KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS.

The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers.

Single centre observational study evaluating the impact of introducing High Flow Nasal Cannula outside of Paediatric Critical Care Unit.

AIM: To evaluate the impact of High Flow Nasal Cannula (HFNC) introduction outside of Paediatric Critical Care Units (PCCU), on PCCU admissions and intubation rates. Secondarily, to identify escalation predictors. METHODS: Retrospective observational study with matched PCCU admissions and intubation rates, 2-years before (Group 1) and 2-years after (Group 2) HFNC introduction outside of PCCU. Within Group 2, we compared those admitted to PCCU (escalation) and those who did not (non-escalation). Observations, change in observations and time to starting HFNC were analysed. RESULTS: Pre- and post-introduction comparison: Of 980 admissions in Group 1, 55 were admitted to PCCU, whereas of 1209 admission in Group 2, there were 85 admissions, P = 0.188. Group 1 had 25 intubations compared to 23 in Group 2, P = 0.309. Over twice as many children had some form of respiratory support in Group 2. Post-introduction: 104 children commenced HFNC, 72% for bronchiolitis. Median age was 4 months in the non-escalation group and 6.5 months in the escalation group, P = 0.663. Thirty-eight children escalated to PCCU: 33 required CPAP/BiPAP, 4 were intubated with 1 remaining on HFNC. Comparisons of age, gender, comorbidities, observations, change in observations and time to starting HFNC showed no significant escalation predictors. CONCLUSIONS: This study identified no statistically significant predictors of escalation. There was an observed increase in PCCU admissions with decreased intubations. The resource implications of this therapy are significant and further studies should examine cost effectiveness of HFNC use outside of PCCU.

Multi-center validation of an artificial intelligence system for detection of COVID-19 on chest radiographs in symptomatic patients.

OBJECTIVES: While chest radiograph (CXR) is the first-line imaging investigation in patients with respiratory symptoms, differentiating COVID-19 from other respiratory infections on CXR remains challenging. We developed and validated an AI system for COVID-19 detection on presenting CXR. METHODS: A deep learning model (RadGenX), trained on 168,850 CXRs, was validated on a large international test set of presenting CXRs of symptomatic patients from 9 study sites (US, Italy, and Hong Kong SAR) and 2 public datasets from the US and Europe. Performance was measured by area under the receiver operator characteristic curve (AUC). Bootstrapped simulations were performed to assess performance across a range of potential COVID-19 disease prevalence values (3.33 to 33.3%). Comparison against international radiologists was performed on an independent test set of 852 cases. RESULTS: RadGenX achieved an AUC of 0.89 on 4-fold cross-validation and an AUC of 0.79 (95%CI 0.78-0.80) on an independent test cohort of 5,894 patients. Delong's test showed statistical differences in model performance across patients from different regions (p < 0.01), disease severity (p < 0.001), gender (p < 0.001), and age (p = 0.03). Prevalence simulations showed the negative predictive value increases from 86.1% at 33.3% prevalence, to greater than 98.5% at any prevalence below 4.5%. Compared with radiologists, McNemar's test showed the model has higher sensitivity (p < 0.001) but lower specificity (p < 0.001). CONCLUSION: An AI model that predicts COVID-19 infection on CXR in symptomatic patients was validated on a large international cohort providing valuable context on testing and performance expectations for AI systems that perform COVID-19 prediction on CXR. KEY POINTS: • An AI model developed using CXRs to detect COVID-19 was validated in a large multi-center cohort of 5,894 patients from 9 prospectively recruited sites and 2 public datasets. • Differences in AI model performance were seen across region, disease severity, gender, and age. • Prevalence simulations on the international test set demonstrate the model's NPV is greater than 98.5% at any prevalence below 4.5%.

Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn.

BACKGROUND: Heartburn that persists despite proton-pump inhibitor (PPI) treatment is a frequent clinical problem with multiple potential causes. Treatments for PPI-refractory heartburn are of unproven efficacy and focus on controlling gastroesophageal reflux with reflux-reducing medication (e.g., baclofen) or antireflux surgery or on dampening visceral hypersensitivity with neuromodulators (e.g., desipramine). METHODS: Patients who were referred to Veterans Affairs (VA) gastroenterology clinics for PPI-refractory heartburn received 20 mg of omeprazole twice daily for 2 weeks, and those with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance-pH monitoring. If patients were found to have reflux-related heartburn, we randomly assigned them to receive surgical treatment (laparoscopic Nissen fundoplication), active medical treatment (omeprazole plus baclofen, with desipramine added depending on symptoms), or control medical treatment (omeprazole plus placebo). The primary outcome was treatment success, defined as a decrease of 50% or more in the Gastroesophageal Reflux Disease (GERD)-Health Related Quality of Life score (range, 0 to 50, with higher scores indicating worse symptoms) at 1 year. RESULTS: A total of 366 patients (mean age, 48.5 years; 280 men) were enrolled. Prerandomization procedures excluded 288 patients: 42 had relief of their heartburn during the 2-week omeprazole trial, 70 did not complete trial procedures, 54 were excluded for other reasons, 23 had non-GERD esophageal disorders, and 99 had functional heartburn (not due to GERD or other histopathologic, motility, or structural abnormality). The remaining 78 patients underwent randomization. The incidence of treatment success with surgery (18 of 27 patients, 67%) was significantly superior to that with active medical treatment (7 of 25 patients, 28%; P = 0.007) or control medical treatment (3 of 26 patients, 12%; P<0.001). The difference in the incidence of treatment success between the active medical group and the control medical group was 16 percentage points (95% confidence interval, -5 to 38; P = 0.17). CONCLUSIONS: Among patients referred to VA gastroenterology clinics for PPI-refractory heartburn, systematic workup revealed truly PPI-refractory and reflux-related heartburn in a minority of patients. For that highly selected subgroup, surgery was superior to medical treatment. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT01265550.).

Distance decay 2.0 - A global synthesis of taxonomic and functional turnover in ecological communities.

Aim: Understanding the variation in community composition and species abundances (i.e., ß-diversity) is at the heart of community ecology. A common approach to examine ß-diversity is to evaluate directional variation in community composition by measuring the decay in the similarity among pairs of communities along spatial or environmental distance. We provide the first global synthesis of taxonomic and functional distance decay along spatial and environmental distance by analysing 148 datasets comprising different types of organisms and environments. Location: Global. Time period: 1990 to present. Major taxa studied: From diatoms to mammals. Method: We measured the strength of the decay using ranked Mantel tests (Mantel r) and the rate of distance decay as the slope of an exponential fit using generalized linear models. We used null models to test whether functional similarity decays faster or slower than expected given the taxonomic decay along the spatial and environmental distance. We also unveiled the factors driving the rate of decay across the datasets, including latitude, spatial extent, realm and organismal features. Results: Taxonomic distance decay was stronger than functional distance decay along both spatial and environmental distance. Functional distance decay was random given the taxonomic distance decay. The rate of taxonomic and functional spatial distance decay was fastest in the datasets from mid-latitudes. Overall, datasets covering larger spatial extents showed a lower rate of decay along spatial distance but a higher rate of decay along environmental distance. Marine ecosystems had the slowest rate of decay along environmental distances. Main conclusions: In general, taxonomic distance decay is a useful tool for biogeographical research because it reflects dispersal-related factors in addition to species responses to climatic and environmental variables. Moreover, functional distance decay might be a cost-effective option for investigating community changes in heterogeneous environments.

COM902, a novel therapeutic antibody targeting TIGIT augments anti-tumor T cell function in combination with PVRIG or PD-1 pathway blockade.

Immune checkpoint inhibitors (ICIs) have emerged as promising therapies for the treatment of cancer. However, existing ICIs, namely PD-(L)1 and CTLA-4 inhibitors, generate durable responses only in a subset of patients. TIGIT is a co-inhibitory receptor and member of the DNAM-1 family of immune modulating proteins. We evaluated the prevalence of TIGIT and its cognate ligand, PVR (CD155), in human cancers by assessing their expression in a large set of solid tumors. TIGIT is expressed on CD4+ and CD8+ TILs and is upregulated in tumors compared to normal tissues. PVR is expressed on tumor cells and tumor-associated macrophages from multiple solid tumors. We explored the therapeutic potential of targeting TIGIT by generating COM902, a fully human anti-TIGIT hinge-stabilized IgG4 monoclonal antibody that binds specifically to human, cynomolgus monkey, and mouse TIGIT, and disrupts the binding of TIGIT with PVR. COM902, either alone or in combination with a PVRIG (COM701) or PD-1 inhibitor, enhances antigen-specific human T cell responses in-vitro. In-vivo, a mouse chimeric version of COM902 in combination with an anti-PVRIG or anti-PD-L1 antibody inhibited tumor growth and increased survival in two syngeneic mouse tumor models. In summary, COM902 enhances anti-tumor immune responses and is a promising candidate for the treatment of advanced malignancies.

Circulating Hybrid Cells: A Novel Liquid Biomarker of Treatment Response in Gastrointestinal Cancers.

BACKGROUND: Real-time monitoring of treatment response with a liquid biomarker has potential to inform treatment decisions for patients with rectal adenocarcinoma (RAC), esophageal adenocarcinoma (EAC), and colorectal liver metastasis (CRLM). Circulating hybrid cells (CHCs), which have both immune and tumor cell phenotypes, are detectable in the peripheral blood of patients with gastrointestinal cancers, but their potential as an indicator of treatment response is unexplored. METHODS: Peripheral blood specimens were collected from RAC and EAC patients after neoadjuvant therapy (NAT) or longitudinally during therapy and evaluated for CHC levels by immunostaining. Receiver operating characteristics (ROCs) and the Kaplan-Meier method were used to analyze the CHC level as a predictor of pathologic response to NAT and disease-specific survival (DSS), respectively. RESULTS: Patients with RAC (n = 23) and EAC (n = 34) were sampled on the day of resection, and 11 patients (32%) demonstrated a pathologic complete response (pCR) to NAT. On ROC analysis, CHC levels successfully discriminated pCR from non-pCR with an area under the curve of 0.82 (95% confidence interval [CI], 0.71-0.92; P < 0.001). Additionally, CHC levels in the EAC patients correlated with residual nodal involvement (P = 0.026) and 1-year DSS (P = 0.029). The patients with RAC who were followed longitudinally during NAT (n = 2) and hepatic arterial infusion therapy for CRLM (n = 2) had CHC levels that decreased with therapy response and increased before clinical evidence of disease progression. CONCLUSION: Circulating hybrid cells are a novel blood-based biomarker with potential for monitoring treatment response and disease progression to help guide decisions for further systemic therapy, definitive resection, and post-therapy surveillance. Additional validation studies of CHCs are warranted.

PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia

This study explored the novel immune checkpoint poliovirus receptor-related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade significantly enhanced NK cell killing of PVRL2+, poliovirus receptor (PVR)lo AML cell lines, and significantly increased NK cell activation and degranulation in the context of patient primary AML blasts. However, in AML patient bone marrow, NK cell PVRIG expression levels were not increased. To understand how PVRIG blockade might potentially be exploited therapeutically, we investigated the biology of PVRIG and revealed that NK cell activation resulted in reduced PVRIG expression on the cell surface. This occurred whether NK cells were activated by tumour cell recognition, cytokines (IL-2 and IL-12) or activating receptor stimulation (CD16 and NKp46). PVRIG was present at higher levels in the cytoplasm than on the cell surface, particularly on CD56bright NK cells, which further increased cytoplasmic PVRIG levels following IL-2 and IL-12 activation. PVRIG was continually transported to the cell surface via the endoplasmic reticulum (ER) and Golgi in both unstimulated and activated NK cells. Taken together, our findings suggest that anti- PVRIG blocking antibody functions by binding to surface-bound PVRIG, which undergoes rapid turnover in both unstimulated and activated NK cells. We conclude that the PVRIGPVRL2 immune checkpoint axis can feasibly be targeted with PVRIG blocking antibody for NK-mediated immunotherapy of PVRL2+ AML.

Operative Shutdown and Recovery: Restructuring Surgical Operations During the SARS-CoV-2 Pandemic.

BACKGROUND: During the 2020 SARS-CoV-2 outbreak in New York City, hospitals canceled elective surgeries to increase capacity for critically ill patients. We present case volume data from our community hospital to demonstrate how this shutdown affected surgical care. METHODS: Between March 16 and June 14, 2020, all elective surgeries were canceled at our institution. All procedures performed during this operating room shutdown (ORS) were logged, as well as those 4 weeks before (PRE) and 4 weeks after (POST) for comparison. RESULTS: A total of 2,475 cases were included in our analysis, with 754 occurring during shutdown. Overall case numbers dropped significantly during ORS and increased during recovery (mean 245.0 ± 28.4 PRE versus 58.0 ± 30.9 ORS versus 186.0±19.4 POST cases/wk, P< 0.001). Emergency cases predominated during ORS (26.4% PRE versus 59.3% ORS versus 31.5% POST, P< 0.001) despite decreasing in frequency (mean 64.5 ± 7.9 PRE versus 34.4 ± 12.1 ORS versus 58.5 ± 4.0 POST cases/wk, P< 0.001). Open surgeries remained constant in all three phases (52.2-54.1%), whereas laparoscopic and robotic surgeries decreased (-3.4% and -3.0%, P< 0.001). General and/or vascular surgery, urology, and neurosurgery comprised a greater proportion of caseload (+9.5%, +3.0%, +2.8%), whereas orthopedics, gynecology, and otolaryngology/plastic surgery all decreased proportionally (-5.0%, -4.4%, -5.9%, P< 0.001). CONCLUSION: Operative volume significantly decreased during the SARS-CoV-2 outbreak. Emergency cases predominated during this time, although there were fewer emergency cases overall. General/vascular surgery became the most active service and open surgeries became more common. This reallocation of resources may be useful for future crisis planning among community hospitals.

A pilot study of the preliminary efficacy of Pain Buddy: A novel intervention for the management of children's cancer-related pain.

OBJECTIVES: Cancer-related pain in children is prevalent and undermanaged. Mobile health (mHealth) applications provide a promising avenue to address the gap in pain management in children with cancer. Pain Buddy is a multicomponent mHealth application developed to manage cancer-related pain in children. The goal of this paper is to present preliminary efficacy data of the impact of Pain Buddy on children's pain severity and frequency. METHODS: In a randomized controlled trial over 60 days, children (N = 48) reported daily pain on a tablet while receiving usual care. Those in the intervention group (N = 20) received remote symptom monitoring and skills training for pain management. Children in the attention control group (N = 28) only reported on their pain. RESULTS: Both groups experienced significant reductions in average daily pain over the study period (B = -0.10, z = -3.40, P = 0.001), with no group differences evident (z = -0.83, P = 0.40). However, the intervention group reported significantly fewer instances of moderate to severe pain compared with the control group, t(4125) = 2.67, P = 0.007. In addition, the intervention group reported no instances of moderate to severe pain toward the end of the study period. CONCLUSION: Pain Buddy is an innovative and interactive mHealth application that aims to improve pain and symptom management among children with cancer. The findings from this pilot study suggest that Pain Buddy may aid in the reduction of pain severity in children during cancer treatment.

The Capricious Nature of Theory of Mind: Does Mental State Understanding Depend on the Characteristics of the Target?

Using a between-groups design and random assignment, this study examined 214 Turkish children's (M = 11.66 years) mindreading and general reasoning about in-group members (Turks), similar out-group members (Syrians within Turkey) and dissimilar out-group members (Northern Europeans). Children heard four mindreading and four general reasoning stories with in-group or out-group members as targets. Whereas children's general reasoning about three groups was equivalent, accuracy of mental state inferences differed by target with more accurate mindreading of in-group targets compared to both sets of out-group targets. In this Turkish sample, mindreading of Syrian targets was the least accurate. Prejudice and perceived realistic threat predicted lower mindreading. These findings have important implications for understanding how similarity and intergroup processes play a role in children's mindreading.

Specific Tumor Characteristics Predict Upstaging in Early-Stage Esophageal Cancer.

BACKGROUND: Early-stage esophageal cancer (stages 0-1) has been shown to have relatively good outcomes after local endoscopic or surgical resection. For this reason, neoadjuvant chemoradiation usually is reserved for higher-stage disease. Some early tumors, however, are found after resection to be more advanced than predicted based on initial clinical staging, termed pathologic upstaging. Such tumors may have benefited from alternate treatment models had their true stage been known preoperatively. This study aimed to identify high-risk features in early esophageal cancers that might predict tumor upstaging and guide more individualized treatment algorithms. METHODS: Through retrospective review of a single-institution foregut disease registry, we evaluated patients who underwent esophagectomy for high-grade dysplasia (Tis) or stage 1 esophageal cancer, searching for factors associated with pathologic upstaging. RESULTS: The review included 110 patients (88% male, median age at diagnosis, 64.5 years) treated between January 2000 and June 2016. Upstaging occurred for 20.9% of the patients, and was more common for patients with angiolymphatic invasion (odds ratio [OR], 11.07; 95% confidence interval [CI], 2.96-41.44; P < 0.001) or signet-ring features (OR, 23.9; 95% CI, 2.6-216.8; P = 0.005). In the absence of other predictors, upstaging was associated with decreased overall survival (P = 0.006). CONCLUSIONS: Approximately 20% of patients with early-stage esophageal cancer may be upstaged at resection. Angiolymphatic invasion and signet-ring features may predict tumors likely to be upstaged, resulting in decreased overall survival.

Mechanisms behind persistence of a fire-sensitive alternative stable state system in the Gibson Desert, Western Australia.

Alternative vegetation types that switch from one to another under contrasting fire regimes are termed fire-mediated alternative stable states (FMASS). Typically, pyrophylic communities (i.e., vegetation assemblages favored by burning) dominate under high frequencies or intensities of fire. Conversely, fire-sensitive (pyrophobic) vegetation types persist under long fire-free conditions. As the persistence traits of plants of FMASS systems are generally poorly researched, threshold levels of pyric disturbance that trigger 'state-switching' are often unknown. Dense thickets of the obligate-seeder shrub waputi (Aluta maisonneuvei ssp. maisonneuvei [Myrtaceae]) form fire-retarding woody islands within highly flammable spinifex (Triodia spp.) grasslands in arid Australia. To examine the tolerance of Aluta thickets to burning, we investigated: (1) the influence of post-fire rainfall and fire severity on recruitment (a field study); (2) soil seedbank densities (a field study); and (3) fire-related dormancy cues in seeds (a germination trial). We found a positive relationship between recruitment and post-fire rainfall volume, and much higher mean recruitment at sites with high- (5.9 seedlings/m2) than low-severity-burnt (2.2 seedlings/m2) and unburnt shrubs (0.03 seedlings/m2). Post-fire regeneration was mediated by dense soil-borne seedbanks, and the germination trial indicated that smoke promoted germination. Although Aluta shrubs are invariably fire-killed, high-severity fires are unlikely to lead to state shifts from shrubland to grassland because of the ability of mature stands to regenerate from dense, fire-cued seedbanks. Nevertheless, given that Aluta seedlings are exceptionally slow-growing, post-fire droughts combined with fire-return intervals less than the Aluta primary juvenile period of c. 5 years could drive conversion from Aluta- to Triodia-dominated vegetation.

The relationship between endometriosis-related pelvic pain and symptom frequency, and subjective wellbeing.

BACKGROUND: This exploratory study sought to establish the relationship between endometriosis-related pelvic pain, endometriosis symptom-frequency, and women's subjective wellbeing (SWB). METHODS: A purposive sample (N = 2061) of women with endometriosis aged between 18 and 62 years (M = 30.49 ± 7.45) completed an online questionnaire containing a measure of pelvic pain (Biberoglu & Behrman Scale; B&B), endometriosis symptom frequency, and an established measure of SWB (Personal Wellbeing Index: PWI). RESULTS: Mean SWB total scores (58.35 ± 17.90) were considerably lower than those of women in the general population (western normative range = 70-80; mean = 76). On average, women reported moderate levels of pelvic pain (B&B mean = 5.96 ± 1.84), with a mean of 10.87 (± 4.81) endometriosis-related symptoms across the sample. Significant relationships were found between pelvic pain and SWB dimension and total scores (r's = - 0.20 to - 0.43, all p's < .001), and significant small to medium associations between symptom frequency and all but one of the dimensions of SWB (r's = - 0.12 to - 0.23, all p's < .007). In multivariate regression models accounting for age and delay in diagnosis, higher levels of pelvic pain were significantly associated with lower SWB scores across all eight dimensions of the PWI and total score (all p's < .002). Greater symptom frequency was significantly associated with lower levels of SWB for the dimensions of health, future security, life as a whole, and total scores (all p's < .002). CONCLUSIONS: SWB was lower in women with endometriosis than SWB in women from the general population, and endometriosis related symptoms and pelvic pain explain significant proportions of the unique variance in women's SWB scores. Psychosocial support is needed for women dealing with endometriosis-related symptoms and pain in order to improve their wellbeing and quality of life.

Endoscopic technique for closure of enterocutaneous fistulas.

BACKGROUND AND OBJECTIVES: Endoscopic over the scope clip (OTSC) closure represents a new technique for endoscopic management of enteric bleeding and tissue defects such as anastomotic leaks and enterocutaneous (EC) fistulas. We aim to describe our technical approach for OTSC closure of EC fistulas and convey our outcomes. METHODS AND PROCEDURES: This retrospective review includes ten patients who underwent OTSC application for EC fistulas by surgical endoscopists at a US tertiary care hospital from July 2015 to October 2017. Demographic data, along with type of defect, location, duration of lesion, success or failure of OTSC, and nutritional status were compiled. The ACS NSQIP surgical risk calculator was used to project the risk of mortality, complications, length of stay, and risk of readmission had our patients undergone surgical correction of their fistula. RESULTS: Overall success for EC fistula closure was 70%. Acute fistulas were closed with a success rate of 86%. Chronic fistulas were closed successfully in only 33% of cases. Of patients successfully closed, NSQIP-predicted rates of mortality, any complication, and median length of stay were 21.1%, 34.5%, and 9.5 days, respectively. With OTSC, these patients experienced 0 mortalities, 0 complications, and had a median length of stay of 4 days. CONCLUSION: OTSC is an effective adjunctive measure to improving rates of successful closure of EC fistulas and compromised anastomosis. OTSC conveys a markedly improved procedural risk profile as compared to standard surgical correction.

Pain relief in the palm of your hand: Harnessing mobile health to manage pediatric pain.

The development and implementation of mobile health (mHealth) interventions provide an opportunity for more optimal management of pediatric pain in the home setting. Leveraging the popularity, mobility, and technological capabilities of digital mobile devices may reduce pediatric pain. Several mHealth applications have already been developed that target the reduction of acute and chronic pediatric pain by digitally delivering intervention strategies in an engaging manner, accumulating pain assessment data, facilitating patient-provider communication, and providing interactive training. Although several mHealth programs have begun to make strides in the management of pediatric pain, there are still many more possibilities for improvement as greater development and adoption of mHealth practices is on the horizon. Recommendations are provided that advocate for continued advancement of pediatric pain mHealth implementation with an emphasis on robust scientific evaluation, a structured approach to development and design elements that enhance engagement. Increased awareness about the positive influence of mHealth along with the encouragement of researchers and healthcare providers to promote and develop mHealth programs has the potential to transform pediatric pain management. This merger of evidence-based pain management strategies and digital technology positions pediatric mHealth to have a profound impact by effectively augmenting standard of care and benefiting healthcare providers, parents, and especially children in need.

Effect of Long-Term Intrathecal Bupivacaine Infusion on Blood Pressure.

OBJECTIVES: The local anesthetic bupivacaine is a common analgesic adjuvant medication used in combination with opioids in intrathecal drug delivery systems (IDDSs). While the acute effects of spinal bupivacaine injection on blood pressure (BP) have been studied, there is a dearth of data regarding long-term effects of continuous intrathecal bupivacaine infusion. MATERIALS AND METHODS: A retrospective review of all noncancer pain patients receiving bupivacaine through IDDSs from January 2013 to November 2017 was performed. Blood pressure values before implantation, and after implant at the 1-week, 3-month, 6-month and 1-year time points are recorded as well as corresponding bupivacaine and opioid doses in the IDDS. RESULTS: Eighty-two patients were included in the study; median patient age was 64 years and intrathecal catheter tips were located predominantly in the lower thoracic spine. Significant decreases in systolic blood pressure (SBP) and mean arterial pressure (MAP) relative to baseline occurred in patients receiving chronic lower thoracic intrathecal bupivacaine delivery at 3, 6, and 12 months post-implant (-12.96 ± 18.21; p < 0.001 and - 6.38 ± 12.04; p < 0.001, respectively). The only significant decrease in DBP was observed at 1 year post-implant (-3.09 ± 11.76; p < 0.05). Similar decreases in BP values occurred in patients with or without hypertension. CONCLUSIONS: Long-term thoracic intrathecal infusion of bupivacaine likely exerts a lowering effect on BP, primarily because of a significant decrease in SBP. This effect is likely due to efferent sympathetic blockade by bupivacaine.

Structural and Biochemical Analyses Reveal the Mechanism of Glutathione S-Transferase Pi 1 Inhibition by the Anti-cancer Compound Piperlongumine.

Glutathione S-transferase pi 1 (GSTP1) is frequently overexpressed in cancerous tumors and is a putative target of the plant compound piperlongumine (PL), which contains two reactive olefins and inhibits proliferation in cancer cells but not normal cells. PL exposure of cancer cells results in increased reactive oxygen species and decreased GSH. These data in tandem with other information led to the conclusion that PL inhibits GSTP1, which forms covalent bonds between GSH and various electrophilic compounds, through covalent adduct formation at the C7-C8 olefin of PL, whereas the C2-C3 olefin of PL was postulated to react with GSH. However, direct evidence for this mechanism has been lacking. To investigate, we solved the X-ray crystal structure of GSTP1 bound to PL and GSH at 1.1 Å resolution to rationalize previously reported structure activity relationship studies. Surprisingly, the structure showed that a hydrolysis product of PL (hPL) was conjugated to glutathione at the C7-C8 olefin, and this complex was bound to the active site of GSTP1; no covalent bond formation between hPL and GSTP1 was observed. Mass spectrometry (MS) analysis of the reactions between PL and GSTP1 confirmed that PL does not label GSTP1. Moreover, MS data also indicated that nucleophilic attack on PL at the C2-C3 olefin led to PL hydrolysis. Although hPL inhibits GSTP1 enzymatic activity in vitro, treatment of cells susceptible to PL with hPL did not have significant anti-proliferative effects, suggesting that hPL is not membrane-permeable. Altogether, our data suggest a model wherein PL is a prodrug whose intracellular hydrolysis initiates the formation of the hPL-GSH conjugate, which blocks the active site of and inhibits GSTP1 and thereby cancer cell proliferation.

Major Barbara Stimson: A Historical Perspective on the American Board of Surgery Through the Accomplishments of the First Woman to Achieve Board Certification.

: Dr. Barbara Bartlett Stimson, AB, MD, MedScD, FACS (1898-1986) was a pioneering orthopedic surgeon from a prominent American family who, in 1940, became the first woman certified by the American Board of Surgery (ABS, certificate number 860). It would be another 7 years and approximately 2500 candidates before the next female surgeon would be certified. A member of the third class to admit women to Columbia Medical School and the second female surgical resident to complete training at Columbia-Presbyterian Medical Center, Dr. Stimson was a confident and exceptionally accomplished trailblazer for women in surgery. In this biographical sketch based upon documents from the ABS, and the archives of Vassar College and the College of Physicians and Surgeons at Columbia-Presbyterian Medical Center, Dr. Stimson's motivations, attitudes, and unique accomplishments emerge as testimony to the exceptional career of this driven, self-possessed woman. Stimson was undaunted by the sex-based conventions of her time, and achieved a notable career as a surgeon in the profession she loved; first honing her skills at a busy urban fracture service in New York, then serving with distinction in the Royal Army Medical Corps during World War II, and finally returning to the states to become a respected leader in her field. Her life story and unprecedented ABS certification affirm her conviction that proven skill and ability can be used as a means of overcoming unfounded biases, and helped pave the way for future generations of board certified female surgeons in the United States.