The corporate information environment develops endogenously as a consequence of information asymmetries and agency problems between investors, entrepreneurs, and managers. We review current research ...on the three main decisions that shape the corporate information environment in capital market settings: (1) managers’ voluntary disclosure decisions, (2) disclosures mandated by regulators, and (3) reporting decisions by analysts. We conclude that, in the last ten years, research has generated several useful insights. Despite this progress, we call for researchers to consider interdependencies between the various decisions that shape the corporate information environment and suggest new and interesting issues for researchers to address.
SpaceOAR, a Food and Drug Administration–approved hydrogel intended to create a rectal–prostate space, was evaluated in a single-blind phase III trial of image guided intensity modulated radiation ...therapy. A total of 222 men were randomized 2:1 to the spacer or control group and received 79.2 Gy in 1.8-Gy fractions to the prostate with or without the seminal vesicles. The present study reports the final results with a median follow-up period of 3 years.
Cumulative (Common Terminology Criteria for Adverse Events, version 4.0) toxicity was evaluated using the log-rank test. Quality of life (QOL) was examined using the Expanded Prostate Cancer Index Composite (EPIC), and the mean changes from baseline in the EPIC domains were tested using repeated measures models. The proportions of men with minimally important differences (MIDs) in each domain were tested using repeated measures logistic models with prespecified thresholds.
The 3-year incidence of grade ≥1 (9.2% vs 2.0%; P=.028) and grade ≥2 (5.7% vs 0%; P=.012) rectal toxicity favored the spacer arm. Grade ≥1 urinary incontinence was also lower in the spacer arm (15% vs 4%; P=.046), with no difference in grade ≥2 urinary toxicity (7% vs 7%; P=0.7). From 6 months onward, bowel QOL consistently favored the spacer group (P=.002), with the difference at 3 years (5.8 points; P<.05) meeting the threshold for a MID. The control group had a 3.9-point greater decline in urinary QOL compared with the spacer group at 3 years (P<.05), but the difference did not meet the MID threshold. At 3 years, more men in the control group than in the spacer group had experienced a MID decline in bowel QOL (41% vs 14%; P=.002) and urinary QOL (30% vs 17%; P=.04). Furthermore, the control group were also more likely to have experienced large declines (twice the MID) in bowel QOL (21% vs 5%; P=.02) and urinary QOL (23% vs 8%; P=.02).
The benefit of a hydrogel spacer in reducing the rectal dose, toxicity, and QOL declines after image guided intensity modulated radiation therapy for prostate cancer was maintained or increased with a longer follow-up period, providing stronger evidence for the benefit of hydrogel spacer use in prostate radiation therapy.
Perirectal spacing, whereby biomaterials are placed between the prostate and rectum, shows promise in reducing rectal dose during prostate cancer radiation therapy. A prospective multicenter ...randomized controlled pivotal trial was performed to assess outcomes following absorbable spacer (SpaceOAR system) implantation.
Overall, 222 patients with clinical stage T1 or T2 prostate cancer underwent computed tomography (CT) and magnetic resonance imaging (MRI) scans for treatment planning, followed with fiducial marker placement, and were randomized to receive spacer injection or no injection (control). Patients received postprocedure CT and MRI planning scans and underwent image guided intensity modulated radiation therapy (79.2 Gy in 1.8-Gy fractions). Spacer safety and impact on rectal irradiation, toxicity, and quality of life were assessed throughout 15 months.
Spacer application was rated as "easy" or "very easy" 98.7% of the time, with a 99% hydrogel placement success rate. Perirectal spaces were 12.6 ± 3.9 mm and 1.6 ± 2.0 mm in the spacer and control groups, respectively. There were no device-related adverse events, rectal perforations, serious bleeding, or infections within either group. Pre-to postspacer plans had a significant reduction in mean rectal V70 (12.4% to 3.3%, P<.0001). Overall acute rectal adverse event rates were similar between groups, with fewer spacer patients experiencing rectal pain (P=.02). A significant reduction in late (3-15 months) rectal toxicity severity in the spacer group was observed (P=.04), with a 2.0% and 7.0% late rectal toxicity incidence in the spacer and control groups, respectively. There was no late rectal toxicity greater than grade 1 in the spacer group. At 15 months 11.6% and 21.4% of spacer and control patients, respectively, experienced 10-point declines in bowel quality of life. MRI scans at 12 months verified spacer absorption.
Spacer application was well tolerated. Increased perirectal space reduced rectal irradiation, reduced rectal toxicity severity, and decreased rates of patients experiencing declines in bowel quality of life. The spacer appears to be an effective tool, potentially enabling advanced prostate RT protocols.
Introduction
Growing evidence shows a causal role of high-risk humane papillomavirus (HPV) infections in the development of head and neck cancer. A recent case report shows two patients suffering ...from tonsillar cancer without any risk factors apart from their work as gynecologists doing laser ablations and loop electrosurgical excision procedures (LEEP). The aim of the present investigation is to evaluate whether surgical plume resulting from routine LEEPs of HSIL of the cervix uteri might be contaminated with the DNA of high-risk HPV.
Materials and methods
The prospective pilot study is done at the Department of Gynecology and Obstetrics of the University of Lübeck, Germany. The primary outcome was defined as HPV subtype in resected cone and in surgical plume resulting from LEEPs of HSIL of the cervix uteri. Plume resulting from LEEPs was analyzed using a Whatman FTA Elute Indicating Card which was placed in the tube of an exhaust suction device used to remove the resulting aerosols. For detection of HPV and analysis of its subtype, the novel EUROArray HPV test was performed. Resected cones of LEEPs were evaluated separately for HPV subtypes.
Results
Four samples of surgical plume resulting from routine LEEPs indicated contamination with high-risk HPV and showed the same HPV subtype as identified in the resected cones.
Conclusion
Surgical plume resulting from routine LEEPs for HSIL of the cervix uteri has the risk of contamination with high-risk HPV. Further investigations of infectiousness of surgical plume are necessary for evaluation of potential hazards to involved healthcare professionals.
Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRASG12C inhibitors. Thus, inhibitors with broad potential for combination ...treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRASG12C inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRASG12C C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).
Socioeconomic factors are associated with worse disease severity at presentation in sarcoidosis, but the relative importance of socioeconomic variables on morbidity and disease burden has not been ...fully elucidated.
To determine the association between income and sarcoidosis outcomes after controlling for socioeconomic and disease-related factors.
Using the Sarcoidosis Advanced Registry for Cures database, we analyzed data from 2,318 patients with sarcoidosis in the United States to determine the effect of income and other variables on outcomes. We divided comorbidities arising after diagnosis into those likely related to steroid use and those likely related to sarcoidosis. We assessed the development of health-related, functional, and socioeconomic outcomes following the diagnosis of sarcoidosis.
In multivariate analysis, low-income patients had significantly higher rates of new sarcoidosis-related comorbidities (<$35,000, odds ratio OR, 2.4 1.7-3.3; $35,000-84,999, OR, 1.4 1.1-1.9; and ≥$85,000 reference (Ref)) and new steroid-related comorbidities (<$35,000, OR, 1.3 0.9-2.0; $35,000-84,999, OR, 1.5 1.1-2.1; and ≥$85,000 Ref), had lower health-related quality of life as assessed by the Sarcoidosis Health Questionnaire (
< 0.001), and experienced more impact on family finances (<$35,000, OR, 7.9 4.9-12.7; $35,000-84,999, OR, 2.7 1.9-3.9; and ≥$85,000 Ref). The use of supplemental oxygen, need for assistive devices, and job loss were more common in lower income patients. Development of comorbidities after diagnosis of sarcoidosis occurred in 63% of patients and were strong independent predictors of poor outcomes. In random forest modeling, income was consistently a leading predictor of outcome.
These results suggest the burden from sarcoidosis preferentially impacts the economically disadvantaged.
RAS-MAPK signalling is fundamental for cell proliferation and is altered in most human cancers
. However, our mechanistic understanding of how RAS signals through RAF is still incomplete. Although ...studies revealed snapshots for autoinhibited and active RAF-MEK1-14-3-3 complexes
, the intermediate steps that lead to RAF activation remain unclear. The MRAS-SHOC2-PP1C holophosphatase dephosphorylates RAF at serine 259, resulting in the partial displacement of 14-3-3 and RAF-RAS association
. MRAS, SHOC2 and PP1C are mutated in rasopathies-developmental syndromes caused by aberrant MAPK pathway activation
-and SHOC2 itself has emerged as potential target in receptor tyrosine kinase (RTK)-RAS-driven tumours
. Despite its importance, structural understanding of the SHOC2 holophosphatase is lacking. Here we determine, using X-ray crystallography, the structure of the MRAS-SHOC2-PP1C complex. SHOC2 bridges PP1C and MRAS through its concave surface and enables reciprocal interactions between all three subunits. Biophysical characterization indicates a cooperative assembly driven by the MRAS GTP-bound active state, an observation that is extendible to other RAS isoforms. Our findings support the concept of a RAS-driven and multi-molecular model for RAF activation in which individual RAS-GTP molecules recruit RAF-14-3-3 and SHOC2-PP1C to produce downstream pathway activation. Importantly, we find that rasopathy and cancer mutations reside at protein-protein interfaces within the holophosphatase, resulting in enhanced affinities and function. Collectively, our findings shed light on a fundamental mechanism of RAS biology and on mechanisms of clinically observed enhanced RAS-MAPK signalling, therefore providing the structural basis for therapeutic interventions.
Background
Simulation-based care pathway approach (CPA) training is a novel approach in surgical education. The objective of the present study was to determine whether CPA was feasible for training ...surgical residents and could improve efficiency in patients’ management. A common disease was chosen: acute appendicitis.
Methods
All five junior residents of our department were trained in CPA: preoperative CPA consisted in virtual patients (VPs) presenting with acute right iliac fossa pain; intraoperative CPA involved a virtual competency-based curriculum for laparoscopic appendectomy (LAPP); finally, post-operative VP were reviewed after LAPP. Thirty-eight patients undergoing appendectomy were prospectively included before (
n
= 21) and after (
n
= 17) the training. All demographic and perioperative data were prospectively collected from their medical records, and time taken from admission to management was measured.
Results
All residents had performed less than 10 LAPP as primary operator. Pre- and intraoperative data were comparable between pretraining and post-training patients. Times to liquid and solid diet were significantly reduced after training 7 h (2–20) vs. 4 (4–6);
P
= 0.004, and 17 h (4–48) vs. 6 (4–24);
P
= 0.005 without changing post-operative morbidity 4 (19%) vs. 0 (0);
P
= 0.11 and length of stay 48 h (30–264) vs. 44 (21–145);
P
= 0.22.
Conclusions
CPA training is feasible in abdominal surgery. In the current study, it improved patients’ management in terms of earlier oral intake.
Background
This study investigated whether deliberate practice leads to an increase in surgical quality in virtual reality (VR) laparoscopic cholecystectomies (LC). Previous research has suggested ...that sustained DP is effective in surgical training.
Methods
Fourteen residents were randomized into deliberate practice (
n
= 7) or control training (
n
= 7). Both groups performed ten sessions of two VR LCs. Each session, the DP group was assigned 30 min of DP activities in between LCs while the control group viewed educational videos or read journal articles. Performance was assessed on speed and dexterity; quality was rated with global (GRS) and procedure-specific (PSRS) rating scales. All participants then performed five porcine LCs.
Results
Both groups improved over 20 VR LCs in time, dexterity, and global rating scales (all
p
< 0.05). After 20 LCs, there were no differences in speed or dexterity between groups. The DP group achieved higher quality of VR surgical performance than control for GRS (26 vs. 20,
p
= 0.001) and PSRS (18 vs. 15,
p
= 0.001). For VR cases, DP subjects plateaued at GRS = 25 after ten cases and control group at GRS = 20 after five cases. At completion of VR training, 100 % of the DP group reached target quality of performance (GRS ≥ 21) compared with 30 % in the control group. There were no significant differences for improvements in time or dexterity over five porcine LCs.
Conclusion
This study suggests that DP leads to higher quality performance in VR LC than standard training alone. Standard training may leave individuals in a state of “arrested development” compared with DP.
Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRAS
inhibitors. Thus, inhibitors with broad potential for combination treatment ...and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRAS
inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRAS
C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).
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