bluuebunny/crossref_metadata_2025 huggingface dataset:
High unbound flucloxacillin fraction in critically ill patients
Authors: Wallenburg Eveline , ter Heine Rob , de Lange Dylan W , van Leeuwen Henk , Schouten Jeroen A , ten Oever Jaap , Kolwijck Eva , Burger David M , Pickkers Peter , Gieling Emilie M , de Maat Monique M , Frenzel Tim , Brüggemann Roger J
Published: August 2021

Objectives

To describe the unbound and total flucloxacillin pharmacokinetics in critically ill patients and to define optimal dosing strategies.

Patients and methods

Observational multicentre study including a total of 33 adult ICU patients receiving flucloxacillin, given as intermittent or continuous infusion. Pharmacokinetic sampling was performed on two occasions on two different days. Total and unbound flucloxacillin concentrations were measured and analysed using non-linear mixed-effects modelling. Serum albumin was added as covariate on the maximum binding capacity and endogenous creatinine clearance (CLCR) as covariate for renal function. Monte Carlo simulations were performed to predict the unbound flucloxacillin concentrations for different dosing strategies and different categories of endogenous CLCR.

Results

The measured unbound concentrations ranged from 0.2 to 110 mg/L and the observed unbound fraction varied between 7.0% and 71.7%. An integral two-compartmental linear pharmacokinetic model based on total and unbound concentrations was developed. A dose of 12 g/24 h was sufficient for 99.9% of the population to achieve a concentration of >2.5 mg/L (100% fT>5×MIC, MIC = 0.5 mg/L).

Conclusions

Critically ill patients show higher unbound flucloxacillin fractions and concentrations than previously thought. Consequently, the risk of subtherapeutic exposure is low.
G. R. Driver’s Contribution to Neb’s Translation of Psalms 51–100
Authors: Clackson Ben
Published: August 2021

The influence of G. R. Driver on the translation of the Old Testament in The New English Bible has been controversial particularly in light of Barr’s critique of his use of comparative philology. This article takes a sample of 18 instances of translations of verses in Psalms 51–100 which reflected proposals made in his articles. It explains the proposals, examines their influence on recent Hebrew lexicography, and shows which proposals were subsequently dropped in Psalms: a New Translation for Worship or The Revised English Bible, in order to reassess which proposals have stood the test of time. It is concluded that about half of Driver’s proposals still seem probable, which suggests that wholesale rejection of Driver’s work is unwarranted.
High-energy radiation from luminous and magnetized stars
Authors: Bednarek W
Published: August 2021

A part of early-type stars is characterized by strong dipole magnetic field that is modified by the outflow of dense wind from the stellar surface. At some distance from the surface (above the Alfvén radius), the wind drives the magnetic field into the reconnection in the equatorial region of the dipole magnetic field. We propose that electrons accelerated in these reconnection regions can be responsible for efficient Comptonization of stellar radiation producing gamma-ray emission. We investigate the propagation of electrons in the equatorial region of the magnetosphere by including their advection with the equatorial wind. The synchrotron and Inverse Compton (IC) spectra are calculated assuming that a significant part of the wind energy is transferred to relativistic electrons. As an example, the parameters of luminous, strongly magnetized star HD 37022 (Θ1 Ori C) are considered. The IC gamma-ray emission is predicted to be detected either in the GeV energy range by the Fermi-LAT telescope or in the sub-TeV energies by the Cherenkov Telescope Array. However, since the stellar winds are often time variable and the magnetic axis can be inclined to the rotational axis of the star, the gamma-ray emission is expected to show variability with the rotational period of the star and, on a longer time-scale, with the stellar circle of the magnetic activity. Those features might serve as tests of the proposed scenario for gamma-ray emission from single, luminous stars.
Imaging results from the legacy Giant Metrewave Radio Telescope Galaxy Cluster Key Project
Authors: George Lijo T , Kale Ruta , Wadadekar Yogesh
Published: August 2021

We have used archival Giant Metrewave Radio Telescope (GMRT) data to image and study 39 galaxy clusters. These observations were made as part of the GMRT Key Project on galaxy clusters between 2001 and 2004. The observations presented in this sample include 14 observations at 610 MHz, 29 at 325 MHz, and three at 244 MHz covering a redshift range of 0.02–0.62. Multifrequency observations were made for eight clusters. We analysed the clusters using the spam processing software and detected the presence of radio halo emission for the first time in the clusters RXC J0510−0801 and RXC J2211.7−0349. We also confirmed the presence of extended emission in 11 clusters which were known from the literature. In clusters where haloes were not detected, upper limits were placed using our own semi-automated program. We plot our detections and non-detections on the empirical LX−P1.4 and M500−P1.4 relation in radio halo clusters and discuss the results. The best fits follow a power law of the form $L_{500} \propto P_{1.4}^{1.82}$ and $M_{500} \propto P_{1.4}^{3.001}$ which is in accordance with the best estimates in the literature.
LMD-05. Phase 1B Study of Avelumab and Whole Brain Radiotherapy (WBRT) in Patients with Leptomeningeal Disease (LMD): Preliminary Results
Authors: Pina Yolanda , Chen Ann , Arrington John , Macaulay Robert , Tran Nam , Liu James , Mokhtari Sepideh , Li Jiannong , Law Vincent , Sahebjam Solmaz , Ahmed Kamran , Creelan Ben , Gray Jhanelle , Khushalani Nikhil , Smalley Inna , Smalley Keiran , Vogelbaum Michael , Yu Michael , Forsyth Peter
Published: August 2021

Background

LMD has a dismal prognosis with median survivals of 8–10 weeks. Recently the first phase 2 trial of PD-1 inhibitor monotherapy in solid tumor LMD showed median overall survival (OS) 3.6 months. We aimed to determine the safety/efficacy of avelumab with WBRT in patients with LMD from solid malignancies (NCT0371768). This combination can treat tumor directly and increase the permeability of the blood-brain-barrier with increased egress of activated T cells into the meninges/CSF and facilitated Avelumab entry into the CSF.

Hypothesis

Combination radioimmunotherapy will produce an activated immunocyte/cytokine profile in CSF.

Methods

Patients received concurrent Avelumab 800mg IV q2weeks x≤5 cycles with WBRT 3000cGy, 10 fractions. Primary endpoints: Safety/DLTs and OS at 3 months. Secondary endpoints: CSF T-cell/cytokine profiles (scRNAseq/phosophoproteomics) and clinical outcomes, to be performed when all 15 patients are accrued to minimize batch effects.

Results

Ten patients (5 breast, 4 lung & 1 undifferentiated sinonasal carcinoma) were enrolled (n=8 females, n=2 males, ages 32–79); n=1 patient did not complete WBRT. Patients who received anti-PD-1/PD-1L/PD-L2/CD137/CTLA-4 therapy within 6 months prior to enrollment were excluded. 30% had grade 3 AEs at least possibly related to treatment (n=3 diarrhea, lymphopenia, decreased WBC count). There were no grade 4–5 toxicities. Six patients (66.7%) were alive at 3 months. The estimated median follow up in 9 patients (regardless whether patients failed or not) is 10.49 months (range, 0.95–19.82 months, 95% CI) and the estimated median follow up survival was 19.8 months assessed using the reverse Kaplan-Meier method. Median PFS is 4.27 months (range, 0.30–16.73 months, 95% CI).

Conclusions

In this pilot study, combination of Avelumab and WBRT is safe, and demonstrates encouraging activity in patients with solid tumor LMD. Multiple platform interrogation of CSF may determine mechanisms of LMD therapeutic effects and differentiate responders from non-responders.
RADI-03. A strategy to personalize the use of radiation in patients with brain metastasis based on S100A9-mediated resistance
Authors: Miarka Lauritz , Moteiro Catia , Dalmasso Celine , Fustero-Torre Coral , Yebra Natalia , Hegarty Aisling , Keelan Stephen , Goy Yvonne , Mohme Malte , Caleiras Eduardo , Damir Vareslija , Young Leonie , Soffietti Riccardo , Fernández-Alén Jose , Blasco Guillermo , Alcazar Lucia , Sepúlveda Juan Manuel , Perez Angel , Lain Aurelio , Siegfried Aurore , Wikman Harriet , Moyal Elisabeth Cohen-Jonathan , Valiente Manuel
Published: August 2021

Finding effective treatment options for patients with brain metastasis remains an unmet need. Given the limitations imposed by the blood-brain-barrier for systemic approaches, radiotherapy offers a superior ability to access the brain. While clinical practice recently adapted the use of stereotactic radiosurgery (SRS), Whole-Brain-Radiotherapy (WBRT) continuous to be an important treatment option, since many patients present with multifocal lesions or bad performance scores, rendering them ineligible for SRS. Unfortunately, overall survival of patients remains unaffected by radiotherapy. Despite this clinical data, the molecular mechanisms that allow metastatic cells to resist radiotherapy in the brain is unknown. We have applied WBRT to experimental brain metastasis from lung and breast adenocarcinoma and validated their resistance in vivo. An unbiased search to identify potential mediators of resistance identified the S100A9-RAGE-NFkB-JunB pathway. Targeting this pathway genetically reverts the resistance to radiotherapy and increases therapeutic benefits in vivo. In two independent cohorts of brain metastasis from lung and breast adenocarcinoma patients, levels of S100A9 correlate with the response to radiotherapy, offering a novel approach to stratify patients according to their expected benefit. In order to make this biomarker also available for brain metastasis patients receiving palliative WBRT without preceding surgery, we complemented our tumor-specimen based approach with the less invasive detection of S100A9 from liquid biopsies. Here, serum S100A9 also correlated with a worse response to WBRT in brain metastasis patients. Furthermore, we have validated the use of a blood-brain-barrier permeable RAGE inhibitor to restore radio-sensitivity in experimental brain metastasis models in vivo and in patient-derived organotypic cultures of radio-resistant brain metastasis ex vivo. In conclusion, we identified S100A9 as a major mediator of radio-resistance in brain metastasis and offer the molecular framework to personalize radiotherapy by exploiting it as a biomarker and as a therapeutic target, thus maximizing the benefits for the patient.
RADI-19. The Incidence of New Brain Metastases in Patients with Non-Small Cell Lung Cancer Following Discontinuation of Systemic Therapy
Authors: London Dennis , Patel Dev , Donahue Bernadine , Navarro Ralph , Gurewitz Jason , Silverman Joshua , Sulman Erik , Bernstein Kenneth , Palermo Amy , Golfinos John , Sabari Joshua , Shum Elaine , Velcheti Vamsidhar , Chachoua Abraham , Kondziolka Douglas
Published: August 2021

Purpose

Patients with non-small cell lung cancer (NSCLC) metastatic to the brain increasingly are living longer due to improvements in systemic therapy and local modalities. The risk of new brain metastases when these patients stop systemic therapy is unknown. Recognizing patterns of new tumor occurrence is necessary to determine the frequency of follow-up and the need for further treatment.

Methods

We included patients in a prospective registry who had non-small cell lung cancer (NSCLC) brain metastases, discontinued systemic therapy for at least 90 days, and underwent active surveillance. 63 patients with 73 off-periods were studied. The risk factors for the development of new tumors were determined using Cox regression and multi-state Markov modeling.

Results

The median time to new brain metastases off systemic therapy was 16.0 months. The probability of developing an additional new tumor at 6, 12, and 18 months was 26%, 40%, and 53%, respectively. There were no additional new tumors 22 months after stopping therapy. Patients who discontinued therapy due to intolerance or progression of the disease and those with mutations in RAS or receptor tyrosine kinase pathways (e.g. KRAS, EGFR) were more likely to develop new tumors (HR: 2.21, 95% CI: 1.25–3.91, p=6.3 x 10–3; HR: 2.03, 95% CI: 1.09–3.77, p=0.026, respectively).

Conclusion

The rate of new brain metastases from NSCLC in patients off systemic therapy decreases over time and is uncommon 2 years after cessation of cancer therapy. Patients who stop therapy due to toxicity or who have RAS or receptor tyrosine kinase pathway mutations have a higher rate of new metastases and should be followed more closely.
SURG-05. Neurosurgery for brain metastases from non-small cell lung cancer: survival outcome and prognostic factors
Authors: Li De-pei , Wang Zhen-ning , Duan Hao , Guo Cheng-cheng , Jiang Xiao-bing , Mou Yong-Gao
Published: August 2021

Background

Surgery is an important approach to treat non-small cell lung cancer (NSCLC) brain metastases (BM). Here, we analyzed the survival outcome and prognostic factors for patients with NSCLC after BM resection.

Methods

The Surveillance Epidemiology and End Results (SEER) database was employed to address the incidence of BM from NSCLC and the current prognosis at population level. 674 contemporaneous NSCLC patients received BM resection at Sun Yat-sen University Cancer Center (SYSUCC) were used for survival comparison and Cox proportional hazards model was applied for identifying prognostic factors.

Results

60,436 NSCLC patients diagnosed between 2010 to 2017 were enrolled from SEER database. Among them, 8,708 (14.4%) BM were identified at primary NSCLC diagnosis (synchronous BM, SBM). Median overall survival (OS) of SBM was 6 months with 1-, and 3-year survival percentages of 30.3% and 9.8%, respectively. Furthermore, the survival of BM patients without extracranial metastasis is significantly longer than those with extracranial metastases (median OS: 10 versus 5 months, P<0.001). 225 SBM (cohort A) and 449 BM with treatment history on primary NSCLC (cohort B) were collected from SYSUCC. In cohort A, 86 BM with extracranial metastases were found (38.2%) and the median OS was significantly shorter than those without extracranial metastases (15.2 versus 23.7 months, P<0.001). In cohort B, 255 cases with extracranial metastases were found (56.8%) and their prognosis was also worse than cases without extracranial metastases (median OS: 18.3 versus 22.1 months, P=0.002). Multivariate analyses revealed that younger age (HR=0.71, P=0.003), without extracranial metastases (HR=0.65, P<0.001) and radiation for BM (HR=0.78, P=0.005) were independent factors for better OS.

Conclusion

Improved survival of patients received BM resection was observed in SYSUCC cohort as comparison with SEER patients with NSCLC and BM. Aggressive local treatment including surgery and radiation is still important in Modern management of BM from NSCLC.
SURG-07. Plasmonic gold nanostars to increase the efficiency and specificity of laser interstitial thermal therapy (LITT) in the treatment of brain tumors
Authors: Srinivasan Ethan , Chongsathidkiet Pakawat , Odion Ren , Liu Yang , Sankey Eric , Vo-Dinh Tuan , Fecci Peter
Published: August 2021

Introduction

Laser interstitial thermal therapy (LITT) is an effective minimally-invasive treatment option for intracranial tumors. Our group produced plasmonics-active gold nanostars (GNS) designed to preferentially accumulate within intracranial tumors and amplify the ablative capacity of LITT while better conforming to tumor boundaries and protecting surrounding tissue.

Materials and Methods: The 12nm GNS were synthesized using reduced HAuCl4 with Na3C6H5O7 seeds, mixed with AgNO3, C6H8O6, and HAuCL4, and coated with polyethylene glycol then functionalized with methoxy PEG thiol. CT-2A glioma cells were intracranially implanted into mice, followed 18 days later by IV injection of GNS. PET-CT was performed at 10-minutes, 24-, and 72-hours post-GNS administration, with autoradiography (AR) and histopathology (HP) on sacrifice after the last scan. To test the impact of GNS on LITT coverage capacity in appropriately sized ex vivo models, we utilized agarose gel-based phantoms incorporating control and GNS-infused central “tumors” in multiple shapes. LITT was administered with the NeuroBlate System.

Results

In vivo, GNS preferentially accumulated within intracranial tumors on PET-CT at the 24- and 72-hour timepoints. AR and HP confirmed high GNS accumulation within tumor. Ex vivo, in cuboid tumor phantoms, the GNS-infused phantom heated 5.5x faster than the control, rising 0.49°C per minute compared to 0.09°C. In a split-cylinder tumor phantom with half containing GNS, the GNS-infused border heated 2x faster and the surrounding area was exposed to 30% lower temperatures. In a GNS-infused star-shaped phantom, the heat spread contoured along phantom boundaries.

Conclusion

Our results provide evidence for use of GNS to improve the specificity, efficiency, and potentially safety of LITT. The in vivo data support selective accumulation within intracranial tumors, and the GNS-infused phantom experiments demonstrate increased rates of heating within the tumor model, heat contouring to tumor borders, and decreased heating of surrounding regions representing normal structures.
SURG-08. Laser Interstitial Thermal Therapy (LITT) versus Resection in the Treatment of Lesions In or Near the Primary Motor Cortex
Authors: Srinivasan Ethan , Lerner Emily , Edwards Ryan , Huie David , Fecci Peter
Published: August 2021

Introduction

Laser interstitial thermal therapy (LITT) is a minimally-invasive treatment option for radiographically-progressive (RP) brain metastases. This study compares the functional outcomes of LITT vs resection (RS) for lesions in or near the primary motor cortex (PMC).

Methods

Retrospective review was performed of patients treated for PMC lesions by LITT or RS. Functional outcomes were graded relative to pre-treatment symptoms and categorized as improved, stable, or worsened at 30, 90, and 180 days post-LITT/RS.

Results

36 patients were identified with median follow-up of 194 days (IQR 72–503), age 64 years (57–72), and estimated baseline KPS 80 (80–90). 35 (98%) had pre-treatment weakness or motor seizure; 15 (42%) received LITT and 21 (58%) RS; all RS were performed with intra-operative motor mapping while LITT were not. All LITT patients were treated for RP lesions (radiation necrosis (RN) or disease progression) vs. 24% of RS patients (p<0.01). LITT patients trended towards smaller lesions (1.9 cm vs 2.7 cm, p=0.03) and were more likely to show RN (67% vs 5%, p<0.01) and be discharged home (87% vs 52%, p=0.04), with shorter ICU (0 vs 1 day, p<0.01) and hospital stays (1 vs. 2 days, p<0.01). At 30 days, 89% of surviving patients who received RS had stable or improved symptoms, compared to 46% of the LITT cohort (p=0.02). At 90 days, the difference was 88% to 50% (p=0.07), and at 180 days 100% to 80% (p=0.2941).

Conclusion

In the short term (30 days), patients with PMC lesions have better functional outcomes when treated with RS compared to LITT, while those who survive to the 180-day timepoint experience similar outcomes. These differences are likely due to transient, expected post-LITT edema that subsides with time. Taken together, prognosis and patient priorities are important considerations in the decision between LITT and RS.
Allostatic hypermetabolic response in PGC1α/β heterozygote mouse despite mitochondrial defects
Authors: Rodriguez‐Cuenca Sergio , Lelliot Christopher J. , Campbell Mark , Peddinti Gopal , Martinez‐Uña Maite , Ingvorsen Camilla , Dias Ana Rita , Relat Joana , Mora Silvia , Hyötyläinen Tuulia , Zorzano Antonio , Orešič Matej , Bjursell Mikael , Bohlooly‐Y Mohammad , Lindén Daniel , Vidal‐Puig Antonio
Published: August 2021

Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1β coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1β [double heterozygous (DH)] to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro‐thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria‐rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ‐specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.
Physical Activity and Perceived Health in People With Parkinson Disease During the First Wave of Covid-19 Pandemic: A Cross-sectional Study From Sweden
Authors: Leavy Breiffni , Hagströmer Maria , Conradsson David Moulaee , Franzén Erika
Published: August 2021

Background:

People with Parkinson disease (PD) are known to be at risk of physical inactivity and may therefore be especially vulnerable to negative health outcomes during the COVID-19 pandemic due to social distancing recommendations.

Purpose:

To investigate sensor-derived physical activity and perceived health of people with PD during the first wave of the COVID-19 pandemic, as well as the factors associated with these outcomes.

Methods:

Physical activity was measured over 7 days using the Actigraph GT3x accelerometer. Data were collected regarding perceived health status and physical activity habits, as well as rehabilitation attendance during the pandemic. Multiple linear and logistic regression analyses were used to identify factors associated with physical activity and perceived changes in health.

Results:

Of 89 participants, a majority (67%) reported a pandemic-related reduction in exercise habits. Women more commonly reported a reduction in scheduled exercise and cancelled rehabilitation than men. Study participants took on average 5876 ± 3180 steps per day. In the multivariate analysis, female gender, being 70 years of age and older, and greater reported mobility problems were associated with being less physically active. A pandemic-induced deterioration in health was reported by 42% and women were 5 times more likely than men to do so (odds ratio: 5.12, 95% confidence interval, 1.87-15.03; P = 0.002).

Discussion and Conclusions:

Despite a pandemic-related reduction in reported exercise habits and rehabilitation, the participants in this Swedish sample were relatively physically active. However, women were less active at moderate-vigorous levels and were at greater risk of deterioration in perceived health during this time.

Video Abstract available for more insight from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A359).
Application of Free Iliac Bone Flap Based on Superficial Circumflex Iliac Perforators in Mandibular Reconstruction
Authors: Sakata Yasuhiro , Nishioka Toshihiko , Asamura Shinichi
Published: August 2021

We introduce the application of mandibular reconstruction with the superficial circumflex iliac artery (SCIA)-based iliac bone flap. Until now, iliac bone flaps based on the SCIA have been used in relatively small bony and plane defects, such as in the orbital floor, maxilla, distal phalanx, and calcaneus. This flap has minimal donor-site morbidity compared with the conventional deep circumflex iliac artery flap, and it can be harvested simultaneously with tumor resection in most reconstructions, including those in the head and neck. A great advantage of the SCIA-based iliac bone flap is the thin and reliable large skin paddle that can be used for intraoral and lip defects. Although there are remaining problems to overcome, such as the blood circulation to the bone, this flap may be an option in mandibular reconstruction where there are large soft tissue defects, or where there is complicated peripheral arteriosclerosis or arterial abnormality.
An Algorithm Recommendation to Detect Specific Pathology of the Lacrimal Sac
Authors: Demirel Soner , Firat Murat , Firat ilknur Tuncer , Dikci Seyhan
Published: August 2021

We aimed to recommend an efficient algorithm to detect the presence of specific pathologies of the lacrimal sac (LS). The charts of 296 patients who had undergone LS biopsy were reviewed retrospectively. The age, gender, history, examination and radiological findings, sac appearance, and pathology results of the patients were recorded. The power of our data to predict the presence of potential specific pathology was identified by regression analysis. After the causality evaluation of the statistical results, an algorithm was created to differentiate specific LS pathologies from chronic dacryocystitis. Our algorithm was mainly formed by deciding on radiological examination and biopsy according to the risk scoring created by the examination findings. A specific LS pathology was observed in 11 (3.7%) patients. When we applied the recommended algorithm to cases with a suspicion of specific pathology and/or found to have a specific pathology, 36.4% of the patients would not require radiological examination and 29.6% of them would not require a biopsy. On the other hand, 80% of the frozen biopsies had been conducted on cases without a specific pathology. Managing the cases according to our algorithm would mean that frozen biopsy would be recommended in only 1 (12.5%) case without a specific pathology. Besides, the detection of cases with a specific pathology would not be prevented and the necessary diagnostic procedures would continue to be performed. Specific LS pathologies can be detected adequately, whereas decreasing unnecessary examinations and procedures in cases without a specific pathology by using our algorithm.
Phylogenomics and antimicrobial resistance of Salmonella Typhi and Paratyphi A, B and C in England, 2016–2019
Authors: Chattaway Marie Anne , Gentle Amy , Nair Satheesh , Tingley Laura , Day Martin , Mohamed Iman , Jenkins Claire , Godbole Gauri
Published: August 2021

The emergence of antimicrobial resistance (AMR) to first- and second-line treatment regimens of enteric fever is a global public-health problem, and routine genomic surveillance to inform clinical and public-health management guidance is essential. Here, we present the prospective analysis of genomic data to monitor trends in incidence, AMR and travel, and assess hierarchical clustering (HierCC) methodology of 1742 isolates of typhoidal salmonellae. Trend analysis of

Salmonella

Typhi and S. Paratyphi A cases per year increased 48 and 17.3%, respectively, between 2016 and 2019 in England, mainly associated with travel to South Asia. S. Paratyphi B cases have remained stable and are mainly associated with travel to the Middle East and South America. There has been an increase in the number of S. Typhi exhibiting a multidrug-resistant (MDR) profile and the emergence of extensively drug resistant (XDR) profiles. HierCC was a robust method to categorize clonal groups into clades and clusters associated with travel and AMR profiles. The majority of cases that had XDR S. Typhi reported recent travel to Pakistan (94 %) and belonged to a subpopulation of the 4.3.1 (H58) clone (HC5_1452). The phenotypic and genotypic AMR results showed high concordance for S. Typhi and S. Paratyphi A, B and C, with 99.99 % concordance and only three (0.01 %) discordant results out of a possible 23 178 isolate/antibiotic combinations. Genomic surveillance of enteric fever has shown the recent emergence and increase of MDR and XDR S. Typhi strains, resulting in a review of clinical guidelines to improve management of imported infections.
SCU-Net: A deep learning method for segmentation and quantification of breast arterial calcifications on mammograms
Authors: Guo Xiaoyuan , O’Neill W Charles , Vey Brianna , Yang Tianen Christopher , Kim Thomas J , Ghassemi Maryzeh , Pan Ian , Gichoya Judy Wawira , Trivedi Hari , Banerjee Imon
Published: August 2021

Purpose

Measurements of breast arterial calcifications (BAC) can offer a personalized, noninvasive approach to risk-stratify women for cardiovascular disease such as heart attack and stroke. We aim to detect and segment breast arterial calcifications in mammograms accurately and suggest novel measurements to quantify detected BAC for future clinical applications.

Methods

To separate BAC in mammograms, we propose a light-weight fine vessel segmentation method Simple Context U-Net (SCU-Net). Due to the large image size of mammograms, we adopt a patch-based way to train SCU-Net and obtain the final whole-image-size results by stitching patch-wise results together. To further quantify calcifications, we test five quantitative metrics to inspect the progression of BAC for subjects: Sum of Mask Probability Metric (𝒫ℳ), Sum of Mask Area Metric (𝒜ℳ), Sum of Mask Intensity Metric (𝒮ℐℳ), Sum of Mask Area with Threshold Intensity Metric (𝒯𝒜ℳX) and Sum of Mask Intensity with Threshold X Metric (𝒯 𝒮ℐℳX). Finally, we demonstrate the ability of the metrics to longitudinally measure calcifications in a group of 26 subjects and evaluate our quantification metrics compared to calcified voxels and calcium mass on breast CT for 10 subjects.

Results

Our segmentation results are compared with state-of-the-art network architectures based on recall, precision, accuracy, F1-score/Dice Score and Jaccard Index evaluation metrics and achieve corresponding values of 0.789, 0.708, 0.997, 0.729, and 0.581 for whole-image-size results. The quantification results all show >95% correlation between quantification measures on predicted masks of SCU-Net as compared to the groundtruth and measurement of calcification on breast CT. For the calcifications quantification measurement, our calcification volume (voxels) results yield R2-correlation values of 0.834, 0.843, 0.832, 0.798, and 0.800 for the 𝒫ℳ, 𝒜ℳ, 𝒮ℐℳ, 𝒯𝒜ℳ100, 𝒯 𝒮ℐℳ100 metrics, respectively; our calcium mass results yield comparable R2-correlation values of 0.866, 0.873, 0.840, 0.774, and 0.798 for the same metrics.

Conclusions

SCU-Net is a simple method to accurately segment arterial calcification retrospectively on routine mammograms. Quantification of the calcifications based on this segmentation in the retrospective cohort study has sufficient sensitivity to detect the normal progression over time and should be useful for future research and clinical applications.
Analytical and Clinical Validation of an Amplicon-based Next Generation Sequencing Assay for Ultrasensitive Detection of Circulating Tumor DNA
Authors: Poh Jonathan , Ngeow Kao Chin , Pek Michelle , Tan Kian-Hin , Lim Jing Shan , Chen Hao , Ong Choon Kiat , Lim Jing Quan , Lim Soon Thye , Lim Chwee Ming , Goh Boon Cher , Choudhury Yukti
Published: August 2021

Next-generation sequencing of circulating tumor DNA presents a promising approach to cancer diagnostics, complementing conventional tissue-based diagnostic testing by enabling minimally invasive serial testing and broad genomic coverage through a simple blood draw to maximize therapeutic benefit to patients. LiquidHALLMARK® is an amplicon-based next-generation sequencing assay developed for the genomic profiling of plasma-derived cell-free DNA. The comprehensive 80-gene panel profiles point mutations, insertions/deletions, copy number alterations, and gene fusions, and further detects oncogenic viruses (EBV and HBV) and microsatellite instability. Here, the analytical and clinical validation of the assay is reported. Analytical validation using reference genetic materials demonstrated a sensitivity of 99.38% for point mutations and 95.83% for insertions/deletions at 0.1% variant allele frequency (VAF), and a sensitivity of 91.67% for gene fusions at 0.5% VAF, with high specificity even at 0.1% VAF (99.11% per-base). The limit of detection for copy number alterations, EBV, HBV, and microsatellite instability were also empirically determined. Orthogonal comparison of EGFR variant calls made by LiquidHALLMARK and a reference allele-specific PCR method for 355 lung cancer specimens revealed an overall concordance of 93.80%, while external validation with cobas® EGFR Mutation Test v2 for 50 lung cancer specimens demonstrated an overall concordance of 84.00%, with a 100% concordance rate for EGFR variants above 0.4% VAF. Clinical application of LiquidHALLMARK in 1,592 consecutive patients demonstrated a high detection rate (74.8% alteration-positive in cancer samples) and broad actionability (50.0% of cancer samples harboring alterations with biological evidence for actionability). Among ctDNA-positive lung cancers, 72.5% harbored at least one biomarker with a guideline-approved drug indication. These results establish the high sensitivity, specificity, accuracy, and precision of the LiquidHALLMARK assay and supports its clinical application for blood-based genomic testing.
Probabilistic comparison of gray and white matter coverage between depth and surface intracranial electrodes in epilepsy: a patient-specific modeling and empirical study
Authors: Anderson Daria Nesterovich , Charlebois Chantel M. , Smith Elliot H. , Arain Amir M. , Davis Tyler S. , Rolston John D.
Published: August 2021

Objective

The objective of this study is to quantify the coverage of gray and white matter during intracranial electroencephalography in a cohort of epilepsy patients with surface and depth electrodes.

Methods

We included 65 patients with strip electrodes (n=12), strip and grid electrodes (n=24), strip, grid, and depth electrodes (n=7), or depth electrodes only (n=22) from the University of Utah spanning 2010-2020. Patient-specific imaging was used to generate probabilistic gray and white matter maps and atlas segmentations. The gray and white matter coverage was quantified based on spherical volumes centered on electrode centroids, with radii ranging from 1-15 mm, along with detailed finite element models of local electric fields

Results

Gray matter coverage was highly dependent on the chosen radius of influence (RoI). Using a 2.5 mm RoI, depth electrodes covered more gray matter than surface electrodes; however, surface electrodes covered more gray matter at RoI larger than 4 mm. White matter coverage was greatest for depth electrodes at all RoIs, which is noteworthy for studies involving stimulation mapping. Depth electrodes were able to record significantly more gray matter from the amygdala and hippocampus than subdural electrodes.

Significance

This study provides the first probabilistic analysis to quantify gray and white matter coverage for multiple categories of intracranial recording configurations. Depth electrodes may offer increased per contact coverage of gray matter over other recording strategies if the desired signals are local to the contact, while subdural grids and strips can sample more gray matter if the desired signals are more diffuse.
Feasibility of an online Langerian mindfulness program for stroke survivors and caregivers
Authors: Demers Marika , Pagnini Francesco , Phillips Deborah , Chang Brianna , Winstein Carolee , Langer Ellen
Published: August 2021

Background

Mindfulness is promising for individuals with neurological disorders and their caregivers to improve psychological well-being. The potential application of a Langerian mindfulness intervention, focused on attention to variability, however, is still unknown.

Objective

To determine the feasibility (usability, satisfaction, and potential effectiveness on psychological well-being) of an online mindfulness intervention for stroke survivors and caregivers.

Methodology

Using mixed-methods, 11 stroke survivors and 3 caregivers participated in a 3-week, online, Langerian mindfulness intervention. A semi-structured interview assessed the intervention’s usability and gathered feedback. Self-reported measures about psychological well-being were documented remotely three times (pre, post, one-month follow-up).

Results

Qualitatively, participants were highly satisfied with the intervention, reported subjective benefits, but the usability of the online platform was poor. None of the self-reported measures changed over time.

Conclusion

This study provided evidence of feasibility of an online Langerian mindfulness intervention in a new population: stroke survivors and caregivers.
Multispectral Imaging for MicroChip Electrophoresis Enables Point-of-Care Newborn Hemoglobin Variant Screening
Authors: An Ran , Huang Yuning , Rocheleau Anne , Avanaki Alireza , Thota Priyaleela , Man Yuncheng , Sekyonda Zoe , Segbefia Catherine I. , Dei-Adomakoh Yvonne , Mensah Enoch , Odame Isaac , Gurkan Umut A.
Published: August 2021

Hemoglobin (Hb) disorders affect nearly 7% of the world’s population. Globally, around 400,000 babies are born annually with sickle cell disease (SCD), primarily in sub-Saharan Africa where morbidity and mortality rates are high. Although treatments are available for Hb disorders, screening, early diagnosis, and monitoring are not widely accessible due to technical challenges and cost, especially in low-and-middle-income countries. We hypothesized that multispectral imaging will allow sensitive hemoglobin variant identification in existing affordable paper-based Hb electrophoresis, which is a clinical standard test for Hb variant screening. To test this hypothesis, we developed the first integrated point-of-care multispectral Hb variant test: Gazelle-Multispectral. Here, we evaluated the accuracy of Gazelle-Multispectral for Hb variant newborn screening in 321 completed tests in subjects younger than 6 months with known hemoglobin variants including hemoglobin A (Hb A), hemoglobin F (Hb F), hemoglobin S (Hb S) and hemoglobin C (Hb C). Gazelle-multispectral detected levels of Hb A, Hb F, Hb S, and Hb C, demonstrated high correlations with the results reported by laboratory gold standard high performance liquid chromatography (HPLC) at Pearson Correlation Coefficient = 0.97, 0.97, 0.89, and 0.94. Gazelle-multispectral demonstrated 100% sensitivity and 100% specificity in both disease vs normal and disease vs trait, 98.1% sensitivity and 97.0% specificity in trait vs normal in comparison to HPLC in newborns. The ability to obtain rapid and accurate results on newborn samples suggest that Gazelle-Multispectral is suitable for large-scale newborn screening and potentially for accurate diagnosis of SCD in low resource settings.
Differences in personality / temperament in the endangered tortoiseTestudo hermanniand their implications on dispersal and conservation
Authors: Rodriguez Alexandra , Caron Sébastien , Ballouard Jean Marie
Published: August 2021

Behavioural studies are more an more implicated in species conservation. Determining individuals personality in the case of reintroduction operations may be very useful. Actually, indiviuals temperament may be associated to their dispersal capacities and their habilities to adapt to novel environments. Considered as asociable species, few studies have been conducted on reptiles and this is even worse in the case of endangered species. Hermann tortoise, Testudo hermanni, an endemic species from Mediterranean region is endangered because of the lost and modification of its habitats. Before conducting reintroduction actions it is important to have more information on individuals personality traits. We have tested the reaction of three groups of tortoises (domestic, wild and from the SOPTOM center) when confronted to a novel environment and to human presence. The aim was to discriminate individuals with « bold » and « shy » behaviours. Behavioural profiles are different between the three groups of tortoises, the domestic group appeared to be bolder than the wild one. Moreover, for the wild group, bold individuals travel longer distances in the field, sometimes outside the protected areas. Thus, it is important to take into account the personality of individuals choosen for translocation projects.
Precision of Mammogram and USG based evaluation of NAST response in breast cancer and its impact on oncoplastic surgery decisions
Authors: Deshpande Pooja , Dixit Santosh , Kelkar Devaki , Gangurde Nutan , Shaikh Shahin , Nagarkar Sanket , Nare Smeeta , Busheri Laleh , Koppiker Chaitanyanand , Varghese Beenu
Published: August 2021

Background

Precise prediction of residual tumour size following neoadjuvant systemic therapy for breast cancer is crucial in assessing response and surgical decision making. Our study is aimed at assessing the performance of conventional imaging modalities like ultrasound and mammography in predicting the residual tumour size after neoadjuvant systemic therapy and in evaluating the impact of imaging on the surgical outcomes.

Methods

We retrospectively compared the tumour size measured by ultrasonography and mammography and the residual tumour size on final histopathology in 109 patients. Concordance was defined as a size difference within 25% of the histopathology size. We also looked at the distribution of concordance between different T status and molecular subtypes, accuracy of USG in predicting pathological complete response and axillary lymph nodal metastasis and also surgical outcomes in the discordant cases.

Results

The concordance rates of mammography and ultrasonography were 68.2% and 52.3% respectively without statistically significant difference between the two modalities (p = 0.081). Combination of both the modalities had a concordance rate of 57.8%. Ultrasonography had accuracy of 81.7% for predicting pathological complete response and 79.8% for predicting axillary nodal metastasis. We did not identify any influence of histologic subtype on the associations between preoperative measurements and pathology size or the accuracy for detecting pathological complete response (p values 0.43 and 0.46 respectively). In 12 cases, the radiology-pathology discordance could have led to large excision volume surgeries. In the overall cohort, recurrence free survival and overall survival rates at median follow up of 19.1 month were 87.2% and 95.4% respectively.

Conclusions

Ultrasound and mammography showed moderate concordance with pathology for estimation of the residual tumour size without any significant difference in the performance between the two. Despite the moderate concordance, surgical outcomes were fairly well managed in the discordant cases with the oncoplastic surgical techniques. Our study highlights the usefulness of the cheaper and widely available conventional imaging modalities in the developing countries where the cost of treatment is to be contained.
Metabolomic signatures of lipid-modifying therapies using drug target Mendelian randomization
Authors: Richardson Tom G , Leyden Genevieve M , Wang Qin , Bell Joshua A , Elsworth Benjamin , Smith George Davey , Holmes Michael V
Published: August 2021

Background

Large-scale molecular profiling and genotyping provide a unique opportunity to systematically compare the genetically predicted effects of therapeutic targets on the human metabolome.

Methods

We firstly constructed genetic risk scores for 8 drug targets on the basis that they primarily modify low-density lipoprotein (LDL) cholesterol (HMGCR, PCKS9 & NPC1L1), high-density lipoprotein (HDL) cholesterol (CETP), or triglycerides (APOC3, ANGPTL3, ANGPTL4 & LPL). We then used Mendelian randomization to evaluate the effect of each score on coronary artery disease (CAD) risk, and to systematically estimate their effects on 249 metabolic traits derived using blood samples from an unprecedented sample size of up to 115,082 UK Biobank participants.

Results

There was strong evidence of an effect of drug-based genetic scores on CAD risk with the exception of ANGPTL3. Genetically predicted effects on the blood metabolome were generally consistent amongst drug targets which were intended to modify the same lipoprotein lipid trait. For example, the linear fit for the MR estimates on all 249 metabolic traits for genetically-predicted inhibition of LDL cholesterol lowering targets HMGCR and PCSK9 was r2=0.91. In contrast, comparisons between drug classes that were designed to modify discrete lipoprotein traits typically had very different effects on metabolic signatures (e.g. HMGCR vs all 4 triglyceride targets had r2<0.02), despite largely consistent effects on risk of CAD. Furthermore, we highlight this discrepancy for specific metabolic traits, for example finding that LDL cholesterol lowering therapies typically had a weak effect on glycoprotein acetyls, a marker of inflammation (e.g. PCSK9: Beta=0.01, 95 CI%=-0.06 to 0.08, P=0.78). In contrast, all of the triglyceride modifying therapies assessed provided evidence of a strong effect on lowering levels of this inflammatory biomarker (e.g. LPL: Beta=-0.43, 95 CI%=-0.37 to -0.48, P=9×10−50).

Conclusions

Multiple lipid-modifying drug targets have therapeutically beneficial effects on CAD risk. Our findings indicate that genetically predicted perturbations of these drug targets on the blood metabolome can drastically differ, with potential implications for biomarkers in clinical development and measuring treatment response.
Titin switches from an extensible spring to a mechanical rectifier upon muscle activation
Authors: Squarci Caterina , Bianco Pasquale , Reconditi Massimo , Caremani Marco , Narayanan Theyencheri , Csizmadia Andras Málnási , Linari Marco , Lombardi Vincenzo , Piazzesi Gabriella
Published: August 2021

In contracting striated muscle titin acts as a spring in parallel with the array of myosin motors in each half-sarcomere and could prevent the intrinsic instability of thousands of serially linked half-sarcomeres, if its stiffness, at physiological sarcomere lengths (SL), were ten times larger than reported. Here we define titin mechanical properties during tetanic stimulation of single fibres of frog muscle by suppressing myosin motor responses with Para-Nitro-Blebbistatin, which is able to freeze thick filament in the resting state. We discover that thin filament activation switches I-band titin spring from the large SL-dependent extensibility of the OFF-state to an ON-state in which titin acts as a SL-independent mechanical rectifier, allowing free shortening while opposing stretch with an effective stiffness 4 pN nm−1 per half-thick filament. In this way during contraction titin limits weak half-sarcomere elongation to a few % and, also, provides an efficient link for mechanosensing-based thick filament activation.