tbuckley/cabot-search huggingface dataset:
A drug target for erectile dysfunction to help improve fertility, sexual activity, and wellbeing: mendelian randomisation study
Authors: Benjamin Woolf, Skanda Rajasundaram, Héléne T Cronjé, James Yarmolinsky, Stephen Burgess, Dipender Gill
Journal: BMJ (2023)

Abstract Objective To investigate the association of genetically proxied (using a surrogate biomarker) inhibition of phosphodiesterase 5 (PDE5), an established drug target for erectile dysfunction, with fertility, sexual behaviour, and subjective wellbeing. Design Two sample cis-mendelian randomisation study. Setting Summary data on genetic associations obtained from the International Consortium for Blood Pressure and UK Biobank. Participants Individuals of European ancestry from the International Consortium for Blood Pressure (n=757 601) for estimating PDE5 inhibition (using the surrogate biomarker of diastolic blood pressure reduction), and UK Biobank (n=211 840) for estimating the fertility, sexual behaviour, and subjective wellbeing outcomes in male participants. Intervention Genetically proxied PDE5 inhibition. Main outcome measures Number of children fathered, number of sexual partners, probability of never having had sexual intercourse, and subjective wellbeing. Results Genetically proxied PDE5 inhibition was associated with male participants having 0.28 (95% confidence interval 0.16 to 0.39) more children (false discovery rate corrected P&lt;0.001). This association was not identified in female participants. No evidence was found of an association between genetically proxied PDE5 inhibition and number of sexual partners, probability of never having had sexual intercourse, or self-reported wellbeing in male participants. Conclusions The findings of this study provide genetic support for PDE5 inhibition potentially increasing the number of children fathered by male individuals. Absence of this association in female participants supports increased propensity for sustained and robust penile erections as a potential underlying mechanism. Further studies are required to confirm this, however, and these findings should not promote indiscriminate use of PDE5 inhibitors, which can also have harmful adverse effects.
Autosomal dominant ApoA4 mutations present as tubulointerstitial kidney disease with medullary amyloidosis
Authors: Tereza Kmochová, Kendrah O. Kidd, Andrew Orr, Aleš Hnízda, Hana Hartmannová, Kateřina Hodaňová, Petr Vyleťal, Karolína Naušová, Vítězslav Brinsa, Helena Trešlová, Jana Sovová, Veronika Barešová, Klára Svojšová, Alena Vrbacká, Viktor Stránecký, Victoria C. Robins, Abbigail Taylor, Lauren Martin, Ana Rivas-Chavez, Riley Payne, Heidi A. Bleyer, Adrienne Williams, Helmut G. Rennke, Astrid Weins, Patrick J. Short, Varun Agrawal, Leroy J. Storsley, Sushrut S. Waikar, Ellen D. McPhail, Surendra Dasari, Nelson Leung, Tom Hewlett, Jake Yorke, Daniel Gaston, Laurette Geldenhuys, Mark Samuels, Adam P. Levine, Michael West, Helena Hůlková, Petr Pompach, Petr Novák, Richard B. Weinberg, Karen Bedard, Martina Živná, Jakub Sikora, Anthony J. Bleyer, Stanislav Kmoch
Journal: Kidney International (2023)

Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m
A proteomic atlas of kidney amyloidosis provides insights into disease pathogenesis
Authors: Charalampos Charalampous, Surendra Dasari, Ellen McPhail, Jason D. Theis, Julie A. Vrana, Angela Dispenzieri, Nelson Leung, Eli Muchtar, Morie Gertz, Marina Ramirez-Alvarado, Taxiarchis Kourelis
Journal: Kidney International (2023)

The mechanisms of tissue damage in kidney amyloidosis are not well described. To investigate this further, we used laser microdissection-mass spectrometry to identify proteins deposited in amyloid plaques (expanded proteome) and proteins overexpressed in plaques compared to controls (plaque-specific proteome). This study encompassed 2650 cases of amyloidosis due to light chain (AL), heavy chain (AH), leukocyte chemotactic factor-2-type (ALECT2), secondary (AA), fibrinogen (AFib), apo AIV (AApoAIV), apo CII (AApoCII) and 14 normal/disease controls. We found that AFib, AA, and AApoCII have the most distinct proteomes predominantly driven by increased complement pathway proteins. Clustering of cases based on the expanded proteome identified two ALECT2 and seven AL subtypes. The main differences within the AL and ALECT2 subtypes were driven by complement proteins and, for AL only, 14-3-3 family proteins (a family of structurally similar phospho-binding proteins that regulate major cellular functions) widely implicated in kidney tissue dysfunction. The kidney AL plaque-specific proteome consisted of 24 proteins, including those implicated in kidney damage (α1 antitrypsin and heat shock protein β1). Hierarchical clustering of AL cases based on their plaque-specific proteome identified four clusters, of which one was associated with improved kidney survival and was characterized by higher overall proteomic content and 14-3-3 proteins but lower levels of light chains and most signature proteins. Thus, our results suggest that there is significant heterogeneity across and within amyloid types, driven predominantly by complement proteins, and that the plaque protein burden does not correlate with amyloid toxicity.
The Intersection of Artificial Intelligence and Social Media in Shaping the New Digital Health Frontier: Powers and Perils
Authors: Nikita R. Bhatt, Esther García Rojo, Vineet Gauhar, Claudia Mercader, Vito Cucchiara, Carla Bezuidenhout, Marc van Gurp, Jarka Bloemberg, Jeremy Yuen-Chun Teoh, Maria J. Ribal, Gianluca Giannarini
Journal: European Urology (2023)
Re: Giuseppe Basile, Giuseppe Fallara, Paolo Verri, et al. The Role of 99mTc-Sestamibi Single-photon Emission Computed Tomography/Computed Tomography in the Diagnostic Pathway for Renal Masses: A Systematic Review and Meta-analysis. Eur Urol. 2024;85:63–71
Authors: Giovanni Lughezzani, Paolo Casale, Laura Evangelista
Journal: European Urology (2023)
miR-222 inhibits pathological cardiac hypertrophy and heart failure
Authors: Xiaojun Liu, Haobo Li, Margaret H Hastings, Chunyang Xiao, Federico Damilano, Colin Platt, Carolin Lerchenmüller, Han Zhu, Xin Paul Wei, Ashish Yeri, Patrick Most, Anthony Rosenzweig
Journal: Cardiovascular Research (2023)

Abstract Aims Physiological cardiac hypertrophy occurs in response to exercise and can protect against pathological stress. In contrast, pathological hypertrophy occurs in disease and often precedes heart failure. The cardiac pathways activated in physiological and pathological hypertrophy are largely distinct. Our prior work demonstrated that miR-222 increases in exercised hearts and is required for exercise-induced cardiac hypertrophy and cardiomyogenesis. Here, we sought to define the role of miR-222 in pathological hypertrophy. Methods and results We found that miR-222 also increased in pathological hypertrophy induced by pressure overload. To assess its functional significance in this setting, we generated a miR-222 gain-of-function model through cardiac-specific constitutive transgenic miR-222 expression (TgC-miR-222) and used locked nucleic acid anti-miR specific for miR-222 to inhibit its effects. Both gain- and loss-of-function models manifested normal cardiac structure and function at baseline. However, after transverse aortic constriction (TAC), miR-222 inhibition accelerated the development of pathological hypertrophy, cardiac dysfunction, and heart failure. Conversely, miR-222-overexpressing mice had less pathological hypertrophy after TAC, as well as better cardiac function and survival. We identified p53-up-regulated modulator of apoptosis, a pro-apoptotic Bcl-2 family member, and the transcription factors, Hmbox1 and nuclear factor of activated T-cells 3, as direct miR-222 targets contributing to its roles in this context. Conclusion While miR-222 is necessary for physiological cardiac growth, it inhibits cardiac growth in response to pressure overload and reduces adverse remodelling and cardiac dysfunction. These findings support the model that physiological and pathological hypertrophy are fundamentally different. Further, they suggest that miR-222 may hold promise as a therapeutic target in pathological cardiac hypertrophy and heart failure.
Productive infection of primary human hepatocytes with SARS-CoV-2 induces antiviral and proinflammatory responses
Authors: Natalie Heinen, Rajendra Khanal, Saskia Westhoven, Mara Klöhn, Simon T Herrmann, Maike Herrmann, Tran Tuoc, Pauline Antonie Ulmke, Hoang Duy Nguyen, Huu Phuc Nguyen, Eike Steinmann, Daniel Todt, Richard J P Brown, Amar Deep Sharma, Stephanie Pfaender
Journal: Gut (2023)
Panel-based RNA fusion sequencing improves diagnostics of pediatric acute myeloid leukemia
Authors: Lina Marie Hoffmeister, Julia Suttorp, Christiane Walter, Evangelia Antoniou, Yvonne Lisa Behrens, Gudrun Göhring, Amani Awada, Nils von Neuhoff, Dirk Reinhardt, Markus Schneider
Journal: Leukemia (2023)

New methods like panel-based RNA fusion sequencing (RNA-FS) promise improved diagnostics in various malignancies. We here analyzed the impact of RNA-FS on the initial diagnostics of 241 cases with pediatric acute myeloid leukemia (AML). We show that, compared to classical cytogenetics (CCG), RNA-FS reliably detected risk-relevant fusion genes in pediatric AML. In addition, RNA-FS strongly improved the detection of cryptic fusion genes like NUP98::NSD1, KMT2A::MLLT10 and CBFA2T3::GLIS2 and thereby resulted in an improved risk stratification in 25 patients (10.4%). Validation of additionally detected non-risk-relevant high confidence fusion calls identified PIM3::BRD1, C22orf34::BRD1, PSPC1::ZMYM2 and ARHGAP26::NR3C1 as common genetic variants and MYB::GATA1 as recurrent aberration, which we here describe in AML subtypes M0 and M7 for the first time. However, it failed to detect rare cytogenetically confirmed fusion events like MNX1::ETV6 and other chromosome 12p-abnormalities. As add-on benefit, the proportion of patients for whom measurable residual disease (MRD) monitoring became possible was increased by RNA-FS from 44.4 to 75.5% as the information on the fusion transcripts' sequence allowed the design of new MRD assays.
Total versus proximal gastrectomy for proximal gastric cancer after neoadjuvant chemotherapy: a multicenter retrospective propensity score-matched cohort study
Authors: Zhen Yuan, Hao Cui, Qixuan Xu, Jingwang Gao, Wenquan Liang, Bo Cao, Xia Lin, Liqiang Song, Jun Huang, Ruiyang Zhao, Hanghang Li, Zhiyuan Yu, Jiajun Du, Shuyuan Wang, Lin Chen, Jianxin Cui, Yongliang Zhao, Bo Wei
Journal: International Journal of Surgery (2023)

Background: This study aimed to analyze and compare the short-term and long-term outcomes of proximal gastrectomy (PG) and total gastrectomy (TG) in patients with locally advanced proximal gastric cancer (GC) following neoadjuvant chemotherapy (NACT). Method: A multicenter retrospective cohort study and propensity score matching (PSM) were employed. We examined 367 patients with proximal GC who received NACT followed by PG (n=164) or TG (n=203) at two Chinese medical institutions between December 2009 and December 2022. Clinical and pathological parameters, postoperative complications, and 5-year overall survival (OS) and recurrence-free survival (RFS) were compared between the two groups. The dissection status and metastasis rate of each lymph node station were assessed. Results: After PSM, 80 patients were enrolled in both TG and PG group, and baseline characteristics were comparable between the groups (all P &gt;0.05). The TG group had a higher total number of lymph nodes retrived ( P &lt;0.001) and longer operative time ( P =0.007) compared to the PG group. The incidence of Clavien-Dindo grade II or higher postoperative complications was similar between the TG group (21.3%, 17/80) and the PG group (23.8%, 19/80) ( P =0.850). The 5-year OS rates were 68.4% for the PG group and 66.0% for the TG group ( P =0.881), while the 5-year RFS rates were 64.8% and 61.9%, respectively ( P =0.571), with no statistically significant differences. Metastasis rates at lymph node stations #4d, #5, #6, and #12a were notably low in the TG group, with values of 2.74%, 0.67%, 1.33%, and 1.74%, respectively. Conclusion: For proximal GC patients following NACT, PG maintains comparable curative potential and oncological efficacy to TG, making it a safe option.
m6A-mediated gluconeogenic enzyme PCK1 upregulation protects against hepatic ischemia-reperfusion injury
Authors: Shanshan Yu, Xiao Liu, Yan Xu, Lijie Pan, Yihan Zhang, Yanli Li, Shuai Dong, Dan Tu, Yuetong Sun, Yiwang Zhang, Zhuowei Zhou, Xiaoqi Liang, Yiju Huang, Jiajie Chu, Silin Tu, Chang Liu, Huaxin Chen, Wenjie Chen, Mian Ge, Qi Zhang
Journal: Hepatology (2023)

Background and Aims: Ischemia-reperfusion (I/R) injury frequently occurs during liver surgery, representing a major reason for liver failure and graft dysfunction after operation. The metabolic shift from oxidative phosphorylation to glycolysis during ischemia increased glucose consumption and accelerated lactate production. We speculate that donor livers will initiate gluconeogenesis, the reverse process of glycolysis in theory, to convert noncarbohydrate carbon substrates (including lactate) to glucose to reduce the loss of hepatocellular energy and foster glycogen storage for use in the early postoperative period, thus improving post-transplant graft function. Approach and Results: By analyzing human liver specimens before and after hepatic I/R injury, we found that the rate-limiting enzyme of gluconeogenesis, PCK1, was significantly induced during liver I/R injury. Mouse models with liver I/R operation and hepatocytes treated with hypoxia/reoxygenation confirmed upregulation of PCK1 during I/R stimulation. Notably, high PCK1 level in human post-I/R liver specimens was closely correlated with better outcomes of liver transplantation. However, blocking gluconeogenesis with PCK1 inhibitor aggravated hepatic I/R injury by decreasing glucose level and deepening lactate accumulation, while overexpressing PCK1 did the opposite. Further mechanistic study showed that methyltransferase 3-mediated RNA N6-methyladinosine modification contributes to PCK1 upregulation during hepatic I/R injury, and hepatic-specific knockout of methyltransferase 3 deteriorates liver I/R injury through reducing the N6-methyladinosine deposition on PCK1 transcript and decreasing PCK1 mRNA export and expression level. Conclusions: Our study found that activation of the methyltransferase 3/N6-methyladinosine-PCK1-gluconeogenesis axis is required to protect against hepatic I/R injury, providing potential intervention approaches for alleviating hepatic I/R injury during liver surgery.
Preclinical efficacy of targeting epigenetic mechanisms in AML with 3q26 lesions and EVI1 overexpression
Authors: Christine E. Birdwell, Warren Fiskus, Tapan M. Kadia, Christopher P. Mill, Koji Sasaki, Naval Daver, Courtney D. DiNardo, Naveen Pemmaraju, Gautam Borthakur, John A. Davis, Kaberi Das, Sunil Sharma, Stephen Horrigan, Xinjia Ruan, Xiaoping Su, Joseph D. Khoury, Hagop Kantarjian, Kapil N. Bhalla
Journal: Leukemia (2023)
Abstract 15666: Comprehensive Biopsy and Clinical Features In Coronavirus Disease 2019 Vaccine-Associated Myocarditis - From Nationwide Survey COMBAT Study in Japan -
Authors: Taku Omori, Kazuaki Maruyama, Kinta Hatakeyama, Keiko Ogo, Hatsue Ishibashi-Ueda, Seiya Kato, Michiaki Hiroe, Kyoko Imanaka-Yoshida, Kaoru Dohi
Journal: Circulation (2023)

Introduction: Few studies have reported on myocardial tissue findings of coronavirus disease 2019 (COVID-19) vaccine-associated myocarditis (CVAM). This study aimed to investigate the clinical and histopathological features of patients with CVAM. Methods: This is a multicenter and retrospective cohort study (COMBAT study) of patients who were clinically diagnosed with CVAM and underwent endomyocardial biopsy in 42 participating centers in Japan. The inclusion criteria were the following; 1. Occurrence of clinical symptoms within 30 days after getting the first or second dose of the COVID-19 vaccine between February 2021 and March 2022. 2. The exclusion of acute coronary syndrome using coronary angiography. 3. Abnormality of laboratory tests. Fulminant myocarditis (FM) was defined as catecholamine or mechanical support use during hospitalization. Results: A total of 44 patients were included. Fifteen of 44 (34%) patients were clinically diagnosed with FM. FM patients were older and showed fewer ratio of males than non-FM. Also, FM patients showed significantly a longer duration from vaccination to the occurrence of symptoms and less frequency of chest pain than non-FM (Table).In hematoxylin-eosin (HE) stained samples, 28 of 44 (64%) patients were histologically diagnosed with acute myocarditis. Among them, 24 patients were diagnosed with lymphocytic myocarditis (LM) and 4 with eosinophilic myocarditis (EM). In HE stained samples, 5 of 24 (21%) LM patients visually showed a high ratio of eosinophils compared to the common type of LM. The 5 LM patients had a significantly larger number of eosinophils using by immunohistochemistry of eosinophilic cationic protein and a higher ratio of eosinophils to CD3 than the common type of LM (Figure). Conclusions: In patients with CVAM, there may be a difference in clinical features between FM and non-FM patients. Also, a relatively larger number of eosinophils in the myocardium could be infiltrated in patients with CVAM.
Fibrous Dysplasia With Atypical Bilateral Upper Extremity Pattern
Authors: Amy Chang, Nathan Franssen, Karine Sahakyan
Journal: Clinical Nuclear Medicine (2023)

Fibrous dysplasia (FD) typically presents unilaterally in the lower limbs, or in the skull, mandible, or pelvis. Bilateral presentation is rarely reported. Most cases are diagnosed in the teens with 75% of patients diagnosed before the age of 30 years. In this case, a 63-year-old woman with suspected diagnosis of malignancy was referred to 99mTc-MDP scan and found to have polyostotic FD in bilateral upper extremities. Nuclear medicine can play an important role in diagnosing FD cases with atypical presentation and help risk stratification for more aggressive transformation.
Risk of severe COVID-19 outcomes after autumn 2022 COVID-19 booster vaccinations: a pooled analysis of national prospective cohort studies involving 7.4 million adults in England, Northern Ireland, Scotland and Wales
Authors: Stuart Bedston, Fatima Almaghrabi, Lynsey Patterson, Utkarsh Agrawal, Lana Woolford, Sneha N. Anand, Mark Joy, Anna Crawford, Rosalind Goudie, Rachel Byford, Hoda Abbasizanjani, Deb Smith, Lynn Laidlaw, Ashley Akbari, Christopher Sullivan, Declan T. Bradley, Ronan A. Lyons, Simon de Lusignan, F.D. Richard Hobbs, Chris Robertson, Sir Aziz Sheikh, Ting Shi
Journal: The Lancet Regional Health - Europe (2023)

UK COVID-19 vaccination policy has evolved to offering COVID-19 booster doses to individuals at increased risk of severe Illness from COVID-19. Building on our analyses of vaccine effectiveness of first, second and initial booster doses, we aimed to identify individuals at increased risk of severe outcomes (i.e., COVID-19 related hospitalisation or death) post the autumn 2022 booster dose.
Prevalence of hypertension, diabetes, obesity, multimorbidity, and related risk factors among adult Gambians: a cross-sectional nationwide study
Authors: Modou Jobe, Islay Mactaggart, Suzannah Bell, Min J Kim, Abba Hydara, Covadonga Bascaran, Modou Njai, Omar Badjie, Pablo Perel, Andrew M Prentice, Matthew J Burton
Journal: The Lancet Global Health (2023)

As countries progress through economic and demographic transition, chronic non-communicable diseases (NCDs) overtake a previous burden of infectious diseases. We investigated the prevalence of hypertension, diabetes, obesity, and multimorbidity in older adults in The Gambia.We embedded a survey on NCDs into the nationally representative 2019 Gambia National Eye Health Survey of adults aged 35 years or older. We measured anthropometrics, capillary blood glucose, and blood pressure together with sociodemographic information, personal and family health history, and information on smoking and alcohol consumption. Hypertension was defined as systolic blood pressure of 140 mmHg or more, diastolic blood pressure of 90 mmHg or more, or receiving treatment for hypertension. Diabetes was defined as fasting capillary blood glucose of 7 mmol/L or more, random blood glucose of 11·1mmol/L or more, or previous diagnosis or treatment for diabetes. Overweight was defined as BMI of 25-29·9 kg/m2 and obesity as 30 kg/m2 or more. Multimorbidity was defined as the coexistence of two or more conditions. We calculated weighted crude and adjusted estimates for each outcome by sex, residence, and selected sociodemographic factors.We analysed data from 9188 participants (5039 [54·8%] from urban areas, 6478 [70·5%] women). The prevalence of hypertension was 47·0%; 2259 (49·3%) women, 2052 (44·7%) men. The prevalence increased with age, increasing from 30% in those aged 35-45 years to over 75% in those aged 75 years and older. Overweight and obesity increased the odds of hypertension, and underweight reduced the odds. The prevalence of diabetes was 6·3% (322 [7·0%] women, 255 [5·6%] men), increasing from 3·8% in those aged 35-44 years to 9·1% in those aged 65-75 years, and then declining. Diabetes was much more common among urban residents, especially in women (peaking at 13% by age 65 years). Diabetes was strongly associated with BMI and wealth index. The prevalence of obesity was 12·0% and was notably higher in women than men (880 [20·2%] vs 170 [3·9%]). Multimorbidity was present in 932 (10·7%), and was more common in women than men (694 [15·9] vs 238 [5·5]). The prevalence of smoking was 9·7%; 5 (0·1%) women, 889 (19·3%) men. Alcohol consumption in the past year was negligible.We have documented high levels of NCDs and associated risk factors in Gambian adults. This presents a major stress on the country's fragile health system that requires an urgent, concerted, and targeted mutisectoral strategy.The Queen Elizabeth Diamond Jubilee Trust and Wellcome Trust.
Vaccinating international seafarers during the COVID-19 pandemic
Authors: David Lucas, Sue Stannard, Natalie Shaw, Rob Verbist, Kevin Walker, Jason Zuidema
Journal: The Lancet Global Health (2023)

Despite their key role in the distribution of essential goods, seafarers were often overlooked in international COVID-19 responses. Border closures isolated them at sea, often for months beyond contract. Distributing vaccines to seafarers was inconsistent and often depended on the creativity of charities and industry and labour stakeholders. Even seafarers who received vaccinations often had them unrecognised in the ports they visited. These oversights should not be repeated in preparation for future pandemics. As a vulnerable population and as key international workers, seafarers' health should be prioritised by national and international health policy.