bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitrite-negative results in urinary tract infection by Enterobacterales: does the nitrite dipstick test have low sensitivity?
Authors: Lopes Araújo-Filho Carlos Eduardo , Santos Galvão Vívian , Fernandes do Espírito Santo Renan , de Souza Santos Monteiro Adriano , Vargas Lordelo Cassia , de Abreu Santos Julio Cezar , Alves da Silva Junior Valter , Machado Cordeiro Soraia , David Couto Ricardo
Published: February 2023

Urinary tract infection (UTI) is one of the most common bacterial infections among humans. Urine culture is the gold standard diagnostic method for UTI; however, the dipstick test for nitrite is a widely used method signalling the presence of urinary nitrate-reducing bacteria. Unlike the gold standard, the dipstick test is easy to perform, while it is also less time-consuming and less expensive, and produces a result in a few minutes. This study investigates the sensitivity of the dipstick test for nitrite compared with the Griess test in urine samples from UTI caused by

Enterobacterales

species. We used the Griess test, which is the gold standard in nitrite measurement, to determine the sensitivity of the nitrite dipstick test. Semiquantitative urine culture was performed using standard procedures, and

Enterobacterales

identification was performed by manual conventional biochemical tests. In the first sample selection, 3 % (8/267) of urine samples suspected of UTI, analysed from March to April 2016, were nitrite-negative by dipstick test but positive for

Enterobacterales

in the urine culture. In the second sample selection, 5 % (2/44) of urine samples from October to December 2022 were also nitrite-negative but showed urine

Enterobacterales

isolation. All nitrite-negative dipstick results were consistent with the Griess test.

Escherichia coli

was the most prevalent bacterium, followed by Klebsiella pneumoniae, independent of sample selection. The dipstick test is a safe alternative for investigating nitrite in urine samples. We believe that the cause of nitrite-negative results is a lack of dietary nitrate, dilution of urine and exogenous interference (e.g. ascorbic acid). These findings support the idea that standard urine culture is necessary to rule out UTI.
Sex-dependent Clinical Presentation, Body Image, and Endocrine Status in Long-term Remitted Anorexia Nervosa
Authors: Schloesser Louisa , Lotter Leon D. , Offermann Jan , Borucki Katrin , Biemann Ronald , Seitz Jochen , Konrad Kerstin , Herpertz-Dahlmann Beate
Published: February 2023

Objective

Although anorexia nervosa (AN) in males has recently gained attention, knowledge of its psychological and physiological outcomes is still scarce. We explore sex-specific characteristics of long-term remitted AN with respect to residual eating disorder psychopathology, body image, and endocrinology.

Method

We recruited 33 patients with AN in remission for at least 18 months (24 women, 9 men) and 36 matched healthy controls (HCs). Eating disorder psychopathology and body image ideals were assessed via clinical interviews, questionnaires, and an interactive 3D body morphing tool. Plasma levels of leptin, free triiodothyronine, cortisol, and sex hormones were quantified. Univariate models controlled for age and weight were used to test for the effects of diagnosis and sex.

Results

Both patient groups showed residual eating disorder psychopathology but normal weight and hormone levels relative to HCs. Male remitted patients demonstrated significantly stronger muscularity-focused body image ideals, evident in interviews, self-reports, and behavioural data, than both female patients and HCs.

Conclusions

Sex-specific body image characteristics in patients with remitted AN point towards the need to adjust test instruments and diagnostic criteria to male-specific psychopathology. In the future, sufficiently powered studies should evaluate the risk of men with AN developing muscle dysmorphia in the long term.

Highlights

Gender-specific residual symptoms have been identified in long-term remitted AN patients, particularly regarding body image disturbance.

The drive for muscularity in male remitted patients suggest a possible risk of transition from male AN to muscle dysmorphic disorder.

Gender-specific criteria, especially muscle-oriented behaviour, need to be included in the description of diagnoses and symptoms in male patients.
Circulating Extracellular Vesicles in Human Cardiorenal Syndrome Promote Renal Injury
Authors: Chatterjee Emeli , Rodosthenous Rodosthenis S. , Kujala Ville , Karalis Katia , Spanos Michail , Lehmann Helge Immo , de Oliveira Getulio Pereira , Shi Mingjian , Miller-Fleming Tyne W , Li Guoping , Gokulnath Priyanka , Ghiran Ionita Calin , Lindenfeld JoAnn , Mosley Jonathan D , Sheng Quanhu , Shah Ravi , Das Saumya
Published: February 2023

Background

Cardiorenal syndrome (CRS)—renal injury during heart failure (HF)—is linked to higher morbidity. Whether circulating extracellular vesicles (EVs) and their RNA cargo directly impact its pathogenesis remains unclear.

Methods

Using a microfluidic kidney chip model (KC), we investigated transcriptional effects of circulating EVs from patients with CRS on renal epithelial/endothelial cells. We used small RNA-seq on circulating EVs and regression to prioritize subsets of EV miRNAs associated with serum creatinine, a biomarker of renal function.In silicopathway analysis, human genetics, and interrogation of expression of miRNA target genes in the KC model and in a separate cohort of individuals post-renal transplant with microarray-based gene expression was performed for validation.

Results

Renal epithelial and endothelial cells in the KC model exhibited uptake of EVs. EVs from patients with CRS led to higher expression of renal injury markers (IL18,NGAL,KIM1) a greater cystatin C secretion relative to non-CRS EVs. Small RNA-seq and regression identified 15 miRNAs related to creatinine, targeting 1143 gene targets specifying pathways relevant to renal injury, including TGF-b and AMPK signaling. We observed directionally consistent changes in expression of TGF-b pathway members (BMP6, FST, TIMP3) in KC model exposed to CRS EVs, as well as in renal tissue after transplant rejection. Mendelian randomization suggested a role for FST in renal function.

Conclusion

EVs from patients with CRS directly elicit adverse transcriptional and phenotypic responses in a KC model by regulating biologically relevant pathways, suggesting a novel role for EVs in CRS.

Trial Registration

ClinicalTrials.govNCT 03345446.

Funding

AHA (SFRN16SFRN31280008), NHLBI (1R35HL150807-01) and NCATS (UH3 TR002878).
Impact of intraoperative use of venovenous extracorporeal membrane oxygenation on the status of von Willebrand factor large multimers during single lung transplantation
Authors: Oishi Hisashi , Okada Yoshinori , Suzuki Yamato , Hirama Takashi , Ejima Yutaka , Fujimaki Shin-ichi , Sugawara Shingo , Okubo Noriyuki , Horiuchi Hisanori
Published: February 2023

Purpose

von Willebrand factors (vWFs), hemostatic factors, are produced as large multimers and are shear stress-dependently cleaved to become the appropriate size. A reduction in vWF large multimers develops in various conditions including the use of extracorporeal life support, which can cause excessive-high shear stress in the blood flow and result in hemostatic disorders. The objective of this prospective study was to investigate the impact of venovenous extracorporeal membrane oxygenation (VV ECMO) use on the status of vWF large multimers and hemostatic disorders during single lung transplantation (SLT).

Methods

We prospectively enrolled 12 patients who underwent SLT at our center. Among them, seven patients were supported by VV ECMO intraoperatively (ECMO group) and the remaining five patients underwent SLT without ECMO support (control group). The vWF large multimer index (%) was defined as the ratio of the large multimer proportion in total vWF (vWF large multimer ratio) derived from a patient’s plasma to that from the standard human plasma.

Results

The vWF large multimer index at the end of the surgery was significantly lower in the ECMO group than in the control group (112.6% vs. 75.8%, respectively;p< 0.05). The intraoperative blood loss and the amounts of intraoperative transfusion products in the ECMO group tended to be greater than those in the control group; however, the differences were not significant.

Conclusion

During SLT, the intraoperative use of VV ECMO caused a decrease in the vWF large multimer index. However, the vWF large multimer index was maintained at > 75% in average at the end of SLT, which did not affect the bleeding complications.
Resilience and social support improve mental health and quality of life in patients with post-COVID-19 syndrome
Authors: Galanis Petros , Katsiroumpa Aglaia , Vraka Irene , Kosiara Katerina , Siskou Olga , Konstantakopoulou Olympia , Katsoulas Theodoros , Gallos Parisis , Kaitelidou Daphne
Published: February 2023

The effects of post-COVID-19 syndrome on patients’ life are significant. As there is no prior study available, we investigated the impact of resilience and social support on anxiety, depression, and quality of life among patients with post-COVID-19 syndrome. We conducted a cross-sectional study with a convenience sample. The measures included demographic and clinical characteristics of patients, the Brief Resilience Scale, the Multidimensional Scale of Perceived Social Support, the Patient Health Questionnaire-4, and the EuroQol-5D-3L. Multivariable analysis identified that resilience and social support reduced anxiety and depression among our patients. Also, we found a significant positive relationship between resilience and social support, and quality of life. In conclusion, our findings suggest that resilience and social support can be protective by reducing anxiety and depression, and improving quality of life among patients with post-COVID-19 syndrome. Policy makers should develop and implement healthcare management programs to provide psychological support to these patients.
The effect of pulsatile Versus nonpulsatile cardiopulmonary bypass on renal function in patients undergoing coronary artery bypass graft surgery, a randomized controlled trial
Authors: Khademi Saeed , Jahromi Marzieh Zamani , Ghazinoor Mohammad , Farrokhi Amirmohammad , Bahmani Kazerooni Mohamad Hosein , Najafi Masoud
Published: February 2023

Background

Coronary artery bypass grafting is of the most major surgeries performed around the world. Even though advances are achieved in the surgical technique, a relatively high complication rate regarding circulation is still observed. These complications are believed to be related to cardiopulmonary bypass flow types, pulsatile and nonpulsatile. With renal complications being one of the most important ones, we aim to evaluate the effect of choice of these two flow types on patients’ renal function in a randomized controlled trial.

Method

The study is a double blind randomized clinical trial. Patients with left ventricular dysfunction who were candidates for CABG and were between the ages of 40 to 75 were included in this study. The patients then were randomly assigned into two groups of intraoperative pulsatile and nonpulsatile flow type. The patients renal function markers such as 24-hour urine output, blood urea nitrogen and serum creatinine levels and creatinine clearance were evaluated before and CABG and afterwards in the ICU ward. The results were then analyzed using SPSS 23 software.

Results

of the initial 80 patients enrolled in this study, 16 patients were dropped due to unwillingness to continue follow-up and limitation of data gathering. Patients demographic data between two groups did not differ significantly. No statistically significant difference was observed between the 24 patients undergoing surgery with pulsatile flow and 40 with nonpulsatile flow regarding renal function. Both groups had a decrease in creatinine clearance during their ICU stay. Patients in the pulsatile flow group had less intubation time, less need for blood transfusion but more bleeding after the surgery.

Conclusion

Our study indicated that there is no difference between the use of pulsatile versus nonpulsatile flow regarding patients’ renal outcome. Our participants had a relatively broader age range than similar studies, including younger patients. This plus having an acceptable number of patients evaluated may illustrate that the differences in these two flow types may be dependent on other risk factors depending on the studied population. Further investigations with focal groups could lead us towards a better understanding how these two flow types differ.
Major outbreak of endophthalmitis after cataract surgery: a retrospective cohort in northern Brazil
Authors: Perez da Silva Pereira Priscilla , Carvalho Sabini Andriely Alayne , Ferreira de Almeida Rosa Maria , Oliveira Pontes Daniela , Bezerra Mororó Alves Márcia Maria , Alves de Sousa Viviane , da Silva Azevedo Magzan , de Souza Botelho Adalgiza , Freire Ramalhaes Surlange , Batista da Silva Edilson
Published: February 2023

Background

Endophthalmitis is one of the most important adverse events after cataract surgery as it can lead to total vision loss. The aim of this study was to describe the occurrence of endophthalmitis after phacoemulsification with intraocular lens implantation among patients assisted during a joint effort in Porto Velho, Rondônia, Brazil.

Method

This is a retrospective cohort study, carried out from a bank with 649 medical records of patients who underwent surgery. Descriptive analysis and multiple analysis using Robust Poisson Regression were performed to estimate relative risks (RR) and 95% confidence intervals (95%CI). A statistical analysis was performed using the statistical program Stata® version 16.0 (College Station, Texas, USA).

Results

The incidence of postoperative endophthalmitis confirmed by culture was 10.88%, the highest ever recorded in the world. A higher risk for endophthalmitis was found, in probable cases, among males (RR: 1.88; 95%CI:1.03; 3.44) and brown and yellow skin color (RR: 2.78; 95 %CI %: 1.17; 6.60). For confirmed and probable cases, bilateral surgery and specific lens model were also risk factors. The predominant etiological agents were gram-negative and the main clinical manifestation was corneal edema. The average number of days to start treatment was eight days and 27.12% used antibiotics.

Conclusion

Specific protocols are needed for cataract surgeries that encompass hiring, performing and monitoring these services to ensure good practices and patient safety.
Sarcopenia, adiposity, and discrepancies in cystatin C versus creatinine-based eGFR in patients with cancer: a cross-sectional study
Authors: Hanna Paul E. , Ouyang Tianqi , Tahir Ismail , Katz-Agranov Nurit , Wang Qiyu , Mantz Lea , Strohbehn Ian , Moreno Daiana , Harden Destiny , Dinulos James E. , Cosar Duru , Seethapathy Harish , Gainor Justin F. , Shah Sachin J. , Gupta Shruti , Leaf David E. , Fintelman Florian J. , Sise Meghan E.
Published: February 2023

Purpose

Creatinine-based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with sarcopenia. While Cystatin C-based eGFR (eGFRCYS) is less affected by muscle mass, it may underestimate kidney function in patients with obesity. We sought to evaluate the relationship between body composition and discrepancies between creatinine and eGFRCREand eGFRCYSin patients with cancer.

Methods

We conducted a cross-sectional study of consecutive adults with cancer who had an abdominal CT scan performed within 90 days of simultaneous eGFRCREand eGFRCYSmeasurements between May 2010-January 2022. Sarcopenia was defined using independent sex-specific cutoffs for skeletal muscle index (SMI) at the level of the third lumbar vertebral body (<39 cm2/m2for women,<55 cm2/m2for men). High adiposity was defined as the highest sex-specific quartile of total (visceral plus subcutaneous) adiposity index in the cohort. The primary outcome was eGFR discrepancy, defined by eGFRCYS>30% lower than eGFRCRE. We estimated the odds of eGFR discrepancy using multivariable logistic regression modeling.

Results

Of 545 included patients (mean age 63 ±14 years, 300 [55%] females, 440 [80.7%] non-Hispanic white), 320 (58.7%) met the criteria for sarcopenia and 136 (25%) had high adiposity. After adjustment for potential confounders, sarcopenia and high adiposity were both associated with >30% eGFR discrepancy (adjusted odds ratio [aOR] 1.90, 95% confidence interval [CI] 1.12–3.24; aOR 2.01, 95% CI 1.15–3.52, respectively).

Conclusion

Discrepancies in eGFRCREand eGFRCYSare common in adult patients with cancer, and sarcopenia and high adiposity are both independently associated with large eGFR discrepancies.

Significance statement

Serum creatinine may overestimate glomerular filtration rate (GFR) in patients with muscle loss, which is particularly common among patients with cancer. Serum cystatin C may perform better than creatinine in such patients, but its accuracy is affected by obesity. We performed body composition analysis using computed tomography scans in 545 adult patients with cancer and found that both sarcopenia and high adiposity were independently associated with greater discrepancies in serum creatinine-vs. cystatin C-based estimated GFR. These findings highlight the need for future studies to improve and personalize GFR assessment in patients with cancer, particularly in those who will receive renally cleared medications and anti-neoplastic therapies with a narrow therapeutic index.
Comparing in-person, blended and virtual training interventions; a real-world evaluation of HIV capacity building programs in 16 countries in sub-Saharan Africa
Authors: Kiguli-Malwadde E , Forster M , Eliaz A , Celentano J , Chilembe E , Couper ID , Dassah ET , De Villiers MR , Gachuno O , Haruzivishe C , Khanyola J , Martin S , Motlhatlhedi K , Mubuuke R , Mteta K A , Moabi P , Rodrigues A , Sears D , Semitala F , von Zinkernagel D , Reid MJA , Suleman F
Published: February 2023

Introduction

We sought to evaluate the impact of transitioning a multi-country HIV training program from in-person to online by comparing digital training approaches implemented during the pandemic with in-person approaches employed before COVID-19.

Methods

We evaluated mean changes in pre-and post-course knowledge scores and self-reported confidence scores for learners who participated in (1) in-person workshops (between October 2019 and March 2020), (2) an entirely asynchronous, Virtual Workshops [VW] (between May 2021 and January 2022), and (3) a blended Online Course [OC] (between May 2021 and January 2022) across 16 SSA countries. Learning objectives and evaluation tools were the same for all three groups.

Results

Across 16 SSA countries, 3023 participants enrolled in the in-person course, 2193 learners participated in the virtual workshop and 527 in the online course. The proportions of women who participated in the VW and OC were greater than the proportion who participated in the in-person course (60.1% and 63.6%, p<0.001). Nursing and midwives constituted the largest learner group overall (1145 [37.9%] vs. 949 [43.3%] vs. 107 [20.5%]).

Across all domains of HIV knowledge and self-perceived confidence, there was a mean increase between pre- and post-course assessments, regardless of how training was delivered. The greatest percent increase in knowledge scores was among those participating in the in-person course compared to VW or OC formats (13.6% increase vs. 6.0% and 7.6%, p<0.001). Gains in self-reported confidence were greater among learners who participated in the in-person course compared to VW or OC formats, regardless of training level (p<0.001) or professional cadre (p<0.001).

Conclusions

In this multi-country capacity HIV training program, in-person, online synchronous and blended synchronous/asynchronous strategies were effective means of training learners from diverse clinical settings. Online learning approaches facilitated participation from more women and more diverse cadres. However, gains in knowledge and clinical confidence were greater among those participating in in-person learning programs.
Uncovering the Heritable Components of Multimorbidities and Disease Trajectories: A Nationwide Cohort Study
Authors: Westergaard David , Jørgensen Frederik Hytting , Waaben Jens , Lademann Mette , Hansen Thomas Folkmann , Cremers Jolien , Ostrowski Sisse Rye , Vesterager Pedersen Ole Birger ,   Danish Blood Donor Study Genomic Consortium, Requant Roc , Jørgensen Isabella Friis , Fitzgerald Tom , Birney Ewan , Banasik Karina , Mortensen Laust , Brunak Søren
Published: February 2023

Quantifying the contribution of genetics and environmental effects on disease initiation and progression, as well as the shared genetics of different diseases, is vital for the understanding of the disease etiology of multimorbidities. In this study, we leverage nationwide Danish registries to provide a granular atlas of the genetic origin of disease phenotypes for a cohort of all Danes 1978-2018 with partially known pedigree (n = 6.3 million). We estimate the heritability and genetic correlation between thousands of disease phenotypes using a novel approach that can be scaled to nationwide data. Our findings confirm the importance of genetics for a number of known associations and increase the resolution of heritability by adding numerous novel associations, some of which point to shared biologically origin of different phenotypes. We also establish the heritability of disease trajectories and the importance of sex-specific genetic contributions.
Effectiveness of bivalent mRNA booster vaccination against SARS-CoV-2 Omicron infection in the Netherlands, September to December 2022
Authors: Huiberts Anne J. , de Gier Brechje , Hoeve Christina E. , de Melker Hester E. , Hahné Susan J.M. , Hartog Gerco den , van de Wijgert Janneke H.H.M. , van den Hof Susan , Knol Mirjam J.
Published: February 2023

We used data of 32,542 prospective cohort study participants who previously received primary and one or two monovalent booster COVID-19 vaccinations. Between 26 September and 19 December 2022, relative effectiveness of bivalent Original/Omicron BA.1 vaccination against self-reported Omicron SARS-CoV-2 infection was 31% in 18-59-year-olds and 14% in 60-85-year-olds. Protection was higher after prior Omicron infection than after bivalent vaccination without prior infection. Although bivalent booster vaccination increases protection against COVID-19 hospitalizations, we found limited added benefit in preventing SARS-CoV-2 infection.
Characteristics and Outcomes of COVID-19 Patients Presumed to be Treated with Sotrovimab in NHS Hospitals in England
Authors: Patel Vishal , Levick Bethany , Boult Stephen , Gibbons Daniel C. , Drysdale Myriam , Lloyd Emily J. , Singh Moushmi , Birch Helen J.
Published: February 2023

Introduction

There is limited real-world evidence describing the effectiveness of early treatments for Coronavirus disease 2019 (COVID-19) during the period where Omicron was the dominant variant. Here we describe characteristics and acute clinical outcomes in patients with COVID-19 treated with a monoclonal antibody (mAb; presumed to be sotrovimab) across six distinct periods covering the emergence and subsequent dominance of Omicron subvariants (BA.1, BA.2 and BA.5) in England.

Methods

Retrospective cohort study using data from Hospital Episode Statistics database between 1stJanuary – 31stJuly 2022. Included patients were aged ≥12 years and received a mAb delivered by a National Health Service (NHS) hospital as a day-case, for which the primary diagnosis was COVID-19. Patients were presumed to have received sotrovimab on the basis of available NHS data showing that 99.98% of individuals who received COVID-19 treatment during the period covered by the study were actually treated with sotrovimab. COVID-19-attributable hospitalisations were reported overall and across six distinct periods of Omicron sub-variant prevalence. A multivariate Poisson regression model was used to estimate incidence rate ratios for each period. Subgroup analyses were conducted in patients with severe renal disease and active cancer.

Results

In total, 10,096 patients were included. The most common high-risk comorbidities were Immune-Mediated Inflammatory Disorders (43.0%;n= 4,337), severe renal disease (14.1%;n= 1,422), rare neurological conditions (10.4%;n= 1,053) and active cancer (9.0%;n= 910). The proportions of patients with a COVID-19-attributable hospitalisation was 1.0% (n= 96), or with a hospital visit due to any cause was 4.6% (n= 465) during the acute period. The percentage of patients who died due to any cause during the acute study period was 0.3% (n= 27). COVID-19-attributable hospitalisation rates were consistent among subgroups and no significant differences (p-values ranged from 0.13 to 0.64) were observed across periods of Omicron subvariants.

Conclusion

Low levels of COVID-19-attributable hospitalisations and deaths were recorded in mAb-treated patients. Results were consistent for patients with severe renal disease and active cancer. No evidence of differences in hospitalisation rates were observed whilst Omicron BA.1, and BA.2 or BA.5 subvariants were predominant, despite reported reductions in in vitro neutralisation activity of sotrovimab against BA.2 and BA.5.
Predicting hospital readmissions in patients receiving novel-dose Sacubitril/Valsartan therapy: A competing-risk, causal mediation analysis
Authors: Hou Changchun , Hao Xinxin , Sun Ning , Luo Xiaolin , Wang Luyu , Yang Enpu , Gao Zhichun , Chen Ling , Wang Zebi , Cui Yun , Zhong Jing , Yang Juhao , Liu Xi , Qin Zhexue
Published: February 2023

Background

The effects of novel-dose Sacubitril/Valsartan (S/V) in patients with heart failure (HF) in the real world have not been adequately studied. We examined the risk for all-cause re-admission in the patients with HF taking novel-dose S/V and the possible mediator role of left ventricular reverse remodeling (LVRR).

Methods and Results

There were 464 patients recruited from December 2017 to September 2021 in our hospital with a median follow-up of 660 days (range, 17-1494). Model 1 and 2 were developed based on the results of univariable competing risk analysis, least absolute shrinkage and selection operator approach, backward stepwise regression and multivariable competing risk analysis. The internal verification (data-splitting method) indicated that Model 1 had better discrimination, calibration, and clinical utility. The corresponding nomogram showed that patients aged 75 years and above, or taking the lowest-dose S/V (≤50mg twice a day), or diagnosed with ventricular tachycardia, or valvular heart disease, or chronic obstructive pulmonary disease, or diabetes mellitus were at the highest risk of all-cause readmission. In the causal mediation analysis, LVRR was considered as a critical mediator that negatively affected the difference of novel-dose S/V in readmission.

Conclusions

A significant association was detected between novel-dose S/V and all-cause readmission in HF patients, in part negatively mediated by LVRR. The web-based nomogram could provide individual prediction of all-cause readmission in HF patients receiving novel-dose S/V. The effects of different novel-dose S/V are still needed to be explored further in the future.
Cross-sectional association between blood cholesterol and calcium levels in genetically diverse strains of mice
Authors: Cousineau Cody M. , Loftus Kaelin , Churchill Gary A. , Bridges Dave
Published: February 2023

Genetically diverse outbred mice allow for the study of genetic variation in the context of high dietary and environmental control. Using a machine learning approach we investigated clinical and morphometric factors that associate with serum cholesterol levels in 840 genetically unique mice of both sexes, and on both a control chow and high fat high sucrose diet. We find expected elevations of cholesterol in male mice, those with elevated serum triglycerides and/or fed a high fat high sucrose diet. The third strongest predictor was serum calcium which correlated with serum cholesterol across both diets and sexes (r=0.39-0.48). This is in-line with several human cohort studies which show associations between calcium and cholesterol, and calcium as an independent predictor of cardiovascular events.
Adaptive Digital Tissue Deconvolution
Authors: Görtler Franziska , Mensching-Buhr Malte , Skaar Ørjan , Schrod Stefan , Sterr Thomas , Schäfer Andreas , Beißbarth Tim , Joshi Anagha , Zacharias Helena U. , Grellscheid Sushma Nagaraja , Altenbuchinger Michael
Published: February 2023

Motivation

The inference of cellular compositions from bulk and spatial transcriptomics data increasingly complements data analyses. Multiple computational approaches were suggested and recently, machine learning techniques were developed to systematically improve estimates. Such approaches allow to infer additional, less abundant cell types. However, they rely on training data which do not capture the full biological diversity encountered in transcriptomics analyses; data can contain cellular contributions not seen in the training data and as such, analyses can be biased or blurred. Thus, computational approaches have to deal with unknown, hidden contributions. Moreover, most methods are based on cellular archetypes which serve as a reference; e.g., a generic T-cell profile is used to infer the proportion of T-cells. It is well known that cells adapt their molecular phenotype to the environment and that pre-specified cell archetypes can distort the inference of cellular compositions.

Results

We propose Adaptive Digital Tissue Deconvolution (ADTD) to estimate cellular proportions of pre-selected cell types together with possibly unknown and hidden background contributions. Moreover, ADTD adapts prototypic reference profiles to the molecular environment of the cells, which further resolves cell-type specific gene regulation from bulk transcriptomics data. We verify this in simulation studies and demonstrate that ADTD improves existing approaches in estimating cellular compositions. In an application to bulk transcriptomics data from breast cancer patients, we demonstrate that ADTD provides insights into cell-type specific molecular differences between breast cancer subtypes.

Availability and implementation

A python implementation of ADTD and a tutorial are available at Gitlab and zenodo (doi:10.5281/zenodo.7548362).

Contact

michael.altenbuchinger@bioinf.med.uni-goettingen.deandsushma.grellscheid@uib.no

Supplementary information

Supplementary material is available atBioinformaticsonline.
Coadaptation of coexisting plants enhances productivity in an agricultural system
Authors: Schmutz Anja , Schöb Christian
Published: February 2023

Growing crops in more diverse crop systems (i.e. intercropping) is one way to produce food more sustainably. Even though intercropping, compared to average monocultures, is generally more productive, the full yield potential of intercropping might not yet have been achieved as modern crop cultivars are bred to be grown in monoculture. Breeding plants for more familiarity in mixtures, i.e. plants that are adapted to more diverse communities (i.e.adaptation) or even to coexist with each other (i.e.coadaptation) might have the potential to sustainably enhance productivity.

In this study, the productivity benefits of familiarity throughevolutionary adaptation, where one species adapts to its neighbourhood, andcoevolutionary coadaptation, where two or more species adapt to each other, were disentangled in a crop system through an extensive common garden experiment. Furthermore, evolutionary and coevolutionary effects on species-level and community-level productivity were linked to corresponding changes in functional traits.

We found evidence for higher productivity and trait convergence with increasing familiarity of the plants composing the community. Furthermore, our results provide evidence forcoevolutionof plants in mixtures leading to higher productivity of coadapted species. However, with the functional traits measured in our study we could not fully explain the productivity benefits found uponcoevolution.

Our study is, to our knowledge, the first study that investigatedcoevolutionamong randomly interacting plants and was able to demonstrate thatcoadaptationthroughcoevolutionof coexisting species in mixtures promote ecosystem functioning (i.e. higher productivity). This result is particularly relevant for the diversification of agricultural and forest ecosystems, demonstrating the added value of artificially selecting plants for the communities they are familiar with.
Evidence that genetic drift not adaptation drivesfast-Zandlarge-Zeffects inFicedulaflycatchers
Authors: Chase Madeline A. , Vilcot Maurine , Mugal Carina F.
Published: February 2023

The sex chromosomes have been hypothesized to play a key role in driving adaptation and speciation across many taxa. The reason for this is thought to be the hemizygosity of the heteromorphic part of sex chromosomes in the heterogametic sex, which exposes recessive mutations to natural and sexual selection. The exposure of recessive beneficial mutations increases their rate of fixation on the sex chromosomes, which results in a faster rate of evolution. In addition, genetic incompatibilities between sex-linked loci are exposed faster in the genomic background of hybrids of divergent species, which makes sex chromosomes contribute disproportionately to reproductive isolation. However, in birds, which show a Z/W sex determination system, the disproportionate role of the Z-chromosome in adaptation and reproductive isolation is still debated. Instead, genetic drift has been proposed as the main driver of the so-calledfast-Zandlarge-Zeffects in birds. Here, we address this question inFicedulaflycatchers based on population resequencing data of six flycatcher species. Our results provide evidence for both thefast-Zandlarge-Zeffects inFicedulaflycatchers and that these two phenomena are driven by genetic drift rather than positive selection. Genomic scans of selective sweeps and fixed differences in fact suggest a reduced action of positive selection on the Z-chromosome. We propose that the observed reduction in the efficacy of purifying selection on the Z-chromosome helps to establish genetic incompatibilities between Z-linked and autosomal loci, which could result in pronounced selective sweep signatures for compensatory mutations on the autosomes.
CAGECAT: The CompArative GEne Cluster Analysis Toolbox for rapid search and visualisation of homologous gene clusters
Authors: van den Belt Matthias , Gilchrist Cameron , Booth Thomas J. , Chooi Yit-Heng , Medema Marnix H. , Alanjary Mohammad
Published: February 2023

Background

Co-localized sets of genes that encode specialized functions are common across microbial genomes and occur in genomes of larger eukaryotes as well. Important examples include Biosynthetic Gene Clusters (BGCs) that produce specialized metabolites with medicinal, agricultural, and industrial value (e.g. antimicrobials). Comparative analysis of BGCs can aid in the discovery of novel metabolites by highlighting distribution and identifying variants in public genomes. Unfortunately, gene-cluster-level homology detection remains inaccessible, time-consuming and difficult to interpret.

Results

The comparative gene cluster analysis toolbox (CAGECAT) is a rapid and user-friendly platform to mitigate difficulties in comparative analysis of whole gene clusters. The software provides homology searches and downstream analyses without the need for command-line or programming expertise. By leveraging remote BLAST databases, which always provide up-to-date results, CAGECAT can yield relevant matches that aid in the comparison, taxonomic distribution, or evolution of an unknown query. The service is extensible and interoperable and implements the cblaster and clinker pipelines to perform homology search, filtering, gene neighbourhood estimation, and dynamic visualisation of resulting variant BGCs. With the visualisation module, publication-quality figures can be customized directly from a web-browser, which greatly accelerates their interpretation via informative overlays to identify conserved genes in a BGC query.

Conclusion

Overall, CAGECAT is an extensible software that can be interfaced via a standard web-browser for whole region homology searches and comparison on continually updated genomes from NCBI. The public web server and installable docker image are open source and freely available without registration at:https://cagecat.bioinformatics.nl
Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and correlation with integrated, multiomic analysis in the NIBIT-M4 trial
Authors: Rosaria Noviello Teresa Maria , Di Giacomo Anna Maria , Caruso Francesca Pia , Covre Alessia , Scala Giovanni , Costa Maria Claudia , Coral Sandra , Fridman Wolf H. , Sautès-Fridman Catherine , Mortarini Roberta , Brich Silvia , Pruneri Giancarlo , Simonetti Elena , Lofiego Maria Fortunata , Bedognetti Davide , Anichini Andrea , Maio Michele , Ceccarelli Michele
Published: February 2023

Association of DNA hypomethylating agents (DHA) with immune-checkpoint inhibitors (ICI) is a promising strategy to improve efficacy of ICI-based therapy. Here we report the five-year clinical outcome and an integrated multi-omics analysis of pre- and on-treatment lesions from advanced melanoma patients enrolled in the phase Ib NIBIT-M4 study, a dose-escalation trial of the DHA agent guadecitabine combined with ipilimumab. With a minimum follow-up of 45 months the median OS was 25.6 months; the 5-year OS rate was 28.9% and the median DoR was 20.6 months. Specific genomic features and extent of T and B cellmediated immunity discriminated lesions of responding compared to non-responding patients. Enrichment for proliferation and EMT-related gene programs, and immune escape mechanisms characterized lesions from non-responding patients. Integration of a genetic immunoediting index (GIE) with an adaptive immunity signature (ICR) stratified patients/lesions into four distinct subsets and discriminated 5-year OS and PFS. These results suggest that coupling of immunoediting with activation of adaptive immunity is a relevant requisite for achieving long term clinical benefit by epigenetic immunomodulation in advanced melanoma patients.
Sensitivity of Rapid Antigen Tests Against SARS-CoV-2 Omicron and Delta Variants
Authors: Rao Anuradha , Westbrook Adrianna , Bassit Leda , Parsons Richard , Fitts Eric , Greenleaf Morgan , McLendon Kaleb , Sullivan Julie A. , O’Sick William , Baugh Tyler , Bowers Heather B. , Frank Filipp , Wang Ethan , Le Mimi , Frediani Jennifer , Roychoudhury Pavitra , Greninger Alexander L. , Jerris Robert , Pollock Nira R. , Ortlund Eric A. , Roback John D. , Lam Wilbur A. , Piantadosi Anne
Published: February 2023

Rapid Antigen Tests (RAT) have become an invaluable tool for combating the COVID-19 pandemic. However, concerns have been raised regarding the ability of existing RATs to effectively detect emerging SARS-CoV-2 variants. We compared the performance of eight commercially available, emergency use authorized RATs against the Delta and Omicron SARS-CoV-2 variants using individual patient and serially diluted pooled clinical samples. The RATs exhibited lower sensitivity for Omicron samples when using PCR Cycle threshold (CT) value (a proxy for RNA concentration) as the comparator. Interestingly, however, they exhibited similar sensitivity for Omicron and Delta samples when using quantitative antigen concentration as the comparator. We further found that the Omicron samples had lower ratios of antigen to RNA, which offers a potential explanation for the apparent lower sensitivity of RATs for that variant when using CTvalue as a reference. Our findings underscore the complexity in assessing RAT performance against emerging variants and highlight the need for ongoing evaluation in the face of changing population immunity and virus evolution.
Prediction of Coronary Artery Disease Using Urinary Proteomics
Authors: Wei Dongmei , Melgarejo Jesus D. , Van Aelst Lucas , Vanassche Thomas , Verhamme Peter , Janssens Stefan , Peter Karlheinz , Zhang Zhen-Yu
Published: February 2023

Aims

Coronary artery disease (CAD) is multifactorial, caused by complex pathophysiology, and contributes to a high burden of mortality worldwide. Urinary proteomic analyses may help to identify predictive biomarkers and provide insights into the pathogenesis of CAD.

Methods

Urinary proteome was analyzed in 965 participants using capillary electrophoresis coupled with mass spectrometry. A proteomic classifier was developed in a discovery cohort with 36 individuals with CAD and 36 matched controls using the support vector machine. The classifier was tested in a validation cohort with 115 individuals who progressed to CAD and 778 controls and compared with two previously developed CAD-associated classifiers, CAD238 and ACSP75. The Framingham risk score was available in 737 participants. Bioinformatics analysis was performed based on the CAD-associated peptides.

Results

The novel proteomic classifier was comprised of 160 urinary peptides, mainly related to collagen turnover, lipid metabolism, and inflammation. In the validation cohort, the classifier provided an AUC of 0.82 (95% CI: 0.78-0.87) for the CAD prediction in 8 years, superior to CAD238 (AUC: 0.71, 95% CI: 0.66-0.77) and ACSP75 (AUC: 0.53, 95% CI: 0.47-0.60). On top of CAD238 and ACSP75, the addition of the novel classifier improved the AUC to 0.84 (95% CI: 0.80-0.89). In a multivariable Cox model, a 1-SD increment in the novel classifier was associated with CAD (HR: 1.54, 95% CI: 1.26-1.89, P<0.0001) higher risk of CAD. The new classifier further improved the risk reclassification of CAD on top of the Framingham risk score (net reclassification index: 0.61, 95% CI: 0.25-0.95, P=0.001).

Conclusions

A novel urinary proteomic classifier related to collagen metabolism, lipids, and inflammation showed potential for the risk prediction of CAD. Urinary proteome provides an alternative approach to personalized prevention.

Lay summary

A biomarker that can predict coronary artery disease (CAD) is in urgently need.

We developed and validated a urinary proteomic classifier for the prediction of CAD.

The proteomic classifier involved in atherosclerosis improved the risk reclassification on top of the clinical risk score.
Microbial genes outperform species and SNVs as diagnostic markers for Crohn’s disease on multicohort fecal metagenomes empowered by artificial intelligence
Authors: Gao Sheng , Gao Xiang , Zhu Ruixin , Wu Dingfeng , Feng Zhongsheng , Jiao Na , Sun Ruicong , Gao Wenxing , He Qing , Liu Zhanju , Zhu Lixin
Published: February 2023

Background

Dysbiosis of gut microbial community is associated with the pathogenesis of CD and may serve as a promising non-invasive diagnostic tool. We aimed to compare the performances of the microbial markers of different biological levels by conducting a multidimensional analysis on the microbial metagenomes of CD.

Methods

We collected fecal metagenomic datasets generated from eight cohorts that altogether include 870 CD patients and 548 healthy controls. The microbial alterations in CD patients were assessed at multidimensional levels including species-, gene- and SNV- level, and then diagnostic models were constructed using artificial intelligence algorithm.

Results

A total of 227 species, 1047 microbial genes and 21877 microbial SNVs were identified that differed between CD and controls. The species-, gene- and SNV- models achieved an average AUC of 0.97, 0.95 and 0.77, respectively. Notably, the gene model exhibited superior diagnostic capability, achieving average AUCs of 0.89 and 0.91 in internal and external validations, respectively. Moreover, the gene model was specific for CD against other microbiome-related diseases. Further, we found that phosphotransferase system (PTS) contributed substantially to the diagnostic capability of the gene model. The outstanding performance of PTS was mainly explained by genescelBandmanY, which demonstrated high predictabilities for CD with the metagenomic datasets and was validated in an independent cohort by qRT-PCR analysis.

Conclusions

Our global metagenomic analysis unravels the multidimensional alterations of the microbial communities in CD, and identifies microbial genes as robust diagnostic biomarkers across geographically and culturally distinct cohorts.
Safety and efficacy of left bundle branch area pacing compared with right ventricular pacing in patients with bradyarrhythmia and conduction system disorders: a systematic review and meta-analysis
Authors: Leventopoulos Georgios , Travlos Christoforos K. , Aronis Konstantinos N. , Anagnostopoulou Virginia , Patrinos Panagiotis , Papageorgiou Aggeliki , Perperis Angelos , Gale Chris P. , Davlouros Periklis
Published: February 2023

Background

Right Ventricular Pacing (RVP) may have detrimental effects in ventricular function. Left Bundle Branch Area Pacing (LBBAP) is a new pacing strategy that appears to have better results. The aim of this systematic review and meta-analysis is to compare the safety and efficacy of LBBAP vs RVP in patients with bradyarrhythmia and conduction system disorders.

Methods

Medline, Embase and Pubmed databases were searched for studies comparing LBBAP with RVP. Outcomes were all-cause mortality, atrial fibrillation (AF) occurrence, heart failure hospitalizations (HFH) and complications. QRS duration, mechanical synchrony and LVEF changes were also assessed. Pairwise meta-analysis was conducted using random and fixed effects models.

Results

Twenty-five trials with 4250 patients (2127 LBBAP) were included in the analysis. LBBAP was associated with lower risk for HFH (RR:0.33, CI 95%:0.21 to 0.50;p<0.001), all-cause mortality (RR:0.52 CI 95%:0.34 to 0.80;p=0.003), and AF occurrence (RR:0.43 CI 95%:0.27 to 0.68;p<0.001) than RVP. Lead related complications were not different between the two groups (p=0.780). QRSd was shorter in the LBBAP group at follow-up (WMD: -32.20 msec, CI 95%: -40.70 to -23.71;p<0.001) and LBBAP achieved better intraventricular mechanical synchrony than RVP (SMD: -1.77, CI 95%: -2.45 to -1.09;p<0.001). LBBAP had similar pacing thresholds (p=0.860) and higher R wave amplitudes (p=0.009) than RVP.

Conclusions

LBBAP has better clinical outcomes, preserves ventricular electrical and mechanical synchrony and has excellent pacing parameters, with no difference in complications compared to RVP.

Clinical Perspective

What is known

Left bundle branch area pacing (LBBAP) is a method of conduction system pacing with higher procedural success rate and less limitations compared to His bundle pacing (HBP).

Right ventricular pacing (RVP) causes electromechanical dyssynchrony, which may result in left ventricular systolic dysfunction in some patients.

What the study adds

We examined in a systematic review and meta-analysis whether there was a difference in clinical outcomes, electromechanical synchronization, and safety between LBBAP and RVP in patients with bradyarrhythmia and conduction system disorders.