The Feasibility of a Novel Recruitment Protocol for Collecting Survivor Data via Disclosure Recipient Referrals

The current arricle describes a novel recruitment protocol for collecting data from sexual assault and intimate partner violence survivors referred to research studies by individuals to whom they had previously disclosed. Challenges in both recruiting participants and interpreting data are described. Only 35.8% of cases had usable data for both survivors and disclosure recipients, suggesting that this referral method had limited success in recruiting matched pairs. Suggestions for modifications to improve the protocol for future research are offered. Potential advantages and drawbacks of various methods for recruiting dyads are described in order to facilitate future research on survivors’ disclosure processes, social reactions, and the influence of social reactions on survivor recovery.

Magnetic resonance imaging in the evaluation of cervical foraminal stenosis: comparison of 3D T2 SPACE with sagittal oblique 2D T2 TSE

Objective The oblique orientation of the cervical neural foramina challenges the implementation of a short MRI protocol with concurrent excellent visualization of the spine. While sagittal oblique T2-weighted sequences permit good evaluation of the cervical neuroforamina, all segments may not be equally well depicted on a single sequence and conspicuity of foraminal stenosis may be limited. 3D T2-weighted sequences can be reformatted in arbitrary planes, including the sagittal oblique. We set out to compare 3D T2w SPACE sequences with sagittal oblique reformations and sagittal oblique 2D T2w TSE sequences for the evaluation of cervical foraminal visibility and stenosis. Materials and methods Sixty consecutive patients who underwent MRI of the cervical spine with sagittal oblique 2D T2w TSE and 3D T2w SPACE sequences were included. Image homogeneity of the sequences was evaluated. Imaging sets were assessed for structure visibility and foraminal stenosis by two independent readers. Results of the sequences were compared by Wilcoxon matched-pairs tests. Interreader agreement was evaluated by weighted κ. Results Visibility of most structures was rated good to excellent on both sequences (mean visibility scores ≥ 4.5 of 5), though neuroforaminal contents were better seen on sagittal oblique T2w TSE (mean scores 4.1–4.6 vs. 3.1–4.1 on 3D T2w SPACE, p < 0.01). Stenosis grades were comparable between sequences (mean 1.1–2.6 of 4), with slightly higher values for 3D T2w SPACE at some levels (difference ≤ 0.3 points). Conclusion 3D T2w SPACE is comparable with sagittal oblique 2D T2w TSE in the evaluation of cervical neural foramina.

Visualization of bone details in a novel photon-counting dual-source CT scanner—comparison with energy-integrating CT

Objectives Photon-counting detector CT (PCD-CT) promises a leap in spatial resolution due to smaller detector pixel sizes than implemented in energy-integrating detector CTs (EID-CT). Our objective was to compare the visualization of smallest bone details between PCD-CT and EID-CT using a mouse as a specimen. Materials and methods Two euthanized mice were scanned at a 20-slice EID-CT and a dual-source PCD-CT in single-pixel mode at various CTDIVol values. Image noise and signal-to-noise ratio (SNR) were evaluated using repeated ROI measurements. Edge sharpness of bones was compared by the maximal slope within CT value plots along sampling lines intersecting predefined bones of the spine. Two readers evaluated bone detail visualization at four regions of the spine on a three-point Likert scale at various CTDIVol’s. Two radiologists selected the series with better detail visualization among each of 20 SNR-matched pairs of EID-CT and PCD-CT series. Results In CTDIVol-matched scans, PCD-CT series showed significantly lower image noise (NoiseCTDI=5 mGy: 16.27 ± 1.39 vs. 23.46 ± 0.96 HU, p < 0.01), higher SNR (SNRCTDI=5 mGy: 20.57 ± 1.89 vs. 14.00 ± 0.66, p < 0.01), and higher edge sharpness (Edge Slopelumbar spine: 981 ± 160 vs. 608 ± 146 HU/mm, p < 0.01) than EID-CT series. Two radiologists considered the delineation of bone details as feasible at consistently lower CTDIVol values at PCD-CT than at EID-CT. In comparison of SNR-matched reconstructions, PCD-CT series were still considered superior in almost all cases. Conclusions In this head-to-head comparison, PCD-CT showed superior objective and subjective image quality characteristics over EID-CT for the delineation of tiniest bone details. Even in SNR-matched pairs (acquired at different CTDIVol’s), PCD-CT was strongly preferred by radiologists. Key Points • In dose-matched scans, photon-counting detector CT series showed significantly less image noise, higher signal-to-noise ratio, and higher edge sharpness than energy-integrating detector CT series. • Human observers considered the delineation of tiny bone details as feasible at much lower dose levels in photon-counting detector CT than in energy-integrating detector CT. • In direct comparison of series matched for signal-to-noise ratio, photon-counting detector CT series were considered superior in almost all cases.

Discordance of PIK3CA and TP53 mutations between breast cancer brain metastases and matched primary tumors

There is limited knowledge of the biology of breast cancer (BC) brain metastasis (BM). We primarily aimed to determine the mutations in BCBM and to compare the mutational pattern with the matched primary breast cancer (BC). Secondary aims were to determine mutations in each subgroup (Luminal A-/B-like, HER2+ and TNBC) of BCBM, and to determine survival according to specific mutations. We investigated 57 BCBMs, including 46 cases with matched primary tumors (PT) by targeted Next Generation Sequencing (NGS) using the Cancer Hotspot Panel v2 (ThermoFisher Scientific) covering 207 targeted regions in 50 cancer related genes. Subtype according to immunohistochemistry was re-evaluated. NGS results fulfilling sequencing quality criteria were obtained from 52 BM and 41 PT, out of which 37 were matched pairs. Pathogenic mutations were detected in 66% of PTs (27/41), and 62% of BMs (32/52). TP53 mutations were most frequent; 49% (20/41) of PTs and 48% (25/52) in BMs, followed by PIK3CA mutations; 22% (9/42) in PTs and 25% (13/52) in BMs. Mutations in CDH1, EGFR, HRAS, RB1 CDKN2A and PTEN were detected in single pairs or single samples. Mutational pattern was discordant in 24% of matched pairs. We show a discordance of PIK3CA and TP53 mutations of roughly 25% indicating the need to develop methods to assess mutational status in brain metastasis where analysis of cell-free DNA from cerebrospinal fluid (CSF) has shown promising results.

Companies under stress: the impact of shocks on the production network

In this paper we analyze the effect of shocks in production networks. Our work is based on a rich dataset that contains information about companies from Slovenia right after the financial crisis of 2008. The processed data spans for 8 years and covers the transaction history as well as performance indicators and various metadata of the companies. We define sales shocks at different levels, and identify companies impacted by them. Next we investigate stress, the potential immediate upstream and downstream impact of a shock within the production network. We base our main findings on a matched pairs analysis of stressed companies. We find that both shock and stress are associated with reporting bankruptcy in the future and that stress foremost impacts the future sales of customers. Furthermore, we find evidence that stress not only results in performance losses but the reconfiguration of the production network as well. We show that stressed companies actively seek for new trading partners, and that these new links often share the industry of the shocked company. These results suggest that both stressed customers and suppliers react quickly to stress and adjust their trading relationships.

Deciphering the Molecular Mechanism of HCV Protease Inhibitor Fluorination as a General Approach to Avoid Drug Resistance

Third generation Hepatitis C virus (HCV) NS3/4A protease inhibitors (PIs), glecaprevir and voxilaprevir, are highly effective across genotypes and against many resistant variants. Unlike earlier PIs, these compounds have fluorine substitutions on the P2-P4 macrocycle and P1 moieties. Fluorination has long been used in medicinal chemistry as a strategy to improve physicochemical properties and potency. However, the molecular basis by which fluorination improves potency and resistance profile of HCV NS3/4A PIs is not well understood. To systematically analyze the contribution of fluorine substitutions to inhibitor potency and resistance profile, we used a multi-disciplinary approach involving inhibitor design and synthesis, enzyme inhibition assays, co-crystallography, and structural analysis. A panel of inhibitors in matched pairs were designed with and without P4 cap fluorination, tested against WT protease and the D168A resistant variant, and a total of 22 high-resolution co-crystal structures were determined. While fluorination did not significantly improve potency against the WT protease, PIs with fluorinated P4 caps retained much better potency against the D168A protease variant. Detailed analysis of the co-crystal structures revealed that PIs with fluorinated P4 caps can sample alternate binding conformations that enable adapting to structural changes induced by the D168A substitution. Our results elucidate molecular mechanisms of fluorine-specific inhibitor interactions that can be leveraged in avoiding drug resistance.

Outcomes in high and low volume hospitals in patients with acute hematochezia in a cohort study

Outcomes of acute lower gastrointestinal bleeding have not been compared according to hospital capacity. We aimed to perform a propensity score-matched cohort study with path and mediation analyses for acute hematochezia patients. Hospitals were divided into high- versus low-volume hospitals for emergency medical services. Rebleeding and death within 30 days were compared. Computed tomography, early colonoscopy (colonoscopy performed within 24 h), and endoscopic therapies were included as mediators. A total of 2644 matched pairs were yielded. The rebleeding rate within 30 days was not significant between high- and low-volume hospitals (16% vs. 17%, P = 0.44). The mortality rate within 30 days was significantly higher in the high-volume cohort than in the low-volume cohort (1.7% vs. 0.8%, P = 0.003). Treatment at high-volume hospitals was not a significant factor for rebleeding (odds ratio [OR] = 0.91; 95% confidence interval [CI], 0.79–1.06; P = 0.23), but was significant for death within 30 days (OR = 2.03; 95% CI, 1.17–3.52; P = 0.012) on multivariate logistic regression after adjusting for patients’ characteristics. Mediation effects were not observed, except for rebleeding within 30 days in high-volume hospitals through early colonoscopy. However, the direct effect of high-volume hospitals on rebleeding was not significant. High-volume hospitals did not improve the outcomes of acute hematochezia patients.

Discordance of PIK3CA and TP53 Mutations Between Breast Cancer Brain Metastases and Matched Primary Tumors

Purpose: There is limited knowledge of the biology of breast cancer (BC) brain metastasis (BM). We primarily aimed to determine the mutations in BCBM and to compare the mutational pattern with the matched primary breast cancer (BC). Secondary aims were to determine mutations in each subgroup (Luminal, HER2+ and TNBC) of BCBM and to determine survival according to specific mutations. Patients and methods: We investigated 57 BCBMs, including 46 cases with matched primary tumors (PT) by targeted Next Generation Sequencing (NGS) using the Cancer Hotspot Panel v2 (ThermoFisher Scientific) covering 207 targeted regions in 50 cancer related genes. Subtype according to immunohistochemistry was re-evaluated. Results: NGS results fulfilling sequencing quality criteria were obtained from 52 BM and 41 PT, out of which 37 were matched pairs. Pathogenic mutations were detected in 66% of PTs (27/41), and 62% of BMs (32/52). TP53 mutations were most frequent; 49% (20/41) of PTs and 48% (25/52) in BMs, followed by PIK3CA mutations; 22% (9/42) in PTs and 25% (13/52) in BMs. Mutations in CDH1, EGFR, HRAS, RB1 CDKN2A and PTEN were detected in single pairs or single samples. Mutational pattern was discordant in 24% of matched pairs. Conclusions: We show a discordance of PIK3CA and TP53 mutations of roughly 25% indicating the need to develop methods to assess mutational status in brain metastasis where analysis of cell-free DNA from cerebrospinal fluid (CSF) has shown promising results.