bluuebunny/crossref_metadata_2025_split huggingface dataset:
Afatinib and Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (ALPHA Study): A Phase II Study with Biomarker Analysis
Authors: Kao Hsiang-Fong , Liao Bin-Chi , Huang Yen-Lin , Huang Huai-Cheng , Chen Chun-Nan , Chen Tseng-Cheng , Hong Yuan-Jing , Chan Ching-Yi , Chia Jean-San , Hong Ruey-Long 
Published: January 2022

AbstractPurpose:EGFR pathway inhibition may promote anti–programmed cell death protein 1 (PD-1) responses in preclinical models, but how EGFR inhibition affects tumor antigen presentation during anti–PD-1 monotherapy in humans remain unknown. We hypothesized that afatinib, an irreversible EGFR tyrosine kinase inhibitor, would improve outcomes in patients treated with pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) by promoting antigen presentation and immune activation in the tumor microenvironment.Patients and Methods:The ALPHA study (NCT03695510) was a single-arm, Phase II study with Simon's 2-stage design. Afatinib and pembrolizumab were administered to patients with platinum-refractory, recurrent, or metastatic HNSCC. The primary endpoint was the objective response rate (ORR). The study applied gene expression analysis using a NanoString PanCancer Immune Profiling Panel and next-generation sequencing using FoundationOne CDx.Results:From January 2019 to March 2020, the study enrolled 29 eligible patients. Common treatment-related adverse events were skin rash (75.9%), diarrhea (58.6%), and paronychia (44.8%). Twelve patients (41.4%) had an objective partial response to treatment. The median progression-free survival was 4.1 months, and the median overall survival was 8.9 months. In a paired tissue analysis, afatinib–pembrolizumab were found to upregulate genes involved in antigen presentation, immune activation, and natural killer cell–mediated cytotoxicity. Unaltered methylthioadenosine phosphorylase and EGFR amplification may predict the clinical response to the therapy.Conclusions:Afatinib may augment pembrolizumab therapy and improve the ORR in patients with HNSCC. Bioinformatics analysis suggested the enhancement of antigen presentation machinery in the tumor microenvironment.
Chimeric Antigen Receptors Directed at Mutant KRAS Exhibit an Inverse Relationship Between Functional Potency and Neoantigen Selectivity
Authors: Tokatlian Talar , Asuelime Grace E. , Naradikian Martin S. , Mock Jee-Young , Daris Mark E. , Martin Aaron D. , Toledo Warshaviak Dora , Kamb Alexander , Hamburger Agnes E. 
Published: January 2022

Neoantigens are among the most intriguing potential immuno-oncology targets because, unlike many cancer targets that are expressed on normal tissues, they are by definition restricted to cancer cells. Medicines directed at common neoantigens such as mutant KRAS are especially interesting because they may offer the convenience and cost of an off-the-shelf therapy. However, all common KRAS mutations produce proteins that differ from the wild type at a single amino acid, creating challenges for molecular discrimination. We have undertaken an effort to optimize single-chain variable fragments (scFv) against peptide/major histocompatibility antigen complexes composed of HLA-A*11 and either G12V- or G12D-mutant KRAS peptides. These scFvs could in principle be used in chimeric antigen receptor (CAR) T-cell therapies for selected patients whose tumors bear either of these mutations. Here we show that optimization of such CARs involves a trade-off between potency and selectivity. We further show that targeting this family without high selectivity engenders risks of cross-reactivity against other members of the G-protein family to which KRAS belongs.Significance:We report an effort to generate high potency, selective CARs directed at mutant KRAS peptides. Although the heavily optimized CARs maintain high selectivity against wild-type KRAS, they lose selectivity against other KRAS-related peptides derived from human proteins. To our knowledge, this work is the first to examine the trade-off between potency and selectivity with regard to KRAS pMHC-directed CARs, illustrating the challenge to achieve both sufficient potency and high selectivity.
Pengembangan Kawasan Wisata pada Rest Area Boja dalam Mendukung Peningkatan Pedapatan Desa Melalui Perilaku Herding (Studi Kasus di Kawasan Wisata Rest Area Desa Boja, Kecamatan Boja, Kabupaten Kendal)
Authors: Ristianawati Yuyun , Nugroho Prihasantyo Siswo , Kiswoyo  
Published: January 2022

The aims of this research is to study the mindset of Herding's behavior on the income level of tourism objects through the results of tourism development in the Rest Area of Boja Kendal Village. In this study, 95 people/MSMEs. In this study, the authors used a purposive random sampling technique.
The results of this study are herding behavior has a positive and significant effect on the income level of MSMEs in the Boja rest area tourist attraction. Herding behavior has no effect on tourism development decisions. The development of tourism objects has no effect on increasing income. Herding behavior has no significant effect on the income level of tourist objects through tourism area development decisions. So that the development of tourist areas is not able to mediate the influence of herding behavior on increasing MSME income in the Boja rest area tourist attraction.
Carotid Atherosclerosis Predicts Blood Pressure Control in Patients With Hypertension: The Campania Salute Network Registry
Authors: Mancusi Costantino , Manzi Maria Virginia , de Simone Giovanni , Morisco Carmine , Lembo Maria , Pilato Emanuele , Izzo Raffaele , Trimarco Valentina , De Luca Nicola , Trimarco Bruno 
Published: January 2022

Background
The 2018 European Society of Cardiology/European Society of Hypertension arterial hypertension guidelines do not recommend routine carotid ultrasound as a tool to identify hypertension‐mediated organ damage, unless clinically indicated. However, carotid plaque (CP) is a strong correlate of increased arterial stiffness, which influences blood pressure (BP) control over time. Thus, we assessed whether evidence of CP at first visit could predict BP control during follow‐up.

Methods and Results

From the CSN (Campania Salute Network) Registry, 6684 patients with hypertension had complete carotid ultrasound examination and were categorized by the presence of CP at baseline. Optimal BP control was defined as average BP <140/90 mm Hg and <135/85 during follow‐up for office and home BP, respectively. At baseline, participants with CP (n=3061) were more likely to be men, to be older, to have diabetes, and to exhibit higher systolic BP, lower diastolic BP, worse lipid profile, and higher prevalence of left ventricular hypertrophy (all
P
<0.0001) than patients without CP. Optimal office BP control was adjudicated in 54% with and 62% without CP (
P
<0.0001), and optimal home BP in 51% with and 58% without CP (
P
<0.01). Presence of CP was significantly associated with the reduced probability of controlled office BP during follow‐up (both
P
<0.0001), independently of significant effect of older age, male sex, higher baseline BP values, classes of medication, and presence of left ventricular hypertrophy, and only attenuated by duration of hypertension.

Conclusions
Presence of CP in treated patients with hypertension is associated with suboptimal BP control during follow‐up, independently of worse metabolic profile and presence of left ventricular hypertrophy.
Blood Pressure Complexity Discriminates Pathological Beat‐to‐Beat Variability as a Marker of Vascular Aging
Authors: Lee Yun‐Kai , Mazzucco Sara , Rothwell Peter M. , Payne Stephen J. , Webb Alastair J. S. 
Published: January 2022

Background
Beat‐to‐beat blood pressure variability (BPV) is associated with an increased risk of stroke but can be driven by both healthy physiological processes and failure of compensatory mechanisms. Blood pressure (BP) complexity measures structured, organized variations in BP, as opposed to random fluctuations, and its reduction may therefore identify pathological beat‐to‐beat BPV.

Methods and Results

In the prospective, population‐based OXVASC (Oxford Vascular Study) Phenotyped Cohort with transient ischemic attack or minor stroke, patients underwent at least 5 minutes of noninvasive beat‐to‐beat monitoring of BP (Finometer) and ECG to derive the following: BPV (coefficient of variation) and complexity (modified multiscale entropy) of systolic BP and diastolic BP, heart rate variability (SD of R‐R intervals), and baroreflex sensitivity (BRS; Welch's method), in low‐ (0.04–0.15 Hz) and high‐frequency (0.15–0.4 Hz) bands. Associations between BPV or BP complexity with autonomic indexes and arterial stiffness were determined (linear regression), unadjusted, and adjusted for age, sex, and cardiovascular risk factors. In 908 consecutive, consenting patients, BP complexity was inversely correlated with BPV coefficient of variation (
P
<0.001) and was similarly reduced in patients with hypertension or diabetes (
P
<0.001). However, although BPV coefficient of variation had a U‐shaped relationship with age, BP complexity fell systematically across age quintiles (quintile 1: 15.1 [14.0–16.1] versus quintile 5: 13.8 [12.4–15.1]) and was correlated with markers of autonomic dysfunction (heart rate variability SD of R‐R intervals:
r
= 0.20; BRS low frequency: 0.19; BRS high frequency: 0.26) and arterial stiffness (pulse wave velocity: −0.21; all
P
<0.001), even after adjustment for clinical variables (heart rate variability SD of R‐R intervals: 0.12; BRS low frequency and BRS high frequency: 0.13 and 0.17; and pulse wave velocity: −0.07; all
P
<0.05).

Conclusions
Loss of BP complexity discriminates BPV because of pathological failure of compensatory mechanisms and may represent a less confounded and potentially modifiable risk factor for stroke.
Bacteriophages Combined With Subtherapeutic Doses of Flucloxacillin Act Synergistically Against
Staphylococcus aureus
Experimental Infective Endocarditis
Authors: Save Jonathan , Que Yok‐Ai , Entenza José M. , Kolenda Camille , Laurent Frédéric , Resch Grégory 
Published: January 2022

Background

The potential of phage therapy for the treatment of endovascular
Staphylococcus aureus
infections remains to be evaluated.

Methods and Results

The efficacy of a phage cocktail combining
Herelleviridae
phage vB_SauH_2002 and
Podoviriae
phage 66 was evaluated against a methicillin‐sensitive
S. aureus
strain in vitro and in vivo in a rodent model of experimental endocarditis. Six hours after bacterial challenge, animals were treated with (1) the phage cocktail. (2) subtherapeutic flucloxacillin dosage, (3) combination of the phage cocktail and flucloxacillin, or (4) saline. Bacterial loads in cardiac vegetations at 30 hours were the primary outcome. Secondary outcomes were phage loads at 30 hours in cardiac vegetations, blood, spleen, liver, and kidneys. We evaluated phage resistance 30 hours post infection in vegetations of rats under combination treatment. In vitro, phages synergized against
S. aureus
planktonic cells and the cocktail synergized with flucloxacillin to eradicated biofilms. In infected animals, the phage cocktail achieved bacteriostatic effect. The addition of low‐dose flucloxacillin elevated bacterial suppression (∆ of −5.25 log
10
colony forming unit/g [CFU/g] versus treatment onset,
P
<0.0001) and synergism was confirmed (∆ of −2.15 log
10
CFU/g versus low‐dose flucloxacillin alone,
P
<0.01). Importantly, 9/12 rats given the combination treatment had sterile vegetations at 30 hours. In vivo phage replication was partially suppressed by the antibiotic and selection of resistance to the
Podoviridae
component of the phage cocktail occurred. Plasma‐mediated inhibition of phage killing activity was observed in vitro.

Conclusions

Combining phages with a low‐dose standard of care antibiotic represents a promising strategy for the treatment of
S. aureus
infective endocarditis.
Risks and Benefits of Early Rhythm Control in Patients With Acute Strokes and Atrial Fibrillation: A Multicenter, Prospective, Randomized Study (the RAFAS Trial)
Authors: Park Junbeom , Shim Jaemin , Lee Jung Myung , Park Jin‐Kyu , Heo JoonNyung , Chang Yoonkyung , Song Tae‐Jin , Kim Dong‐Hyeok , Lee Hye Ah , Yu Hee Tae , Kim Tae‐Hoon , Uhm Jae‐Sun , Kim Young Dae , Nam Hyo Suk , Joung Boyoung , Lee Moon‐Hyoung , Heo Ji Hoe , Pak Hui‐Nam ,   for the RAFAS Investigators*
Published: January 2022

Background
The purpose of the RAFAS (Risk and Benefits of Urgent Rhythm Control of Atrial Fibrillation in Patients With Acute Stroke) trial was to explore the risks and benefits of early rhythm control in patients with newly documented atrial fibrillation (AF) during an acute ischemic stroke (IS).

Method and Results

An open‐label, randomized, multicenter trial design was used. If AF was diagnosed, the patients in the early rhythm control group started rhythm control within 2 months after the occurrence of an IS, unlikely the usual care. The primary end points were recurrent IS within 3 and 12 months. The secondary end points were a composite of all deaths, unplanned hospitalizations from any cause, and adverse arrhythmia events. Patients (n=300) with AF and an acute IS (63.0% men, aged 69.6±8.5 years; 51.2% with paroxysmal AF) were randomized 2:1 to early rhythm control (n=194) or usual care (n=106). A total of 273 patients excluding those lost to follow‐up (n=27) were analyzed. The IS recurrences did not differ between the groups within 3 months of the index stroke (2 [1.1%] versus 4 [4.2%]; hazard ratio [HR], 0.257 [log‐rank
P
=0.091]) but were significantly lower in the early rhythm control group at 12 months (3 [1.7%] versus 6 [6.3%]; HR, 0.251 [log‐rank
P
=0.034]). Although the rates of overall mortality, any cause of hospitalizations (25 [14.0%] versus 16 [16.8%]; HR, 0.808 [log‐rank
P
=0.504]), and arrhythmia‐related adverse events (5 [2.8%] versus 1 [1.1%]; HR, 2.565 [log‐rank
P
=0.372]) did not differ, the proportion of sustained AF was lower in the early rhythm control group than the usual care group (60 [34.1%] versus 59 [62.8%],
P
<0.001) in 12 months.

Conclusions
The early rhythm control strategy of an acute IS decreased the sustained AF and recurrent IS within 12 months without an increase in the composite adverse outcomes.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT 02285387.
Fractional Flow Reserve and Instantaneous Wave‐Free Ratio Predict Pathological Wall Shear Stress in Coronary Arteries: Implications for Understanding the Pathophysiological Impact of Functionally Significant Coronary Stenoses
Authors: Wong Christopher C. Y. , Javadzadegan Ashkan , Ada Cuneyt , Lau Jerrett K. , Bhindi Ravinay , Fearon William F. , Kritharides Leonard , Ng Martin K. C. , Yong Andy S. C. 
Published: January 2022

Background
The pathophysiological mechanism behind adverse outcomes associated with ischemia‐inducing epicardial coronary stenoses and microcirculatory dysfunction remains unclear. Wall shear stress (WSS) plays an important role in atherosclerotic plaque progression and vulnerability. We aimed to evaluate the relationship between WSS, functionally significant epicardial coronary stenoses, and microcirculatory dysfunction.

Methods and Results
Patients undergoing invasive coronary physiology testing were included. Fractional flow reserve, instantaneous wave‐free ratio, and the index of microcirculatory resistance were measured. Quantitative coronary angiography was used to obtain the lesion percentage diameter stenosis. Computational fluid dynamics analysis was performed to calculate WSS parameters. Multiple regression analysis was performed to calculate the standardized regression coefficient (β) for the coronary physiology indices.

A total of 107 vessels from 88 patients were included. Fractional flow reserve independently predicted the total area of low WSS (β=−0.44; 95% CI, −0.62 to −0.25;
P
<0.001) and maximum lesion WSS (β=−0.53; 95% CI, −0.70 to −0.36;
P
<0.001) after adjusting for percentage diameter stenosis and index of microcirculatory resistance. Similarly, instantaneous wave‐free ratio also independently predicted the total area of low WSS (β=−0.45; 95% CI, −0.62 to −0.28;
P
<0.001) and maximum lesion WSS (β=−0.58; 95% CI, −0.73 to −0.43;
P
<0.001). The index of microcirculatory resistance did not predict either low or high WSS.

Conclusions
Fractional flow reserve and instantaneous wave‐free ratio independently predicted the total burden of low WSS and maximum lesion WSS in coronary arteries. No relationship was found between microcirculatory dysfunction and WSS.
Where does the moisture for North Atlantic tropical cyclones come from?
Authors: Pérez-Alarcón Albenis , Sorí Rogert , Fernández-Alvarez José C. , Nieto Raquel , Gimeno Luis 
Published: January 2022

AbstractIn this study, we identified the origin of the moisture associated with the tropical cyclones (TCs) precipitation in the North Atlantic Ocean basin during their three well-differentiated life stages between 1980 and 2018. The HURDAT2 database was used to detect the location of 598 TCs during their genesis, maximum intensification peak, and dissipation phases. The global outputs of the Lagrangian FLEXPART model were then used to determine the moisture sources. Using a K-means cluster analysis technique, seven different regions were identified as the most common locations for the genesis and maximum intensity of the TC phases, while six regions were found for the dissipation points. Our results showed that the origin of moisture precipitating was not entirely local over the areas of TC occurrence. The North Atlantic Ocean to the north of the Inter Tropical Convergence Zone at 10°N (NATL) -especially from tropical latitudes, the Caribbean Sea and the Gulf of Mexico- provides most of the moisture for TCs (∼87%). The Atlantic Ocean basin southward the ITCZ (SATL) played a non-negligible role (∼11%), with its contribution being most pronounced during the TC genesis phase, while the eastern tropical Pacific Ocean made the smallest contribution (∼2%). The moisture supported by TCs varied depending on their category, being higher for hurricanes than for major hurricanes or tropical storms. Additionally, the approach permitted to estimate the mean residence time of the water vapour uptake that produce the precipitation during TC activity, which ranged between 2.6 and 2.9 days.
Air contamination of therapeutic drug monitoring assay reagents results in falsely high plasma ammonia levels
Authors: Tsukushi Tomoaki , Shinohara Ryota , Adachi Yuzuru , Kurosaki Yoshifumi , Ishii Naohito , Katagiri Masato , Munekata Shinichi , Kanoh Yuhsaku 
Published: January 2022

Background Accumulating evidence shows that contamination of blood samples by atmospheric ammonia affects blood ammonia test levels; however, reports on the effect of ammonia contamination of assay reagents are limited. Here, we aimed to clarify the effect of ammonia contamination of assay reagents, particularly the therapeutic drug monitoring (TDM) reagents, on the detection levels of blood ammonia using enzymatic assays. Methods Ammonia gas was measured in the refrigerator compartment of the automatic analyser and the reaction tank water, probe wash water and drain outlets connected to the automatic analyser. At different time points following the closure of the cold storage, ammonia levels in quality control plasma samples were measured using three commercial assay reagents to evaluate the effect of air contamination. The distribution of evaporated ammonia in the reagent was measured using the CicaLiquid NH3 assay kit containing the assay reagent most affected by air contamination. Results It was confirmed that ammonia gas was generated in the cold storage of the automatic analyser. More than half of the reagents detected >0.25 ppm ammonia, and the highest concentration was detected in the TDM reagent. The ammonia levels obtained using all three reagents increased significantly after 3 h of air contamination. The effect was resolved by measuring a ‘dummy’ sample or mixing the reagents by inversion. Conclusions We demonstrated that air contamination by TDM reagents placed in cold storage could result in significantly falsely high ammonia measurements. Preventing this effect would improve the accuracy of ammonia measurements.
Trimester-specific reference intervals for cystatin C and neutrophil gelatinase-associated lipocalin during pregnancy
Authors: Schmitz Ellen MH , Langelaan Marloes LP , de Groot Monique JM , Ermens Ton AM , Joosen Annemiek MCP 
Published: January 2022

Background During normal pregnancy, the glomerular filtration rate (GFR) increases dramatically. Failure to obtain this physiological increase is an important risk factor for morbidity and mortality for both mother and child. The estimated GFR (eGFR) using serum creatinine levels is unsuitable for accurate measurement of renal function during pregnancy. Therefore, new biomarkers have been proposed. Elevated levels of Cystatin C (CysC) and Neutrophil Gelatinase-Associated Lipocalin (NGAL) are associated with renal failure and preeclampsia (PE). In this study, we determined reference intervals for CysC and NGAL during pregnancy. Methods Healthy pregnant women were recruited and blood samples were collected at 9–13 weeks (T1), 27–29 weeks (T2), and 36–39 weeks (T3) of gestation and at 4–13 weeks postpartum (PP). The samples from women with uncomplicated pregnancy were analyzed to determine median values and upper reference limits (URLs, 97.5 percentiles) of creatinine, CysC, and NGAL. Results A total of 175 women were included. Longitudinal changes and median values of creatinine, CysC, and NGAL were determined using only complete data sets ( n=59). URLs were determined using all available data. The URL at T1, T2, T3, and PP were 60, 63, 74, 93 μmol/L for creatinine; 0.93, 1.04, 1.61, 1.23 mg/L for CysC; and 87, 84, 88, 95 ng/mL for NGAL. Conclusions CysC concentrations are highly dynamic and increase during pregnancy. NGAL concentrations are less dynamic, but well below the URL specified by the manufacturer for non-pregnant women. It is therefore recommended to use trimester-specific reference values for both CysC and NGAL.