5%, p < 0.001). The scene time and scene-to-hospital time showed no significant differences. For gender disparities, the acceptance of PHECG in female patients was significantly lower in those approached by EMT-II (59.3% vs. 99.2%, p < 0.001). The scene time and scene-to-hospital time were generally longer in the female patients, especially in the younger and middle age groups. Compared to EMT-P, both were significantly longer in the female patients approached by EMT-II. Conclusions: The acceptance of PHECG was lower in those approached by EMT-II, especially in females. Although there were generally no significant differences between EMT-II and EMT-P, the scene time and scene-to-hospital time were significantly longer in female patients, especially in those aged < 75 years approached by EMT-II.

Efficacy and safety of rucaparib treatment in patients with BRCA-mutated, relapsed ovarian cancer: final results from Study 10.

BACKGROUND: Study 10, a four-part Phase 1/2 study, evaluated oral rucaparib monotherapy in patients with advanced solid tumours. Here we report the final efficacy and safety results in heavily pretreated patients with ovarian cancer who received rucaparib in Study 10 Parts 2A and 2B. METHODS: Parts 2A and 2B (Phase 2 portions) enrolled patients with relapsed, high-grade, platinum-sensitive or platinum-resistant, BRCA-mutated ovarian cancer who had received 2-4 (Part 2A) or 3-4 (Part 2B) prior chemotherapies. Patients received oral rucaparib 600 mg twice daily (starting dose). The primary endpoint was the investigator-assessed objective response rate (ORR) by RECIST v1.1. RESULTS: Fifty-four patients were enrolled: 42 in Part 2A (all had platinum-sensitive disease) and 12 in Part 2B (4 with platinum-sensitive disease; 8 with platinum-resistant disease). ORR was 59.3% (95% CI 45.0-72.4%). The median time to onset of the most common nonhaematological treatment-emergent adverse events (TEAEs) was typically early (<56 days) and was later for haematological TEAEs (53-84 days). The median duration of grade ≥3 TEAEs was ≤13 days. CONCLUSIONS: In patients with relapsed, platinum-sensitive or platinum-resistant germline BRCA-mutant high-grade ovarian cancer who had received ≥2 prior chemotherapies, rucaparib had robust antitumour activity with a safety profile consistent with prior reports. CLINICAL TRIAL REGISTRATION: NCT01482715.

Intraoperative Use of Albumin in Major Noncardiac Surgery: Incidence, Variability, and Association With Outcomes.

BACKGROUND: The impact of albumin use during major surgery is unknown, and a dearth of evidence governing its use in major noncardiac surgery has long precluded its standardization in clinical guidelines. OBJECTIVE: In this study, we investigate institutional variation in albumin use among medical centers in the United States during major noncardiac surgery and explore the association of intraoperative albumin administration with important postoperative outcomes. METHODS: The study is an observational retrospective cohort analysis performed among 54 U.S. hospitals in the Multicenter Perioperative Outcomes Group and includes adult patients who underwent major noncardiac surgery under general anesthesia between January 2014 and June 2020. The primary endpoint was the incidence of albumin administration. Secondary endpoints are acute kidney injury (AKI), net-positive fluid balance, pulmonary complications, and 30-day mortality. Albumin-exposed and albumin-unexposed cases were compared within a propensity score-matched cohort to evaluate associations of albumin use with outcomes. RESULTS: Among 614,215 major surgeries, predominantly iso-oncotic albumin was administered in 15.3% of cases and featured significant inter-institutional variability in use patterns. Cases receiving intraoperative albumin involved patients of higher American Society of Anesthesiologists physical status and featured larger infused crystalloid volumes, greater blood loss, and vasopressor use. Overall, albumin was most often administered at high-volume surgery centers with academic affiliation, and within a propensity score-matched cohort (n=153,218), the use of albumin was associated with AKI (aOR 1.24, 95% CI 1.20-1.28, P <0.001), severe AKI (aOR 1.45, 95% CI 1.34-1.56, P <0.001), net-positive fluid balance (aOR 1.18, 95% CI 1.16-1.20, P <0.001), pulmonary complications (aOR 1.56, 95% CI 1.30-1.86, P <0.001), and 30-day all-cause mortality (aOR 1.37, 95% CI 1.26-1.49, P <0.001). CONCLUSIONS: Intravenous albumin is commonly administered among noncardiac surgeries with significant inter-institutional variability in use in the United States. Albumin administration was associated with an increased risk of postoperative complications.

Probing Acid-Induced Compaction of Denatured Proteins by High-Pressure Electrospray Mass Spectrometry.

Further increase in the acidity in the most denaturing acidic solution is known to induce compaction of the fully unfolded protein into a compact molten globule. The phenomenon of "acid-induced folding of proteins" takes place at pH ∼1 in strong acid aqueous solutions with high electrical conductivity and surface tension, a condition that is difficult to handle using conventional electrospray ionization methods for mass spectrometry. Here, high-pressure electrospray ionization (HP-ESI) is used to produce well-resolved mass spectra for proteins in strong acids with pH as low as 1. The compaction of protein conformation is indicated by a large shift in the charge state from high charges to native-like low charges. The addition of salt to the protein in the most denaturing condition also reproduces the compaction effect, thereby supporting the role of anions in this phenomenon. Similar compaction of proteins is also observed in organic solvent/acid mixtures. The charge state of the compacted protein depends on the type of anions that formed ion pairs with a positive charge on the protein. The dissociation of ion pairs during the ionization process forms neutral acids that can be observed by HP-ESI using a soft ion introduction configuration.

Feedback Control of Electrospray with and without an External Liquid Pump Using the Spray Current and the Apex Angle of a Taylor Cone for ESI-MS.

An electrospray operated in the steady cone-jet mode is highly stable but the operating state can shift to pulsation or multijet modes owing to changes in flow rate, surface tension, and electrostatic variables. Here, a simple feedback control system was developed using the spray current and the apex angle of a Taylor cone to determine the error signal for correcting the emitter voltage. The system was applied to lock the cone-jet mode operation against external perturbations. For a pump-driven electrospray at a regulated flow rate, the apex angle of the Taylor cone decreased with increasing voltage. In contrast, for a voltage-driven electrospray with low flow resistance, the angle was found to increase with the emitter voltage. A simple algorithm based on iterative learning control was formulated and implemented using a personal computer to automatically correct the emitter voltage in response to the error signal. For voltage-driven electrospray ionization (ESI), the feedback control of the spray current can also be used to regulate the flow rate to an arbitrary value or pattern. Electrospray ionization-mass spectrometry (ESI-MS) with feedback control was demonstrated to produce ion signal acquisition with long-term stability that was insusceptible to the emulated external disturbances.

Same day service: A genetic testing station model to improve germline genetic testing in patients with ovarian cancer.

OBJECTIVE: Genetic testing for ovarian cancer (OC) patients is essential to consideration of PARP inhibitor therapy. To improve access, we piloted a Genetic Testing Station (GTS) allowing patients to have a same-day genetic testing visit facilitated by Genetic Counselor Assistants (GCAs) under the supervision of Genetic Counselors (GCs). METHODS: The GTS was implemented December 2018 and operated through February 2020. Gynecologic Oncologists offered ovarian cancer patients a same-day GTS visit with a GCA. The patient received education via videos designed by GCs and then provided consent, a brief family history, and a sample for a standardized 133-gene panel. Results were provided by a GC. Patients were retrospectively identified by querying the medical record for OC patients seen 12 months prior to and 18 months after GTS implementation. RESULTS: A total of 482 patients pre-GTS were compared to 625 patients post-GTS. Genetic testing increased from 68.5% to 75.4% (p = 0.012) after implementation, primarily in patients with epithelial histologies (80% vs 89% in pre-GTS vs post-GTS, p = 0.005). Time from referral for genetic testing to obtaining results was evaluated in the post-GTS cohort, comparing patients who had traditional counseling to those who utilized the GTS. Time to obtaining results was 21 days in the GTS group (95% CI [10, 34]) compared to 56 days (95% CI [41,76]) in the traditional genetic counseling group. CONCLUSIONS: The GTS reduces barriers to care and facilitates discussion of precision treatment within a timely fashion while optimizing GC clinic time. Access improvement remains integral to improving uptake of genetic testing.