Detectability of Surface Biosignatures for Directly Imaged Rocky Exoplanets.

Modeling the detection of life has never been more opportune. With next-generation space telescopes, such as the currently developing Habitable Worlds Observatory (HWO) concept, we will begin to characterize rocky exoplanets potentially similar to Earth. However, few realistic planetary spectra containing surface biosignatures have been paired with direct imaging telescope instrument models. Therefore, we use a HWO instrument noise model to assess the detection of surface biosignatures affiliated with oxygenic, anoxygenic, and nonphotosynthetic extremophiles. We pair the HWO telescope model to a one-dimensional radiative transfer model to estimate the required exposure times necessary for detecting each biosignature on planets with global microbial coverage and varying atmospheric water vapor concentrations. For modeled planets with 0-50% cloud coverage, we determine pigments and the red edge could be detected within 1000 hr (100 hr) at distances within 15 pc (11 pc). However, tighter telescope inner working angles (2.5 λ/D) would allow surface biosignature detection at further distances. Anoxygenic photosynthetic biosignatures could also be more easily detectable than nonphotosynthetic pigments and the photosynthetic red edge when compared against a false positive iron oxide slope. Future life detection missions should evaluate the influence of false positives on the detection of multiple surface biosignatures.

Developmental order, fibre caliber, and vascularization predict tract-wise declines: Testing retrogenesis and physiological predictions in white matter aging.

To understand the consistently observed spatial distribution of white-matter (WM) aging, developmentally driven theories of retrogenesis have gained traction, positing that the order WM development predicts declines. Regions that develop first are often expected to deteriorate the last, i.e. "last-in-first-out". Alternatively, regions which develop most rapidly may also decline most rapidly in aging, or the "gains-predict-loss" model. The validity of such theories remains uncertain, in part due to lack of clarity on the definition of developmental order. Our recent findings also suggest that WM degeneration may vary by physiological parameters such as perfusion. Furthermore, it is informative to link perfusion to fibre metabolic need, which varies with fibre size. Here we address the question of whether WM degeneration is determined by development trajectory or physiological state across both microstructural and perfusion measures using data drawn from the Human Connectome Project in Aging (HCP-A). Our results indicate that developmental order of tract myelination provides the strongest support for the retrogenesis hypothesis, with the last to complete myelination the first to decline. Moreover, higher mean axon diameter and lower macrovascular density are associated with lower degrees of WM degeneration across measures. Tract perfusion, in turn also tends to be higher and the arterial transit time longer for tracts that appear first. These findings suggest that WM degeneration in different tracts may be governed by their developmental trajectories and physiology, and ultimately influenced by each tract's metabolic demand.

The impact of inflammation and acute phase activation in cancer cachexia.

The development of cachexia in the setting of cancer or other chronic diseases is a significant detriment for patients. Cachexia is associated with a decreased ability to tolerate therapies, reduction in ambulation, reduced quality of life, and increased mortality. Cachexia appears intricately linked to the activation of the acute phase response and is a drain on metabolic resources. Work has begun to focus on the important inflammatory factors associated with the acute phase response and their role in the immune activation of cachexia. Furthermore, data supporting the liver, lung, skeletal muscle, and tumor as all playing a role in activation of the acute phase are emerging. Although the acute phase is increasingly being recognized as being involved in cachexia, work in understanding underlying mechanisms of cachexia associated with the acute phase response remains an active area of investigation and still lack a holistic understanding and a clear causal link. Studies to date are largely correlative in nature, nonetheless suggesting the possibility for a role for various acute phase reactants. Herein, we examine the current literature regarding the acute phase response proteins, the evidence these proteins play in the promotion and exacerbation of cachexia, and current evidence of a therapeutic potential for patients.

Conscious expectancy rather than associative strength elicits brain activity during single-cue fear conditioning.

The neurocognitive processes underlying Pavlovian conditioning in humans are still largely debated. The conventional view is that conditioned responses (CRs) emerge automatically as a function of the contingencies between a conditioned stimulus (CS) and an unconditioned stimulus (US). As such, the associative strength model asserts that the frequency or amplitude of CRs reflects the strength of the CS-US associations. Alternatively, the expectation model asserts that the presentation of the CS triggers conscious expectancy of the US, which is responsible for the production of CRs. The present study tested the hypothesis that there are dissociable brain networks related to the expectancy and associative strength theories using a single-cue fear conditioning paradigm with a pseudo-random intermittent reinforcement schedule during functional magnetic resonance imaging. Participants' (n = 21) trial-by-trial expectations of receiving shock displayed a significant linear effect consistent with the expectation model. We also found a positive linear relationship between the expectancy model and activity in frontoparietal brain areas including the dorsolateral prefrontal cortex (PFC) and dorsomedial PFC. While an exploratory analysis found a linear relationship consistent with the associated strength model in the insula and early visual cortex, our primary results are consistent with the view that conscious expectancy contributes to CRs.

Bilateral Renal Auto-Transplantation for Retroperitoneal Sarcomas: Is It Underutilized?

Sarcomas are a rare tumor of mesenchymal origin. The liposarcoma is the most common sarcoma of the retroperitoneum. Liposarcomas are typically low grade, and present at an advanced stage and a large size. We report a case of a large retroperitoneal liposarcoma, approximately 50 kg, encasing both kidneys, which was managed via a two-stage resection and staged renal auto-transplantation into the intra-peritoneal pelvis. The patient maintained normal renal function throughout, and remains disease free two years post-resection. Renal auto-transplantation with pelvic placement may facilitate improved margin-free resection. Renal relocation may allow the use of curative-intent ablative therapies such as radiofrequency ablation and radiation in cases of retroperitoneal recurrence.

A CXCR4 inhibitor (balixafortide) enhances docetaxel-mediated antitumor activity in a murine model of prostate cancer bone metastasis.

BACKGROUND: Prostate cancer (PCa) bone metastases have been shown to be more resistant to docetaxel than soft tissue metastases. The proinflammatory chemokine receptor CXCR4 has been shown to confer resistance to docetaxel (DOC) in PCa cells. Balixafortide (BLX) is a protein epitope mimetic inhibitor of CXCR4. Accordingly, we hypothesized that BLX would enhance DOC-mediated antitumor activity in PCa bone metastases. METHODS: PC-3 luciferase-labeled cells were injected into the tibia of mice to model bone metastases. Four treatment groups were created: vehicle, DOC (5 mg/kg), BLX (20 mg/kg), and combo (receiving both DOC and BLX). Mice were injected twice daily subcutaneously with either vehicle or BLX starting on Day 1 and weekly intraperitoneally with DOC starting on Day 1. Tumor burden was measured weekly via bioluminescent imaging. At end of study (29 days), radiographs were taken of the tibiae and blood was collected. Serum levels of TRAcP, IL-2, and IFNγ levels were measured using ELISA. Harvested tibiae were decalcified and stained for Ki67, cleaved caspase-3, and CD34 positive cells or microvessels were quantified. RESULTS: Tumor burden was lower in the combo group compared to the DOC alone group. Treatment with the combination had no impact on the number of mice with osteolytic lesions, however the area of osteolytic lesions was lower in the combo group compared to the vehicle and BLX groups, but not the DOC group. Serum TRAcP levels were lower in the combo compared to vehicle group, but not the other groups. No significant difference in Ki67 staining was found among the groups; whereas, cleaved caspase-3 staining was lowest in the Combo group and highest in the BLX group. The DOC and combo groups had more CD34+ microvessels than the control and BLX groups. There was no difference between the treatment groups for IL-2, but the combo group had increased levels of IFNγ compared to the DOC group. CONCLUSIONS: Our data demonstrate that a combination of BAL and DOC has greater antitumor activity in a model of PCa bone metastases than either drug alone. These data support further evaluation of this combination in metastatic PCa.

Ablative Therapy in Non-HCC Liver Malignancy.

Surgical extirpation of liver tumors remains a proven approach in the management of metastatic tumors to the liver, particularly those of colorectal origin. Ablative, non-resective therapies are an increasingly attractive primary therapy for liver tumors as they are generally better tolerated and result in far less morbidity and mortality. Ablative therapies preserve greater normal liver parenchyma allowing better post-treatment liver function and are particularly appropriate for treating subsequent liver-specific tumor recurrence. This article reviews the current status of ablative therapies for non-hepatocellular liver tumors with a discussion of many of the clinically available approaches.

Addressing the Barriers to Clinical Trials Accrual in Community Cancer Centres Using a National Clinical Trials Navigator:A Cross-Sectional Analysis.

INTRODUCTION: Clinical trials, although academically accepted as the most effective treatment available for cancer patients, poor accrual to clinical trials remains a significant problem. A clinical trials navigator (CTN) program was piloted where patients and/or their healthcare professionals could request a search and provide a list of potential cancer clinical trials in which a patient may be eligible based on their current status and disease. OBJECTIVES: This study examined the outcomes of a pilot program to try to improve clinical trials accrual with a focus on patients at medium to small sized cancer programs. Outcomes examined included patient disposition (referral to and accrual to interventional trials), patient survival, sites of referral to the CTN program. METHODS: One 0.5 FTE navigator was retained. Stakeholders referred to the CTN through the Canadian Cancer Clinical Trials Network. Demographic and outcomes data were recorded. RESULTS: Between March 2019 and February 2020, 118 patients from across Canada used the program. Seven per cent of patients referred were enrolled onto treatment clinical trials. No available trial excluded 39% patients, and 28% had a decline in their health and died before they could be referred or enrolled onto a clinical trial. The median time from referral to death was 109 days in those that passed. CONCLUSION: This novel navigator pilot has the potential to increase patient accrual to clinical trials. The CTN program services the gap in the clinical trials system, helping patients in medium and small sized cancer centres identify potential clinical trials at larger centres.

Differential immune landscapes in appendicular versus axial skeleton.

Roughly 400,000 people in the U.S. are living with bone metastases, the vast majority occurring in the spine. Metastases to the spine result in fractures, pain, paralysis, and significant health care costs. This predilection for cancer to metastasize to the bone is seen across most cancer histologies, with the greatest incidence seen in prostate, breast, and lung cancer. The molecular process involved in this predilection for axial versus appendicular skeleton is not fully understood, although it is likely that a combination of tumor and local micro-environmental factors plays a role. Immune cells are an important constituent of the bone marrow microenvironment and many of these cells have been shown to play a significant role in tumor growth and progression in soft tissue and bone disease. With this in mind, we sought to examine the differences in immune landscape between axial and appendicular bones in the normal noncancerous setting in order to obtain an understanding of these landscapes. To accomplish this, we utilized mass cytometry by time-of-flight (CyTOF) to examine differences in the immune cell landscapes between the long bone and vertebral body bone marrow from patient clinical samples and C57BL/6J mice. We demonstrate significant differences between immune populations in both murine and human marrow with a predominance of myeloid progenitor cells in the spine. Additionally, cytokine analysis revealed differences in concentrations favoring a more myeloid enriched population of cells in the vertebral body bone marrow. These differences could have clinical implications with respect to the distribution and permissive growth of bone metastases.

Mental imagery can generate and regulate acquired differential fear conditioned reactivity.

Mental imagery is an important tool in the cognitive control of emotion. The present study tests the prediction that visual imagery can generate and regulate differential fear conditioning via the activation and prioritization of stimulus representations in early visual cortices. We combined differential fear conditioning with manipulations of viewing and imagining basic visual stimuli in humans. We discovered that mental imagery of a fear-conditioned stimulus compared to imagery of a safe conditioned stimulus generated a significantly greater conditioned response as measured by self-reported fear, the skin conductance response, and right anterior insula activity (experiment 1). Moreover, mental imagery effectively down- and up-regulated the fear conditioned responses (experiment 2). Multivariate classification using the functional magnetic resonance imaging data from retinotopically defined early visual regions revealed significant decoding of the imagined stimuli in V2 and V3 (experiment 1) but significantly reduced decoding in these regions during imagery-based regulation (experiment 2). Together, the present findings indicate that mental imagery can generate and regulate a differential fear conditioned response via mechanisms of the depictive theory of imagery and the biased-competition theory of attention. These findings also highlight the potential importance of mental imagery in the manifestation and treatment of psychological illnesses.

Emergent robotic versus laparoscopic surgery for perforated gastrojejunal ulcers: a retrospective cohort study of 44 patients.

BACKGROUND: Perforated gastrojejunal ulcers are a known complication following Roux-en-Y gastric bypass (RYGB) surgery requiring emergent surgical repair. The robotic approach has not been evaluated for emergency general surgery. METHODS: A retrospective cohort study from 2015 to 2019 was performed identifying all patients who underwent repair of perforated gastrojejunal ulcers after RYGB at a single institution. Patient characteristics and outcomes were compared by robotic or laparoscopic approach. RESULTS: Of the 44 patients analyzed, there were 24 robotic and 20 laparoscopic repairs of perforated gastrojejunal ulcers. No patients were initially approached with open surgery. In-room-to-surgery-start time was significantly faster in the robotic group than the laparoscopic group (25 versus 31 min, p = 0.01). Complication rate, complication severity, operating time, hospital length of stay, postoperative vasopressor requirement, discharge to home, hospital length of stay and 30-day readmission were all improved in the robotic group, although these were not statistically significant. Both total inpatient and procedural costs were more in the robotic group than the laparoscopic group. CONCLUSION: Perforated hollow viscus is not a contraindication for the use of the surgical robot, which may improve outcomes.

Effects of Analgesics on Tumor Growth in Mouse Models of Prostate Cancer Bone Metastasis.

Murine models of tumor development often require invasive procedures for tumor implantation, potentially causing pain or distress. However, analgesics are often withheld during implantation because of concerns that they may adversely affect tumor development. Previous studies examining the effects of analgesics on the development and metastasis of various tumor lines show that the effect of analgesics depends on the tumor line and analgesic used. A blanket statement that analgesics affect the general growth of tumors is not adequate scientific justification for withholding pain relief, and pilot studies or references are recommended for each specific tumor cell line and treatment combination. In this study, we evaluated the effects of 2 commonly used analgesics on tumor growth in 2 models of prostate cancer (PCa) bone metastasis. We hypothesized that a one-time injection of analgesics at the time of intratibial injection of tumor cells would not significantly impact tumor growth. Either C57BL/6 or SCID mice were injected subcutaneously with an analgesic (carprofen [5 mg/kg], or buprenorphine [0.1 mg/kg]) or vehicle (0.1 mL of saline) at the time of intratibial injection with a PCa cell line (RM1 or PC3, n = 10 to 11 per group). Tumor growth (measured by determination of tumor burden and the extent of bone involvement) and welfare (measured by nociception, locomotion, and weight) were monitored for 2 to 4 wk. Neither carprofen or buprenorphine administration consistently affected tumor growth or indices of animal welfare as compared with the saline control for either cell line. This study adds to the growing body of literature demonstrating that analgesia can be compatible with scientific objectives, and that a decision to withhold analgesics must be scientifically justified and evaluated on a model-specific basis.

The demographics of patients presenting for sexual assault to US emergency departments.

BACKGROUND: Few studies address the demographics/epidemiology of patients presenting to emergency departments (ED) for evaluation of sexual assault across an entire nation. It was the purpose of this study to analyze the demographics of sexual assault using a national data base. METHODS: This was a retrospective study of prospectively collected data from National Electronic Injury Surveillance System - All Injury Program for years 2005-2013. Patients presenting for sexual assault were analyzed. Descriptive and logistic regression statistical analyses were performed with SUDAAN 11.0.01™ software. A p < 0.05 was considered statistically significant. RESULTS: Sexual assault accounted for an estimated 657,719 ED visits (0.24% of all injuries, and 3.4% of injuries due to violence). When an assault victim presented to the ED, a sexual assault was most likely when the patient was 0-14 years old (OR = 19.48 [12.02, 31.57]), White (OR = 2.12 [1.30, 3.47]), the perpetrator being a stranger (OR = 10.51 [8.21, 13.46]), and occurring at home (OR = 10.05 [6.61, 15.27]). The average annual incidence of ED visits for sexual assault per 10,000 US population was 2.39; 0.47 for males and 4.92 for females. The average was 19.6 years; 90.3% were female. Assaults occurred in the home in 45.6%, and were more common in the summer. The perpetrator was unknown in 37.5%, a friend/acquaintance in 24.8%, other relative in 9.4%, multiple perpetrators in 9.3%, spouse/partner in 6.8%, with the remaining 12.7% from other groups. Racial composition was White in 60.9%, Black in 25.9%, Amerindian in 12.5%, and Asian in 0.5%. The perpetrator was a close relative nearly twice as frequently for male victims compared to female victims. Hospital admission overall was 2.7%: 7.1% when the assault occurred on the street, 1.8% when at school or sporting locations, 4.9% for males and 1.5% for females. Nearly all (98.2%) extremity injuries occurred in females. CONCLUSIONS: Sexual assaults account for 4.4% of ED visits for violence. There was a decrease in the number of sexual assaults occurring on the street and at school/sporting locations over time while the number of assaults by strangers increased. For males, 54.1% occurred in those <10 years of age. The differences between patients by demographic and event characteristics is important information for health care providers.

Blind nasogastric tube advancement following sleeve gastrectomy: an animal model.

BACKGROUND: Sleeve gastrectomy is an effective surgical treatment for morbid obesity. The major technical risk of this procedure is staple line dehiscence. Some surgeons are reluctant to place a nasogastric tube (NGT) blindly due to the perceived risk of damage to the staple line. We sought to determine whether such concern was warranted. METHODS: A porcine tissue model (Animal Technologies, Inc., Tyler, TX) was used. Sleeve gastrectomy was performed using a flexible gastroscope as a guide for the Endo GIA stapler (Covidien, New Haven, CT) in an identical fashion used in our patients. The specimen was then placed in a plastic model of the thorax (VATS Trainers, LLC. Lansing, MI). The NGT was blindly advanced to 55 cm for a total of 50 passes, and to 75 cm for another 50 passes. Endoscopy with water submersion was performed to evaluate for injury or leak. RESULTS: After multiple passes of the NGT, no significant injuries, leaks, or perforations were observed to the gastric model, except for several small petechiae of the gastric mucosa, the largest measuring approximately 3 mm. None were of full thickness or penetrated the mucosa. The staple line showed no evidence of trauma. CONCLUSION: In this porcine model, blind NGT placement was not associated with significant mucosal injury or any damage to the sleeve gastrectomy staple line.

Intrapericardial diaphragmatic hernia in a 6-month-old girl: A case report and review of the literature.

INTRODUCTION: Intrapericardial congenital diaphragmatic hernia (IPCDH) is extremely rare: only 18 cases in children have been reported in the literature since 1981. We report the 19th case of infantile IPCDH in a 6-month-old girl and compare with previous reports. PRESENTATION OF CASE: Our patient initially presented with four days of dyspnea and was diagnosed with CDH by preoperative radiography. She was taken to the operating room, where an IPCDH was discovered, and successfully reduced. DISCUSSION: CDH may present with cardiopulmonary compromise, but IPCDH directly compress the heart, leading to acute or subacute heart failure. CONCLUSION: Pediatric surgeons should be aware of and prepared for the possibility of IPCDH when making surgical plans to correct CDH.

Targeted Notch1 inhibition with a Notch1 antibody, OMP-A2G1, decreases tumor growth in two murine models of prostate cancer in association with differing patterns of DNA damage response gene expression.

Notch plays a protumorigenic role in many cancers including prostate cancer (PCa). Global notch inhibition of multiple Notch family members using γ-secretase inhibitors has shown efficacy in suppressing PCa growth in murine models. However, global Notch inhibition is associated with marked toxicity due to the widespread function of many different Notch family members in normal cell physiology. Accordingly, in the current study, we explored if specific inhibition of Notch1 would effectively inhibit PCa growth in a murine model. The androgen-dependent VCaP and androgen-independent DU145 cell lines were injected subcutaneously into mice. The mice were treated with either control antibody 1B7.11, anti-Notch1 antibody (OMP-A2G1), docetaxel or the combination of OMP-A2G1 and docetaxel. Tumor growth was measured using calipers. At the end of the study, tumors were assessed for proliferative response, apoptotic response, Notch target gene expression, and DNA damage response (DDR) expression. OMP-A2G1 alone inhibited tumor growth of both PCa cell lines to a greater extent than docetaxel alone. There was no additive or synergistic effect of OMP-A2G1 and docetaxel. The primary toxicity was weight loss that was controlled with dietary supplementation. Proliferation and apoptosis were affected differentially in the two cell lines. OMP-A2G1 increased expression of the DDR gene GADD45α in VCaP cells but downregulated GADD45α in Du145 cells. Taken together, these data show that Notch1 inhibition decreases PCa xenograft growth but does so through different mechanisms in the androgen-dependent VCaP cell line vs the androgen-independent DU145 cell line. These results provide a rationale for further exploration of targeted Notch inhibition for therapy of PCa.

Intellectual Property Protection and Drug Plan Coverage: Evidence From Ontario.

Canada has strengthened intellectual property (IP) protections for pharmaceutical drugs several times over the last 3 decades. This study investigates whether the IP changes had an effect on the market exclusivity time of brand products on the Ontario Drug Benefit (ODB) formulary. We constructed a database that included the first brand approval date for drugs launched between 1974 and 2012, the first ODB listing date of the brand drug, and the first ODB listing date of the generic form of the drug. We then calculated the time of formulary exclusivity to detect any changes in market exclusivity times associated with changes to Canada's IP regimen. There were 595 drugs launched between 1974 and 2012 that were available for analysis. Exclusivity gradually declined from the late 1970s to 1990. Drugs approved in 2004 received 7.6 years of exclusivity, and drugs approved in 2005 received 5 years of exclusivity. Over the time period we analyzed, market exclusivity time of brand drugs experienced marked changes, but we did not detect any systematic effects of Canada's stronger pharmaceutical IP laws on the market exclusivity.

Exoplanet Biosignatures: A Framework for Their Assessment.

Finding life on exoplanets from telescopic observations is an ultimate goal of exoplanet science. Life produces gases and other substances, such as pigments, which can have distinct spectral or photometric signatures. Whether or not life is found with future data must be expressed with probabilities, requiring a framework of biosignature assessment. We present a framework in which we advocate using biogeochemical "Exo-Earth System" models to simulate potential biosignatures in spectra or photometry. Given actual observations, simulations are used to find the Bayesian likelihoods of those data occurring for scenarios with and without life. The latter includes "false positives" wherein abiotic sources mimic biosignatures. Prior knowledge of factors influencing planetary inhabitation, including previous observations, is combined with the likelihoods to give the Bayesian posterior probability of life existing on a given exoplanet. Four components of observation and analysis are necessary. (1) Characterization of stellar (e.g., age and spectrum) and exoplanetary system properties, including "external" exoplanet parameters (e.g., mass and radius), to determine an exoplanet's suitability for life. (2) Characterization of "internal" exoplanet parameters (e.g., climate) to evaluate habitability. (3) Assessment of potential biosignatures within the environmental context (components 1-2), including corroborating evidence. (4) Exclusion of false positives. We propose that resulting posterior Bayesian probabilities of life's existence map to five confidence levels, ranging from "very likely" (90-100%) to "very unlikely" (<10%) inhabited. Key Words: Bayesian statistics-Biosignatures-Drake equation-Exoplanets-Habitability-Planetary science. Astrobiology 18, 709-738.