bluuebunny/crossref_metadata_2025 huggingface dataset:
ICD-10 codes for surveillance of non-fatal abusive head trauma in Aotearoa New Zealand: a retrospective cohort study
Authors: Knappstein Joanne , Reed Peter W , Kelly Patrick
Published: June 2023

Objectives

To assess the validity of an International Classification of Diseases (ICD) code based definition of non-fatal head trauma caused by child abuse (abusive head trauma) for population surveillance in New Zealand.

Design

A retrospective cohort study of hospital inpatient records.

Setting

A tertiary children’s hospital in Auckland, New Zealand.

Participants

1731 children less than 5 years of age who were discharged after a non-fatal head trauma event over a 10-year period from 1 January 2010 to 31 December 2019.

Outcome measures

The outcome of assessment by the hospital’s multidisciplinary child protection team (CPT) was compared with the outcome of ICD, Tenth Revision (ICD-10) discharge coding for non-fatal abusive head trauma (AHT). The ICD-10 code definition of AHT was derived from an ICD, Ninth Revision, Clinical Modification definition developed by the Centers for Disease Control, Atlanta, Georgia, which requires both a clinical diagnosis code and a cause-of-injury code.

Results

There were 1755 head trauma events with 117 determined as AHT by the CPT. The ICD-10 code definition had a sensitivity of 66.7% (95% CI 57.4 to 75.1) and specificity of 99.8% (95% CI 99.5 to 100). There were only three false positives but 39 false negatives, with 18 of the false negatives coded with X59 (exposure to unspecified factor).

Conclusions

The ICD-10 code broad definition of AHT is a reasonable epidemiological tool for passive surveillance of AHT in New Zealand but it underestimates the incidence. Its performance could be improved by clear documentation of child protection conclusions in clinical notes, clarifying coding practice and removing the exclusion criteria from the definition.
Rapidly building surge capacity within a pandemic response using simulation-based clinical systems testing
Authors: Davis Nichole R , Doughty Cara B , Kerr Tarra , Elegores Gemma , Davis Kasey I , Kaziny Brent D
Published: June 2023

Introduction

As the SARS-CoV-2 virus spread across the globe, hospitals around the USA began preparing for its arrival. Building on previous experience with alternative care sites (ACS) during surge events, Texas Children’s Hospital (TCH) opted to redeploy their mobile paediatric emergency response teams. Simulation-based clinical systems testing (SbCST) uses simulation to test preoccupancy spaces and new processes. We developed rapid SbCST with social distancing for our deployed ACS, with collaboration between emergency management, paediatric emergency medicine and the simulation team.

Methods

A two-phased approach included an initial virtual tabletop activity followed by SbCST at each campus, conducted simultaneously in-person and virtually. These activities were completed while also respecting the need for social distancing amidst a pandemic response. Each activity’s discussion was facilitated using Promoting Excellence and Reflective Learning in Simulation (PEARLS) for systems integration debriefing methodology and was followed by compilation of a failure mode and effects analysis (FMEA), which was then disseminated to campus leaders.

Results

Within a 2-week period, participants from 20 different departments identified 109 latent safety threats (LSTs) across the four activities, with 71 identified as being very high or high priority items. Very high and high priority threats were prioritised in mitigation efforts by hospital leadership.

Discussion

SbCST can be rapidly implemented to hone pandemic responses and identify LSTs. We used SbCST to allow for virtual participation and social distancing within a rapidly accelerated timeline. With prioritised FMEA reporting, leadership was able to mitigate concerns surrounding the four Ss of surge capacity: staff, stuff, structure and systems.
Outcomes and a prognostic classifier in patients with microsatellite instability-high metastatic gastric cancer receiving PD-1 blockade
Authors: Randon Giovanni , Aoki Yu , Cohen Romain , Provenzano Leonardo , Nasca Vincenzo , Klempner Samuel J , Maron Steven B , Cerantola Riccardo , Chao Joseph , Fornaro Lorenzo , Ferrari Bravo Walter , Ghelardi Filippo , Ambrosini Margherita , Manca Paolo , Salati Massimiliano , Kawazoe Akihito , Zhu Valerie , Cowzer Darren , Genovesi Virginia , Lonardi Sara , Shitara Kohei , André Thierry , Pietrantonio Filippo
Published: June 2023

Background

Subgroup analyses of randomized trials suggest the superiority of immune checkpoint inhibitor-based therapy over chemotherapy in patients with mismatch-repair deficient (dMMR) and/or microsatellite instability-high (MSI-high) advanced gastric or gastroesophageal junction adenocarcinoma. However, these subgroups are small and studies examining prognostic features within dMMR/MSI-high patients are lacking.

Methods

We conducted an international cohort study at tertiary cancer centers and collected baseline clinicopathologic features of patients with dMMR/MSI-high metastatic or unresectable gastric cancer treated with anti-programmed cell death protein-1 (PD-1)-based therapies. The adjusted HRs of variables significantly associated with overall survival (OS) were used to develop a prognostic score.

Results

One hundred and thirty patients were included. At a median follow-up of 25.1 months, the median progression-free survival (PFS) was 30.3 months (95% CI: 20.4 to NA) and 2-year PFS rate was 56% (95% CI: 48% to 66%). Median OS was of 62.5 months (95% CI: 28.4 to NA) and 2-year OS rate was 63% (95% CI: 55% to 73%). Among the 103 Response Evaluation Criteria in Solid Tumors-evaluable patients, objective response rate was 66% and disease control rate 87% across lines of therapy. In the multivariable models, Eastern Cooperative Oncology Group Performance Status of 1 or 2, non-resected primary tumor, presence of bone metastases and malignant ascites were independently associated with poorer PFS and OS. These four clinical variables were used to build a three-category (ie, good, intermediate, and poor risk) prognostic score. Compared with patients with good risk, patients with intermediate risk score had numerically inferior PFS and OS (2-year PFS rate: 54.3% versus 74.5%, HR 1.90, 95% CI: 0.99 to 3.66; 2-year OS rate: 66.8% versus 81.2%, HR 1.86, 95% CI: 0.87 to 3.98), whereas patients with poor risk score had significantly inferior PFS and OS (2-year PFS rate: 10.6%, HR 9.65, 95% CI: 4.67 to 19.92; 2-year OS rate: 13.3%, HR 11.93, 95% CI: 5.42 to 26.23).

Conclusions

Overall outcomes with anti-PD-1-based therapies are favorable in MSI-high gastroesophageal adenocarcinomas. However, within this overall favorable subgroup a more accurate prognostication using baseline clinical characteristics might identify patients at higher risk of rapid disease progression who may deserve intensified immunotherapy combination strategies.
Quantifying the burden of steroid-related damage in SLE in the Hopkins
Lupus Cohort
Authors: Davidson Julie E , Fu Qinggong , Rao Sapna , Magder Laurence S , Petri Michelle
Published: June 2023

Objective

Corticosteroids are a mainstay of SLE treatment; however, cumulative
steroid exposure may lead to organ damage. This study aimed to quantify
the risk of new diabetes, hypertension, cataracts, osteoporosis and
avascular necrosis that is attributable to cumulative corticosteroid
exposure in SLE.

Methods

Using data from the Hopkins Lupus Cohort, a longitudinal study of
lupus activity, organ damage and quality of life in patients with SLE,
five matched case–control analyses nested within a prospectively
enrolled SLE cohort were performed. Two randomly selected controls were
matched to each case using incidence-density sampling from defined risk
sets. Attributable risk was calculated for steroid exposure (dose and
duration, separately). Cumulative steroid dose was modelled as a
four-level categorical variable using clinically relevant thresholds:
0 g (no exposure); >0 and <3.65 g (<10 mg/day for a year);
≥3.65 g and <18.25 g (1–5 years at 10 mg/day); and ≥18.25 g (>5
years at 10 mg/day).

Results

Eligible cases were identified for diabetes (n=42), hypertension
(n=79), cataract (n=132), osteoporosis (n=118) and avascular necrosis
(n=38). The unadjusted OR for a one-category increase in cumulative
steroid exposure ranged from 1.157 (cataract (0.889 to 1.506); p=0.2779)
to 2.183 (avascular necrosis (1.162 to 4.103); p=0.0153). After
adjusting for confounding variables, a one-category increase in the
cumulative steroid dose was significantly associated with risk of
cataract (OR (95% CI) 1.855 (1.190 to 2.892); p=0.0064) and osteoporosis
(OR (95% CI) 1.604 (1.067 to 2.412); p=0.0232). ORs for avascular
necrosis, diabetes and hypertension suggested a moderately increased
risk (not significant). Duration of steroid exposure was not associated
with any of the outcomes. The proportion of risk attributable to steroid
exposure after adjustment for covariates was 0.711 for cataract and
0.540 for osteoporosis.

Conclusions

Cumulative steroid exposure was associated with an increased risk of
cataract and osteoporosis in patients with SLE.

Trial registration number

NCT01616472.
Type I interferon receptor blockade with anifrolumab corrects innate and
adaptive immune perturbations of SLE
Authors: Casey Kerry A , Guo Xiang , Smith Michael A , Wang Shiliang , Sinibaldi Dominic , Sanjuan Miguel A , Wang Liangwei , Illei Gabor G , White Wendy I
Published: June 2023

Objective

Anifrolumab is a fully human immunoglobulin G1κ
monoclonal antibody specific for subunit 1 of the type I interferon
(IFN) α receptor. In a phase IIb study of adults with moderate to severe
SLE, anifrolumab treatment demonstrated substantial reductions in
multiple clinical endpoints. Here, we evaluated serum proteins and
immune cells associated with SLE pathogenesis, type I interferon gene
signature (IFNGS) test status and disease activity, and how anifrolumab
affected these components.

Methods

Whole blood samples were collected from patients enrolled in MUSE
(NCT01438489) for serum protein and cellular
assessments at baseline and subsequent time points. Data were parsed by
IFNGS test status (high/low) and disease activity. Protein expression
and immune cell subsets were measured using multiplex immunoassay and
flow cytometry, respectively. Blood samples from healthy donors were
analysed for comparison.

Results

Baseline protein expression differed between patients with SLE and
healthy donors, IFNGS test-high and -low patients, and patients with
moderate and severe disease. Anifrolumab treatment lowered
concentrations of IFN-induced chemokines associated with B, T and other
immune cell migration in addition to proteins associated with
endothelial activation that were dysregulated at baseline. IFNGS
test-high patients and those with high disease activity were
characterised by low baseline numbers of lymphocytes, circulating memory
T-cell subsets and neutrophils. Anifrolumab treatment reversed
lymphopenia and neutropenia in the total population, and normalised
multiple T-cell subset counts in IFNGS test-high patients compared with
placebo.

Conclusions

Anifrolumab treatment reversed IFN-associated changes at the protein
and cellular level, indicating multiple modes of activity.

Trial registration number

NCT01438489.
Pharmacodynamic and pharmacokinetic effects and safety of verinurad in
combination with febuxostat in adults with gout: a phase IIa, open-label
study
Authors: Fleischmann Roy , Winkle Peter , Hall Jesse , Valdez Shakti , Liu Sha , Yan Xiaohong , Hicks Liz , Lee Caroline , Miner Jeffrey N , Gillen Michael , Hernandez-Illas Martha
Published: June 2023

Objective

Verinurad (RDEA3170) is a high-affinity, selective URAT1 inhibitor
in development for treating gout and asymptomatic hyperuricaemia. This
study evaluated the pharmacodynamics, pharmacokinetics and safety of
verinurad in combination with febuxostat in adults with gout.

Methods

The phase IIa, open-label, multicentre study randomised 64 subjects
into one of five cohorts to receive febuxostat (40 or 80 mg) alone or in
combination with verinurad 2.5–20 mg. Serial plasma/serum and urine
samples were assayed for verinurad and uric acid. Safety was assessed by
adverse events, chemistry panels, ECGs and physical
examinations.

Results

Serum pharmacodynamic data demonstrated the maximum percent decrease
in serum urate (sUA) from baseline (Emax) at
8–12 hours after dosing. Verinurad with febuxostat decreased sUA in a
dose-dependent manner. Emaxfor verinurad with
febuxostat 40 mg ranged from 52% to 77% vs 42% for febuxostat 40 mg
alone; Emaxfor verinurad with febuxostat 80 mg was
62%–82% vs 55% for febuxostat 80 mg alone. Urinary uric acid excretion
rate was reduced below baseline by febuxostat alone and was comparable
to baseline for verinurad with febuxostat. Verinurad plasma exposure
increased with dose and was comparable when combined with febuxostat. No
drug-drug interactions were observed. Verinurad was well tolerated with
no clinically meaningful changes in laboratory values.

Conclusion

Verinurad administered with febuxostat produced dose-dependent
decreases in sUA while maintaining urinary uric acid levels comparable
to baseline. These dose combinations of verinurad and febuxostat were
generally well tolerated. These data support continued investigation of
oral verinurad in patients with gout.

Trial registration number

NCT02246673
Efficiency of a self-organizing Ising model of financial markets
Authors: Antenorcruz Jude Maria V. , Batac Rene C.
Published: June 2023

Individual agents in financial markets decide based on market conditions, external news and information, and personal idiosyncrasies; from the collective action of such agents arise the unpredictable market dynamics. These actions affect the overall market efficiency, which measures how well the price reflects all available information. Here, we implement the self-organizing Ising model of Zhou and Sornette [Eur. Phys. J. B 55, 175 (2007)] to probe the efficiency of simulated financial markets under various conditions. Efficiency is parametrized by the dispersion of the generalized Hurst exponents obtained from multifractal detrended fluctuation analysis. Scanning different model parameter sets reveals the regimes of efficiency values in simulated markets that compare with those obtained from real-world data.
Thermodynamics analysis for Darcy model induced by beating waves of cilia under Hall impact
Authors: Saleem Maria , Liu Haihu , Nadeem Akif
Published: June 2023

This study conducts the thermodynamics analysis of creeping viscous nanofluid influenced by metachronical waves in an inclined ciliated tube and investigates the effects of magnetic field, porous medium and Hall current. Moreover, heat transport analysis is performed to consider the viscous dissipation phenomena. Thermal conductivity of the fluid is made more effective by adopting water-based titanium dioxide nanoparticles. [Formula: see text] is chosen as it has many remarkable implications in nanobio-sensing, medical implants, drug delivery and antibacterial fields. The governing equations are formulated which are converted into ordinary differential system by taking into account the similarity variables. The analytical solution are obtained for momentum, pressure gradient and energy profiles. It is found that the entropy generation is an increasing function of the Eckert number, Prandtl number and dimensionless temperature difference. Both Darcy and Eckert numbers enhance the energy of flow system. The fluid velocity drops quickly with increasing magnetic parameter.
Variable thermophysical properties of magnetohydrodynamic cross fluid model with effect of energy dissipation and chemical reaction
Authors: Awais Muhammad , Salahuddin T.
Published: June 2023

In this study, magnetohydrodynamic cross fluid model is used to formulate the 2D boundary layer equations of fluid moving on the parabolic surface. The surface is assumed to be in vertical shape due to the convection. The underlying effects of viscous dissipation and chemical reaction are modeled to observe the transportation of heat and mass rate. To understand fluid behavior, the thermophysical properties are considered as variable because they have huge influence in food processing, viscometers, lubricants and various industrial works. The assumed geometry of fluid flows is similar in shape of bullet, submarine, aircraft and car’s bonnet, namely paraboloid surface. The modeled equations of cross fluid with mentioned effects are obtained in form of PDEs and then converted these equations in form of ODEs by assuming set of scaling transformations. For the sake of numerical and graphical outcomes, the resulting equations are solved numerically on Matlab software via BVP4c method. Results achieved across velocity indicate that the decay happens by numerous values of Weissenberg number, power law index, viscosity parameter and Hartmann number. The temperature and concentration fields attained increasing influence by thermal conductivity coefficient, Eckert number and thermal diffusivity parameter.
Equivalence principle, de-Sitter space, and cosmological twistors
Authors: Dunajski Maciej
Published: June 2023

In this paper, I discuss the impact of the positive cosmological constant on the interplay between the equivalence principle in general relativity, and the rules of quantum mechanics. At the nonrelativistic level, there is an ambiguity in the definition of a phase of a wave function measured by inertial and accelerating observes. This is the cosmological analogue of the Penrose effect, which can also be seen as a nonrelativistic limit of the Unruh effect. The symmetries of the associated Schrödinger equation are generated by the Newton–Hooke algebra, which arises from a nonrelativistic limit of a cosmological twistor space.
SURFACE TOPOGRAPHY AND MORPHOLOGICAL STUDY OPTIMIZATION OF EDMED WORK SURFACE OF INCONEL 601 OBTAINED USING SOLID CYLINDRICAL CROSS-SECTIONED COPPER TOOL ELECTRODE
Authors: SINGH SHAMBHAVI , SINGH SWEETY , RAHUL  , CHOUDHARY RAJAN
Published: June 2023

Inconel alloy has been a solution to diverse fields where automobile industry, aircraft, nuclear reactor are the foremost and major applicants of Inconel alloy. But the aim is precise manufacturing in minimum time. Inconel is known for its hard to machine characteristic. This paper illustrates the machining effect on Inconel 601 in EDM. Electrode discharge machining with its ability to machine hard conductive metals is the most recognized and suitable nonconventional machine for the purpose. Experiments with four level of variation and five parameters, (that is, OCV, peak current, pulse on time, duty factor and flushing pressure) have been conducted in 16 different combinations under L16 orthogonal array. Metal removal rate (MRR), surface roughness ([Formula: see text]), surface crack density (SCD), and white layer thickness (WLT) have been calculated herein. Surface roughness has been depicted with the help of Taylor Hobson materialize finishing tester. The view of the fact that conventional Taguchi technique cannot be used to solve the multiple response optimization problem independently, so TOPSIS method has been used in this paper to convert multiple responses into an aggregated performance index (called closeness coefficient [Formula: see text]) which has been optimized finally by the Taguchi technique. In this, MRR and Ra have been optimized by using the TOPSIS technique and it is found that by using optimal setting i.e. A4B1C2D1E[Formula: see text] MRR will be higher while Ra will be lower. Moreover, micro-graphical studies have been conducted to analyze various surface irregularities (SCD and WLT) of EDMed Inconel 601. SCD and WLT have been investigated with respect to optimal settings (A4B1C2D1E2) and obituary settings run no. 10 (A3B2C4D3E1) and better results have been obtained in optimal settings as compared to obituary settings.
Technological Upgrade in Emerging Markets: The Importance of Interorganizational Cooperation for Product and Process Upgrades
Authors: Pereira Rafael Morais , Borini Felipe Mendes , Oliveira Moacir de Miranda
Published: June 2023

Considering the relevance of different market partners and research partners with which companies can cooperate for innovation, we wonder whether cooperation with such partners is essential for the technological upgrade of products and processes. Therefore, as our main aim, we propose to analyze the importance of cooperating with market and research partners to technologically upgrade products and processes in an emerging market. To do this, we used data from the Brazilian national innovation survey stratified by sectors of the economy. The data analysis technique adopted for this study was panel data. Our results add to the existing studies on the importance of considering the effects of different partners on types of upgrades (product and process) that are relevant to a technological upgrade in emerging countries. Furthermore, this research demonstrated which kind of partnership is the most suitable for each type of upgrade.
Managing the risk of embedded options in non-traded credit using portfolio modeling
Authors: Engelmann Bernd
Published: June 2023

A framework for measuring and managing the risk of embedded options in non-traded credit is developed. For typical bank clients there is no market information related to their ability to pay (bond or CDS spreads) available. The absence of market information is a key assumption of this paper. In this case, a bank has to rely solely on statistical data to judge the credit quality of a borrower. To value a loan with embedded options like prepayment rights, a model is proposed that combines an interest rate derivatives pricing model with statistical information on default and recovery rates. Using this for evaluating the risk of embedded options in loans, it is shown how the concepts of credit risk management can be applied after defining a suitable concept of risk. It turns out that this modeling framework combines the theories of derivatives pricing and credit risk modeling in the sense that derivatives pricing theory measures the costs for hedging optional components in loans while credit risk modeling measures the risk that these hedging costs turn out to be inadequate. This risk depends not only on the single loan’s risk characteristics but also on the dependence structure and the granularity of the total loan portfolio.
Renoprotective effects of GLP-1 receptor agonists and SGLT-2 inhibitors—is hemodynamics the key point?
Authors: Lee Blaire , Holstein-Rathlou Niels-Henrik , Sosnovtseva Olga , Sørensen Charlotte M.
Published: June 2023

Two novel treatments for diabetic kidney disease have emerged after decades with little progression. Both agents were developed for improved glycemic control in patients with type-2 diabetes. However, large clinical trials showed renoprotective effects beyond their ability to lower plasma glucose levels, body weight, and blood pressure. How this renal protection occurs is unknown. We will discuss their physiological effects, with special focus on the renal effects. We discuss how these drugs affect the function of the diabetic and nondiabetic kidneys to elucidate mechanisms by which the renoprotection could arise. Diabetic kidney disease affects the glomerular capillaries, which are usually protected by the renal autoregulatory mechanisms, the myogenic response, and the tubuloglomerular feedback mechanism. Animal models with reduced renal autoregulatory capacity develop chronic kidney disease. Despite different cellular targets, both drugs are suspected to affect renal hemodynamics through changes in the renal autoregulatory mechanisms. The glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert a direct vasodilatory effect on the afferent arteriole (AA) positioned just before the glomerulus. Paradoxically, this effect is expected to increase glomerular capillary pressure, causing glomerular injury. In contrast, the sodium-glucose transporter-2 inhibitors (SGLT2i) are believed to activate the tubuloglomerular feedback mechanism to elicit vasoconstriction of the afferent arteriole. Because of their opposing effects on the renal afferent arterioles, it appears unlikely that their renoprotective effects can be explained by common effects of renal hemodynamics, but both drugs appear to add protection to the kidney beyond what can be obtained with classical treatment targeted at lowering blood glucose levels and blood pressure.
A Comprehensive Analysis of Clinical Crowns in Young of Han Nationality with Normal Occlusion Using Intraoral Scanning
Authors: Cao Rongkai , Qiu Piaopiao , Ni Jianzhao , Xu Hui , Pan Haoxin , Cao Yujie
Published: June 2023

Background. The measurement and analysis of clinical crowns play a crucial role in stomatology, anthropology, and studies of genetic and environmental variables in oral and maxillofacial development. Purpose. The objective of the present study was to measure the parameters of clinical crowns of permanent dentition in youth of Han nationality using intraoral scanning and identify potential influencing factors. Materials and Methods. A total of 100 subjects (50 males and 50 females) of Han nationality aged 18–24 with normal occlusion were selected. An intraoral scanner was used to obtain the digital dental impressions, and Materialise Magics 21 software was used to measure the mesiodistal diameter (MDD), buccolingual diameter (BLD), height, mesiodistal angle (MDA), and vestibulo-oral angle (VOA) of clinical crowns. The central height was calculated based on the height of clinical crowns. SPSS 27.0 software was used for statistical analysis. The two-independent-samplet-test was used to assess discrepancies in clinical crowns between males and females. The paired t-test was used to determine differences between antimetric pairs of clinical crowns within the same arch. The repeatability of intraoral scanning was tested using the paired t-test between two measurements at one-month intervals. The overall estimated effect was considered significant whereP < 0.05. Results. The MDD, BLD, height, MDA, and VOA of clinical crowns in the youth of Han nationality were measured, and the central height was calculated. No significant difference was found in terms of MDA and VOA between genders and antimetric pairs within the same arch. Regarding the distance parameters, the MDD, BLD, and height of clinical crowns in males were significantly larger than those in females (MDD: U1, U3, U7, L2, L3, L6, and L7:P<0.01; BLD: U1:P=0.02; U3–U7 and L1–L7:P<0.01; height: U2:P=0.03; and U1, U3–U7, and L3–L7:P<0.01). No significant difference was found in clinical crowns between antimetric pairs within the same arch. Intraoral scanning demonstrated good repeatability in the measurement of clinical crowns. Conclusions. Apart from MDA and VOA, the parameters of clinical crowns in males were significantly larger than in females. Antimetric pairs of clinical crowns within the same arch demonstrated similar tooth dimensions. In future clinical practice and scientific research in the oral and maxillofacial region, a comprehensive design of sexual and ethnic characteristics should be considered.
Breast Cancer Mutations HER2V777L and PIK3CAH1047R Activate the p21–CDK4/6–Cyclin D1 Axis to Drive Tumorigenesis and Drug Resistance
Authors: Cheng Xiaoqing , Sun Yirui , Highkin Maureen , Vemalapally Nagalaxmi , Jin Xiaohua , Zhou Brandon , Prior Julie L. , Tipton Ashley R. , Li Shunqiang , Iliuk Anton , Achilefu Samuel , Hagemann Ian S. , Edwards John R. , Bose Ron
Published: June 2023

In metastatic breast cancer, HER2-activating mutations frequently co-occur with mutations in PIK3CA, TP53, or CDH1. Of these co-occurring mutations, HER2 and PIK3CA are the most commonly comutated gene pair, with approximately 40% of HER2-mutated breast cancers also having activating mutations in PIK3CA. To study the effects of co-occurring HER2 and PIK3CA mutations, we generated genetically engineered mice with the HER2V777L; PIK3CAH1047R transgenes (HP mice) and studied the resulting breast cancers both in vivo as well as ex vivo using cancer organoids. HP breast cancers showed accelerated tumor formation in vivo and increased invasion and migration in in vitro assays. HP breast cancer cells were resistant to the pan-HER tyrosine kinase inhibitor, neratinib, but were effectively treated with neratinib plus the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan. Proteomic and RNA-seq analysis of HP breast cancers identified increased gene expression of cyclin D1 and p21WAF1/Cip1 and changes in cell-cycle markers. Combining neratinib with CDK4/6 inhibitors was another effective strategy for treating HP breast cancers, with neratinib plus palbociclib showing a statistically significant reduction in development of mouse HP tumors as compared to either drug alone. The efficacy of both the neratinib plus trastuzumab deruxtecan and neratinib plus palbociclib combinations was validated using a human breast cancer patient-derived xenograft with very similar HER2 and PIK3CA mutations to the HP mice. Further, these two drug combinations effectively treated spontaneous lung metastasis in syngeneic mice transplanted with HP breast cancer organoids. This study provides valuable preclinical data to support the ongoing phase 1 clinical trials of these drug combinations in breast cancer.

Significance:

In HER2-mutated breast cancer, PIK3CA mutation activates p21–CDK4/6–cyclin D1 signaling to drive resistance to HER2-targeted therapies, which can be overcome using CDK4/6 inhibitors.
Data from NL-201 upregulates MHC-I expression and intratumoral TCR diversity, and demonstrates robust antitumor activity as monotherapy and in combination with PD-1 blockade
Authors: Mortales Christie , Dutzar Benjamin , Chen Jerry , Chen Alex , Huard Justin , Walkey Carl , Swanson Ryan
Published: June 2023

Abstract
Cytokine engineering has shown promise as a means to create novel immunomodulatory agents or to improve upon the therapeutic potential of natural cytokines. NL-201, a de novo, hyperstable, interleukin-2 receptor alpha (IL-2Rα)-independent agonist of the receptors for IL-2 and IL-15, elicits robust preclinical activity in syngeneic murine cancer models, including those resistant to immune checkpoint inhibitors (ICIs). Here, we report that NL-201 monotherapy converts ‘cold’ tumor microenvironments to immunologically ‘hot’ states by driving pro-inflammatory gene expression, enhancing IFNγ-dependent MHC-I expression, and expanding both T-cell number and clonal diversity. Additionally, the combination of NL-201 and anti–PD-1 resulted in complementary antitumor activity in the immunologically ‘cold’ and ICI resistant B16F10, EMT6, and Renca syngeneic models. In the B16F10 model, treatment with NL-201 plus anti-PD-1 increased the abundance of CD4+ and CD8+ effector T cells in the tumor microenvironment. These findings reveal an important mechanistic basis for the antitumor activity of NL-201 both as a monotherapy and in combination with PD-1 antagonists, and provide further context for the role of IL2Rα-based signaling in ICI-resistant tumors.
Phidon abismus sp. nov. from Patagonian forests of Argentina (Blattaria: Pseudophyllodromiidae)
Authors: BRAMARDI MARTINA A. , MOCCIA TOBÍAS , KUN MARCELO E.
Published: June 2023

Phidon abismus sp. nov. is described from north-western Patagonian forests in Argentina. The specimens were collected under dead tree bark of Austrocedrus chilensis, Nothofagus dombeyi and Nothofagus pumilio. A detailed description of the male including abdominal apex, genitalia, tegmen and wing venation and front femur armament type B2 is provided as well as a description of the A type oviparity. The genus Phidon is recorded from Argentina for the first time. The key of Rehn (1933) for the known males of the genus is updated.
Identification of evolutionary mechanisms of myelomatous effusion by single-cell RNA sequencing
Authors: Sun Zhengxu , Ji Jiamei , Li Yating , Cui Yunqi , Fan Lei , Li Jianyong , Qu Xiaoyan
Published: June 2023

Myelomatous effusion (ME) is a rare manifestation of extramedullary multiple myeloma (MM) with limited therapeutic options and poor outcomes. The molecular mechanisms underlying ME are incompletely understood. We profiled transcriptomes of bone marrow, peripheral blood (PB), and pleural effusion/ascites from 3 patients with ME using single-cell RNA sequencing analysis. We found that ME contained a higher percentage of cytotoxic T cells, whereas PB contained a higher proportion of naive T cells. Malignant cells varied within and between sites and patients in their expression of signatures. We identified a gene module highly expressed in intramedullary and extramedullary plasma cell clusters and defined cell clusters expressing this gene set as extramedullary-initiating cells (EMICs). This gene set was associated with increased cellular proliferation, involved in p53 signaling, and related to poor prognosis in MM. The transcriptional regulators E2F1, YY1, and SMAD1 were activated in EMICs. Leukocyte immunoglobulin–like receptor subfamily B4 (LILRB4) was upregulated in extramedullary EMICs. We confirmed that LILRB4 promoted MM cell migration in vitro. This study provided insight into the evolutionary mechanisms of ME and defined EMICs and LILRB4 associated with extramedullary development.
Pegaspargase-modified risk-oriented program for adult acute lymphoblastic leukemia: results of the GIMEMA LAL1913 trial
Authors: Bassan Renato , Chiaretti Sabina , Della Starza Irene , Spinelli Orietta , Santoro Alessandra , Paoloni Francesca , Messina Monica , Elia Loredana , De Propris Maria Stefania , Scattolin Anna Maria , Audisio Ernesta , Marbello Laura , Borlenghi Erika , Zappasodi Patrizia , Mauro Elisa , Martinelli Giovanni , Mattei Daniele , Fracchiolla Nicola , Bocchia Monica , De Fabritiis Paolo , Bonifacio Massimiliano , Candoni Anna , Cassibba Vincenzo , Di Bartolomeo Paolo , Latte Giancarlo , Trappolini Silvia , Guarini Anna , Vitale Antonella , Fazi Paola , Piciocchi Alfonso , Rambaldi Alessandro , Foà Robin
Published: June 2023

Pediatric-inspired chemotherapy is the standard of care for younger adults with Philadelphia chromosome–negative acute lymphoblastic leukemia/lymphoma (Ph– ALL/LL). In LAL1913 trial, the Gruppo Italiano Malattie EMatologiche dell’Adulto added pegaspargase 2000 IU/m2 to courses 1, 2, 5, and 6 of an 8-block protocol for patients aged from 18 to 65 years, with dose reductions in patients aged >55 years. Responders were risk stratified for allogeneic hematopoietic cell transplantation (HCT) or maintenance per clinical characteristics and minimal residual disease (MRD). Of 203 study patients (median age, 39.8 years), 91% achieved a complete remission. The 3-year overall survival, event-free, and disease-free survival (DFS) rates were 66.7%, 57.7%, and 63.3%, respectively, fulfilling the primary study end point of a 2-year DFS >55%. Although based on the intention-to-treat, the DFS being 74% and 50% in the chemotherapy (n = 94) and HCT (n = 91) assignment cohorts, respectively, a time-dependent analysis proved the value of HCT in patients who were eligible (DFS HCT 70% vs no HCT 26%; P <.0001). In multivariate analysis, age and MRD were independent factors predicting DFS rates of 86% (age ≤ 40 and MRD-negative), 64%-65% (MRD-positive or age > 40) and 25% (age > 40 and MRD-positive); P < .0001. Grade ≥2 pegaspargase toxicity was mainly observed at course 1, contributing to induction death in 2 patients but was rare thereafter. This program improved outcomes of patients with Ph– ALL/LL aged up to 65 years in a multicenter national setting. This trial was registered at www.clinicaltrials.gov as #NCT02067143.
Is book reading always best? Children learn and transfer complex scientific explanations from books or animations
Authors: Ronfard Samuel , Brown Sarah A. , Pitt Emma , Kelemen Deborah
Published: June 2023

Background

Storybooks are an effective tool for teaching complex scientific mechanisms to young children when presented in child-friendly, joint-attentional contexts like read-aloud sessions. However, static storybooks are limited in their ability to convey change across time and, relative to animated storybooks, are harder to disseminate to a wide audience. This study examined second graders’ abilities to learn the deeply counterintuitive concepts of adaptation and speciation from multi-day interventions centered around two storybooks about natural selection that were either read-aloud (static) or watched on a screen (animated). The storybook sequence was progressive and first explained—in counter-essentialist and non-teleological terms—how the relative distribution of a terrestrial mammal’s trait changed over time due to behavioral shifts in their primary food resource (adaptation, book 1). It then explained how–after a sub-population of this species became geographically isolated–they evolved into an entirely different aquatic species over many generations via selection on multiple foraging-relevant traits (speciation, book 2). The animated and static versions of the storybooks used the same text and illustrations, but while the animations lacked joint-attentional context, they more dynamically depicted successive reproductive generations. Storybook and animation presentations were interspersed with five parallel talk-aloud assessment interviews over three days.

Results

Findings revealed substantial learning from the read-aloud static storybook sequence. They also revealed substantial learning from the animation condition with patterns suggesting that the dynamic representations of change over time particularly scaffolded acquisition of the deeply counterintuitive idea that a species can evolve into an entirely different category of species by natural selection.

Conclusions

The results provide much-needed optimism in a context of increasing demands for scalable solutions to promote effective learning: animated storybooks are just as good (and may even be better) than static storybooks.
Correlation between KRAS and NRAS mutational status and clinicopathological features in 414 cases of metastatic colorectal cancer in Morocco: the largest North African case series
Authors: Mahdi Youssef , Khmou Mouna , Souadka Amine , Agouri Hajar El , Ech-charif Soumaya , Mounjid Chaimaa , Khannoussi Basma El
Published: June 2023

Background

Advances in molecular biology have improved understanding of the molecular features of carcinogenesis and progression of colorectal cancer. It is clear that the efficacy of anti-EGFR depends upon the RAS mutational status, since any mutation in RAS is associated with resistance to anti-EGFR therapy. The aim of this study is to report the largest North African description of KRAS and NRAS status in metastatic colorectal cancer and to describe the association of these mutations with clinicopathological characteristics.

Methods

This is a prospective study of all consecutive unselected metastatic colorectal cancer samples, collected from the Laboratory of Pathology at the National Institute of Oncology of Rabat, Morocco, from January 1st 2020 to December 31st 2021. The molecular analysis was performed on the Idylla™ platform (fully automated real-time polymerase chain reaction-based assay) for KRAS and NRAS mutations in exons 2, 3 and 4. These mutations were correlated to gender, primary tumor site, histological type and degree of differentiation of tumor using adequate statistical methods.

Results

Four hundred fourteen colorectal tumors were screened for KRAS and NRAS mutations. These mutations occurred in 51.7% of tumors for KRAS (mainly in exon 12) and in 3% of tumors for NRAS. There was a significant correlation between NRAS mutation and age of colorectal patients in this study. The low rate of invalid RAS tests (1.7% for KRAS and 3.1% for NRAS) was certainly obtained due to the strict respect of pre-analytical factors such as cold ischemia time and formalin fixation.

Conclusion

We report the largest North African analysis of NRAS and KRAS status in colorectal metastatic patients. This study showed the ability in low middle income countries to perform a high rate of valid tests and the unusual trend towards older patients for NRAS mutations.
Assessment of Anti-SARS-CoV-2 antibody levels among university students vaccinated with different COVID-19 primary and booster doses — fall 2021, Wisconsin
Authors: DeJonge Peter M. , Lambrou Anastasia S. , Segaloff Hannah E. , Bateman Allen , Sterkel Alana , Griggs Carol , Baggott Jake , Kelly Patrick , Thornburg Natalie , Epperson Monica , Desamu-Thorpe Rodel , Abedi Glen , Hsu Christopher H. , Nakayama Jasmine Y. , Ruffin Jasmine , Turner-Harper Darlene , Matanock Almea , Almendares Olivia , Whaley Melissa , Chakrabarti Ayan , DeGruy Kyle , Daly Michele , Westergaard Ryan , Tate Jacqueline E. , Kirking Hannah L.
Published: June 2023

Background

University students commonly received COVID-19 vaccinations before returning to U.S. campuses in the Fall of 2021. Given likely immunologic variation among students based on differences in type of primary series and/or booster dose vaccine received, we conducted serologic investigations in September and December 2021 on a large university campus in Wisconsin to assess anti-SARS-CoV-2 antibody levels.

Methods

We collected blood samples, demographic information, and COVID-19 illness and vaccination history from a convenience sample of students. Sera were analyzed for both anti-spike (anti-S) and anti-nucleocapsid (anti-N) antibody levels using World Health Organization standardized binding antibody units per milliliter (BAU/mL). Levels were compared across categorical primary COVID-19 vaccine series received and binary COVID-19 mRNA booster status. The association between anti-S levels and time since most recent vaccination dose was estimated by mixed-effects linear regression.

Results

In total, 356 students participated, of whom 219 (61.5%) had received a primary vaccine series of Pfizer-BioNTech or Moderna mRNA vaccines and 85 (23.9%) had received vaccines from Sinovac or Sinopharm. Median anti-S levels were significantly higher for mRNA primary vaccine series recipients (2.90 and 2.86 log [BAU/mL], respectively), compared with those who received Sinopharm or Sinovac vaccines (1.63 and 1.95 log [BAU/mL], respectively). Sinopharm and Sinovac vaccine recipients were associated with a significantly faster anti-S decline over time, compared with mRNA vaccine recipients (P<.001). By December, 48/172 (27.9%) participants reported receiving an mRNA COVID-19 vaccine booster, which reduced the anti-S antibody discrepancies between primary series vaccine types.

Conclusions

Our work supports the benefit of heterologous boosting against COVID-19. COVID-19 mRNA vaccine booster doses were associated with increases in anti-SARS-CoV-2 antibody levels; following an mRNA booster dose, students with both mRNA and non-mRNA primary series receipt were associated with comparable levels of anti-S IgG.
Benefit finding in men affected by prostate cancer prior to and following radical prostatectomy – a cross-sectional study with a stratified sample
Authors: Jahnen Matthias , Bayer Patrick , Meissner Valentin H. , Schiele Stefan , Schulwitz Helga , Gschwend Jürgen E. , Herkommer Kathleen , Dinkel Andreas
Published: June 2023

Background

Benefit finding (BF) - the occurrence of positive life-changes in the aftermath of traumatic live events - has been repeatedly reported in prostate cancer (PCa) survivors, but it remains unclear in which way BF might vary over time. The current study aimed to investigate the extent of BF and associated factors in different phases of the survivorship continuum.

Methods

In this cross-sectional study, men affected by PCa who were either already treated with radical prostatectomy or going to be treated with radical prostatectomy at a large German PCa center were included. These men were stratified into four groups (prior to surgery, up to 12 months after surgery, 2–5 years and ≥ 6–10 years after surgery). BF was assessed using the German version of the 17-item Benefit Finding Scale (BFS). The items are rated on a five-point Likert scale ranging from 1 to 5. A total mean score ≥ 3 was considered as moderate-to-high BF. Associations with clinical and psychological factors were assessed in men presenting before and in those who participated after surgery. Multiple linear regression was applied to identify intendent determinants of BF.

Results

2,298 men affected by PCa (mean age at survey: 69.5,SD = 8.2; median follow-up: 3 years (25th -75th percentile 0.5-7)) were included. 49.6% of men reported moderate-to-high BF. The mean BF score was 2.91 (SD = 0.92). BF reported by men before surgery did not differ significantly from BF reported by men in the years after surgery (p = 0.56). Higher BF prior to and following radical prostatectomy was associated with higher perceived severity of the disease (pre-surgery: ß = 0.188, p = 0.008; post-surgery: ß = 0.161, p = < 0.0001) and higher cancer-related distress (pre-surgery: ß ? 0.155, p = 0.03; post-surgery: ß = 0.089, p < 0.0001). Post radical prostatectomy BF was also associated with biochemical recurrence during follow-up (ß = 0.089, p = 0.001), and higher quality of life (ß = 0.124, p < 0.001).

Conclusions

Many men affected by PCa perceive BF already soon after diagnosis. The subjective perception of threat or severity associated with the diagnosis of PCa is an essential factor for higher levels of BF, probably more important than objective indicators of the severity of the disease. The early onset of BF and the high degree of similarity of BF reported across the different phases of survivorship suggests that BF is, to a large extent, a dispositional personal characteristic and a cognitive strategy of positively coping with cancer.
Human cornea thermo-viscoelastic behavior modelling using standard linear solid model
Authors: Ahmed Hassan M. , Salem Nancy M. , Al-Atabany Walid
Published: June 2023

Background

Corneal biomechanics is of great interest to researchers recently. Clinical findings relate them to corneal diseases and to outcomes of refractive surgery. To have a solid understanding of corneal diseases’ progression, it is important to understand corneal biomechanics. Also, they are essential for better explaining outcomes of refractive surgeries and their undesired consequences. There is a difficulty for studying corneal biomechanics in-vivo and multiple limitations arise for ex-vivo studies. Hence mathematical modelling is considered as a proper solution to overcome such obstacles. Mathematical modelling of cornea in-vivo allows studying corneal viscoelasticity with taking into consideration all boundary conditions existing in real in-vivo situation.

Methods

Three mathematical models are used to simulate corneal viscoelasticity and thermal behavior in two different loading situations: constant and transient loading. Two models of the three are used for viscoelasticity simulation which are Kelvin-Voigt and standard linear solid models. Also, temperature rise due to the ultrasound pressure push is calculated using bioheat transfer model for both the axial direction and as a 2D spatial map using the third model (standard linear solid model).

Results

Viscoelasticity simulation results show that standard linear solid model is efficient for describing the viscoelastic behavior of human cornea in both loading conditions. Results show also that the deformation amplitude obtained from standard linear solid model is more reasonable for corneal soft-tissue deformation with respect to corresponding clinical findings than that obtained from Kelvin-Voigt model. Thermal behavior results estimated corneal temperature rise to be roughly 0.2 °C, which conforms with FDA regulations for soft tissue safety.

Conclusion

Standard Linear Solid (SLS) model is better describing the human corneal behavior in response to constant and transient load more efficiently. Temperature rise (TR) for the corneal tissue of about 0.2 °C is conforming with FDA regulations and even less than the FDA regulations for soft tissue safety.