tbuckley/cabot-search huggingface dataset:
Predicting Functional Consequences of Recent Natural Selection in Britain
Authors: Lin Poyraz, Laura L Colbran, Iain Mathieson
Journal: Molecular Biology and Evolution (2024)

Abstract Ancient DNA can directly reveal the contribution of natural selection to human genomic variation. However, while the analysis of ancient DNA has been successful at identifying genomic signals of selection, inferring the phenotypic consequences of that selection has been more difficult. Most trait-associated variants are noncoding, so we expect that a large proportion of the phenotypic effects of selection will also act through noncoding variation. Since we cannot measure gene expression directly in ancient individuals, we used an approach (Joint-Tissue Imputation [JTI]) developed to predict gene expression from genotype data. We tested for changes in the predicted expression of 17,384 protein coding genes over a time transect of 4,500 years using 91 present-day and 616 ancient individuals from Britain. We identified 28 genes at seven genomic loci with significant (false discovery rate [FDR] &amp;lt; 0.05) changes in predicted expression levels in this time period. We compared the results from our transcriptome-wide scan to a genome-wide scan based on estimating per-single nucleotide polymorphism (SNP) selection coefficients from time series data. At five previously identified loci, our approach allowed us to highlight small numbers of genes with evidence for significant shifts in expression from peaks that in some cases span tens of genes. At two novel loci (SLC44A5 and NUP85), we identify selection on gene expression not captured by scans based on genomic signatures of selection. Finally, we show how classical selection statistics (iHS and SDS) can be combined with JTI models to incorporate functional information into scans that use present-day data alone. These results demonstrate the potential of this type of information to explore both the causes and consequences of natural selection.
177Lu-FAP-2286 Therapy in a Metastatic Bone Malignant Solitary Fibrous Tumor
Authors: Hongyu Yang, Huipan Liu, Hongmei Li, Yu Zhang, Yue Chen
Journal: Clinical Nuclear Medicine (2024)

Abstract A 57-year-old woman with a metastatic bone malignant solitary fibrous tumor received 177 Lu-FAP-2286 therapy. After 1 treatment cycle, 68 Ga-FAP-2286 PET/CT revealed remission of the lesions. Moreover, the patient did not report any adverse effects.
Treatment of Refractory Status Epilepticus With Continuous Intravenous Anesthetic Drugs
Authors: Yu Kan Au, Mohammed F. Kananeh, Rahul Rahangdale, Timothy Eoin Moore, Gregory A. Panza, Nicolas Gaspard, Lawrence J. Hirsch, Andres Fernandez, Syed Omar Shah
Journal: JAMA Neurology (2024)

Importance Multiple continuous intravenous anesthetic drugs (CIVADs) are available for the treatment of refractory status epilepticus (RSE). There is a paucity of data comparing the different types of CIVADs used for RSE. Objective To systematically review and compare outcome measures associated with the initial CIVAD choice in RSE in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Evidence Review Data sources included English and non-English articles using Embase, MEDLINE, PubMed, and Web of Science (January 1994-June 2023) as well as manual search. Study selection included peer-reviewed studies of 5 or more patients and at least 1 patient older than 12 years with status epilepticus refractory to a benzodiazepine and at least 1 standard antiseizure medication, treated with continuously infused midazolam, ketamine, propofol, pentobarbital, or thiopental. Independent extraction of articles was performed using prespecified data items. The association between outcome variables and CIVAD was examined with an analysis of variance or χ 2 test where appropriate. Binary logistic regressions were used to examine the association between outcome variables and CIVAD with etiology, change in mortality over time, electroencephalography (EEG) monitoring (continuous vs intermittent), and treatment goal (seizure vs burst suppression) included as covariates. Risk of bias was addressed by listing the population and type of each study. Findings A total of 66 studies with 1637 patients were included. Significant differences among CIVAD groups in short-term failure, hypotension, and CIVAD substitution during treatment were observed. Non–epilepsy-related RSE (vs epilepsy-related RSE) was associated with a higher rate of CIVAD substitution (60 of 120 [50.0%] vs 11 of 43 [25.6%]; odds ratio [OR], 3.11; 95% CI, 1.44-7.11; P = .006) and mortality (98 of 227 [43.2%] vs 7 of 63 [11.1%]; OR, 17.0; 95% CI, 4.71-109.35; P &amp;amp;lt; .001). Seizure suppression was associated with mortality (OR, 7.72; 95% CI, 1.77-39.23; P = .005), but only a small subgroup was available for analysis (seizure suppression: 17 of 22 [77.3%] from 3 publications vs burst suppression: 25 of 98 [25.5%] from 12 publications). CIVAD choice and EEG type were not predictors of mortality. Earlier publication year was associated with mortality, although the observation was no longer statistically significant after adjusting SEs for clustering. Conclusions and Relevance Epilepsy-related RSE was associated with lower mortality compared with other RSE etiologies. A trend of decreasing mortality over time was observed, which may suggest an effect of advances in neurocritical care. The overall data are heterogeneous, which limits definitive conclusions on the choice of optimal initial CIVAD in RSE treatment.
Approach to Obesity Treatment in Primary Care
Authors: Susan Z. Yanovski, Jack A. Yanovski
Journal: JAMA Internal Medicine (2024)

Importance More than 40% of US adults have obesity, which increases the risks for multiple chronic diseases and premature mortality. Historically, nonsurgical interventions often have not led to sufficient weight loss and maintenance to improve health, but highly effective antiobesity medications (AOMs) have recently become available, and additional effective therapeutics are under development. Given that most medical care for adults with obesity is delivered in primary care settings, guidance for integrating weight-management approaches is needed. Observations Lifestyle interventions can lead to a mean weight loss of 2% to 9% of initial weight at 1 year and increase the likelihood of weight loss of 5% or more, but weight regain over time is common even with continued treatment. Adjunctive treatments, including AOMs and surgical approaches, can lead to larger, more sustained weight loss and improvements in numerous obesity-associated medical conditions. Highly effective AOMs, including nutrient-stimulated hormone-based therapies, induce mean weight loss of 15% or more. Barriers to intervention, including access to care, have a disproportionate influence on populations most affected by obesity and its consequences. Conclusions and Relevance Primary care clinicians play a vital role in the assessment, management, and support of patients with obesity. With careful clinical assessment and shared decision-making, a flexible treatment plan can be developed that reflects evidence of treatment efficacy, patient preference, and feasibility of implementation. Adjunctive therapies to lifestyle interventions, including more effective pharmacotherapeutics for obesity, offer hope to patients and the potential for considerable improvements in health and quality of life.
Opioid Prescribing and Outcomes in Patients With Sickle Cell Disease Post–2016 CDC Guideline
Authors: Hyeun Ah Kang, Bofei Wang, Jamie C. Barner, Kenneth I. Ataga, Robert C. Mignacca, Alicia Chang, Yahan Zhang
Journal: JAMA Internal Medicine (2024)

Although the intention of the 2016 US Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain was not to limit pain treatment for patients with sickle cell disease (SCD), clinicians and patients have recognized the possibility that the guideline may have altered outcomes for this population. However, the outcomes of the 2016 guideline for this patient population are unknown.
Race and Ethnicity Data in Electronic Health Records—Striving for Clarity
Authors: Lahia Yemane, Camila M. Mateo, Angel N. Desai
Journal: JAMA Network Open (2024)

Rama A. Salhi, MD, MHS, MSc; Michelle L. Macy, MD, MS; Margaret E. Samuels-Kalow, MD, MPhil, MSHP; Megan Hogikyan, MPH; Keith E. Kocher, MD, MPH
Cost-Effectiveness of Strategies for Treatment Timing for Perinatally Acquired Hepatitis C Virus
Authors: Megan Rose Curtis, Rachel L. Epstein, Pamela Pei, Benjamin P. Linas, Andrea L. Ciaranello
Journal: JAMA Pediatrics (2024)

Importance Prevalence of chronic hepatitis C virus (HCV) infection among pregnant people is increasing in the US. HCV is transmitted vertically in 7% to 8% of births. Direct-acting antiviral (DAA) therapy was recently approved for children with HCV who are 3 years or older. The clinical and economic impacts of early DAA therapy for young children with HCV, compared with treating at older ages, are unknown. Objective To develop a state-transition model to project clinical and economic outcomes for children with perinatally acquired HCV to investigate the cost-effectiveness of treating at various ages. Design, Setting, and Participants The study team modeled the natural history of perinatally acquired HCV to simulate disease progression and costs of a simulated a cohort of 1000 US children with HCV from 3 years old through death. Added data were analyzed January 5, 2021, through July 1, 2022. Interventions The study compared strategies offering 8 weeks of DAA therapy at 3, 6, 12, or 18 years old, as well as a comparator of never treating HCV. Main Outcomes and Measures Outcomes of interest include life expectancy from 3 years and average lifetime per-person health care costs. Other clinical outcomes include cases of cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma (HCC). Results The study team projected that treating HCV at 3 years old was associated with lower mean lifetime per-person health care costs ($148 162) than deferring treatment until 6 years old ($164 292), 12 years old ($171 909), or 18 years old ($195 374). Projected life expectancy was longest when treating at 3 years old (78.36 life years [LYs]) and decreased with treatment deferral until 6 years old (76.10 LYs), 12 years old (75.99 LYs), and 18 years old (75.46 LYs). In a cohort of 1000 children with perinatally acquired HCV, treating at 3 years old prevented 89 projected cases of cirrhosis, 27 cases of HCC, and 74 liver-related deaths compared with deferring treatment until 6 years old. In sensitivity analyses, increasing loss to follow-up led to even greater clinical benefits and cost savings with earlier treatment. Conclusions and Relevance These study results showed that DAA therapy for 3-year-old children was projected to reduce health care costs and increase survival compared with deferral until age 6 years or older. Measures to increase DAA access for young children will be important to realizing these benefits.
Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study
Authors: Sung Won Chung, Hye-Sung Moon, Hyunjae Shin, Hyein Han, Sehoon Park, Heejin Cho, Jeayeon Park, Moon Haeng Hur, Min Kyung Park, Sung-Ho Won, Yun Bin Lee, Eun Ju Cho, Su Jong Yu, Dong Ki Kim, Jung-Hwan Yoon, Jeong-Hoon Lee, Yoon Jun Kim
Journal: Hepatology (2024)

No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes.
Reply: Emerging role of statin therapy in the prevention and management of cirrhosis, portal hypertension, and HCC
Authors: Suzanne Sharpton, Rohit Loomba
Journal: Hepatology (2024)

We would like to thank the authors for their comments regarding our recent comprehensive review of the utility of statins in cirrhosis and its complications.1 Given there are multiple potential clinical scenarios in which statins may benefit persons with cirrhosis, ranging from management of portal hypertensive bleeding to chemoprevention for HCC, we felt it was important to synthesize available data into clinically relevant sections as outlined in our review. The authors cite concern regarding our conclusion that data on the use of and the safety profile of statins in decompensated cirrhosis, specifically in Child-Pugh class C liver disease, is scarce. One of the cited articles is a prospective uncontrolled trial examining the use of simvastatin in 30 patients with decompensated cirrhosis.2 However, this study included only 2 patients with Child-Pugh class C cirrhosis, limiting conclusions in this patient population. Moreover, over 50% of enrolled patients (the majority of which were Child-Pugh class B) experienced an adverse effect while on statin therapy, with the most significant side effect representing muscle injury. The LIVERHOPE-SAFETY trial, which was included in our review, also found a significant increase in the need for treatment discontinuation, primarily due to rhabdomyolysis, in those persons with Child-Pugh B and C cirrhosis.3 This was most notable in those trial participants receiving simvastatin 40 mg daily, as compared to a lower dose (20 mg) of simvastatin. While we certainly agree that these rigorous clinical trials have bolstered our understanding on the use of statins in decompensated cirrhosis, additional studies with larger sample sizes are needed to delineate the best clinical practice regarding the use of statins in patients in the most advanced stages of liver disease and high vigilance for statin-associated muscle symptoms is warranted in this population.
Perfusable adipose decellularized extracellular matrix biological scaffold co-recellularized with adipose-derived stem cells and L6 promotes functional skeletal muscle regeneration following volumetric muscle loss
Authors: Wei Liang, Meng Han, Guan Li, Wanwen Dang, Huiting Wu, Xiaoyu Meng, Yonghuan Zhen, Weibo Lin, Rigele Ao, Xiaoqing Hu, Yang An
Journal: Biomaterials (2024)
A BMP-controlled metabolic/epigenetic signaling cascade directs midfacial morphogenesis
Authors: Jingwen Yang, Lingxin Zhu, Haichun Pan, Hiroki Ueharu, Masako Toda, Qian Yang, Shawn A. Hallett, Lorin E. Olson, Yuji Mishina
Journal: Journal of Clinical Investigation (2024)

Craniofacial anomalies, especially midline facial defects, are among the most common birth defects in patients associated with increased mortality or require lifelong treatment. During mammalian embryogenesis, specific instructions arising at genetic, signaling, and metabolic levels are important for stem cell behaviors and fate determination, but how these functionally relevant mechanisms are coordinated to regulate craniofacial morphogenesis remain unknown. Here, we report that BMP signaling in cranial neural crest cells (CNCCs) is critical for glycolytic lactate production and subsequent epigenetic histone lactylation, thereby dictating craniofacial morphogenesis. Elevated BMP signaling in CNCCs through constitutively activated ACVR1 (ca-ACVR1) suppressed glycolytic activity and blocked lactate production via a p53-dependent process that resulted in severe midline facial defects. By modulating epigenetic remodeling, BMP signaling-dependent lactate generation drived histone lactylation levels to alter essential genes of Pdgfra thus regulating CNCC behavior in vitro as well as in vivo. These findings define an axis wherein the BMP signaling controls a metabolic-epigenetic cascade to direct craniofacial morphogenesis, thus providing a conceptual framework for understanding the interaction between genetic and metabolic cues operative during embryonic development. These findings indicate potential preventive strategies of congenital craniofacial birth defects via modulating metabolic-driven histone lactylation.
Correction: When less is more: lower esophageal sphincter-preserving peroral endoscopic myotomy is effective for non-achalasia esophageal motility disorders
Authors: Varan Perananthan, Sunil Gupta, Anthony Whitfield, Ana Craciun, Oliver Cronin, Timothy O'Sullivan, Karen Byth, Mayenaaz Sidhu, Luke F. Hourigan, Spiro Raftopoulos, Nicholas G. Burgess, Michael J. Bourke
Journal: Endoscopy (2024)

Correction to: When less is more: lower esophageal sphincter-preserving peroral endoscopic myotomy is effective for non-achalasia esophageal motility disordersEndoscopy eFirstDOI: 10.1055/a-2239-7371
Elimination of transmission of onchocerciasis (river blindness) with long-term ivermectin mass drug administration with or without vector control in sub-Saharan Africa: a systematic review and meta-analysis
Authors: Nyamai Mutono, Maria-Gloria Basáñez, Ananthu James, Wilma A Stolk, Anita Makori, Teresia Njoki Kimani, T Déirdre Hollingsworth, Andreia Vasconcelos, Matthew A Dixon, Sake J de Vlas, S M Thumbi
Journal: The Lancet Global Health (2024)
Divergent performance of vaccines in the UK autumn 2023 COVID-19 booster campaign
Authors: Marianne Shawe-Taylor, David Greenwood, Agnieszka Hobbs, Giulia Dowgier, Rebecca Penn, Theo Sanderson, Phoebe Stevenson-Leggett, James Bazire, Ruth Harvey, Vincenzo Libri, George Kassiotis, Steve Gamblin, Nicola S Lewis, Bryan Williams, Charles Swanton, Sonia Gandhi, Edward J Carr, Mary Y Wu, David L V Bauer, Emma C Wall
Journal: The Lancet (2024)
Syndemic and dermatology: A case study in hidradenitis suppurativa
Authors: Tonia Samela, Giulia Raimondi, Giorgia Cordella, Luca Fania, Francesca Sampogna, Simona Mastroeni, Roberta Fusari, Valeria Antinone, Damiano Abeni
Journal: Journal of the American Academy of Dermatology (2024)

To the Editor: With this preliminary work, we wanted to investigate the burden of hidradenitis suppurativa (HS) on patients, in the framework of the Syndemic theory. 1 Singer M. A dose of drugs, a touch of violence, a case of AIDS: conceptualizing the SAVA syndemic. Free Inq Creat Sociol. 1996; 24: 99-110 Google Scholar In other words, we want to understand if the simultaneous presence of different clinical, psychosocial, and sociodemographic factors is associated with increasing HS severity. This cross-sectional study included 599 patients with HS who completed self-report questionnaires to assess sociodemographic and clinical variables (ie, disease severity, presence of psychological distress, and quality of life). A combined, cumulative effect of factors was commuted as "Syndemic scores" and calculated as follows: Syndemic-3 refers to the scores obtained by summing the presence of "pain," "depression," and "smoking" variables; Syndemic-4 refers to the scores obtained by summing all Syndemic-3 variables plus "diagnostic delay"; and Syndemic-5 refers to the scores obtained by all Syndemic-4 variables plus "place of residence." One point was added for each single above-cutoff factor observed. Analysis of variances were used to calculate mean levels for all variables according to the numbers of factors for each Syndemic score.
Intrahepatic IgA complex induces polarization of cancer-associated fibroblasts to matrix phenotypes in the tumor microenvironment of HCC
Authors: Jong Geun Park, Pu Reun Roh, Min Woo Kang, Sung Woo Cho, Suhyun Hwangbo, Hae Deok Jung, Hyun Uk Kim, Ji Hoon Kim, Jae-Sung Yoo, Ji Won Han, Jeong Won Jang, Jong Young Choi, Seung Kew Yoon, Young Kyoung You, Ho Joong Choi, Jae Yong Ryu, Pil Soo Sung
Journal: Hepatology (2024)

Background and Aims: Cancer-associated fibroblasts (CAFs) play key roles in the tumor microenvironment. IgA contributes to inflammation and dismantling antitumor immunity in the human liver. In this study, we aimed to elucidate the effects of the IgA complex on CAFs in Pil Soo Sung the tumor microenvironment of HCC. Approach and Results: CAF dynamics in HCC tumor microenvironment were analyzed through single-cell RNA sequencing of HCC samples. CAFs isolated from 50 HCC samples were treated with mock or serum-derived IgA dimers in vitro. Progression-free survival of patients with advanced HCC treated with atezolizumab and bevacizumab was significantly longer in those with low serum IgA levels ( p &lt;0.05). Single-cell analysis showed that subcluster proportions in the CAF-fibroblast activation protein-α matrix were significantly increased in patients with high serum IgA levels. Flow cytometry revealed a significant increase in the mean fluorescence intensity of fibroblast activation protein in the CD68 + cells from patients with high serum IgA levels ( p &lt;0.001). We confirmed CD71 (IgA receptor) expression in CAFs, and IgA-treated CAFs exhibited higher programmed death-ligand 1 expression levels than those in mock-treated CAFs ( p &lt;0.05). Coculture with CAFs attenuated the cytotoxic function of activated CD8 + T cells. Interestingly, activated CD8 + T cells cocultured with IgA-treated CAFs exhibited increased programmed death-1 expression levels than those cocultured with mock-treated CAFs ( p &lt;0.05). Conclusions: Intrahepatic IgA induced polarization of HCC-CAFs into more malignant matrix phenotypes and attenuates cytotoxic T-cell function. Our study highlighted their potential roles in tumor progression and immune suppression.
Neuroimaging of brain tumors: back to the standardized MRI-protocol
Authors: N. E. Zakharova, I. N. Pronin, A. I. Batalov, I. V. Chekhonin, A. N. Tyurina
Journal: Radiology - Practice (2024)

Despite the widespread application of MRI in brain tumor MR-imaging, the standardized MRI protocol has not yet been approved. This fact creates obstacles for interpreting of the obtained data and even limits the diagnostic power of MRI. Standardization of MRI studies facilitates successful planning of surgery, chemotherapy, or radiation therapy and provides more reliable follow-up. In this regard, uniﬁcation of image acquisition parameters and protocols remains relevant. We propose a standard MRI protocol that includes axial and coronal T2-weighted images, axial or 3D T2-FLAIR, 3D T2* (gradient echo), diﬀusion-weighted imaging, axial T1-weighted images, contrast-enhanced spin-echo T1-weighted images (either axial or three planes) and obligatory subsequent isotropic 3D T1 images. The following combination of sequences facilitates the correct diagnosis and follow-up. The least magnetic ﬁeld strength should be 1.5 T.
Magnetic resonance relaxometry in assessment of morphological properties of brain gliomas: state of the art
Authors: I. V. Chekhonin, A. I. Batalov, N. E. Zakharova, V. N. Kornienko, I. N. Pronin
Journal: Radiology - Practice (2024)

Magnetic resonance (MR) relaxometry, or measurement of tissue magnetic relaxation properties, is a technology intended to quantitatively depict the physical basis of structural MR imaging. This review is devoted to perspective directions of studies and application of MR relaxometry in brain glioma preoperative and pretherapeutic diagnosis. The current data advocate for emerging capabilities of relaxometry in glioma grading (despite possible overlap between diﬀerent grades) and diﬀerentiating between gliomas and tumors of other origin. Some studies showed features of relaxometric values within the perifocal inﬁltrative edema zone possibly related to glioma inﬁltrative growth. We separately reviewed the works aimed at searching for the most aggressive and malignant foci in glioma tissue and extremely useful for tumor biopsy or removal. No less important are capabilities of relaxometry in radiogenomics, ﬁrst of all, in IDH status prediction. The relaxometric method possesses perspective in multiparametric brain glioma diagnostics.