bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing patient risk, benefit, and outcomes in drug development: A decade of ramucirumab clinical trials
Authors: Khan Adam , Khan Hassan , Hughes Griffin K. , Ladd Chase , McIntire Ryan , Gardner Brooke , Peña Andriana M. , Schoutko Abigail , Tuia Jordan , Minley Kirstien , Haslam Alyson , Prasad Vinay , Vassar Matt
Published: May 2024

Objective

This study aims to evaluate published clinical trials of ramucirumab to assess the risk/benefit profile and burden over time for patients.

Background

The burden of oncologic drug development on patients paired with increasing clinical trial failure rates emphasizes the need for reform of drug development. Identifying and addressing patterns of excess burden can guide policy, ensure evidence‐based protections for trial participants, and improve medical decision‐making.

Methods

On May 25, 2023 a literature search was performed on Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov for clinical trials using ramucirumab as monotherapy or in combination with other interventions for cancer treatment. Authors screened titles and abstracts for potential inclusion in a masked, duplicate fashion. Following data screening, data was extracted in a masked, duplicate fashion. Trials were classified as positive when meeting their primary endpoint and safety, negative or indeterminate.

Results

Ramucirumab was initially approved for gastric cancer but has since been tested in 20 cancers outside of its FDA approved indications. In our analysis of ramucirumab trials, there were a total of 10,936 participants and 10,303 adverse events reported. Gains in overall survival and progression‐free survival for patients were 1.5 and 1.2 months, respectively. FDA‐approved indications have reported more positive outcomes in comparison to off‐label indications.

Conclusion

We found that FDA‐approved indications for ramucirumab had better efficacy outcomes than non‐approved indications. However, a concerning number of adverse events were observed across all trials assessed. Participants in ramucirumab randomized controlled trials saw meager gains in overall survival when evaluated against a comparison group. Clinicians should carefully weigh the risks associated with ramucirumab therapy given its toxicity burden and poor survival gains.
N‐Hydroxyalkanamide Based Organo/hydrogels as Novel Scaffolds for pH‐Dependent Metronidazole and Theophylline Release
Authors: Monika  , Meenakshi  , Brahma Mettle , Maruthi Mulaka , Selvakumar Sermadurai , Ansari Azaj , Gupta Manoj K.
Published: May 2024

The traditional delivery of metronidazole and theophylline presents challenges like bitter taste, variable absorption, and side effects. However, gel‐based systems offer advantages including enhanced targeted drug delivery, minimized side effects, and improved patient compliance, effectively addressing these challenges. Consequently, a cost‐effective synthesis of N‐hydroxyalkanamide gelators with varying alkyl chain lengths was achieved in a single‐step reaction procedure. These gelators formed self‐assembled aggregates in DMSO/water solvent system, resulting in organo/hydrogels at a minimum gelation concentration of 1.5 % w/v. Subsequently, metronidazole and theophylline were encapsulated within the gel core and released through gel‐to‐sol transition triggered by pH variation at 37 °C, while maintaining the structural‐activity relationship. UV‐vis spectroscopy was employed to observe the drug release behavior. Furthermore, in vitro cytotoxicity assays revealed cytotoxic effects against A549 lung adenocarcinoma cells, indicating anti‐proliferative activity against human lung cancer cells. Specifically, the gel containing theophylline (16HAD+Th) exhibited cytotoxicity on cancerous A549 cells with IC50 values of 19.23±0.6 μg/mL, followed by the gel containing metronidazole (16HAD+Mz) with IC50 values of 23.75±0.7 μg/mL. Moreover, the system demonstrated comparable antibacterial activity against both gram‐negative (E. coli) and gram‐positive bacteria (S. aureus).
Discovery of Novel Cholinesterase Inhibitors Easily Crossing the Blood‐Brain Barrier via Structure‐Property Relationship Investigation: Methylenedioxy‐Cinnamicamide Containing Tertiary Amine Side Chain
Authors: Shi Qing , Yang Zhi‐Yu , Wang Yi‐Hui , Yi Bi‐Xin , Gao Xiao‐Hui , Ding Yu‐Jie , Peng Dian , Chen Yan‐Ling , Liu Hao‐Ran
Published: May 2024

In the present investigation, a series of dimethoxy or methylenedioxy substituted‐cinnamamide derivatives containing tertiary amine moiety (N. N‐Dimethyl, N, N‐diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood‐brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC50: 1.52±0.19 μmol/L) and good blood‐brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography‐mass/mass spectrometry (UPLC‐MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72±93.56 ng/g) after dosing 30 min. Its half‐life in the serum is 331 min (5.52 h), and the CBrain/CSerum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24 hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs.
Percutaneous balloon mitral valvuloplasty with shockwave lithotripsy for the treatment of calcific mitral valve stenosis
Authors: Alnasser Sami M. , Moey Melissa , Ali Noman , Almazroa Loai , Al‐Shaibi Abdulaziz , Liauw Samantha , Claeys Mathias , Ong Geraldine , Fam Neil P.
Published: May 2024

Background

Calcific mitral stenosis (calcific MS) presents a challenge for surgical treatment and is a contraindication for most contemporary transcatheter mitral valve replacement devices (TMVR), rendering patients with very limited therapeutic options.

Aims

This study aims to assess the clinical and hemodynamic follow‐up after mitral valve lithotripsy (MVL).

Methods

All consecutive patients who underwent MVL to treat symptomatic calcific MS at St Michael's Hospital, Toronto, Canada, were included. Patients were deemed unsuitable for mitral surgery or TMVR after heart team assessment. Patients with rheumatic MS or ≥moderate mitral regurgitation (MR) were excluded. The primary endpoint was a reduction in the invasive mitral gradient by ≥50% without significant (≥moderate) MR.

Results

Fifteen patients underwent MVL between 2021 and 2023 with a mean age of 74 ± 9 years; 53% were female, with a mean STS score of 10% ± 0.1%. Following MVL, there was a reduction in the invasively measured mean trans‐mitral gradient compared to baseline (14 mmHg vs. 6 mmHg; p < 0.05). The primary endpoint was achieved in 8 patients (53%) with no major procedural complications. At follow‐up (median 90 days, IQR 58‐115 days), 14 (93%) patients reported improved symptoms from New York Heart Association (NYHA) Class III–IV to NYHA Class I–II (p < 0.01) with stable echo‐derived mean gradient (7.7 mmHg ± 2 mmHg vs. 8.4 mmHg ± 2.9 mmHg (p = 0.7).

Conclusions

In selected patients with symptomatic inoperable calcific MS, MVL was safe and associated with significant short‐term clinical and hemodynamic improvement. MVL may represent a new compassionate therapy for this challenging cohort. Further studies are needed to determine the long‐term outcomes and help define the role of IVL technology in treating calcific valvular conditions.
Perianal tuberculosis presenting as a Fournier's gangrene
Authors: Lalanda Raquel , Barão Andreia , Draiblate Beatriz , Malcato Ester , Matos Hélder , Girão José , Rosa Rosário , Freire José Paulo , Miranda Luís
Published: May 2024

Key Clinical Message

In the setting of Fournier's gangrene, atypical clinical manifestations and complications in an immunocompetent patient warrant consideration of perineal tuberculosis as a potential underlying cause.

Tuberculosis cutis orificialis is a rare form of extrapulmonary tuberculosis that affects the perianal region. Fournier's gangrene is an aggressive necrotizing fasciitis that primarily involves the perianal area and external genitalia. A previously healthy 38‐year‐old man presented with a left perianal abscess. His condition deteriorated, leading to septic shock and multiorgan dysfunction syndrome. A CT scan displayed extensive necrotizing fasciitis. Treatment included broad‐spectrum antibiotics, numerous surgical perineal debridements, a transverse loop colostomy, and hyperbaric oxygen therapy. We believe the patient had pre‐existing asymptomatic, non‐diagnosed perianal tuberculosis, and a subsequent bacterial superinfection resulted in a perineal local abscess that progressed to severe Fournier's gangrene. The diagnosis of tuberculosis was confirmed through positive cultures and molecular identification in perineal biopsies. The patient experienced a complex clinical course with complications such as myocardial necrosis, acute respiratory distress syndrome, rhabdomyolysis with severe critical illness polyneuromyopathy and internal jugular thrombosis. Fournier's gangrene resulted in air dissection throughout the perineal fasciae, extending to the abdominal wall muscles resulting in an infected extraperitoneal spontaneous hematoma, probably caused by therapeutic anticoagulation. An extraperitoneal surgical drainage was performed. This case emphasizes the complexities in diagnosing and managing both perianal tuberculosis and Fournier's gangrene.
Unusual painful pelvic masses: Extramedullary hematopoiesis with extramedullary multiple myeloma
Authors: Cai Jennifer , Varda Marian , Sin David , Overby Halline , Yeh James J.
Published: May 2024

Key Clinical Message

The coexistence of extramedullary hematopoiesis and extramedullary multiple myeloma can occur and present as painful pelvic masses. In such a case, normal hematopoietic cells may outnumber clonal plasma cells, posing a diagnostic challenge.
Facile Preparation of Stable NiII‐ and CoII‐Tetraaminophthalocyanine Electropolymers for Highly Efficient Heterogeneous Carbon Dioxide Reduction
Authors: Luangchaiyaporn Jirapong , Chairat Permsak , Sodkhomkhum Rapheepraew , Sariciftci Niyazi Serdar , Thamyongkit Patchanita
Published: May 2024

This study focused on preparation of stable polymer films of NiII‐ and CoII‐tetraaminophthalocyanines, p‐NiTAPc and p‐CoTAPc, respectively, for highly efficient heterogeneous electrochemical carbon dioxide (CO2) reduction in a flow electrolysis cell. Major development represented in this work was fabrication of p‐NiTAPc and p‐CoTAPc films via electropolymerization of their corresponding monomers on carbon‐based substrates without using binder or conducting additive materials to obtain efficient gas diffusion electrodes (GDEs) for scalable, productive and selective CO2‐to‐CO conversion. The target polymers were characterized by UV‐visible spectrophotometry, attenuated total reflection‐Fourier transform infrared spectroscopy, scanning electron microscopy, energy dispersive X‐ray spectroscopy and cyclic voltammetry. According to controlled potential electrolysis and gas chromatography, p‐NiTAPc‐catalyzed CO2 reduction at −0.99 V vs. reversible hydrogen electrode (RHE) gave 953 mL of CO in a period of 16 hours with current density and Faradaic efficiency (FE) of 109±1 mA ⋅ cm−2 and 99±2 %, respectively. A p‐CoTAPc‐modified GDE exhibited superior catalytic performance to the case of p‐NiTAPc in terms of catalyst stability and CO productivity by performing the continuous CO2 reduction at the potential of −1.10 V vs. RHE for up to 41 hours and affording almost 3 times higher amount of CO with the current density of 161±5 mA⋅cm–2 and 95±2 % FE.
Chiral Induction in a Self‐Assembled Pd4 Coordination Cage with Chiral Guests
Authors: Singha Raghunath , Maity Pankaj , Samanta Dipak
Published: May 2024

The dynamic interplay of coordination bonds within metal‐organic cages offers a unique avenue for structural evolution in response to external stimuli, presenting a promising strategy for the construction of chiral assemblies. This adaptability is crucial for the selective synthesis of homochiral assemblies and advancement of asymmetric catalysis. In this study, we report the self‐assembly of an achiral square‐planar Pd(II) acceptor with a C2‐symmetric tetrapyridyl donor resulted in the formation of a racemic mixture of the chiral octahedral cage Pd4L2. The existence of this racemic mixture was confirmed using circular dichroism spectroscopy as well as single crystal X‐ray diffraction analysis. We encoded chiral information into the asymmetric cavity of the cage by encapsulating chiral aromatic guests through efficient π‐π stacking and hydrophobic interactions in aqueous media. The inclusion of a chiral guest induces a preference for one enantiomeric conformation of the cage over the other, effectively shifting the equilibrium towards a single, enantiopure host‐guest complex. While the concept of chiral guest recognition by a chiral host is well‐established, this work constitutes a remarkable example of guest‐mediated chirality transfer leading to the formation of a single enantiopure coordination complex from achiral building blocks.
Ring Fusion Elevates the Electronic Mobility of Azabenzannulated Perylene Diimide
Authors: Yang Fan , Wang Cui , Liang Laiyu , Wang Zhiqiang , You Xiaoxiao , Shao Guangwei , Wu Di , Xia Jianlong
Published: May 2024

The backwardness of n‐type organic semiconductors still exists compared with the p‐type counterparts. Thus, the development of high‐performance n‐type organic semiconductors is of great importance for organic electronic devices and their integrated circuits. In recent years, azabenzannulated perylene diimide (PDI), as one of immense bay‐region‐annulated PDI derivatives, has drawn considerable attentions. However, the electronic mobilities of azabenzannulated PDI derivatives are barely satisfactory. In this contribution, the peripheral benzene ring in azabenzannulated PDI 2 was fused to the ortho position by intramolecular C−H arylation cyclization. This endows the resultant azabenzannulated PDI 4 a planar configuration as well as electron deficient pentagonal ring. As a result, the electronic mobility of 4 is almost two orders of magnitude higher than that of the nonfused azabenzannulated PDI 2. This work shall pave a new avenue in elevating the performance of azabenzannulated PDI in organic electronics.
Controlling the Uptake and Release of Semiochemicals in Channel‐Type Metal‐Organic Frameworks Through Pore Expansion
Authors: Nicks Joshua , Shearer Greig C. , Paul‐Taylor Joseph , Lai‐Morrice James , Dadswell Chris , Guest Daniel , Hughes William O. H. , Spencer John , Düren Tina , Burrows Andrew D.
Published: May 2024

Semiochemicals can be used to manipulate insect behaviour for sustainable pest management strategies, but their high volatility is a major issue for their practical implementation. Inclusion of these molecules within porous materials is a potential solution to this issue, as it can allow for a slower and more controlled release. In this work, we demonstrate that a series of Zr(IV) and Al(III) metal‐organic frameworks (MOFs) with channel‐type pores enable controlled release of three semiochemicals over 100 days by pore size design, with the uptake and rate of release highly dependent on the pore size. Insight from grand canonical Monte Carlo simulations indicates that this is due to weaker MOF‐guest interactions per guest molecule as the pore size increases. These MOFs are all stable post‐release and can be reloaded to show near‐identical re‐release profiles. These results provide valuable insight on the diffusion behaviour of volatile guests in MOFs, and for the further development of porous materials for sustainable agriculture applications.
Vibrational Circular Dichroism of a Chiral Triplet Nitrene Investigated Under Matrix‐Isolation Conditions in Parahydrogen
Authors: Beyer Frederike , Grassin Corentin , Rowen Julien F. , Sander Wolfram , Merten Christian
Published: May 2024

Vibrational circular dichroism (VCD) spectra of chiral high‐spin organic radicals are expected to show a strong intensity enhancement and are thought to be difficult to predict using state‐of‐the‐art theoretical methods. Herein we show that the chiral triplet nitrene obtained from photochemical cleavage of N2 from enantiopure 2‐azido‐9H‐fluorenol does not feature extraordinarily strong intensities and that the experimental spectra match nicely with calculated ones. Thereby, this study demonstrates the general feasibility of studies on chiral high‐spin organics by matrix‐isolation VCD.
Enantiomeric separation of tryptophan via novel chiral polyamide composite membrane
Authors: Peng Xinwei , Wei Yongming , Peng Yangfeng , Zhao Hongliang , Tong Tianzhong , He Quan
Published: May 2024

The separation of chiral drugs continues to pose a significant challenge. However, in recent years, the emergence of membrane‐based chiral separation has shown promising effectiveness due to its environmentally friendly, energy‐efficient, and cost‐effective characteristics. In this study, we prepared chiral composite membrane via interfacial polymerization (IP), utilizing β‐cyclodextrin (β‐CD) and piperazine (PIP) as mixed monomers in the aqueous phase. The chiral separation process was facilitated by β‐CD, serving as a chiral selective agent. The resulting membrane were characterized using SEM, FT‐IR, and XPS. Subsequently, the chiral separation performance of the membrane for DL‐tryptophan (Trp) was investigated. Lastly, the water flux, dye rejection, and stability of the membrane were also examined. The results showed that the optimized chiral PIP0.5β‐CD0.5 membrane achieved an enantiomeric excess percentage (ee%) of 43.0% for D‐Trp, with a solute flux of 66.18 nmol·cm−2·h−1, and maintained a good chiral separation stability. Additionally, the membrane demonstrated positive performance in the selective separation of mixed dyes, allowing for steady operation over a long period of time. This study offers fresh insights into membrane‐based chiral separations.
Wegner estimate and upper bound on the eigenvalue condition number of non‐Hermitian random matrices
Authors: Erdős László , Ji Hong Chang
Published: May 2024

We consider non‐Hermitian random matrices of the form , where is a general deterministic matrix and consists of independent entries with zero mean, unit variance, and bounded densities. For this ensemble, we prove (i) a Wegner estimate, that is, that the local density of eigenvalues is bounded by and (ii) that the expected condition number of any bulk eigenvalue is bounded by ; both results are optimal up to the factor . The latter result complements the very recent matching lower bound obtained by Cipolloni et al. and improves the ‐dependence of the upper bounds by Banks et al. and Jain et al. Our main ingredient, a near‐optimal lower tail estimate for the small singular values of , is of independent interest.
A comparison of procedures for evaluating and selecting alfalfa landrace germplasm for tolerance to salinity
Authors: Pecetti Luciano , Tlahig Samir , Confalonieri Massimo , Cornacchione Mónica V. , Hayek Taoufik , Angueira Salvador Prieto , Annicchiarico Paolo
Published: May 2024

In arid and semiarid regions, salinity may affect alfalfa (Medicago sativa) productivity and survival due to either cultivation on salt‐affected soils or the use of salinized irrigation water. Exploiting germplasm evolved under salt‐stress conditions offers opportunities for crop tolerance improvement. In the first phase of the current study, four reportedly salt‐tolerant landraces originated from stress‐prone areas of West Asia or North Africa and two reference commercial cultivars underwent three evaluation trials according to different methods, namely, seed germination in saline water, in vitro testing of young plants, and greenhouse evaluation of adult plants in Cone‐tainers. Experimental populations obtained by intercrossing landrace genotypes selected according to each evaluation method were subsequently evaluated under stressful field conditions in two regions featuring different salt stress type, namely, southern Tunisia (irrigation with saline water) and northwestern Argentina (rainfed cropping in saline soil). Landrace ranking for salt tolerance differed somewhat depending on the evaluation method, and the proportion of selected plants per landrace depended accordingly on the method. In each field experiment, there were two evaluation phases, and the second phase corresponded in both cases to harsher conditions. The in vitro evaluation and selection resulted in potentially more useful selected germplasm than the other evaluation methods. The field experiments highlighted the large specific adaptation effects that affected the response of salt‐tolerant germplasm across the two regions.
Input‐harmonic manipulated wideband high‐efficiency series of continuous mode power amplifier
Authors: Xuan Xuefei , Cheng Zhiqun , Zhang Zhiwei , Le Chao , Gong Tinwei
Published: May 2024

In this paper, a systematic research of the effects of second source harmonics caused by gate‐source capacitance in the design of a series of continuous mode (SCM) power amplifiers (PAs) is first presented. The research results show that, compared to the conventional SCMs that require the input second harmonic to be short circuited, SCMs under the impact of input nonlinearity have a more flexible input second harmonic manipulation space, and to further improve and maintain the performance of PAs in wideband operations, a new impedance design space is explored through analysis. For practical validation, SCMs PA considering the effects of the input nonlinearity is designed and fabricated with a 10‐W gallium nitride (GaN) device, acquiring 39.1–42 dBm output power and 60.6–71.5% drain efficiency (DE) performance at a 3 dB gain compression level operating over the 0.5–3.5 GHz frequency range with a relative bandwidth of 150%.
An overwinter protocol for detecting wolverines and other carnivores at camera traps paired with automated scent dispensers
Authors: Long Robert A. , MacKay Paula , Sauder Joel D. , Sinclair Mike , Aubry Keith B. , Raley Catherine M.
Published: May 2024

Camera traps deployed with olfactory attractants are used to survey rare and elusive carnivores. Study areas with deep snowpack and rugged terrain present challenges and risks to field personnel, who traditionally must revisit camera stations regularly to refresh attractants. In such locations, alternative overwinter survey protocols that include a persistent attractant would improve both the safety and efficiency of camera‐trap surveys. We present a protocol for installing camera traps and automated scent dispensers on trees at above‐average maximum snow depth to eliminate the need for interim service visits and to enable standardized surveys to be conducted throughout the year. Our protocol proved to be effective at attracting and detecting numerous and repeated visits by wolverines, fishers, and other carnivores in two montane regions of the western contiguous United States. The volume, timing, and composition of liquid scent lure released by automated scent dispensers can be varied to target multiple species of interest, and the dispenser can be used in situations where bait rewards may influence the behavior of target species and/or pose human safety concerns.
Identification and outcomes of KDIGO‐defined chronic kidney disease in 1.4 million U.S. Veterans with heart failure
Authors: Patel Samir S. , Raman Venkatesh K. , Zhang Sijian , Deedwania Prakash , Zeng‐Treitler Qing , Wu Wen‐Chih , Lam Phillip H. , Bakris George , Moore Hans , Heidenreich Paul A. , Rangaswami Janani , Morgan Charity J. , Cheng Yan , Sheriff Helen M. , Faselis Charles , Mehta Ravindra L. , Anker Stefan D. , Fonarow Gregg C. , Ahmed Ali
Published: May 2024

Aims

According to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline, the definition of chronic kidney disease (CKD) requires the presence of abnormal kidney structure or function for >3 months with implications for health. CKD in patients with heart failure (HF) has not been defined using this definition, and less is known about the true health implications of CKD in these patients. The objective of the current study was to identify patients with HF who met KDIGO criteria for CKD and examine their outcomes.

Methods and results

Of the 1 419 729 Veterans with HF not receiving kidney replacement therapy, 828 744 had data on ≥2 ambulatory serum creatinine >90 days apart. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 (n = 185 821) or urinary albumin‐to‐creatinine ratio (uACR) >30 mg/g (n = 32 730) present twice >3 months apart. Normal kidney function (NKF) was defined as eGFR ≥60 ml/min/1.73 m2, present for >3 months, without any uACR >30 mg/g (n = 365 963). Patients with eGFR <60 ml/min/1.73 m2 were categorized into four stages: 45–59 (n = 72 606), 30–44 (n = 74 812), 15–29 (n = 32 077), and <15 (n = 6326) ml/min/1.73 m2. Five‐year all‐cause mortality occurred in 40.4%, 57.8%, 65.6%, 73.3%, 69.7%, and 47.5% of patients with NKF, four eGFR stages, and uACR >30mg/g (albuminuria), respectively. Compared with NKF, hazard ratios (HR) (95% confidence intervals [CI]) for all‐cause mortality associated with the four eGFR stages and albuminuria were 1.63 (1.62–1.65), 2.00 (1.98–2.02), 2.49 (2.45–2.52), 2.28 (2.21–2.35), and 1.22 (1.20–1.24), respectively. Respective age‐adjusted HRs (95% CIs) were 1.13 (1.12–1.14), 1.36 (1.34–1.37), 1.87 (1.84–1.89), 2.24 (2.18–2.31) and 1.19 (1.17–1.21), and multivariable‐adjusted HRs (95% CIs) were 1.11 (1.10–1.12), 1.24 (1.22–1.25), 1.46 (1.43–1.48), 1.42 (1.38–1.47), and 1.13 (1.11–1.16). Similar patterns were observed for associations with hospitalizations.

Conclusion

Data needed to define CKD using KDIGO criteria were available in six out of ten patients, and CKD could be defined in seven out of ten patients with data. HF patients with KDIGO‐defined CKD had higher risks for poor outcomes, most of which was not explained by abnormal kidney structure or function. Future studies need to examine whether CKD defined using a single eGFR is characteristically and prognostically different from CKD defined using KDIGO criteria.
Hepatocellular carcinoma after direct‐acting antivirals for hepatitis C is associated with KIR‐HLA types predicting weak NK cell‐mediated immunity
Authors: Ryan James C. , Haight Christina , Niemi Erene C. , Grab Joshua D. , Dodge Jennifer L. , Lanier Lewis L. , Monto Alexander
Published: May 2024

Background and aims

Second‐generation direct‐acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV‐associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC.

Methods

Participants underwent full HLA class I/KIR typing and long‐term HCV follow‐up.

Results

A total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow‐up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA‐treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell‐mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK‐cell‐mediated immunity did not predict HCC.

Conclusion

Cirrhosis is the main risk state predisposing to HCC, but weak NK‐cell‐mediated immunity may predispose to post‐2G DAA HCC more than intermediate or strong NK‐cell‐mediated immunity.
Prediction of hydrogel swelling states using machine learning methods
Authors: Wang Yawen , Wallmersperger Thomas , Ehrenhofer Adrian
Published: May 2024

In the field of material informatics, artificial neural networks (ANNs) contribute to the investigation of the processing‐structure‐properties‐performance relationship of materials. This inspires us to leverage the capabilities of ANNs to decode properties of hydrogels, thereby customizing these active materials for sensors or actuators. In the current work, we introduce an approach to predict discrete swelling states of temperature‐responsive hydrogels, especially PNIPAAm, based on their synthesis parameters, utilizing ANN models. To build the database, we analyze literature on temperature‐responsive hydrogels and compile essential synthesis parameters. The corresponding data points related to these synthesis parameters are then extracted. We propose different variants of ANN models and compare their accuracy on the acquired dataset. The selected model can predict the swelling states of hydrogel samples within the test dataset with relative prediction error of 0.11. This approach is applied to predict the expected properties. Subsequently, the hydrogels can be synthesized, and their properties can be experimentally verified. Our approach can be extended to other types of hydrogels and in the prediction of additional properties. The identified synthesis parameters serve as a valuable foundation for the expansion of the database with further literature resources. An enriched database will enhance the performance of the data‐driven model, thereby improving its predictive capabilities.
Correlation between climatic environment and characteristic components of 14 kinds of huajiao by thermal analysis techniques, GC‐MS and HS‐IMS
Authors: Chang Dandan , Yang Yu , Tao Feiyan , Ding Yu , Jian Meiling , Huang Qinwan
Published: May 2024

Huajiao (Zanthoxylum bungeanum Maxim.) is extensively cultivated in various countries, including China, Korea, and India, owing to its adaptability to diverse environments. This study comprehensively analyzed the volatile substance composition of 14 varieties of red huajiao with distinct geographical origins. Thermal analysis methods, gas chromatography‐mass spectrometry (GC‐MS), and headspace‐ion mobility chromatography (HS‐IMS) were employed to evaluate the total volatile substance composition and content. The study revealed minor variations in water content, volatile matter content, and fractions among the geographically sourced huajiao samples. Utilizing correlation analysis based on GC‐MS and orthogonal partial least squares discriminant analysis (OPLS‐DA) with HS‐IMS, a robust classification method for the 14 types of huajiao was developed. Applying the variable importance in the projection (VIP) method, seven distinctive components were identified as potential markers for distinguishing the geographical origins of red huajiao. By integrating climatic and topographical factors of the 14 huajiao varieties, the correlation analysis of GC‐MS, and OPLS‐DA classification outcomes from HS‐IMS elucidated the influence of geo‐environmental factors on huajiao components and contents. This research provides insights into the impact of diverse geographic environments on the constituents and characteristics of huajiao. It offers valuable guidance for selecting optimal cultivation locations to enhance huajiao quality, aiding consumers in making informed choices.
Cetin Dam – stabilising troubled abutment slopes
Authors: Pöschl Irmina , Kleberger Johannes , Dinis João , Hizal Teoman
Published: May 2024

The 420 MW Cetin Dam Project in Turkey was subject to severe setbacks, including substantial geotechnical problems. Since 2011, several concessionaires, contractors and designers were involved. In June 2016, a major failure occurred at a high cut slope of the right bank (RB) valley flank. In 2017, contractor Limak took over the project with a US$ 600 mio concession contract. To secure the contractual agreement for state‐guaranteed energy remuneration, Cetin Dam and hydro hydroelectric power plant (HEPP) had to be operative in 2020. Missing the time target would have implied high economic losses for the concessionaire, and this set‐in‐stone deadline imposed extraordinary pressure for developing fast and reliable solutions. Worryingly, progressing failure became evident at the failed RB cut slope, while rehabilitation works were ongoing. In late December 2017, shortly after a review of geotechnical conditions and slope design for the troubled RB slope had started, also parts of the left bank (LB) cut slope failed below crest level and threatened to grow into a global slope failure. With only 26 months’ time left for starting energy production, the slope instabilities jeopardised the economic success of the entire project. Within a 3‐month emergency mission for both RB and LB slopes, a dedicated team succeeded in understanding the geotechnical problems, planning and implementing immediate mitigation measures, and developing design solutions. Operation of Cetin Dam and HEPP commenced in 2020.
Understanding the behavioural challenges of companion parrots
Authors: Baldrey Vicki , Rogerson Molly
Published: May 2024

Background: Parrots can make excellent companions; however, it is important to understand that they are not a truly domesticated species. Their behaviours will be similar to their wild counterparts. Parrots are highly intelligent and have complex social and environmental needs, which can be challenging for an owner to meet. Problem behaviours may be truly pathological, such as feather destructive behaviour and self‐mutilation, or may be normal behaviours, perceived by the owner to be a problem, such as screaming. Enrichment provision is a vital part of their husbandry to encourage species‐appropriate behaviours, in particular, foraging.

Aim of the article: This article aims to discuss the most common problem behaviours seen in clinical practice, and to describe a logical approach to their management. Behaviour modification techniques and provision of appropriate enrichment are also discussed.
Extended N‐centered ensemble density functional theory of double electronic excitations
Authors: Cernatic Filip , Fromager Emmanuel
Published: May 2024

A recent work (arXiv:2401.04685) has merged N‐centered ensembles of neutral and charged electronic ground states with ensembles of neutral ground and excited states, thus providing a general and in‐principle exact (so‐called extended N‐centered) ensemble density functional theory of neutral and charged electronic excitations. This formalism made it possible to revisit the concept of density‐functional derivative discontinuity, in the particular case of single excitations from the highest occupied Kohn–Sham (KS) molecular orbital, without invoking the usual “asymptotic behavior of the density” argument. In this work, we address a broader class of excitations, with a particular focus on double excitations. An exact implementation of the theory is presented for the two‐electron Hubbard dimer model. A thorough comparison of the true physical ground‐ and excited‐state electronic structures with that of the fictitious ensemble density‐functional KS system is also presented. Depending on the choice of the density‐functional ensemble as well as the asymmetry of the dimer and the correlation strength, an inversion of states can be observed. In some other cases, the strong mixture of KS states within the true physical system makes the assignment “single excitation” or “double excitation” irrelevant.
Comparison of cervicovaginal fluid extracellular vesicles isolated from paired cervical brushes and vaginal swabs
Authors: Paterson Emily Sarah Jane , Scheck Simon , McDowell Simon , Bedford Nick , Girling Jane Eleanor , Henry Claire Elizabeth
Published: May 2024

Endometriosis is a common gynaecological condition, with a long diagnostic delay. Surgery is required to confirm a diagnosis, highlighting the need for a non‐invasive biomarker. Extracellular vesicles (EVs) may have a role in endometriosis pathogenesis, yet there is limited EV biomarker literature available. This study aimed to investigate the feasibility of isolating cervico‐vaginal fluid EVs sampled using cervical brushes and vaginal swabs and to compare these methods. After providing informed consent, patients undergoing surgery for suspected endometriosis had cervical brush and vaginal swab samples collected under general anaesthetic. Isolated EVs were characterised through negative stain transmission electron microscopy (TEM), Western blotting (TSG101, CD63, Calnexin, ApoB, Albumin), tunable resistive pulse sensing (TRPS), microBCA assays and RT‐qPCR of miRNAs. PCR was performed on samples prior to EV isolation to assess bacteria present in samples. Cervical brush and vaginal swab EVs were intact vesicles with limited co‐isolated contaminants. Cervical brushes had higher concentrations of particles compared to match vaginal swabs, although both samples had low concentrations. Protein and miRNA yield were similar between matched samples. PCR demonstrated only a small amount DNA within samples was bacterial (>0.5%). Cervico‐vaginal fluids EVs were successfully isolated from cervical brushes and vaginal swabs, demonstrating a new method of sampling reproductive EVs. EV yield from both sample types was low. Similar protein and miRNA levels suggest either sampling method may be suitable for biomarker studies.
Development of antibiotic metrics for hospitalists via multi‐institutional modified Delphi survey
Authors: Bond Allison , Oreper Sandra , Prasad Priya , Abdoler Emily , Doernberg Sarah
Published: May 2024

Background

Closing the gap between evidence‐supported antibiotic use and real‐world prescribing among clinicians is vital for curbing excessive antibiotic use, which fosters antimicrobial resistance and exposes patients to antimicrobial side effects. Providing prescribing information via scorecard improves clinician adherence to quality metrics.

Objective

We aimed to delineate actionable, relevant antimicrobial prescribing metrics extractable from the electronic health record in an automated way.

Design

We used a modified Delphi consensus‐building approach.

Settings and Participants

Our study entailed two iterations of an electronic survey disseminated to hospital medicine physicians at 10 academic medical centers nationwide.

Main Outcomes and Measures

Main outcomes comprised consensus metrics describing the quality of antibiotic prescribing to hospital medicine physicians.

Results

Twenty‐eight participants from 10 United States institutions completed the first survey version containing 38 measures. Sixteen respondents completed the second survey, which contained 37 metrics. Sixteen metrics, which were modified based on qualitative survey feedback, met criteria for inclusion in the final scorecard. Metrics considered most relevant by hospitalists focused on the appropriate de‐escalation of antimicrobial therapy, selection of guideline‐concordant antibiotics, and appropriate duration of treatment for common infectious syndromes. Next steps involve prioritization and implementation of these metrics based on quality gaps at our institution, focus groups exploring impressions of clinicians who receive a scorecard, and analysis of antibiotic prescribing patterns before and after metric implementation. Other institutions may be able to implement metrics from this scorecard based on their own quality gaps to provide hospitalists with automated feedback related to antibiotic prescribing.
Does Aid Improve Local Wealth? Micro‐Level Evidence from Africa
Authors: Atitianti Philip Akrofi , Asiamah Samuel Kofi , Arthur Benedict , Duku John Archison
Published: May 2024

This paper adopts a micro‐level analysis to assess the effect of aid from China and the World Bank on the wealth of locals residing near aid project sites. We match geospatial data on aid projects financed by China and the World Bank in 35 African countries between 2008 and 2014 to respondents from rounds 5 and 6 of the Afrobarometer survey. The results indicate that aid from these two donors increases the wealth of the local population. Our transmission mechanism test suggests that aid impacts wealth by promoting employment opportunities.
Region‐dependent meteorological conditions of thunderstorm based on clustering analysis of stability and precipitable water indices
Authors: Ye Wanheng , Yu Yueyue , Cao Jie
Published: May 2024

Thunderstorms contribute to a large number of destructive weather events. However, due to the availability of comprehensive thunderstorm datasets, current researches on thresholds of stability indices during thunderstorms have always been limited within a specific local area during a relatively short time span. This study uses observations of thunderstorms data and ERA5 reanalysis data in summer (June–August) at 0600 and 1200 UTC from 1995 to 2019 to investigate the region‐dependent thresholds of four indices for indicating the occurrence of thunderstorm. The indices include the K index (K), the Showalter index (SI), convective available potential energy (CAPE), and precipitable water (PW). By applying the K‐means clustering method on the composite mean fields of four indices on thunderstorm days, China is objectively divided into three regions based on three stability indices (K, SI, and CAPE) and two regions based on PW index. Region‐dependent thresholds have been established for each index related to thunderstorms. When these thresholds are applied, accuracy rate of detecting thunderstorms exceeds 60% at 85% of the stations over China. The remarkable regional difference in the thresholds of the four indices are further attributed to the climatic backgrounds. Summer climatological means of surface potential temperature and surface relative humidity play a pivotal role in shaping the distinctive thresholds of K, CAPE, and PW across diverse regions, while surface potential temperature and topography are pivotal for the region‐dependent thresholds of SI. Based on the terrain characteristics and relevant summer climatology in each region, the thunderstorm thresholds can be potentially applied to regions with limited thunderstorm records but exhibiting similar climatic features beyond China. These findings would provide a reliable reference for thunderstorm monitoring by meteorological departments and related decision‐making services.
Biomarkers predicting the effect of anti‐TNF treatment in paediatric and adult inflammatory bowel disease
Authors: Winter Dwight A. , de Bruyne Pauline , van der Woude Janneke , Rizopoulos Dimitris , de Ridder Lissy , Samsom Janneke , Escher Johanna C.
Published: May 2024

Objectives

Paediatric and adult inflammatory bowel disease (pIBD, aIBD) patients may lose response to anti‐tumour necrosis factor (TNF) treatment within the first year. Adult‐extrapolated weight‐based dosing is incorrect in children, due to age‐related pharmacokinetic differences. We investigated biomarkers for initial and maintenance of response to infliximab (IFX) or adalimumab (ADA), comparing pIBD and aIBD patients.

Methods

In this prospective, observational study, pIBD (n = 24) and aIBD (n = 21) patients were included when initiating anti‐TNF. Escalation from standard dosing and continued anti‐TNF at 12 and 18 months were assessed. Biomarkers included clinical laboratory parameters, faecal calprotectin (FCP) and IFX trough levels (TLs). Plasma proteomics was performed in pIBD.

Results

During our study, treatment escalation (in clinical loss of response) occurred more common in pIBD versus aIBD (p = 0.02). We established that IFX therapy escalation in pIBD patients was not due to low infliximab levels. We identified 9 pro‐inflammatory proteins that were elevated in patients losing response.

Conclusion

Anti‐TNF exposure‐response relationship may be different in pIBD versus aIBD. No biomarkers for maintained response were identified, but 9 inflammatory proteins were of interest as potential predictors for loss of response in pIBD.
Impact of Coronavirus disease 2019 pandemic in children with functional abdominal pain disorders: Data from long‐term follow‐up
Authors: Martinelli Massimo , Strisciuglio Caterina , Lu Peter , Lev Michal Rozenfeld Bar , Beinvogl Beate , Di Lorenzo Carlo , Cenni Sabrina , Nurko Samuel , Pearlstein Haley , Rosen Rachel , Shamir Raanan , Staiano Annamaria
Published: May 2024

Objective

We aimed to compare symptom frequency and severity in children with functional abdominal pain disorders (FAPDs) and to evaluate anxiety, quality of life (QoL) and global health during Coronavirus disease 2019 (COVID‐19) related quarantine and after 17 months.

Methods

Children diagnosed with FAPDs between October 2019 and February 2020 at 5 different centers were enrolled and prospectively interviewed during the COVID‐19 quarantine and 17 months later when schools, hospital services, and routine activities had re‐opened to the public. The patients were asked to complete the Rome IV questionnaire, the Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0) Generic Core Scale, the Patient‐Reported Outcomes Measurement Information System (PROMIS) anxiety and global health questionnaires. Data about COVID‐19 infection and its clinical outcome were also collected.

Results

Ninety‐nine out of 180 (55%) children completed the follow‐up. The number of patients reporting a worsening of their symptoms was significantly higher at follow‐up when compared to the quarantine period (24/99 [24.2%] vs. 12/99 [12.1%]; p = 0.04). The PedsQL 4.0 subtotal score at follow‐up significantly decreased at 17 months of follow‐up (65.57 [0−100]) when compared to the quarantine (71 [0−100], p = 0.03). Emotional functioning was the most significantly reduced (Follow‐up: 64.7 [0−100] vs. Quarantine: 75 [0−100]; p = 0.006). We did not identify significant differences in symptoms and QoL between COVID‐19 infected children and the remaining cohort at the two time points.

Conclusions

An improvement of symptoms and QoL was observed during the quarantine, followed by a worsening at‐follow‐up. These findings reinforce the hypothesis that the nest effect overweighted COVID‐19 fears during the quarantine and highlight the importance of psychological factors in symptom exacerbation