bluuebunny/crossref_metadata_2025 huggingface dataset:
Efecto del precalentamiento en la microdureza superficial de seis resinas compuestas
Authors: Moreno Abello Gloria Cristina , Castro Kavhas , Ovalle Barrera Paula Alejandra , Bernal Paula , Lara Hernández Laura Catalina
Published: June 2024

Antecedentes: El precalentamiento de las resinas ha demostrado mejorar propiedades físicas como la microdureza superficial. Algunas resinas compuestas de bajo costo no han sido muy estudiadas y el precalentamiento podría mejorar sus propiedades. Objetivo: evaluar si el precalentamiento aumenta la microdureza superficial de 6 resinas compuestas y si la microdureza de las de bajo costo precalentadas iguala a las otras resinas Método: En esta Investigación experimental In vitro se usaron 6 resinas, EnaHri UE2® y UD2® (Micerium, Génova Italia) como control, Z350TM y Z250TM (3M ESPE, Minnesota Estados Unidos) resinas de uso convencional y LUNA ® y ROK ® (SDI, Victoria Australia) como resinas de bajo costo. Se realizaron especímenes sin precalentar (sp) y precalentados a 39°C (p) para cada resina.  Se polimerizó según indicaciones de los fabricantes. Se realizaron 3 mediciones por muestras usando un microdurómetro aplicando 300 g de carga por 10 segundos. Resultados: La microdureza de resinas-esmalte: LUNA ® sp 69.93 HV (IC 95 % 62.02-77.85), Z350TM sp 89.9 HV (IC 95 % 80.56-99.23), LUNA ® p 70.05 HV (IC 95 % 62.97-77.12), Z350TM p 87.47 HV (IC 95 % 78.71-96.23). La microdureza de resinas-dentina: ROK ® sp 85.16 HV (IC 95 % 69.91-100.4), Z250TM sp 95.99 HV (IC 95 % 74.8-117.2), ROK ® p 92.19 HV (IC 95 % 80.83-103.6), Z250TM p 104.7 HV (IC 95 % 97.76-111.6). El precalentamiento no aumentó significativamente la microdureza a excepción de las resinas control. ROK ® sp es equivalente a Z250TM sp (p 0.2825). Conclusiones: El precalentamiento no aumenta la microdureza superficial de las resinas compuestas analizadas. La microdureza de la resina ROK ® sp es equivalente a la Z350TM sp.
Evaluación del manejo quirúrgico en hiperplasia condilar: desde el diagnóstico hasta la monitorización del tratamiento
Authors: Tovío-Martínez Eilien Gisek , Urbano del Valle Samuel Enrique , Giraldo-Rendón Leidy Laura , Córdoba-Mosquera Jarlinson
Published: June 2024

Antecedentes: La hiperplasia condilar es un crecimiento anormal que afecta la articulación temporomandibular causado por células hiperactivas en el cóndilo mandibular. Es relativamente raro y se desconoce la frecuencia exacta de ésta. Objetivo: Describir las características clínicas, radiográficas, e histológicas de la patología de dos pacientes con  hiperplasia condilar activa, cuyo fin es enfocarse en el tratamiento quirúrgico específico de la hiperplasia condilar sin necesidad de manejo adicional con cirugía ortognática y su evolución satisfactoria. Métodos: Se llevó a cabo una revisión sistemática de la literatura a través de la búsqueda en diferentes bases de datos como LiLACS, PubMed, ScienceDirect y Scopus se consideran artículos publicados entre 2008 y 2023, lapso de 15 años. Fueron seleccionados 41 artículos correspondientes a revisiones de literatura, casos clínicos y revisiones sistemáticas. Resultados: el manejo quirúrgico de condilectomía versus combinado con cirugía ortognática se encontró que en el 63,64 % de los artículos analizados se trataron únicamente con condilectomía alta y posterior ortodoncia, mientras que el 36,36 % de éstos se manejaron con condilectomía alta más cirugía ortognática en el mismo acto quirúrgico o en un segundo tiempo quirúrgico. Presentación de casos: Se realiza la presentación de dos casos clínicos de hiperplasia condilar quienes refieren cambios estéticos y funcionales, tratados con condilectomía del lado afectado. Conclusiones: La hiperplasia condilar es un trastorno patológico caracterizado por generar asimetrías y deformaciones faciales, desviaciones, maloclusiones, alteraciones funcionales, estéticas y psicológicas, siendo la condilectomía el procedimiento de elección, pudiendo complementarse con cirugía ortognática y ortodoncia.
Resistencia a la fractura de una nanocerámica CAD/CAM reparada con dos tratamientos de superficie: estudio in vitro
Authors: Cascante-Calderón Marcelo Geovanny , Reascos Flores Kevin Alejandro , Villacís-Altamirano Inés María , Bayas Salinas Anggely Maite , Taraguay Galindo Jessica Elizabeth
Published: June 2024

Antecedentes: Las fracturas de las restauraciones en boca son inevitables. Cuando ello sucede, el clínico debería poder repararlas de una manera sencilla y confiable. Objetivo: Medir la adhesión en un composite para Cad/Cam, cuando ha sido arenado o grabado con ácido. Métodos: 50 láminas de Brava Block fueron divididas en 5 grupos de n= 10; y envejecidas a 5000 ciclos térmicos. 100 cilindros de resina de 3 mm de diámetro fueron cementados a las láminas. Los grupos: óxido de aluminio (AL10) y oxido de aluminio con silano (ALS 10) fueron arenados y los grupos ácido fluorhídrico (HF10) Y ácido fluorhídrico con silano (HFS10) fueron grabados. El grupo (óxido de aluminio más acido fluorhídrico con silano) AHS fue arenado y grabado con ácido. Los cilindros se cementaron con cemento de resina. Todos los grupos fueron cizallados en una máquina de ensayo universal. Las fallas en la adhesión fueron analizadas con un microscopio a 40X. Toda la estadística se trabajó con un α= 0,05. Resultados: Los grupos tuvieron similares fuerzas de adhesión.  Al ser envejecidos, sus valores disminuyeron a 11,15 y 8,15 MPa, en promedio.  Los fallos fueron: Adhesivos 12 %; Cohesivos 68 % y mixtos 20 %, mayor prevalencia cohesiva y mixta en los grupos arenados con rupturas del 80-90 %. Conclusiones: Ambos tratamientos producen similares FA entre un composite para Cad/Cam y un cemento resinoso. Sin embargo, los grupos arenados sufrieron un mayor porcentaje de fracturas del material.
Diagnóstico histopatológico de 1.978 lesiones orales en un periodo de 22 años en Cali- Colombia. Estudio retrospectivo
Authors: Noguera Oll Harold Samuel , Orejuela Charria Óscar Fernando , Jaramillo Johana , Mera Andrés , Tasamá Carlos , Aristizábal Dolly , Martínez Carlos , Escobar Paola , Amaya Sánchez Sandra
Published: June 2024

Objetivo:  Determinar la frecuencia de los diagnósticos histopatológicos de 1978 biopsias de lesiones orales   en un periodo de 20 años en la ciudad de Cali, Colombia. Métodos y materiales: Se realizó un estudio observacional descriptivo retrospectivo de 1978 diagnósticos histopatológicos de biopsias de lesiones en la cavidad oral realizadas durante el periodo de 2000-2022. La investigación se realiza cumpliendo con los requerimientos de ética.  La información se obtuvo de los registros de reportes de biopsias de dos patólogos orales de la ciudad de Cali, la recolección de datos la realizaron los semilleros de 3 universidades de Cali previamente capacitados y calibrados. Se realizo la unificación de la información en una sola base de datos de Excel, los criterios de inclusión fueron cualquier edad, cualquier sexo y reportes completos. Se realizó el análisis estadístico descriptivo con el programa IBM SPSS Statics. Resultados: De los 1978 reportes, el 39% correspondió al género masculino y el 61 % al género femenino. El promedio de edad fue 45,33 ± 17,5 (Rango 2-93). El diagnóstico histopatológico más frecuente fue la hiperplasia (23.8 %), seguido por granulomas (15.07 %). La encía (17.09 %), la zona periapical (16.03 %) y los labios (13.30 %) fueron los sitios que reportaron más lesiones. Histológicamente, el tejido conectivo (51.82 %) y el tejido epitelial (25.63 %) fueron los más reportados, y la técnica de biopsia excisional fue la más utilizada (79.22 %). Conclusión: Las lesiones orales hiperplásicas fueron las más frecuentes, se presentaron más en mujeres, en cualquier sitio de cavidad oral y en cualquier edad. Es muy importante un adecuado diagnóstico, la realización de biopsias y aumentar la evidencia a nivel local y nacional.
Incidence of Sleep Disturbances, Stress and Possible Bruxism Presence among Dental Students
Authors: Bazán Puig Claudia , Tomàs Aliberas Jordi , Figueras Álvarez Óscar , Felipe Spada Natalia
Published: June 2024

Background: One of the most prevalent conditions in the population is bruxism, which is defined as the repetitive activity of the jaw muscles that involves clenching, grinding of the teeth, and jaw thrusting. There is no scientific evidence about the stress levels that dental students are subjected to and its relationship with waking and sleeping bruxism and its poor quality. Objective: To determine the relationship between the presence of waking or sleeping bruxism with the level of sleep quality and stress in students in the 3rd and 5th year of Dentistry and to analyze whether there are significant differences according to gender and between courses. Methods: An observational study was carried out based on data collection through surveys and a descriptive design. 125 students participated in the study by completing three questionnaires. These three variables to be studied were evaluated using the Pittsburgh Sleep Quality Index, Perceived Stress Scale and Self-reported Bruxism Questionnaire. Results: 3rd and 5th year undergraduate dental students presented a high prevalence of sleep disorders and a low prevalence of waking and sleeping bruxism. Statistically significant differences were found at the gender level and between courses. Conclusions: It is established that poor sleep quality and high levels of stress can have a negative impact on student concentration and performance as well as being part of the initiation and development of parafunctional habits.
Rapid Failure of Lubricated Contacts With Grease Under Zero Entraining Velocity Condition
Authors: Du Hengrui , Xie Weidong , Wang Jing , Venner C. H.
Published: June 2024

In response to the rapid failure of grease lubrication under low surface speed with zero entraining velocity, a common occurrence in ball screws or cageless rolling element bearings, detailed observations were conducted through optical interferometric experiments. It was observed that despite a constant surface speed and load, the motion remained transient due to the transition between outlet cavitation and inlet starvation. The reciprocating motion of the cavitation zone rapidly depleted the contact area, leading to severe surface peeling. However, as the surface speed increased, this phenomenon was alleviated and eventually disappeared. To enhance lubrication performance, bilateral grooves were created using laser technology, proving to be advantageous for grease lubrication life under low surface speed conditions. Despite the occurrence of rapid surface failure, grease lubrication demonstrated clear benefits over oil lubrication when operating at low surface speeds.
Choroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2
Authors: Shaker Mohammed R. , Slonchak Andrii , Al-mhanawi Bahaa , Morrison Sean D. , Sng Julian D. J. , Cooper-White Justin , Khromykh Alexander A. , Wolvetang Ernst J.
Published: June 2024

Why individuals with Down syndrome (DS) are more susceptible to SARS-CoV-2–induced neuropathology remains elusive. Choroid plexus (ChP) plays critical roles in barrier function and immune response modulation and expresses the ACE2 receptor and the chromosome 21–encoded TMPRSS2 protease, suggesting its substantial role in establishing SARS-CoV-2 infection in the brain. To explore this, we established brain organoids from DS and isogenic euploid iPSC that consist of a core of functional cortical neurons surrounded by a functional ChP-like epithelium (ChPCOs). DS-ChPCOs recapitulated abnormal DS cortical development and revealed defects in ciliogenesis and epithelial cell polarity in ChP-like epithelium. We then demonstrated that the ChP-like epithelium facilitates infection and replication of SARS-CoV-2 in cortical neurons and that this is increased in DS. Inhibiting TMPRSS2 and furin activity reduced viral replication in DS-ChPCOs to euploid levels. This model enables dissection of the role of ChP in neurotropic virus infection and euploid forebrain development and permits screening of therapeutics for SARS-CoV-2–induced neuropathogenesis.
Deep random forest with ferroelectric analog content addressable memory
Authors: Yin Xunzhao , Müller Franz , Laguna Ann Franchesca , Li Chao , Huang Qingrong , Shi Zhiguo , Lederer Maximilian , Laleni Nellie , Deng Shan , Zhao Zijian , Imani Mohsen , Shi Yiyu , Niemier Michael , Hu Xiaobo Sharon , Zhuo Cheng , Kämpfe Thomas , Ni Kai
Published: June 2024

Deep random forest (DRF), which combines deep learning and random forest, exhibits comparable accuracy, interpretability, low memory and computational overhead to deep neural networks (DNNs) in edge intelligence tasks. However, efficient DRF accelerator is lagging behind its DNN counterparts. The key to DRF acceleration lies in realizing the branch-split operation at decision nodes. In this work, we propose implementing DRF through associative searches realized with ferroelectric analog content addressable memory (ACAM). Utilizing only two ferroelectric field effect transistors (FeFETs), the ultra-compact ACAM cell performs energy-efficient branch-split operations by storing decision boundaries as analog polarization states in FeFETs. The DRF accelerator architecture and its model mapping to ACAM arrays are presented. The functionality, characteristics, and scalability of the FeFET ACAM DRF and its robustness against FeFET device non-idealities are validated in experiments and simulations. Evaluations show that the FeFET ACAM DRF accelerator achieves ∼10
6
×/10× and ∼10
6
×/2.5× improvements in energy and latency, respectively, compared to other DRF hardware implementations on state-of-the-art CPU/ReRAM.
Volcanic arc rigidity variations illuminated by coseismic deformation of the 2011 Tohoku-oki M9
Authors: Puel Simone , Becker Thorsten W. , Villa Umberto , Ghattas Omar , Liu Dunyu
Published: June 2024

Rock strength has long been linked to lithospheric deformation and seismicity. However, independent constraints on the related elastic heterogeneity are missing, yet could provide key information for solid Earth dynamics. Using coseismic Global Navigation Satellite Systems (GNSS) data for the 2011 M9 Tohoku-oki earthquake in Japan, we apply an inverse method to infer elastic structure and fault slip simultaneously. We find compliant material beneath the volcanic arc and in the mantle wedge within the partial melt generation zone inferred to lie above ~100 km slab depth. We also identify low-rigidity material closer to the trench matching seismicity patterns, likely associated with accretionary wedge structure. Along with traditional seismic and electromagnetic methods, our approach opens up avenues for multiphysics inversions. Those have the potential to advance earthquake and volcano science, and in particular once expanded to InSAR type constraints, may lead to a better understanding of transient lithospheric deformation across scales.
HMMR triggers immune evasion of hepatocellular carcinoma by inactivation of phagocyte killing
Authors: Wu Hong , Liu Yiqiang , Liu Qianshi , Li Zhaoshen , Wan Yejian , Cao Chenhui , Wu Binghuo , Liu MingXin , Liang Renchuan , Hu Lanlin , Zhang Wenyi , Lan Mei , Yao Quan , Zhou Hang , Lan Haitao , Chen Liang , Zhang Yu , Zhang Xia , Bian Xiu-Wu , Xu Chuan
Published: June 2024

Hepatocellular carcinoma (HCC) acquires an immunosuppressive microenvironment, leading to unbeneficial therapeutic outcomes. Hyaluronan-mediated motility receptor (HMMR) plays a crucial role in tumor progression. Here, we found that aberrant expression of HMMR could be a predictive biomarker for the immune suppressive microenvironment of HCC, but the mechanism remains unclear. We established an HMMR
−/−
liver cancer mouse model to elucidate the HMMR-mediated mechanism of the dysregulated “don't eat me” signal. HMMR knockout inhibited liver cancer growth and induced phagocytosis. HMMR
high
liver cancer cells escaped from phagocytosis via sustaining CD47 signaling. Patients with HMMR
high
CD47
high
expression showed a worse prognosis than those with HMMR
low
CD47
low
expression. HMMR formed a complex with FAK/SRC in the cytoplasm to activate NF-κB signaling, which could be independent of membrane interaction with CD44. Notably, targeting HMMR could enhance anti–PD-1 treatment efficiency by recruiting CD8
+
T cells. Overall, our data revealed a regulatory mechanism of the “don't eat me” signal and knockdown of HMMR for enhancing anti–PD-1 treatment.
How sensor Amt-like proteins integrate ammonium signals
Authors: Pflüger Tobias , Gschell Mathias , Zhang Lin , Shnitsar Volodymyr , Zabadné Annas J. , Zierep Paul , Günther Stefan , Einsle Oliver , Andrade Susana L. A.
Published: June 2024

Unlike aquaporins or potassium channels, ammonium transporters (Amts) uniquely discriminate ammonium from potassium and water. This feature has certainly contributed to their repurposing as ammonium receptors during evolution. Here, we describe the ammonium receptor Sd-Amt1, where an Amt module connects to a cytoplasmic diguanylate cyclase transducer module via an HAMP domain. Structures of the protein with and without bound ammonium were determined to 1.7- and 1.9-Ångstrom resolution, depicting the ON and OFF states of the receptor and confirming the presence of a binding site for two ammonium cations that is pivotal for signal perception and receptor activation. The transducer domain was disordered in the crystals, and an AlphaFold2 prediction suggests that the helices linking both domains are flexible. While the sensor domain retains the trimeric fold formed by all Amt family members, the HAMP domains interact as pairs and serve to dimerize the transducer domain upon activation.
Ultranarrow-bandgap small-molecule acceptor enables sensitive SWIR detection and dynamic upconversion imaging
Authors: Chen Yongjie , Zheng Yingqi , Wang Jing , Zhao Xuan , Liu Guanhao , Lin Yi , Yang Yubo , Wang Lixiang , Tang Zheng , Wang Ying , Fang Yanjun , Zhang Wenkai , Zhu Xiaozhang
Published: June 2024

Short-wavelength infrared (SWIR) light detection plays a key role in modern technologies. Emerging solution-processed organic semiconductors are promising for cost-effective, flexible, and large-area SWIR organic photodiodes (OPDs). However, the spectral responsivity (R) and specific detectivity (D*) of SWIR OPDs are restricted by insufficient exciton dissociation and high noise current. In this work, we synthesized an SWIR small molecule with a spectral coverage of 0.3 to 1.3 micrometers peaking at 1100 nanometers. The photodiode, with optimized exciton dissociation, charge injection, and SWIR transmittance, achieves a record highRof 0.53 ampere per watt andD* of 1.71 × 1013Jones at 1110 nanometers under zero bias. TheD* at 1 to 1.2 micrometers surpasses that of the uncooled commercial InGaAs photodiode. Furthermore, large-area semitransparent all-organic upconversion devices integrating the SWIR photodiode realized static and dynamic SWIR-to-visible imaging, along with excellent upconversion efficiency and spatial resolution. This work provides alternative insights for developing sensitive organic SWIR detection.
Reading dies in complexity: Online news consumers prefer simple writing
Authors: Shulman Hillary C. , Markowitz David M. , Rogers Todd
Published: June 2024

Over 30,000 field experiments with
The Washington Post
and
Upworthy
showed that readers prefer simpler headlines (e.g., more common words and more readable writing) over more complex ones. A follow-up mechanism experiment showed that readers from the general public paid more attention to, and processed more deeply, the simpler headlines compared to the complex headlines. That is, a signal detection study suggested readers were guided by a simpler-writing heuristic, such that they skipped over relatively complex headlines to focus their attention on the simpler headlines. Notably, a sample of professional writers, including journalists, did not show this pattern, suggesting that those writing the news may read it differently from those consuming it. Simplifying writing can help news outlets compete in the competitive online attention economy, and simple language can make news more approachable to online readers.
An ultrathin membrane mediates tissue-specific morphogenesis and barrier function in a human kidney chip
Authors: Mou Xingrui , Shah Jessica , Roye Yasmin , Du Carolyn , Musah Samira
Published: June 2024

Organ-on-chip (OOC) systems are revolutionizing tissue engineering by providing dynamic models of tissue structure, organ-level function, and disease phenotypes using human cells. However, nonbiological components of OOC devices often limit the recapitulation of in vivo–like tissue-tissue cross-talk and morphogenesis. Here, we engineered a kidney glomerulus-on-a-chip that recapitulates glomerular morphogenesis and barrier function using a biomimetic ultrathin membrane and human-induced pluripotent stem cells. The resulting chip comprised a proximate epithelial-endothelial tissue interface, which reconstituted the selective molecular filtration function of healthy and diseased kidneys. In addition, fenestrated endothelium was successfully induced from human pluripotent stem cells in an OOC device, through in vivo–like paracrine signaling across the ultrathin membrane. Thus, this device provides a dynamic tissue engineering platform for modeling human kidney–specific morphogenesis and function, enabling mechanistic studies of stem cell differentiation, organ physiology, and pathophysiology.
Multiscale 3D printing via active nozzle size and shape control
Authors: Kang Seok Won , Mueller Jochen
Published: June 2024

Three-dimensional (3D) printers extruding filaments through a fixed nozzle encounter a conflict between high resolution, requiring small diameters, and high speed, requiring large diameters. This limitation is especially pronounced in multiscale architectures featuring both bulk and intricate elements. Here, we introduce adaptive nozzle 3D printing (AN3DP), a technique enabling dynamic alteration of nozzle diameter and cross-sectional shape during printing. The AN3DP nozzle consists of eight independently controllable, tendon-driven pins arrayed around a flexible, pressure-resistant membrane. The design incorporates a tapered angle optimized for extruding shear-thinning inks and a pointed tip suitable for constrained-space printing, such as conformal and embedded printing. AN3DP’s efficacy is demonstrated through the fabrication of components with continuous gradients, eliminating the need for discretization, and achieving enhanced density and contour precision compared to traditional 3D printing methods. This platform substantially expands the scope of extrusion-based 3D printers, thus facilitating diverse applications, including bioprinting cell-laden and hierarchical implants with bone-like microarchitecture.
Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration
Authors: Liu Jian , Copland David A. , Clare Alison J. , Gorski Mathias , Richards Burt T. , Scott Louis , Theodoropoulou Sofia , Greferath Ursula , Cox Katherine , Shi Gongyu , Bell Oliver H. , Ou Kepeng , Powell Jenna Le Brun , Wu Jiahui , Robles Luis Martinez , Li Yingxin , Nicholson Lindsay B. , Coffey Peter J. , Fletcher Erica L. , Guymer Robyn , Radeke Monte J. , Heid Iris M. , Hageman Gregory S. , Chan Ying Kai , Dick Andrew D.
Published: June 2024

Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor–associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants ofIRAK3, which encodes IRAK-M, were associated with an increased likelihood of developing AMD. In human samples and mouse models, IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD.Irak3-knockout mice exhibited an increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M led to a disruption in RPE cell homeostasis, characterized by compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of adeno-associated virus (AAV)–expressing humanIRAK3rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration inIrak3-knockout mice. Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration.
Comparative analysis of Bcl-2 family protein overexpression in CAR T cells alone and in combination with BH3 mimetics
Authors: Korell Felix , Olson Michael L. , Salas-Benito Diego , Leick Mark B. , Larson Rebecca C. , Bouffard Amanda , Silva Harrison , Gasparetto Alessandro , Berger Trisha R. , Kann Michael C. , Mergen Markus , Kienka Tamina , Wehrli Marc , Haradhvala Nicholas J. , Bailey Stefanie R. , Letai Anthony , Maus Marcela V.
Published: June 2024

Approximately 50% of patients with hematologic malignancies relapse after chimeric antigen receptor (CAR) T cell treatment; mechanisms of failure include loss of CAR T persistence and tumor resistance to apoptosis. We hypothesized that both of these challenges could potentially be overcome by overexpressing one or more of the Bcl-2 family proteins in CAR T cells to reduce their susceptibility to apoptosis, both alone and in the presence of BH3 mimetics, which can be used to activate apoptotic machinery in malignant cells. We comprehensively investigated overexpression of different Bcl-2 family proteins in CAR T cells with different signaling domains as well as in different tumor types. We found that Bcl-xL and Bcl-2 overexpression in CAR T cells bearing a 4-1BB costimulatory domain resulted in increased expansion and antitumor activity, reduced exhaustion, and decreased apoptotic priming. In addition, CAR T cells expressing either Bcl-xL or a venetoclax-resistant Bcl-2 variant led to enhanced antitumor efficacy and survival in murine xenograft models of lymphoma and leukemia in the presence or absence of the BH3 mimetic venetoclax, a clinically approved BH3 mimetic. In this setting, Bcl-xL overexpression had stronger effects than overexpression of Bcl-2 or the Bcl-2(G101V) variant. These findings suggest that CAR T cells could be optimally engineered by overexpressing Bcl-xL to enhance their persistence while opening a therapeutic window for combination with BH3 mimetics to prime tumors for apoptosis.
Muscle-bone cross-talk through the FNIP1-TFEB-IGF2 axis is associated with bone metabolism in human and mouse
Authors: Mao Yan , Jin Zhen , Yang Jing , Xu Dengqiu , Zhao Lei , Kiram Abdukahar , Yin Yujing , Zhou Danxia , Sun Zongchao , Xiao Liwei , Zhou Zheng , Yang Likun , Fu Tingting , Xu Zhisheng , Jia Yuhuan , Chen Xinyi , Niu Feng-Nan , Li Xihua , Zhu Zezhang , Gan Zhenji
Published: June 2024

Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle dysfunction–related bone loss in humans with limb-girdle muscular dystrophy is associated with decreased expression of folliculin-interacting protein 1 (FNIP1) in muscle tissue. Supporting this finding, murine gain- and loss-of-function genetic models demonstrated that muscle-specific ablation of FNIP1 caused decreased bone mass, increased osteoclastic activity, and mechanical impairment that could be rescued by myofiber-specific expression of FNIP1. Myofiber-specific FNIP1 deficiency stimulated expression of nuclear translocation of transcription factor EB, thereby activating transcription of insulin-like growth factor 2 (
Igf2
) at a conserved promoter-binding site and subsequent IGF2 secretion. Muscle-derived IGF2 stimulated osteoclastogenesis through IGF2 receptor signaling. AAV9-mediated overexpression of IGF2 was sufficient to decrease bone volume and impair bone mechanical properties in mice. Further, we found that serum IGF2 concentration was negatively correlated with bone health in humans in the context of osteoporosis. Our findings elucidate a muscle-bone cross-talk mechanism bridging the gap between muscle dysfunction and bone loss. This cross-talk represents a potential target to treat musculoskeletal diseases and osteoporosis.
Genomic investigation and clinical correlates of the
in vitro
β-lactam: NaHCO
3
responsiveness phenotype among methicillin-resistant
Staphylococcus aureus
isolates from a randomized clinical trial
Authors: Petersiel Neta , Giulieri Stefano , Daniel Diane S. , Fan Sook-Ha , Ersoy Selvi C. , Davis Joshua S. , Bayer Arnold S. , Howden Benjamin P. , Tong Steven Y. C. ,   on behalf of the CAMERA2 study group, Lye David C. , Yahav Dafna , Sud Archana , Robinson J. Owen , Nelson Jane , Archuleta Sophia , Roberts Matthew A. , Cass Alan , Paterson David L. , Foo Hong , Paul Mical , Guy Stephen D. , Tramontana Adrian R. , Walls Genevieve B. , McBride Stephen , Bak Narin , Ghosh Niladri , Rogers Benjamin A. , Ralph Anna P. , Davies Jane , Ferguson Patricia E. , Dotel Ravindra , McKew Genevieve L. , Gray Timothy J. , Holmes Natasha E. , Smith Simon , Warner Morgyn S. , Kalimuddin Shirin , Young Barnaby E. , Runnegar Naomi , Andresen David N. , Anagnostou Nicholas A. , Johnson Sandra A. , Chatfield Mark D. , Cheng Allen C. , Fowler Vance G. , Howden Benjamin P. , Meagher Niamh , Price David J. , van Hal Sebastiaan J. , O'Sullivan Matthew V. N.
Published: June 2024

NaHCO
3
responsiveness is a novel phenotype where some methicillin-resistant
Staphylococcus aureus
(MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO
3
. NaHCO
3
responsiveness correlated with treatment response to β-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO
3
-responsive strains with β-lactams was associated with faster clearance of bacteremia. The CAMERA2 trial (Combination Antibiotics for Methicillin-Resistant
Staphylococcus aureus
) randomly assigned participants with MRSA bloodstream infections to standard therapy, or to standard therapy plus an anti-staphylococcal β-lactam (combination therapy). For 117 CAMERA2 MRSA isolates, we determined by broth microdilution the MIC of cefazolin and oxacillin, with and without 44 mM of NaHCO
3
. Isolates exhibiting ≥4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO
3
were considered “NaHCO
3
-responsive” to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO
3
-responsive and non-responsive strains, and that were assigned to combination treatment with a β-lactam. Thirty-one percent (36/117) and 25% (21/85) of MRSA isolates were NaHCO
3
-responsive to cefazolin and oxacillin, respectively. The NaHCO
3
-responsive phenotype was significantly associated with sequence type 93, SCC
mec
type IVa, and
mecA
alleles with substitutions in positions −7 and −38 in the regulatory region. Among participants treated with a β-lactam, there was no association between the NaHCO
3
-responsive phenotype and persistent bacteremia (cefazolin,
P
= 0.82; oxacillin,
P
= 0.81). In patients from a randomized clinical trial with MRSA bloodstream infection, isolates with an
in vitro
β-lactam-NaHCO
3
-responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a β-lactam.
The human malaria-
Aotus
monkey model: a historical perspective in antimalarial chemotherapy research at the Gorgas Memorial Laboratory-Panama
Authors: Obaldía Nicanor
Published: June 2024

The human malaria-
Aotus
monkey model has served the malaria research community since its inception in 1966 at the Gorgas Memorial Laboratory (GML) in Panama. Spanning over five decades, this model has been instrumental in evaluating the
in vivo
efficacy and pharmacokinetics of a wide array of candidate antimalarial drugs, whether used singly or in combination. The animal model could be infected with drug-resistant and susceptible
Plasmodium falciparum
and
Plasmodium vivax
strains that follow a characteristic and reproducible course of infection, remarkably like human untreated and treated infections. Over the years, the model has enabled the evaluation of several synthetic and semisynthetic endoperoxides, for instance, artelinic acid, artesunate, artemether, arteether, and artemisone. These compounds have been evaluated alone and in combination with long-acting partner drugs, commonly referred to as artemisinin-based combination therapies, which are recommended as first-line treatment against uncomplicated malaria. Further, the model has also supported the evaluation of the primaquine analog tafenoquine against blood stages of
P. vivax
, contributing to its progression to clinical trials and eventual approval. Besides, the
P. falciparum
/
Aotus
model at GML has also played a pivotal role in exploring the biology, immunology, and pathogenesis of malaria and in the characterization of drug-resistant
P. falciparum
and
P. vivax
strains. This minireview offers a historical overview of the most significant contributions made by the Panamanian owl monkey (
Aotus lemurinus lemurinus
) to malaria chemotherapy research.
Human cytomegalovirus glycoprotein variants governing viral tropism and syncytium formation in epithelial cells and macrophages
Authors: Cimato Giorgia , Zhou Xuan , Brune Wolfram , Frascaroli Giada
Published: June 2024

Human cytomegalovirus (HCMV) displays a broad cell tropism, and the infection of biologically relevant cells such as epithelial, endothelial, and hematopoietic cells supports viral transmission, systemic spread, and pathogenesis in the human host. HCMV strains differ in their ability to infect and replicate in these cell types, but the genetic basis of these differences has remained incompletely understood. In this study, we investigated HCMV strain VR1814, which is highly infectious for epithelial cells and macrophages and induces cell-cell fusion in both cell types. A VR1814-derived bacterial artificial chromosome (BAC) clone, FIX-BAC, was generated many years ago but has fallen out of favor because of its modest infectivity. By sequence comparison and genetic engineering of FIX, we demonstrate that the high infectivity of VR1814 and its ability to induce syncytium formation in epithelial cells and macrophages depends on VR1814-specific variants of the envelope glycoproteins gB, UL128, and UL130. We also show that UL130-neutralizing antibodies inhibit syncytium formation, and a FIX-specific mutation in UL130 is responsible for its low infectivity by reducing the amount of the pentameric glycoprotein complex in viral particles. Moreover, we found that a VR1814-specific mutation in US28 further increases viral infectivity in macrophages, possibly by promoting lytic rather than latent infection of these cells. Our findings show that variants of gB and the pentameric complex are major determinants of infectivity and syncytium formation in epithelial cells and macrophages. Furthermore, the VR1814-adjusted FIX strains can serve as valuable tools to study HCMV infection of myeloid cells.

IMPORTANCE

Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and the leading cause of congenital infections. HCMV infects various cell types, including epithelial cells and macrophages, and some strains induce the fusion of neighboring cells, leading to the formation of large multinucleated cells called syncytia. This process may limit the exposure of the virus to host immune factors and affect pathogenicity. However, the reason why some HCMV strains exhibit a broader cell tropism and why some induce cell fusion more than others is not well understood. We compared two closely related HCMV strains and provided evidence that small differences in viral envelope glycoproteins can massively increase or decrease the virus infectivity and its ability to induce syncytium formation. The results of the study suggest that natural strain variations may influence HCMV infection and pathogenesis in humans.
Sensorineural hearing impairment among preterm children: a Norwegian population-based study
Authors: Hemmingsen Dagny , Moster Dag , Engdahl Bo Lars , Klingenberg Claus
Published: June 2024

Objective

To investigate the risk for sensorineural hearing impairment (SNHI) in preterm infants, and to what extent the risk is attributed to perinatal morbidities and therapies.

Design

Population-based cohort study using data from several nationwide registries.

Setting

Norwegian birth cohort 1999–2014, with data on SNHI until 2019.

Participants

60 023 live-born preterm infants, divided in moderate-late preterm (MLP) infants (32–36 weeks), very preterm (VP) infants (28–31 weeks) and extremely preterm (EP) infants (22–27 weeks), and a reference group with all 869 797 term-born infants from the study period.

Main outcome measures

SNHI defined by selected ICD-10 codes, recorded during minimum 5-year observation period after birth.

Results

The overall SNHI prevalence in the preterm cohort was 1.4% compared with 0.7% in the reference group. The adjusted risk ratios (95% CIs) for SNHI were 1.7 (1.5–1.8) in MLP infants, 3.3 (2.8–3.9) in VP infants and 7.6 (6.3–9.1) in EP infants. Among EP infants, decreasing gestational age was associated with a steep increase in the risk ratio of SNHI reaching 14.8 (7.7–28.7) if born at 22–23 weeks gestation. Among the VP and MLP infants, mechanical ventilation and antibiotic therapy had strongest association with increased risk of SNHI, but infants not receiving these therapies remained at increased risk. Among EP infants intracranial haemorrhage increased the already high risk for SNHI. We found no signs of delayed or late-onset SNHI in preterm infants.

Conclusion

Preterm birth is an independent risk factor for SNHI. Invasive therapies and comorbidities increase the risk, predominantly in infants born after 28 weeks gestation.
Association between metformin use with circumpapillary retinal nerve fibre layer thickness and capillary vessel density in glaucoma
Authors: Nishida Takashi , Moghimi Sasan , Gunasegaran Gopikasree , Walker Evan , Wu Jo-Hsuan , Rahmatnejad Kamran , Zangwill Linda M , Baxter Sally L , Weinreb Robert N
Published: June 2024

Background/aims

To investigate the association between use of metformin and circumpapillary retinal nerve fibre layer (cpRNFL) thickness, as well as whole image capillary density (wiCD), in patients with glaucoma.

Methods

This cross-sectional study included patients with glaucoma suspect or primary open-angle glaucoma (POAG) underwent optical coherence tomography angiography imaging. Use and duration of antidiabetic medications were assessed at the time of imaging. Multivariable linear mixed-effect modelling was used to estimate the effect of diabetes medication on wiCD and cpRNFL while controlling for covariates including age, race, body mass index, diagnosis, 24–2 visual field mean deviation, and intraocular pressure, average signal strength index as well as any variables that showed a p &0.1 in the univariable analysis.

Results

A total of 577 eyes (330 POAG and 247 glaucoma suspect) of 346 patients were included. Sixty-five patients (23%) had diabetes, of whom 55 (78.5%) used metformin, and 17 (26.2%) used insulin. After adjusting for covariates, the association between metformin use and wiCD (1.56 (95% CI 0.40 to 2.71); p=0.008), duration of metformin use and wiCD (0.12 (95% CI 0.02 to 0.22) per 1 year longer; p=0.037), and metformin use and cpRNFL thickness (5.17 (95% CI 1.24 to 9.10) µm; p=0.010) had statistically significant associations in each model.

Conclusions

Metformin use was associated with higher wiCD and thicker cpRNFL. These findings indicate a potential association, underscoring the need for longitudinal studies to determine if metformin plays a role in the retinal conditions of patients with glaucoma.

Trial registration number

NCT00221897
Approaching the SDG targets with sustained political commitment: drivers of the notable decline in maternal and neonatal mortality in Morocco
Authors: Elomrani Sanae , Bezad Rachid , De Brouwere Vincent , Campbell Oona Maeve Renee , L Lange Isabelle , Oswald William Edward , Assarag Bouchra
Published: June 2024

Background

Between 2000 and 2017/2018, Morocco reduced its maternal mortality ratio by 68% and its neonatal mortality rate by 52%—a higher improvement than other North African countries. We conducted the Exemplars in Maternal and Neonatal Health study to systematically and comprehensively research factors associated with this rapid reduction in mortality over the past two decades.

Methods

The study was conducted from September 2020 to December 2021 using mixed methods, including: literature, database and document reviews, quantitative analyses of national data sets and qualitative key-informant interviews at national and district levels. Analyses were based on a conceptual framework of drivers of health and survival of mothers and neonates.

Results

A favourable political and economic environment, and a high political commitment encouraged prioritisation of maternal and neonatal health (MNH) by aligning evidence-based policy and technical approaches. Five main factors accounted for Morocco’s success: (1) continuous increases in antenatal care and institutional delivery and reductions socioeconomically-based inequalities in MNH service usage; (2) health-system strengthening by expanding the network of health facilities, with increased uptake of facility birthing, scale-up of the production of midwives, reductions in financial barriers and, later in the process, attention to improving the quality of care; (3) improved underlying health status of women and changes in reproductive patterns; (4) a supportive policy and infrastructure environment; and 5) increased education and autonomy of women.

Conclusion

Our study provides evidence that supportive changes in Morocco’s policy environment for maternal health, backed by greater political will and increased resources, significantly contributed to the dramatic progress in reducing maternal and neonatal mortality. While these efforts were successful in improving MNH in Morocco, several implementation challenges still require special attention and renewed political attention is needed.
Learning from success: the main drivers of the maternal and newborn health transition in seven positive-outlier countries and implications for future policies and programmes
Authors: Campbell Oona Maeve Renee , Amouzou Agbessi , Blumenberg Cauane , Boerma Ties
Published: June 2024

Currently, about 8% of deaths worldwide are maternal or neonatal deaths, or stillbirths. Maternal and neonatal mortality have been a focus of the Millenium Development Goals and the Sustainable Development Goals, and mortality levels have improved since the 1990s. We aim to answer two questions: What were the key drivers of maternal and neonatal mortality reductions seen in seven positive-outlier countries from 2000 to the present? How generalisable are the findings?

We identified positive-outlier countries with respect to maternal and neonatal mortality reduction since 2000. We selected seven, and synthesised experience to assess the contribution of the health sector to the mortality reduction, including the roles of access, uptake and quality of services, and of health system strengthening. We explored the wider context by examining the contribution of fertility declines, and the roles of socioeconomic and human development, particularly as they affected service use, the health system and fertility. We analysed government levers, namely policies and programmes implemented, investments in data and evidence, and political commitment and financing, and we examined international inputs. We contextualised these within a mortality transition framework.

We found that strategies evolved over time as the contacts women and neonates had with health services increased. The seven countries tended to align with global recommendations but could be distinguished in that they moved progressively towards implementing their goals and in scaling-up services, rather than merely adopting policies. Strategies differed by phase in the transition framework—one size did not fit all.
Does proactive care in care homes improve survival? A quality improvement project
Authors: Attwood David , Hope Suzy V , Spicer Stuart G , Gordon Adam L , Boorer James , Ellis Wendy , Earley Michelle , Denovan Jillian , Hart Gerard , Williams Maria , Burdett Nicholas , Lemon Melissa
Published: June 2024

Background

NHS England’s ‘Enhanced Health in Care Homes’ specification aims to make the healthcare of care home residents more proactive. Primary care networks (PCNs) are contracted to provide this, but approaches vary widely: challenges include frailty identification, multidisciplinary team (MDT) capability/capacity and how the process is structured and delivered.

Aim

To determine whether a proactive healthcare model could improve healthcare outcomes for care home residents.

Design and setting

Quality improvement project involving 429 residents in 40 care homes in a non-randomised crossover cohort design. The headline outcome was 2-year survival.

Method

All care home residents had healthcare coordinated by the PCN’s Older Peoples’ Hub. A daily MDT managed the urgent healthcare needs of residents. Proactive healthcare, comprising information technology-assisted comprehensive geriatric assessment (i-CGA) and advanced care planning (ACP), were completed by residents, with prioritisation based on clinical needs.

Time-dependent Cox regression analysis was used with patients divided into two groups:

Control group: received routine and urgent (reactive) care only.

Intervention group: additional proactive i-CGA and ACP.

Results

By 2 years, control group survival was 8.6% (n=108), compared with 48.1% in the intervention group (n=321), p<0.001. This represented a 39.6% absolute risk reduction in mortality, 70.2% relative risk reduction and the number needed to treat of 2.5, with little changes when adjusting for confounding variables.

Conclusion

A PCN with an MDT-hub offering additional proactive care (with an i-CGA and ACP) in addition to routine and urgent/reactive care may improve the 2-year survival in older people compared with urgent/reactive care alone.