bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychological well-being and needs of parents and carers of children and young people with mental health difficulties: a quantitative systematic review with meta-analyses
Authors: Martin Faith , Dahmash Dania , Wicker Sarah , Glover Sarah-Lou , Duncan Charlie , Anastassiou Andrea , Docherty Lucy , Halligan Sarah
Published: August 2024

Question

For parents of children and young people (CYP) with diagnosed mental health difficulties, what are the levels of parents’ well-being and psychological need?

Study selection and analysis

Medline, PsycINFO, EMBASE, AMED, CINAHL, Web of Science and Cochrane Library of Registered Trials were searched from inception to June 2023. Inclusion criteria: parents of CYP aged 5–18 years with formal mental health diagnosis. Data were extracted from validated measures of well-being or psychological needs with established cut-off points or from a controlled study.

Findings

32 of the 73 310 records screened were included. Pooled means showed clinical range scores for one measure of depression, and all included measures of anxiety, parenting stress and general stress. Meta-analyses showed greater depression (g=0.24, 95% CI 0.11 to 0.38) and parenting stress (g=0.34, 95% CI 0.20 to 0.49) in parents of CYP with mental health difficulties versus those without. Mothers reported greater depression (g=0.42, 95% CI 0.18 to 0.66) and anxiety (g=0.73, 95% CI 0.27 to 1.18) than fathers. Narrative synthesis found no clear patterns in relation to CYP condition. Rates of parents with clinically relevant levels of distress varied. Typically, anxiety, parenting stress and general stress scored above clinical threshold. Quality appraisal revealed few studies with a clearly defined control group, or attempts to control for important variables such as parent gender.

Conclusions

The somewhat mixed results suggest clinical anxiety, parenting and general stress may be common, with sometimes high depression. Assessment and support for parents of CYP with mental health problems is required. Further controlled studies, with consideration of pre-existing parental mental health difficulties are required.

PROSPERO registration number

CRD42022344453.
Combination of a monofocal and one type of extended depth-of-focus (zonal refractive) intraocular lens (COMEDI) in bilateral cataract surgery protocol: a monocentric, randomised, parallel group trial in cataract surgery
Authors: Termote Karolien , Van Schoor Roger , Krolo Iva , Oellerich Silke , Cools Wilfried , Delbeke Heleen , Ni Dhubhghaill Sorcha
Published: August 2024

Introduction

Modern intraocular lens (IOL) designs for cataract treatment can be broadly classified into three focal range categories; monofocal, extended depth-of-focus (EDOF) and multifocal IOLs.

Monofocal IOLs allow spectacle independence for one focus, typically distance. In contrast, EDOF IOLs provide a greater range of vision, extending spectacle independence to intermediate distance, while multifocal IOLs enable spectacle independence at all distances with the drawback of positive dysphotopsias and reduced contrast perception.

EDOF lenses are an attractive compromise with fewer dysphotopic side effects than multifocals. The purpose of this study is to assess whether implanting an EDOF IOL in the second eye of a patient who received a monofocal IOL in the first eye can improve spectacle independence while maintaining the same optical quality as bilateral monofocal IOL implantation.

Methods and analysis

This study compares combined monofocal and EDOF IOL implantation versus bilateral monofocal IOL implantation in terms of clinical and patient-reported outcomes in a monocentric, randomised, patient-masked and assessor-masked, parallel group trial in 88 bilateral cataract patients. The primary outcome measure is binocular photopic distance corrected intermediate visual acuity. The secondary outcome measures include (un)corrected distance and near visual acuity, reading speed at intermediate distance, quality of visual function assessments, patient-reported spectacle independence, contrast sensitivity, aberrometry, stereopsis and straylight measurement at the 3-month follow-up.

Ethics and dissemination

The protocol was approved by the ethical committee of the University Hospital of Brussels (BUN 23219_EDOF).

Trial registration number

NCT06002399
Novel truncating germline variant reinforces
TINF2
as a susceptibility gene for familial non-medullary thyroid cancer
Authors: Oriola Josep , Díez Orland , Mora Mireia , Halperin Irene , Martínez Sandra , Masas Miriam , Tenes Anna , Bernal Anna , Duran Rafael , Orois Aida
Published: August 2024

Background

It has long been observed that there are families in which non-medullary thyroid cancer (NMTC) occurs, but few syndromes and genes have been described to date. Proteins in the shelterin complex have been implied in cancer. Here, we have studied shelterin genes in families affected by NMTC (FNMTC).

Methods

We performed whole-exome sequencing (WES) in 10 affected individuals from four families with at least three affected members. Polymerase chain reaction (PCR) and Sanger sequencing were performed to search for variants in the
TINF2
gene in 40 FNMTC families. TINF2 transcripts and loss of heterozygosity (LOH) were studied in several affected patients of one family.

Results

We found the c.507G>T variant in heterozygosis in the
TINF2
gene in one family, co-segregating in all five affected members. This variant affects the normal splicing. LOH was not observed.

Conclusions

Our results reinforce the
TINF2
gene as a susceptibility cause of FNMTC suggesting the importance of location of frameshift variants in
TINF2
. According to our data and previous literature,
TINF2
pathogenic variants appear to be a significant risk factor for the development of NMTC and/or melanoma.
Ivory tower in MD/PhD programmes: sticky floor, broken ladder and glass ceiling
Authors: Lail Achint , Ding Jeffrey , Leyva Brayden K , Jalal Sabeena , Nakae Sunny , Fares Saleh , Khosa Faisal
Published: August 2024

Objective

Achieving gender equity in academic medicine is not only a matter of social justice but also necessary in promoting an innovative and productive academic community. The purpose of this study was to assess gender distribution in dual MD/PhD academic programme faculty members across North America.

Methods

Academic metrics were analysed to quantify the relative career success of academic faculty members in MD/PhD programmes. Measured parameters included academic and leadership ranks along with nominal research factors such as peer-reviewed research publications, H-index, citation number and years of active research.

Results

Χ² analysis revealed a statistically significant (p<0.0001, χ²=114.5) difference in the gender distribution of faculty and leadership across North American MD/PhD programmes. Men held 74.2% of full professor positions, 64% of associate professor positions, 59.4% of assistant professor positions and 62.8% of lecturer positions. Moreover, men occupied a larger share of faculty leadership roles with a statistically significant disparity across all ranks (p<0.001, χ²=20.4). A higher proportion of men held positions as department chairs (79.6%), vice chairs (69.1%) and programme leads (69.4%).

Conclusion

Gender disparity was prevalent in the MD/PhD programmes throughout North America with women achieving a lower degree of professional stature than men. Ultimately, steps must be taken to support women faculty to afford them better opportunities for academic and professional advancement.
Reentrant Hawking–Page phase transition of charged Gauss–Bonnet-AdS black holes in the grand canonical ensemble
Authors: Hu Xiao-yan , Cui Yuan-zhang , Xu Wei
Published: August 2024

In this paper, we study the reentrant Hawking–Page transition in the grand canonical ensemble of Gauss–Bonnet AdS spacetime. We find that the four-dimensional Gauss–Bonnet hyperbolic AdS black hole always has a reentrant Hawking–Page transition in the range of electric potential $$0<\Phi <\Phi _{tr}$$

0
<
Φ
<

Φ

tr

, accompanied by the appearance of the triple point. However, once the potential exceeds a certain upper limit $$\Phi _{tr}$$

Φ

tr

, i.e. $$\Phi >\Phi _{tr}$$

Φ
>

Φ

tr

, the Hawking–Page transition disappears. In the spacetime of five and higher dimensional Gauss–Bonnet hyperbolic AdS black hole, the reentrant Hawking–Page transition is solely observed to occur when the electric potential $$\Phi $$
Φ
lies between two specific thresholds ($$\Phi _{c}<\Phi <\Phi _{tr}$$

Φ
c

<
Φ
<

Φ

tr

). In scenarios where the electric potential is below $$\Phi _{c}$$

Φ
c

($$\Phi <\Phi _{c}$$

Φ
<

Φ
c

), only the standard Hawking–Page transition as in the the Einstein gravity is observed. Similar to the four-dimensional case, the Hawking–Page transition is negated when the electric potential exceeds $$\Phi _{tr}$$

Φ

tr

($$\Phi >\Phi _{tr}$$

Φ
>

Φ

tr

). We give the coexistence line, the triple point and critical point of the Hawking–Page transition in the phase diagram of the Gauss–Bonnet hyperbolic AdS black hole. The observed reentrant Hawking–Page transitions and triple points in the context of Gauss–Bonnet hyperbolic AdS black holes may correspond to the phase transitions and triple points in QCD phase diagrams, following the spirit of the AdS/CFT correspondence. To be a complete research, the Hawking–Page transition of d-dimensional charged spherical Gauss–Bonnet-AdS black hole in the grand canonical ensemble is also study in the Appendix, for which there exists a standard Hawking–Page transition with the transition temperature depending on the Gauss–Bonnet constant $$\alpha $$
α
.
Innovative Application of Intelligent Internet of Things in Smart Cities
Authors: Yang Qin
Published: August 2024

The Internet of Things, as an important component of the new generation of information technology system, regards the Internet as the main carrier of information, enabling all ordinary physical objects that can be independently addressed to achieve interconnectivity. This is the key to promoting urban modernization and building smart cities. This paper analyzes and studies the application of Internet of Things technology in smart cities. Based on the understanding of relevant concepts, it aims to understand the relationship between IoT technologies and smart city construction, clarify the role of Internet of Things in smart city construction, and the challenges currently faced by IoT technologies in smart city application. Therefore, taking the smart community as the starting point, the application of the smart Internet of Things in the smart community is completed through eight steps: demand analysis, planning and design, sensor and device deployment, data collection, data storage, data analysis, control and scheduling, and user application development. The experiment results show that after establishing a smart community control platform based on smart IoT technologies, the failure rate of the comprehensive information sending end, receiving end, output system, and hardware system is low, the user experience satisfaction is high, and the platform performance is strong.
Improved Arithmetic Optimization Algorithm with Transfer Learning based Arabic Sign Language Identification System
Authors: Alzaidi Muhammad
Published: August 2024

The Arabic sign language (ArSL) has witnessed ground-breaking research activities to identify hand gestures and signs through the deep learning (DL) model. SL is a unique communication tool that bridges the gaps between people with hearing impairment and ordinary people. The ArSL recognition system is of immense importance for different groups of people since it enables individuals with hearing impairment to communicate effectively. In SLs, signs are characterized by discrepancies in hand positions, shapes, motions, body parts, and facial expressions, posing a crucial threat to visual recognition in computer vision (CV). An automated sign detection technique needs two primary courses of action: the recognition of specific features and the classification of the input dataset. Previously, several approaches for detecting and classifying SLs had been proposed. In this study, an Improved Metaheuristics with Transfer Learning based Arabic Sign Language Identification System (IMTL-ArSL) method is developed. The primary objective of the IMTL-ArSL method is to detect and classify the existence of various signs in the Arabic language. In the IMTL-ArSL model, the bilateral filtering (BF) model is initially used for preprocessing. Besides, the Residual Network (ResNet50v2) model is applied for extracting features, and an improved arithmetic optimization algorithm (IAOA) model is utilized for hyperparameter tuning. Finally, a gated recurrent unit (GRU) network is exploited to identify sign languages. The empirical analysis of the IMTL-ArSL approach is tested using a benchmark dataset. The experimental values of the IMTL-ArSL approach portrayed a superior accuracy value of 93.87% over other techniques.
Review—Advances in Rechargeable Lithium-Ion Batteries Utilizing Polyoxometalate-Functionalized Nanocarbon Materials
Authors: Shahsavarifar Samaneh , Rezapour Morteza , Mehrpooya Mehdi , Ehrlich Hermann , Jesionowski Teofil , Ganjali Mohammad Reza , Luque Rafael , Rahimi-Nasrabadi Mehdi
Published: August 2024

Polyoxometalates (POMs) are inorganic nanoclusters that consist of oxygen and transition metals. These nanoclusters serve as excellent precursors for creating electrode materials that contain transition metals. Additionally, the interaction between POMs and carbon substrates produces positive synergistic effects. There has been considerable attention on employing POMs and carbon nanostructures (for example carbon nanotubes, graphene, and mesoporous carbon) in composite materials for diverse purposes including catalysis, transformation, storage of energy, molecular detection, and electrical detection. By combining the reactive nature of POMs with the exceptional electrical properties of carbon nanostructures, highly desirable composite features can be achieved. This review delves into the extensive use of POM/nanocarbon materials for constructing rechargeable lithium-ion batteries, providing an in-depth analysis of the characteristics of POMs and the techniques employed for binding carbon.
Multi-Walled Carbon Nanotubes and Copper Oxide Nanoparticles Composite Used as Transducer Medias in Nitrate Ion-Selective Electrodes
Authors: Morawska Klaudia , Malinowski Szymon , Krawczyk Joanna , Wardak Cecylia
Published: August 2024

To improve the performance of nitrate solid contact ion-selective electrodes, their design was modified with a composite material consisting of multi-walled carbon nanotubes and copper oxide nanoparticles. The nanocomposite was used in the electrodes as a component of the ion-sensitive membrane (GCE/NC+ISM) and as a solid contact material applied by drop casting (GCE/NC/ISM). A series of comparative studies were conducted to determine which type of modification more favorably affected the performance of each electrode. A classical glassy carbon electrode with a membrane without a nanocomposite was used as a control electrode. The best electrode turned out to be the one in which transducer media in the form of a composite was implemented into the membrane. For the GCE/NC+ISM electrode, the highest sensitivity of 60.41 mV/decade, the lowest detection limit of 5.13 × 10−7 M, and the widest linearity range of 1 × 10−6–1 × 10−1 M were obtained. The presence of the nanocomposite in the membrane contributed to a significant improvement in electrical performance relative to the unmodified electrode, which in turn resulted in obtaining good potential reversibility and low potential drift—0.085 μV s−1. The prepared electrode was used to determine the concentration of nitrates in environmental water samples.
Effects of sodium bicarbonate ingestion on ventilatory and cerebrovascular responses in resting heated humans
Authors: Katagiri Akira , Fujii Naoto , Dobashi Kohei , Lai Yin-Feng , Tsuji Bun , Nishiyasu Takeshi
Published: August 2024

Hyperthermia leads to hyperventilation and associated cerebral hypoperfusion, both of which may impair heat tolerance. This hyperthermia-induced hyperventilation may be mediated by peripheral chemoreceptors, which can be activated by reductions in arterial pH. However, our results suggest that sodium bicarbonate ingestion, which can increase arterial pH, is not an effective intervention in alleviating hyperthermia-induced hyperventilation and cerebral hypoperfusion in resting heated humans.
Expanding the Phenotype of Congenital Glucocorticoid Deficiency: An Iranian Patient with Cholestasis due to Pathogenic Variants in the MC2R Gene
Authors: Maleknejad Shohreh , Dalili Setila , Sharifi Ameneh , Hassanzadeh Rad Afagh , Bayat Reza , Rabbani Bahareh , Mahdieh Nejat
Published: August 2024

Familial glucocorticoid deficiency is caused by variants in the MC2R and MRAP genes. We report an Iranian patient with congenital glucocorticoid deficiency and cholestasis due to pathogenic variants in the MC2R gene. This is the first documented case of a patient with conditions. Clinical evaluations and lab assessments were conducted on a six‐month‐old male infant. Next‐generation sequencing identified the genetic causes of the disease, and Sanger sequencing confirmed the variants through segregation analysis. The clinical presentation included prolonged jaundice, progressive skin hyperpigmentation, seizures, fever, and a large umbilical hernia. Two variants in the MC2R gene, c.560delT and c.676G > C, were detected and classified as pathogenic and likely pathogenic, respectively. The cooccurrence of cholestasis and glucocorticoid deficiency illustrates the clinical heterogeneity caused by MC2R variants. The prevalence of c.560delT and c.676G > C between Iranian populations suggests these variants may be common. The high frequency of c.560delT could be attributed to a founder effect.
Acetic Acid Production from Aspergillus terreus Isolated from Some Agricultural Soils Collected from Selected Locations within the North Gondar Zone, Amhara Region, Ethiopia
Authors: Alemayehu Kidist , Jiru Tamene Milkessa , Berhane Nega
Published: August 2024

Acetic acid, a substance with numerous uses as a bulk chemical, may be produced novelty by Aspergillus terreus. With the newfound understanding of Aspergillus species catabolism of glucose, fermentation techniques for the generation of secondary metabolites like acetic acid in the Ethiopian north Gondar zone can be developed with glucose feeding and pH feedback management. Previous works done on extracting organic acids including acetic acid from filamentous fungi in Ethiopia and at the global level are scanty. Therefore, this study aimed to produce acetic acid from A. terreus isolated from agricultural soils in the north Gondar zone of Ethiopia using barely straw as a substrate. In the current study, Aspergillus isolates were obtained in the samples taken from three different locations. The isolates were screened for acetic acid production. The optimum temperature and pH for the maximum production of acetic acid by the selected isolate were also undertaken. The potential isolates were further cultured using barley straw as a local substrate. Preliminary identification of the selected isolates was based on morphological methods. Molecular characterization (amplification and sequencing of the two intergenic spacers, ITS1 and ITS2, and the intervening 5.8S gene of the ribosomal RNA) was carried out to confirm the identity of the Aspergillus isolates. When the isolates were screened for the production of acetic acid, an isolate from low land (isolate LL2) had the highest yield (72.5 ± 1.65 g/l) on basal screening media. The optimum temperature and pH for the maximum production of acetic acid by this isolate were 30°C and pH 5.0. A sequence similarity of 98.5% to A. terreus isolate LL2 (KIA) was obtained by comparing the Aspergillus isolate to a reference sequence in the GenBank using the BLAST algorithm. It can be concluded from this study that A. terreus isolated from agricultural soil in the north Gondar zone of Ethiopia could produce more acetic acid using barely straw as a substrate.
By‐Products of the Babassu Agribusiness for Ruminant Diets
Authors: Portela Ygor Nascimento , Bandeira Danrley Martins , Ferreira Daniele de Jesus , Parente Henrique Nunes , Parente Michelle de Oliveira Maia , Cunha Ivo Alexandre Leme da , Gois Glayciane Costa , Campos Fleming Sena , Sousa Francisca Claudia da Silva de , Rodrigues Luana Milena Pinheiro , Oliveira Jessica Maria de Sousa , Zanine Anderson de Moura
Published: August 2024

The use of babassu agro‐industrial residues in animal feed, in addition to being an economic option of great importance in reducing the environmental impact in regions of the Brazilian Cerrado, provides the production of good quality foods of animal origin due to its nutritional characteristics. However, information related to the nutritional components of babassu by‐industrial residues has not yet been sufficiently explored. The aim of this study was to evaluate the nutritional potential of some by‐products from the babassu production chain through chemical composition and in situ degradability analyses. The experiment was conducted in a completely randomized experimental design, with 4 by‐products from babassu processing (cake, greasy, fine flour, and 95 µm flour) and 5 replications. The by‐products differ in terms of chemical composition, except for the hemicellulose content. For the degradability of fraction “a” of dry matter, it presented a higher percentage for 95 µm flour. Fine flour and 95 µm flour presented the highest fractions “b” and “c,” potential, and effective degradability of dry matter. For the degradation of crude protein, the highest percentages of potential and effective degradability were observed for greasy and 95 µm flour. The highest standardized potentially degradable fraction and the highest passage rate were obtained by 95 µm flour, which also showed greater degradation for dry matter, crude protein, and neutral detergent fiber. Among the by‐products studied, the babassu cake has superior chemical composition; however, the 95 µm flour presented nutritional value and satisfactory rumen degradation to be used as an additive or in partial replacement of traditional concentrates.
Development of a High‐Frequency Ophthalmic Real‐Time Ultrasound Imaging System Based on a 20 MHz Annular‐Array Transducer
Authors: Wang Xiaochun , Li Zemeng , Zhou Sheng
Published: August 2024

Objective. Ophthalmic ultrasound imaging is a widely used diagnostic method for examining ophthalmic diseases in the clinic. A single‐element transducer is adopted in the traditional ophthalmic ultrasound imaging systems. Although full depth focusing can be achieved using a linear‐array transducer, it is unsuitable for ophthalmic imaging due to its inability to be tightly coupled to the eyeball and its higher cost. Annular‐array‐based systems provide an alternative, striking a balance between image quality and cost. Methods. Here, we present a newly developed high‐frequency ophthalmic real‐time ultrasound imaging system based on an annular‐array transducer. This system uses a custom‐made five‐element, 20 MHz annular‐array transducer encapsulated in a stainless steel housing and mounted in a commercially available handheld mechanical probe designed specifically for clinical ophthalmic imaging. The system uses a printed circuit board scheme and FPGA as the core to complete the hardware system design and realize the ultrasonic echo signal processing and system timing management. Full depth dynamic focusing of each scanning beam was achieved by designing the transmit and receive beamforming. Combined with advanced integrated circuits, the miniaturization and low cost of the overall system are realized. Results. Extensive tests, including hardware, wire phantom, and tissue mimicking phantom measurements, were conducted to demonstrate good performance of the system. The results showed that the designed system can effectively improve the imaging resolution and enhance the depth of field of the image, particularly reducing the blind area of the near‐field. Conclusion. The high‐frequency ophthalmic real‐time ultrasound imaging system based on an annular‐array transducer meets the needs of clinical diagnosis and has a good clinical application prospect.
Characterization of Anoectochilus roxburghii Bioactive Compounds and Its Inhibition on the Metabolism‐Related Enzyme Activities In Vitro
Authors: Yuan Jiahao , Wu Xiuna , Karrar Emad , Zhang Lingyu , Huang Zhiyong , Wu Daren , Li Jian
Published: August 2024

In this study, the Anoectochilus roxburghii (A. roxburghii) was studied for its chemical composition and biological activities. The first aim of this work was to isolate and purify compounds from A. roxburghii using Sephadex LH‐20 and HPLC. The identification of seven compounds was achieved, with 5,4′‐dihydroxy‐3,3′,7‐trimethoxy‐flavone and 5‐hydroxy‐3,4‐dimethyl‐5‐pentylfuran‐2(5H)‐one being isolated from A. roxburghii for the first time. The second aim was to describe its inhibition on the metabolism‐related enzyme activities in vitro. Further, 3,5‐dihydroxy‐7,3′,4′‐trimethoxyflavone and 5‐hydroxy‐3,4‐dimethyl‐5‐pentylfuran‐2(5H)‐one showed inhibitory activity on xanthine oxidase, while isorhamnetin‐3‐O‐rutinoside (IC50 = 87.45 μg/mL) may be potential inhibitors of α‐amylase. Molecular docking analysis revealed that isorhamnetin‐3‐O‐rutinoside exhibited the highest binding affinity towards PL. In addition to scientifically expanding the compound library of A. roxburghii, the discovery is also a vital reference for finding new insights in the field of medication research, especially as natural metabolism‐related enzyme inhibitors.
Bartonella henselae Hepatic Abscesses and Associated Osteomyelitis in a Pediatric Patient
Authors: Antonson Molly , Klingemann Lauren , Neemann Kari
Published: August 2024

Bartonella henselae is a Gram‐negative bacillus transmitted to humans via cat saliva or scratch. Cat scratch disease, the typical clinical manifestation of B. henselae infection, presents as localized cutaneous or regional lymphadenopathy. Rare, atypical presentations, generally reflecting bloodborne disseminated disease, can include hepatosplenic, cardiac, ocular, neurologic, or musculoskeletal involvement. Here, we present a case of disseminated B. henselae with hepatic abscesses and associated ischial osteomyelitis in an immunocompetent 2‐year‐old male patient. Although osteomyelitis is a rare manifestation of B. henselae infection, it should be included in the differential diagnosis in pediatric patients presenting with fever of unknown origin and musculoskeletal pain, especially in the setting of cat exposure. Hepatic involvement of B. henselae infection is associated with significant morbidity; therefore, abdominal imaging is critical in the diagnostic workup. This patient was successfully treated after a 6‐week course of azithromycin and rifampin, as evidenced by symptom resolution and improved fluid collections on repeat imaging. While most cases of B. henselae resolve without treatment, in severe or disseminated infection such as this case, antibiotics such as azithromycin and rifampin should be considered for treatment.
Extrapyramidal Syndrome due to Aripiprazole Overdose in a Young Woman: An Unusual Case Report
Authors: Talabaki Homa , Taghizadeh Ensiyeh , Zakariaei Zakaria
Published: August 2024

Aripiprazole is an atypical antipsychotic medication indicated for the treatment of schizophrenia and bipolar disorders. The drug has been shown to exhibit acceptable efficacy and is often preferred as a first‐line psychiatric treatment option owing to its lower incidence of adverse effects. While first‐generation antipsychotics are associated with extrapyramidal syndrome (EPS), atypical antipsychotics such as aripiprazole are generally associated with a lower frequency of EPS. In this case, we present a 31‐year‐old woman with a history of bipolar disorder who developed EPS after ingesting 200 mg of aripiprazole. Fortunately, her symptoms improved with the administration of biperiden, and she was discharged five days after ingestion. This case highlights the potential for significant consequences associated with aripiprazole, even within its therapeutic index.
Figure 5 from Tumor-Intrinsic Activity of Chromobox 2 Remodels the Tumor Microenvironment in High-grade Serous Carcinoma
Authors: Iwanaga Ritsuko , Yamamoto Tomomi M. , Gomez Karina , Nguyen Lily L. , Woodruff Elizabeth R. , Post Miriam D. , Mikeska Railey G. , Danis Etienne , Danhorn Thomas , Boorgula Meher P. , Mitra Siddhartha S. , Marjon Nicole A. , Bitler Benjamin G. , Brubaker Lindsay W.
Published: August 2024

Knockdown of Cbx2 in a syngeneic mouse model of HGSC leads to shift in composition of the TIME. A, Diagram of ID8 syngeneic mouse model. B, RT-PCR analysis confirming Cbx2 knockdown in ID8 Trp53−/−Brca2−/− cells (internal control, 18S), C, Tumor dissemination sites and (D) total tumor weight of knockdown vs. control tumors. E, NanoString transcriptomic differential expression of shCbx2 compared with control, derived from solid tumors. F, NanoString pathway scores for cell proliferation, cytokine signaling score, immune cell and migration score, and myeloid comparison score between control and shCbx2. G, Comparison of CD3+ (T cells) and F480 (macrophages) without Ki67 positivity and (H) with Ki67 positivity in control vs. shCbx2. Error bars, SEM. Statistical test, unpaired t test and multicomparison ANOVA.
Role of Forkhead Box P3 in IFNγ-Mediated PD-L1 Expression and Bladder Cancer Epithelial-to-Mesenchymal Transition
Authors: Zhang Hanwei , Ly Ann , Chou Emily , Wang Liang , Zhang Paul , Prado Kris , Gu Yiqian , Pellegrini Matteo , Chin Arnold I.
Published: August 2024

Antagonism of the PD-1/PD-L1 axis is a critical therapeutic strategy for patients with advanced bladder cancer. IFNγ functions as a key regulator of PD-L1 in both immune as well as cancer cells. Forkhead box P3 (FOXP3) is a transcription factor synonymous in T regulatory cell function but with increasingly described functions in cancer cells. Here, we investigated the relationship between FOXP3 and PD-L1 in bladder cancer. We showed that FOXP3 is critical in the ability for IFNγ to activate PD-L1 in bladder cancer cells. FOXP3 can bind to the PD-L1 promoter and induces a gene program that leads to regulation of multiple immune-related genes and genes involved in epithelial-to-mesenchymal transition (EMT). Using in vitro and in vivo human and murine models, we showed that FOXP3 can influence bladder cancer EMT as well as promote cancer metastases. Furthermore, FOXP3 may be a convergent factor for multiple activators of PD-L1, including the chemotherapeutic drug cisplatin.

Significance:

Historically a key transcription factor driving T regulatory cell function, FOXP3 has an increasingly recognized role in cancer cells. In bladder cancer, we defined a novel mechanism whereby FOXP3 mediates the activation of the immune checkpoint PD-L1 by the cytokine IFNγ. We also showed that FOXP3 induces other immune checkpoints as well as genes involved in EMT, promoting immune resistance and cancer metastases.
Characterizing Relationships between T-cell Inflammation and Outcomes in Patients with High-Risk Neuroblastoma According to Mesenchymal and Adrenergic Signatures
Authors: Kaufman Maria E. , Vayani Omar R. , Moore Kelley , Chlenski Alexandre , Wu Tong , Lee Sang Mee , Desai Ami V. , He Chuan , Cohn Susan L. , Applebaum Mark A.
Published: August 2024

Recent insights have identified adrenergic (ADRN) and mesenchymal (MES) cell lineages as distinct biologic cell types and T-cell inflammation as a prognostic marker in neuroblastoma. We hypothesized that elucidating unique and overlapping aspects of these biologic features could serve as novel biomarkers for informing ongoing efforts to improve therapeutic approaches for children with high-risk neuroblastoma. We identified lineage-specific, single-stranded super-enhancers to define ADRN and MES specific genes. Publicly available RNA-seq of diagnostic tumor biopsies was used in Discovery and Validation cohorts. Each tumor was assigned a relative MES score and T-cell inflammation (TCI) score. Survival was assessed using the Kaplan–Meier method, and differences were assessed by the log-rank test. Inflammation scores were correlated with MES scores and anticorrelated with MYCN-amplification in both cohorts. Among patients with high-risk, ADRN tumors, those with TCI tumors had superior overall survival to those with non-inflamed tumors. A similar, but nonsignificant, trend was observed in the Validation cohort. Conversely, there was no difference according to TCI status in the MES cohort in either the Discover or Validation cohorts. High-inflammation scores were correlated with improved survival in some patients with high-risk, ADRN but not MES neuroblastoma. Our findings bolster support for further developing T-cell-based and immunotherapy-based approaches for children with high-risk neuroblastoma of varying MES and ADRN expression.

Significance:

Adrenergic (ADRN) and mesenchymal (MES) lineages are distinct biologic cell types in neuroblastoma. We defined ADRN and MES specific genes and found that high-risk, ADRN tumors harboring elevated T-cell inflammation signatures had superior overall survival. Our findings bolster support for further developing immunotherapy-based approaches for children with high-risk neuroblastoma.
Secondary Endpoint Utilization and Publication Rate among Phase III Oncology Trials
Authors: Beck Esther J. , Sherry Alexander D. , Florez Marcus A. , Kouzy Ramez , Abi Jaoude Joseph , Lin Timothy A. , Miller Avital M. , Passy Adina H. , Kupferman Gabrielle S. , Patel Roshal R. , Chino Fumiko , Higbie Victoria Serpas , Parseghian Christine M. , Overman Michael J. , Minsky Bruce D. , Thomas Charles R. , Tang Chad , Msaouel Pavlos , Ludmir Ethan B.
Published: August 2024

Secondary endpoints (SEP) provide crucial information in the interpretation of clinical trials, but their features are not yet well understood. Thus, we sought to empirically characterize the scope and publication rate of SEPs among late-phase oncology trials. We assessed SEPs for each randomized, published phase III oncology trial across all publications and ClinicalTrials.gov, performing logistic regressions to evaluate associations between trial characteristics and SEP publication rates. After screening, a total of 280 trials enrolling 244,576 patients and containing 2,562 SEPs met the inclusion criteria. Only 22% of trials (62/280) listed all SEPs consistently between ClinicalTrials.gov and the trial protocol. The absolute number of SEPs per trial increased over time, and trials sponsored by industry had a greater number of SEPs (median 9 vs. 5 SEPs per trial; P < 0.0001). In total, 69% of SEPs (1,770/2,562) were published. The publication rate significantly varied by SEP category [X2 (5, N = 2,562) = 245.86; P < 0.001]. SEPs that place the most burden on patients, such as patient-reported outcomes and translational correlatives, were published at 63% (246/393) and 44% (39/88), respectively. Trials with more SEPs were associated with lower overall SEP publication rates. Overall, our findings are that SEP publication rates in late-phase oncology trials are highly variable based on the type of SEP. To avoid undue burden on patients and promote transparency of findings, trialists should weigh the biological and clinical relevance of each SEP together with its feasibility at the time of trial design.

Significance:

In this investigation, we characterized the utilization and publication rates of SEPs among late-phase oncology trials. Our results draw attention to the proliferation of SEPs in recent years. Although overall publication rates were high, underpublication was detected among endpoints that may increase patient burden (such as translational correlatives and patient-reported outcomes).
Haptoglobin Administration for Intravascular Hemolysis: A Systematic Review
Authors: Baldetti Luca , Labanca Rosa , Belletti Alessandro , Dias-Frias André , Peveri Beatrice , Kotani Yuki , Fresilli Stefano , Calvo Francesco , Fominskiy Evgeny , Pieri Marina , Ajello Silvia , Scandroglio Anna Mara
Published: August 2024

Introduction: Exogenous haptoglobin administration may enhance plasma-free hemoglobin (pfHb) clearance during hemolysis and reduce its end-organ damage: we systematically reviewed and summarized available evidence on the use of haptoglobin as a treatment for hemolysis of any cause. Methods: We included studies describing haptoglobin administration as treatment or prevention of hemolysis-related complications. Only studies with a control group reporting at least one of the outcomes of interest were included in the quantitative synthesis. Primary outcome was the change in pfHb concentration 1 h after haptoglobin infusion. Results: Among 573 articles, 13 studies were included in the review (677 patients, 52.8% received haptoglobin). Median initial haptoglobin intravenous bolus was 4,000 (2,000, 4,000) IU. Haptoglobin was associated with lower pfHb 1 h (SMD −11.28; 95% CI: −15.80 to −6.75; p < 0.001) and 24 h (SMD −2.65; 95% CI: −4.73 to −0.57; p = 0.001) after infusion. There was no difference in all-cause mortality between haptoglobin-treated patients and control group (OR 1.41; 95% CI: 0.49–4.95; p = 0.520). Haptoglobin was associated with a lower incidence of acute kidney injury (OR 0.64; 95% CI: 0.44–0.93; p = 0.020). No adverse events or side effects associated with haptoglobin use were reported. Conclusions: Haptoglobin administration has been used in patients with hemolysis from any cause to treat or prevent hemolysis-associated adverse events. Haptoglobin may reduce levels of pfHb and preserve kidney function without increase in adverse events.
Is Cholecystectomy Necessary after Choledocholithiasis Treatment for the Elderly or Patients with Many Comorbidities?
Authors: Shiihara Masahiro , Sudo Yasuhiro , Matsushita Norimasa , Kubota Takeshi , Hibi Yasuhiro , Osugi Harushi , Inoue Tatsuo
Published: August 2024

Introduction: We evaluated the prognosis after endoscopic treatment for choledocholithiasis, particularly in patients with borderline tolerance to surgery. Stone removal and cholecystectomy are generally recommended for patients with choledocholithiasis combined with gallstones to prevent recurrent biliary events. However, the prognosis after choledocholithiasis treatment in patients with borderline tolerance to surgery, such as the elderly or those with many comorbidities, remains controversial. Methods: We retrospectively analyzed data from patients with choledocholithiasis treated at our facility between January 2012 and December 2021. Patients who underwent endoscopic sphincterotomy were dichotomized into the cholecystectomy (CHOLE) and conservation (CONS) groups depending on whether cholecystectomy was performed, and their prognoses were subsequently compared. Furthermore, we performed a logistic regression analysis of the factors contributing to recurrent biliary events in patients with high age-adjusted Charlson Comorbidity Index (aCCI) scores. Results: Of 169 participants, 110 had gallstones and were divided into the CHOLE (n = 56) and CONS (n = 54) groups. The CONS group was significantly ordered, had more comorbidities, and higher aCCI scores, whereas the CHOLE group had fewer recurrent biliary events, although not significant (p = 0.122). No difference was observed in the recurrent incidence of grade ≥2 biliary infections and mortality related to biliary events between the groups. In patients with aCCI scores ≥5, conservation without cholecystectomy was not an independent risk factor for recurrent biliary events. Conclusion: Cholecystectomy after choledocholithiasis treatment prevents recurrent biliary events, but conservation without cholecystectomy is a feasible option for patients with high aCCI scores.
Influence of Age on Outcomes of Endovascular Treatment in Posterior versus Anterior Circulation Stroke: A Comparative Analysis in a Nationwide Registry
Authors: Pop Raoul , Finitsis Stephanos , Lapergue Bertrand , Consoli Arturo , Gory Benjamin ,   On behalf of the ETIS Registry Investigators
Published: August 2024

Introduction: It is unknown whether the influence of age on clinical outcomes post endovascular treatment (EVT) is similar in posterior circulation stroke (PCS) compared to anterior circulation stroke (ACS). Methods: Data were extracted from the ETIS registry, a nationwide prospective, multicenter, observational registry for stroke EVT procedures in France. We included patients treated with EVT for PCS or ACS between January 2015 and August 2023. The relationship between patient age and clinical outcome variables was studied using regression analysis. Good clinical outcome was defined as modified Rankin scale score ≤2 at 90 days. Results: The study included 935 patients with PCS and 11,427 patients with ACS. There were no significant differences between PCS and ACS in the influence of age on the likelihood of good clinical outcome. The influence of age on the likelihood of mortality was significantly different. Mortality was higher for PCS between 30 and 85 years, without significant differences in younger or older patients. Elderly patients (≥80 years) with PCS had similar rates of good clinical outcome and mortality compared to patients with ACS from the same age group. Conclusion: In this comparative analysis assessing the impact of age on EVT outcomes in posterior versus anterior circulation stroke, differences were observed in middle-aged patients, whereas outcomes tended to converge in young and elderly age groups. Elderly PCS patients had similar outcomes as ACS patients from the same age group.
Toll-Like Receptor 7-Expressed Macrophages Are Involved in the Pathogenesis of Esophageal Achalasia and Esophagogastric Junction Outflow Obstruction
Authors: Kaizuka Masatoshi , Tatsuta Tetsuya , Kawaguchi Shogo , Yoshizawa Tadashi , Yoshida Shukuko , Tateda Tetsuyuki , Sawada Yohei , Ota Shinji , Hayamizu Shiro , Hasui Keisuke , Kikuchi Hidezumi , Hiraga Hiroto , Chinda Daisuke , Muroya Takahiro , Hakamada Kenichi , Kijima Hiroshi , Mikami Tatsuya , Fukuda Shinsaku , Sakuraba Hirotake
Published: August 2024

Introduction: Esophageal achalasia is a typical esophageal motility disorder (EMD). Although viral infections have been hypothesized to play a role in the pathogenesis of esophageal achalasia, its etiology remains unclear. This study used esophageal muscle layer specimens collected during per-oral endoscopic myotomy (POEM) procedures to investigate the association between esophageal achalasia and esophagogastric junction outflow obstruction (EGJOO) and pattern recognition receptors. Methods: Patients with esophageal achalasia and EGJOO who underwent POEM were allocated to the EMD group. Biopsies of the inner circular muscle were conducted during the POEM procedure. The control group comprised individuals diagnosed with esophageal squamous cell carcinoma who underwent surgical resection. Expression of pattern recognition receptors, including Toll-like receptor (TLR) 7, was examined by polymerase chain reaction. Immunohistochemical staining was performed to determine TLR7 expression sites in the esophageal muscle layer, and the relationship between TLR7 mRNA expression and clinical score was investigated. Results: Our analysis revealed a notable upregulation of TLR7 mRNA levels within the muscle layer of esophageal achalasia and EGJOO, in contrast to those of control specimens. In contrast, the correlation between TLR7 and clinical score was not significant. Immunohistochemical staining revealed increased numbers of TLR7-expressing macrophages between the muscle layers. Conclusions: TLR7-expressing macrophages are involved in the innate immune response underlying esophageal achalasia and EGJOO. This result will lead to the elucidation of new pathogenetic mechanisms and the development of novel therapeutic targets.
Bacurau: entre permanências e rupturas de representações do Nordeste
Authors: Rodrigues Ana Bárbara Machado , Teixeira Marina Lages Gonçalves , Castral Paulo César
Published: August 2024

El artículo tiene como objetivo discutir las representaciones del Noreste de Brasil, entre rupturas y permanencias, a través de la película Bacurau. Se utiliza un método cualitativo, utilizando la herramienta del análisis cinematográfico, recorriendo representaciones de poder, naturaleza y cultura mostradas en Bacurau, relacionándolas con la discusión sobre la “invención del Noreste”
Omega-3 Fatty Acids and Arrhythmias
Authors: Marcus Mason D. , Link Mark S.
Published: August 2024

The pro- and antiarrhythmic effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been extensively studied in preclinical and human trials. Despite early evidence of an antiarrhythmic role of n-3 PUFA in the prevention of sudden cardiac death and postoperative and persistent atrial fibrillation (AF), subsequent well-designed randomized trials have largely not shown an antiarrhythmic benefit. Two trials that tested moderate and high-dose n-3 PUFA demonstrated a reduction in sudden cardiac death, but these findings have not been widely replicated, and the potential of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to reduce arrhythmic death in combination, or as monotherapy, remains uncertain. The accumulated clinical evidence does not support supplementation of n-3 PUFA for postoperative AF or secondary prevention of AF. Several large, contemporary, randomized controlled trials of high-dose n-3 PUFA for primary or secondary cardiovascular prevention have demonstrated a small, significant, dose-dependent increased risk of incident AF compared with mineral oil or corn oil comparator. These findings were reproduced with both icosapent ethyl monotherapy and a mixed EPA+DHA formulation. The proarrhythmic mechanism of increased AF in contemporary cohorts exposed to high-dose n-3 PUFA is unknown. EPA and DHA and their metabolites have pleiotropic cardiometabolic and pro- and antiarrhythmic effects, including modification of the lipid raft microenvironment; alteration of cell membrane structure and fluidity; modulation of sodium, potassium, and calcium currents; and regulation of gene transcription, cell proliferation, and inflammation. Further characterization of the complex association between EPA, EPA+DHA, and DHA and AF is needed. Which formulations, dose ranges, and patient subgroups are at highest risk, remain unclear.