tbuckley/cabot-search huggingface dataset:
Oxygen-Saturation Targets and Cognitive and Functional Outcomes in Mechanically Ventilated Adults
Authors: Matthew F. Mart, Matthew W. Semler, Cathy A. Jenkins, Guanchao Wang, Jonathan D. Casey, E. Wesley Ely, James C. Jackson, Amy L. Kiehl, Patsy T. Bryant, Shannon K. Pugh, Li Wang, Stephanie DeMasi, Todd W. Rice, Gordon R. Bernard, Robert E. Freundlich, Wesley H. Self, Jin H. Han
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Rationale: Among mechanically ventilated critically ill adults, the PILOT (Pragmatic Investigation of Optimal Oxygen Targets) trial demonstrated no difference in ventilator-free days among lower, intermediate, and higher oxygen-saturation targets. The effects on long-term cognition and related outcomes are unknown.Objectives: To compare the effects of lower (90% [range, 88–92%]), intermediate (94% [range, 92–96%]), and higher (98% [range, 96–100%]) oxygen-saturation targets on long-term outcomes.Methods: Twelve months after enrollment in the PILOT trial, blinded neuropsychological raters conducted assessments of cognition, disability, employment status, and quality of life. The primary outcome was global cognition as measured using the Telephone Montreal Cognitive Assessment. In a subset of patients, an expanded neuropsychological battery measured executive function, attention, immediate and delayed memory, verbal fluency, and abstraction.Measurements and Main Results: A total of 501 patients completed follow-up, including 142 in the lower, 186 in the intermediate, and 173 in the higher oxygen target groups. Median (interquartile range) peripheral oxygen saturation values in the lower, intermediate, and higher target groups were 94% (91–96%), 95% (93–97%), and 97% (95–99%), respectively. Telephone Montreal Cognitive Assessment score did not differ between lower and intermediate (adjusted odds ratio [OR], 1.36 [95% confidence interval (CI), 0.92–2.00]), intermediate and higher (adjusted OR, 0.90 [95% CI, 0.62–1.29]), or higher and lower (adjusted OR, 1.22 [95% CI, 0.83–1.79]) target groups. There was also no difference in individual cognitive domains, disability, employment, or quality of life.Conclusions: Among mechanically ventilated critically ill adults who completed follow-up at 12 months, oxygen-saturation targets were not associated with cognition or related outcomes.
Spectrum of Diabetic Neuropathy: New Insights in Diagnosis and Treatment
Authors: Brendan R. Dillon, Lynn Ang, Rodica Pop-Busui
Journal: Annual Review of Medicine (2024)

Diabetic neuropathy is a highly prevalent complication of diabetes. It consists of a broad range of neuropathic conditions, such as distal symmetric polyneuropathy and various forms of autonomic neuropathies involving the cardiovascular, gastrointestinal, and urogenital systems. Prevention or diagnosis in early stages of disease is crucial to prevent symptomatic onset and progression, particularly in the absence of current disease-modifying therapies. In this review, we describe the four main types of diabetic neuropathy. We review current understanding with respect to diagnosis and treatment while highlighting knowledge gaps and future directions.
Challenging the gold standard: the limitations of molecular assays for detection of<i>Mycobacterium tuberculosis</i>heteroresistance
Authors: Sarah N Danchuk, Ori E Solomon, Thomas Andreas Kohl, Viola Dreyer, Ivan Barilar, Christian Utpatel, Stefan Niemann, Dick van Soolingen, Richard Anthony, Jakko van Ingen, Joy S Michael, Marcel A Behr
Journal: Thorax (2024)

Heteroresistant infections are defined as infections in which a mixture of drug-resistant and drug-susceptible populations are present. In
Small molecule conjugates with selective estrogen receptor β agonism promote anti-aging benefits in metabolism and skin recovery
Authors: Tarik Zahr, Vijay K. Boda, Jian Ge, Lexiang Yu, Zhongzhi Wu, Jianwen Que, Wei Li, Li Qiang
Journal: Acta Pharmaceutica Sinica B (2024)

Estrogen is imperative to mammalian reproductivity, metabolism, and aging. However, the hormone activating estrogen receptor (ERs) α can cause major safety concerns due to the enrichment of ERα in female tissues and certain malignancies. In contrast, ERβ is more broadly expressed in metabolic tissues and the skin. Thus, it is desirable to generate selective ERβ agonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERα activation. Here, we report the design and production of small molecule conjugates containing selective non-steroid ERβ agonists Gtx878 or genistein. Treatment of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity, visceral adipose integrity, skeletal muscle function, and skin health, with validation in vitro. We further uncovered the benefits of ERβ conjugates in the skin using two inducible skin injury mouse models, showing increased skin basal cell proliferation, epidermal thickness, and wound healing. Therefore, our ERβ-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.
Inhibition of adenylyl cyclase 8 prevents the upregulation of Orai1 channel, which improves cardiac function after myocardial infarction
Authors: Débora Falcón, Eva M. Calderón-Sánchez, Isabel Mayoral-González, Marta Martín-Bórnez, Alejandro Dominguez-Rodriguez, Encarnación Gutiérrez-Carretero, Antonio Ordóñez-Fernández, Juan Antonio Rosado, Tarik Smani
Journal: Molecular Therapy (2024)
Which structure generates paradoxical (REM) sleep: The brainstem, the hypothalamus, the amygdala or the cortex?
Authors: Pierre-Hervé Luppi, Amarine Chancel, Justin Malcey, Sébastien Cabrera, Patrice Fort, Renato M. Maciel
Journal: Sleep Medicine Reviews (2024)

Paradoxical or Rapid eye movement (REM) sleep (PS) is a state characterized by REMs, EEG activation and muscle atonia. In this review, we discuss the contribution of brainstem, hypothalamic, amygdalar and cortical structures in PS genesis. We propose that muscle atonia during PS is due to activation of glutamatergic neurons localized in the pontine sublaterodorsal tegmental nucleus (SLD) projecting to glycinergic/GABAergic pre-motoneurons localized in the ventro-medial medulla (vmM). The SLD PS-on neurons are inactivated during wakefulness and slow-wave sleep by PS-off GABAergic neurons localized in the ventrolateral periaqueductal gray (vPAG) and the adjacent deep mesencephalic reticular nucleus. Melanin concentrating hormone (MCH) and GABAergic PS-on neurons localized in the posterior hypothalamus would inhibit these PS-off neurons to initiate the state. Finally, the activation of a few limbic cortical structures during PS by the claustrum and the supramammillary nucleus as well as that of the basolateral amygdala would also contribute to PS expression. Accumulating evidence indicates that the activation of these limbic structures plays a role in memory consolidation and would communicate to the PS-generating structures the need for PS to process memory. In summary, PS generation is controlled by structures distributed from the cortex to the medullary level of the brain.
Non-canonical G protein signaling
Authors: Bernd Nürnberg, Sandra Beer-Hammer, Ellen Reisinger, Veronika Leiss
Journal: Pharmacology & Therapeutics (2024)

The original paradigm of classical - also referred to as canonical - cellular signal transduction of heterotrimeric G proteins (G protein) is defined by a hierarchical, orthograde interaction of three players: the agonist-activated G protein-coupled receptor (GPCR), which activates the transducing G protein, that in turn regulates its intracellular effectors. This receptor-transducer-effector concept was extended by the identification of regulators and adapters such as the regulators of G protein signaling (RGS), receptor kinases like βARK, or GPCR-interacting arrestin adapters that are integrated into this canonical signaling process at different levels to enable fine-tuning. Finally, the identification of atypical signaling mechanisms of classical regulators, together with the discovery of novel modulators, added a new and fascinating dimension to the cellular G protein signal transduction. This heterogeneous group of accessory G protein modulators was coined "activators of G protein signaling" (AGS) proteins and plays distinct roles in canonical and non-canonical G protein signaling pathways. AGS proteins contribute to the control of essential cellular functions such as cell development and division, intracellular transport processes, secretion, autophagy or cell movements. As such, they are involved in numerous biological processes that are crucial for diseases, like diabetes mellitus, cancer, and stroke, which represent major health burdens. Although the identification of a large number of non-canonical G protein signaling pathways has broadened the spectrum of this cellular communication system, their underlying mechanisms, functions, and biological effects are poorly understood. In this review, we highlight and discuss atypical G protein-dependent signaling mechanisms with a focus on inhibitory G proteins (Gi) involved in canonical and non-canonical signal transduction, review recent developments and open questions, address the potential of new approaches for targeted pharmacological interventions.
Nighttime Bracing or Exercise in Moderate-Grade Adolescent Idiopathic Scoliosis
Authors: Anastasios Charalampidis, Elias Diarbakerli, Marlene Dufvenberg, Kourosh Jalalpour, Acke Ohlin, Anna Aspberg Ahl, Hans Möller, Allan Abbott, Paul Gerdhem, Birgitta Öberg, Hans Tropp, Anna Grauers, Ylva Bodén, Mats Hoffsten, Per Näsman, Henrik Hedevik
Journal: JAMA Network Open (2024)

Importance Moderate-grade adolescent idiopathic scoliosis (AIS) may be treated with full-time bracing. For patients who reject full-time bracing, the effects of alternative, conservative interventions are unknown. Objective To determine whether self-mediated physical activity combined with either nighttime bracing (NB) or scoliosis-specific exercise (SSE) is superior to a control of physical activity alone (PA) in preventing Cobb angle progression in moderate-grade AIS. Design, Setting, and Participants The Conservative Treatment for Adolescent Idiopathic Scoliosis (CONTRAIS) randomized clinical trial was conducted from January 10, 2013, through October 23, 2018, in 6 public hospitals across Sweden. Male and female children and adolescents aged 9 to 17 years with an AIS primary curve Cobb angle of 25° to 40°, apex T7 or caudal, and skeletal immaturity based on estimated remaining growth of at least 1 year were included in the study. Dates of analysis were from October 25, 2021, to January 28, 2023. Interventions Interventions included self-mediated physical activity in combination with either NB or SSE or PA (control). Patients with treatment failure were given the option to transition to a full-time brace until skeletal maturity. Main Outcomes and Measures The primary outcome was curve progression of 6° or less (treatment success) or curve progression of more than 6° (treatment failure) seen on 2 consecutive posteroanterior standing radiographs compared with the inclusion radiograph before skeletal maturity. A secondary outcome of curve progression was the number of patients undergoing surgery up until 2 years after the primary outcome. Results The CONTRAIS study included 135 patients (45 in each of the 3 groups) with a mean (SD) age of 12.7 (1.4) years; 111 (82%) were female. Treatment success was seen in 34 of 45 patients (76%) in the NB group and in 24 of 45 patients (53%) in the PA group (odds ratio [OR], 2.7; 95% CI, 1.1-6.6). The number needed to treat to prevent curve progression with NB was 4.5 (95% CI, 2.4-33.5). Treatment success occurred in 26 of 45 patients (58%) in the SSE group (OR for SE vs PA, 1.2; 95% CI, 0.5-2.8). Up to 2 years after the primary outcome time point, 9 patients in each of the 3 groups underwent surgery. Conclusions and Relevance In this randomized clinical trial, treatment with NB prevented curve progression of more than 6° to a significantly higher extent than did PA, while SSE did not; in addition, allowing transition to full-time bracing after treatment failure resulted in similar surgical frequencies independent of initial treatment. These results suggest that NB may be an effective alternative intervention in patients rejecting full-time bracing. Trial Registration ClinicalTrials.gov Identifier: NCT01761305
Building CRISPR Gene Therapies for the Central Nervous System
Authors: Sally E. Salomonsson, Claire D. Clelland
Journal: JAMA Neurology (2024)

Gene editing using clustered regularly interspaced short palindromic repeats (CRISPR) holds the promise to arrest or cure monogenic disease if it can be determined which genetic change to create without inducing unintended cellular dysfunction and how to deliver this technology to the target organ reliably and safely. Clinical trials for blood and liver disorders, for which delivery of CRISPR is not limiting, show promise, yet no trials have begun for central nervous system (CNS) indications.
Novel mitophagy inducer alleviates lupus nephritis by reducing myeloid cell activation and autoantigen presentation
Authors: Huijing Wang, Mingdi Shen, Yanhong Ma, Lan Lan, Xue Jiang, Xufeng Cen, Gangqiang Guo, Qin Zhou, Mengmeng Yuan, Jianghua Chen, Hongguang Xia, Liang Xiao, Fei Han
Journal: Kidney International (2024)

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE), but its mechanism of onset remains unclear. Since impaired mitophagy has been implicated in multiple organs in SLE, we hypothesized that mitophagy dysfunction is critical in the development of LN and that pharmacologically targeting mitophagy would ameliorate this disease. Therefore, lupus-prone MRL/MpJ-Faslpr (MRL/lpr) and NZBWF1/J mice were treated with a novel mitophagy inducer, UMI-77, during their onset of LN. This treatment effectively mitigated kidney inflammation and damage as assessed by histology and flow cytometry. Furthermore, dendritic cell (DC)-T cell coculture assay indicated that UMI-77 treatment attenuated DC function that would drive T cell proliferation but did not directly influence the potent T cell proliferation in lupus mice. UMI-77 also restored mitochondrial function and attenuated proinflammatory phenotypes in lupus DCs. Adoptive transfer of DCs from MRL/lpr mice augmented serum anti-dsDNA IgG, urine protein and T cell infiltration of the kidney in MRL/MpJ mice, which could be prevented by either treating lupus donors in vivo or lupus DCs directly with UMI-77. UMI-77 also restored mitochondrial function in myeloid cells from patients with LN in vitro as evidenced by increased ATP levels. Thus, enhancing mitophagy in SLE restrains autoimmunity and limits kidney inflammation for LN development. Hence, our findings suggest targeting mitophagy as a tangible pathway to treat LN.
Characterizing Chemical Exposure Trends from NHANES Urinary Biomonitoring Data
Authors: Zachary Stanfield, R. Woodrow Setzer, Victoria Hull, Risa R. Sayre, Kristin K. Isaacs, John F. Wambaugh
Journal: Environmental Health Perspectives (2024)

Xenobiotic metabolites are widely present in human urine and can indicate recent exposure to environmental chemicals. Proper inference of which chemicals contribute to these metabolites can inform human exposure and risk. Furthermore, longitudinal biomonitoring studies provide insight into how chemical exposures change over time.
Improving risk models for patients having emergency bowel cancer surgery using linked electronic health records: a national cohort study
Authors: Helen A. Blake, Linda D. Sharples, Jemma M. Boyle, Angela Kuryba, Suneetha R. Moonesinghe, Dave Murray, James Hill, Nicola S. Fearnhead, Jan H. van der Meulen, Kate Walker
Journal: International Journal of Surgery (2024)

Background: Life-saving emergency major resection of colorectal cancer (CRC) is a high-risk procedure. Accurate prediction of postoperative mortality for patients undergoing this procedure is essential for both healthcare performance monitoring and preoperative risk assessment. Risk-adjustment models for CRC patients often include patient and tumour characteristics, widely available in cancer registries and audits. The authors investigated to what extent inclusion of additional physiological and surgical measures, available through linkage or additional data collection, improves accuracy of risk models. Methods: Linked, routinely-collected data on patients undergoing emergency CRC surgery in England between December 2016 and November 2019 were used to develop a risk model for 90-day mortality. Backwards selection identified a ‘selected model’ of physiological and surgical measures in addition to patient and tumour characteristics. Model performance was assessed compared to a ‘basic model’ including only patient and tumour characteristics. Missing data was multiply imputed. Results: Eight hundred forty-six of 10 578 (8.0%) patients died within 90 days of surgery. The selected model included seven preoperative physiological and surgical measures (pulse rate, systolic blood pressure, breathlessness, sodium, urea, albumin, and predicted peritoneal soiling), in addition to the 10 patient and tumour characteristics in the basic model (calendar year of surgery, age, sex, ASA grade, TNM T stage, TNM N stage, TNM M stage, cancer site, number of comorbidities, and emergency admission). The selected model had considerably better discrimination compared to the basic model (C-statistic: 0.824 versus 0.783, respectively). Conclusion: Linkage of disease-specific and treatment-specific datasets allowed the inclusion of physiological and surgical measures in a risk model alongside patient and tumour characteristics, which improves the accuracy of the prediction of the mortality risk for CRC patients having emergency surgery. This improvement will allow more accurate performance monitoring of healthcare providers and enhance clinical care planning.
Impact of preoperative infection on the outcomes of liver transplant recipients: a national propensity score-matched retrospective cohort study in China
Authors: Ze Xiang, Yisu Song, Jianrong Liu, Chenhao Xu, Zhisheng Zhou, Jiarui Li, Renyi Su, Wenzhi Shu, Zhengyang Lu, Xuyong Wei, Jiayin Yang, Yang Yang, Shusen Zheng, Xiao Xu
Journal: International Journal of Surgery (2024)

Background: Impact of preoperative infection on liver transplantation (LT) needs further investigation. Materials and methods: From 1 January 2015 to 31 December 2022, 24 122 eligible patients receiving LT were enrolled from the China Liver Transplant Registry database. The outcomes of LT were compared after using the propensity score-matched analysis. Results: Compared to the noninfection group, patients in the infection group were more likely to have postoperative effusion, infection, abdominal bleeding, and biliary complications (all P &lt;0.01), and they had shorter 30-day, 90-day survival, and overall survival (all P &lt;0.01). Cox proportional hazards regression analysis revealed that MELD score and cold ischemia time were risk factors for the overall survival in the infection group (both P &lt;0.05). Besides, compared to the nonpulmonary group, patients in the pulmonary group were more likely to have postoperative effusion and infection (both P &lt;0.0001), and less likely to have postoperative abscess and early allograft dysfunction (both P &lt;0.05). Patients in the nonabdominal group also had a higher proportion of postoperative infection than those in the abdominal group ( P &lt;0.05). Furthermore, compared to the number=1 group, patients in the number ≥2 group were more prone to postoperative effusion and infection (both P &lt;0.01), and they also had shorter 30-day and 90-day survival (both P &lt;0.05). Conclusion: Preoperative infection can result in a higher incidence of early postoperative complications and shorter survival in liver transplant recipients. The types and number of infection sites will also influence the prognosis of liver transplant recipients.
Mechanisms of telomere maintenance and associated therapeutic vulnerabilities in malignant gliomas
Authors: Matthew S Waitkus, Elise N Erman, Zachary J Reitman, David M Ashley
Journal: Neuro-Oncology (2024)

Abstract A majority of cancers (~85%) activate the enzyme telomerase to maintain telomere length over multiple rounds of cellular division. Telomerase-negative cancers activate a distinct, telomerase-independent mechanism of telomere maintenance termed alternative lengthening of telomeres (ALT). ALT uses homologous recombination to maintain telomere length and exhibits features of break-induced DNA replication. In malignant gliomas, the activation of either telomerase or ALT is nearly ubiquitous in pediatric and adult tumors, and the frequency with which these distinct telomere maintenance mechanisms (TMMs) is activated varies according to genetically defined glioma subtypes. In this review, we summarize the current state of the field of TMMs and their relevance to glioma biology and therapy. We review the genetic alterations and molecular mechanisms leading to telomerase activation or ALT induction in pediatric and adult gliomas. With this background, we review emerging evidence on strategies for targeting TMMs for glioma therapy. Finally, we comment on critical gaps and issues for moving the field forward to translate our improved understanding of glioma telomere maintenance into better therapeutic strategies for patients.
Complex Congenital Heart Disease in the Adult
Authors: Sarah A. Goldstein, Richard A. Krasuski
Journal: Annual Review of Medicine (2024)

Congenital heart disease (CHD), a heterogeneous group of structural abnormalities of the cardiovascular system, is the most frequent cause of severe birth defects. Related to improved pediatric outcomes, there are now more adults living with CHD, including complex lesions, than children. Adults with CHD are at high risk for complications related to their underlying anatomy and past surgical palliative interventions. Adults with CHD require close monitoring and proactive management strategies to improve outcomes.
Copy number gain of FAM131B-AS2 promotes the progression of glioblastoma by mitigating replication stress
Authors: Shaobo Wang, Yanhua Qi, Rongrong Zhao, Ziwen Pan, Boyan Li, Wei Qiu, Shulin Zhao, Xiaofan Guo, Shilei Ni, Gang Li, Hao Xue
Journal: Neuro-Oncology (2024)

Abstract Background Glioblastoma (GBM) is characterized by chromosome 7 copy number gains, notably 7q34, potentially contributing to therapeutic resistance, yet the underlying oncogenes have not been fully characterized. Pertinently, the significance of long noncoding RNAs (lncRNAs) in this context has gained attention, necessitating further exploration. Methods FAM131B-AS2 was quantified in GBM samples and cells using qPCR. Overexpression and knockdown of FAM131B-AS2 in GBM cells were used to study its functions in vivo and in vitro. The mechanisms of FAM131B-AS2 were studied using RNA-seq, qPCR, Western blotting, RNA pull-down, coimmunoprecipitation assays, and mass spectrometry analysis. The phenotypic changes that resulted from FAM131B-AS2 variation were evaluated through CCK8 assay, EdU assay, comet assay, and immunofluorescence. Results Our analysis of 149 primary GBM patients identified FAM131B-AS2, a lncRNA located in the 7q34 region, whose upregulation predicts poor survival. Mechanistically, FAM131B-AS2 is a crucial regulator of the replication stress response, stabilizing replication protein A1 through recruitment of ubiquitin-specific peptidase 7 and activating the ataxia telangiectasia and rad3-related protein kinase pathway to protect single-stranded DNA from breakage. Furthermore, FAM131B-AS2 overexpression inhibited CD8+ T-cell infiltration, while FAM131B-AS2 inhibition activated the cGAS-STING pathway, increasing lymphocyte infiltration and improving the response to immune checkpoint inhibitors. Conclusions FAM131B-AS2 emerges as a promising indicator for adjuvant therapy response and could also be a viable candidate for combined immunotherapies against GBMs.