bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting Readmission or Death After Discharge From the ICU: External Validation and Retraining of a Machine Learning Model
Authors: de Hond Anne A. H. , Kant Ilse M. J. , Fornasa Mattia , Cinà Giovanni , Elbers Paul W. G. , Thoral Patrick J. , Sesmu Arbous M. , Steyerberg Ewout W.
Published: December 2022

OBJECTIVES:

Many machine learning (ML) models have been developed for application in the ICU, but few models have been subjected to external validation. The performance of these models in new settings therefore remains unknown. The objective of this study was to assess the performance of an existing decision support tool based on a ML model predicting readmission or death within 7 days after ICU discharge before, during, and after retraining and recalibration.

DESIGN:

A gradient boosted ML model was developed and validated on electronic health record data from 2004 to 2021. We performed an independent validation of this model on electronic health record data from 2011 to 2019 from a different tertiary care center.

SETTING:

Two ICUs in tertiary care centers in The Netherlands.

PATIENTS:

Adult patients who were admitted to the ICU and stayed for longer than 12 hours.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We assessed discrimination by area under the receiver operating characteristic curve (AUC) and calibration (slope and intercept). We retrained and recalibrated the original model and assessed performance via a temporal validation design. The final retrained model was cross-validated on all data from the new site. Readmission or death within 7 days after ICU discharge occurred in 577 of 10,052 ICU admissions (5.7%) at the new site. External validation revealed moderate discrimination with an AUC of 0.72 (95% CI 0.67–0.76). Retrained models showed improved discrimination with AUC 0.79 (95% CI 0.75–0.82) for the final validation model. Calibration was poor initially and good after recalibration via isotonic regression.

CONCLUSIONS:

In this era of expanding availability of ML models, external validation and retraining are key steps to consider before applying ML models to new settings. Clinicians and decision-makers should take this into account when considering applying new ML models to their local settings.
Efficacy, safety, and cost-effectiveness of triple therapy in preventing relapse in rheumatoid arthritis: A randomized controlled trial (ESCoRT study)
Authors: Zhao Juan , Zhou Wei , Wu Yangfeng , Yan Xiaoyan , Yang Li , Zhang Zhuoli
Published: December 2022

Background:

Biological agents, such as tumor necrosis factor inhibitors (TNFi), have been widely used in rheumatoid arthritis (RA) patients and greatly improved goal achievement. The aim of this study was to investigate whether conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) combination was better in reducing relapse than methotrexate (MTX) monotherapy, and more cost-effective than continuing TNFi plus MTX in RA patients who achieved low disease activity (LDA) with TNFi and MTX therapy.

Methods:

RA patients who failed to csDMARDs received an induction therapy of MTX plus TNFi for maximally 12 weeks. Those achieving LDA in 12 weeks were randomly assigned at a 1:1:1 ratio into three groups: (A) adding hydroxychloroquine and sulfasalazine for the first 12 weeks and then discontinuing TNFi for the following 48 weeks; (B) maintaining TNFi and MTX for 60 weeks; and (C) maintaining TNFi and MTX for the first 12 weeks and then discontinuing TNFi for the following 48 weeks. The primary outcome was relapse.

Results:

A total of 117 patients were enrolled for induction therapy and 67 patients who achieved LDA within 12 weeks were randomized, with 24, 21, and 22 patients in groups A, B, and C, respectively. The relapse rates of groups A and B during the entire 60 weeks were comparable [10/22 (45.5%) vs. 7/20 (35.0%), χ2 = 0.475, P = 0.491], however, significantly lower than that of group C [10/22 (45.5%) vs. 17/20 (85.0%), χ2 = 5.517, P = 0.019; 7/20 (35.0%) vs. 17/20 (85.0%), χ2 = 11.035, P = 0.004, respectively]. Taking RMB 100,000 Yuan as the threshold of willingness to pay, compared to MTX monotherapy (group C), both TNFi maintenance and triple csDMARDs therapies were cost-effective, but triple csDMARDs therapy was better.

Conclusion:

For RA patients who have achieved LDA with TNFi and MTX, csDMARDs triple therapy was a cost-effective option in favor of reducing relapse.

Trial registration:

ClinicalTrials.gov, NCT02320630.
Treatments for resectable esophageal cancer: from traditional systemic therapy to immunotherapy
Authors: Yan Yan , Feng Xijia , Li Chengqiang , Lerut Toni , Li Hecheng
Published: December 2022

Esophageal cancer (EC) has a high incidence and poor prognosis. The two major histological types, squamous cell carcinoma and adenocarcinoma, differ in their epidemiology and treatment options. Patients with locally advanced EC benefit from multimodal therapy concepts including neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, and perioperative chemotherapy. Currently, immunotherapy for the solid tumor is a hot spot. Treatment with adjuvant immune checkpoint inhibitors (ICIs) is the first immunotherapy for resectable EC listed in the latest National Comprehensive Cancer Network Guidelines for the Esophageal and Esophagogastric Junction Cancers. Recent clinical trials have established ICIs for three treatment models of resectable EC. Their short-term results demonstrated ideal efficacy and tolerable toxicity, though some concerns remain. This review summarizes the novel data on the ICIs for resectable EC and lists the registered related clinical trials. Hopefully, this review can provide a reference for ongoing research on the treatment options for resectable EC.
A qualitative exploration of the perspectives of international medical students residing in university hostels amid COVID-19 pandemic lockdown
Authors: Khadka Sitaram , Usman Muhammad , Saleem Mohammad , Ali Moshin , Rasheed Huma , Giri Santoshi , Gupta Ravi Prasad , Bajgain Yogesh , Shahi Janak
Published: December 2022

Background:

The coronavirus disease 2019 (COVID-19) pandemic has portentously frightened the existence of life globally. The lockdown approach was adopted as a containment strategy as the disease itself has manifested severe social, economic, and psychiatric implications. This study was conducted to explore the perception and preparedness of international medical students residing in university hostels amid the COVID-19 pandemic lockdown.

Methods:

A total of 11 international medical students were selected through the purposive sampling technique and interviewed face-to-face through the semi-structured interview guide. All the interviews were audio-taped, transcribed verbatim, and then analyzed for thematic content by standard content analysis framework.

Results:

The 5 major themes were yielded: familiarity with COVID-19, perceptions and attitudes toward COVID-19, preparedness for safety against COVID-19, barriers to lifestyle, and psychological perspectives. Adequate knowledge regarding the overview of COVID-19; preventive approaches such as social distancing, use of masks, gloves, and sanitizers; and compliance with the lockdown measures were reported by the respondents. The pertinent issue raised by the respondents was the disturbance in normal routine due to distortion in social life and isolation.

Conclusion:

The findings from this study lighten the people’s perspectives that help the government to prepare public health strategies based on population-focused approaches. The present study demonstrates the respondents’ opinion on COVID-19 management through personal hygiene, social distancing, and complying with the lockdown measures. Furthermore, it demands the adoption of timely and evidence-based teaching-learning techniques for students’ engagement which ensures mental health and self-motivation as well.
A novel professional automated auscultatory blood pressure monitor with visual display of Korotkoff sounds: InBody BPBIO480KV validation according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization Universal Standard
Authors: Ntineri Angeliki , Theodosiadi Aikaterini , Menti Ariadni , Kyriakoulis Konstantinos G. , Ntousopoulos Vasileios , Kollias Anastasios , Stergiou George S.
Published: December 2022

Objective:

A novel automated auscultatory upper arm-cuff blood pressure (BP) monitor (InBody BPBIO480KV) for office use was developed. An electronic stethoscope embedded in the device cuff records the Korotkoff sounds, which are audible to the user and graphically displayed during cuff deflation. Automated BP measurements are provided, while allowing the user to assess the Korotkoff sounds. The device accuracy was tested using the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Universal Standard (ISO 81060-2:2018) and its Amendment 1.2020-01.

Methods:

Participants were recruited to fulfil the age, sex, BP, arm circumference and cuff distribution criteria of the Universal Standard in general population using the same arm sequential measurement method. Three cuffs of the test device were used for arm circumference 23–28, 28–35 and 33–42 cm.

Results:

Data from 85 individuals were analysed [mean age 57.3 ± 15.0 (SD) years, 53 men, arm circumference 23–42 cm]. For validation of criterion 1, the mean ± SD of the differences between the test device and reference BP readings (N = 255) was 0.3 ± 5.5/0.6 ± 4.7 mmHg (systolic/diastolic; threshold ≤5 ± 8 mmHg). For criterion 2, the SD of the averaged BP differences per individual (N = 85) was 3.76/3.61 mmHg (systolic/diastolic; threshold ≤6.95/6.91 mmHg).

Conclusion:

The InBody BPBIO480KV device for office use, which provides automated auscultatory measurements while reproducing and displaying the Korotkoff sounds, comfortably fulfilled the AAMI/ESH/ISO Universal Standard requirements in general population and can be recommended for clinical use. The assessment of Korotkoff sounds by healthcare professionals for evaluating the quality of automated measurements requires further evaluation.
Overcoming Challenges to HIV Medical Care-seeking and Treatment Among Data-to-Care Program Clients in Baton Rouge and New Orleans, Louisiana
Authors: Carey James W. , Roland Katherine B. , Bessler Patricia A. , Tesfaye Casey Langer , Randall Laura A. , Frew Paula M.
Published: December 2022

Data to Care (D2C) uses US public health surveillance data to identify persons with diagnosed HIV who are not receiving adequate medical care. These persons are linked to care and ancillary social services through personalized outreach. We conducted semistructured interviews with 36 adults with HIV in Louisiana who were engaged for the first time or reengaged back into HIV care through D2C efforts. Before D2C program staff contact, nearly 40% were not contemplating HIV care. Program clients cited barriers to HIV care, including difficulties with appointment scheduling and transportation, health care service and drug costs, low motivation, and competing non-HIV health needs. Thirty-four of the 36 clients said that D2C staff helped them overcome these barriers. Clients also described psychosocial support from D2C staff. After receiving D2C program assistance, more than 90% of clients reported consistently receiving HIV medical care and taking medications. Our findings suggest that D2C staff successfully identified client needs and provided tailored assistance.
Whole-body single photon emission computed tomography/computed tomography for assessment of oncological bone disease – is an extended field of view (from vertex to toes) of clinical value?
Authors: Komber Hend , Redman Stewart , Graham Richard , Anane-Adusei Sarah , Little David
Published: December 2022

Objectives

Whole-body single photon emission computed tomography/computed tomography (WB-SPECT/CT) is useful for diagnosing bone metastases. When performed on a dual-headed gamma camera, this may cover from clavicles to proximal femurs due to time constraints. In contrast, the novel 360o cadmium-zinc-telluride scanner can perform WB-SPECT/CT (from vertex to toes) in approximately 20 min. The aim was to assess the prevalence of additional findings above the clavicles and below the lesser trochanters and the prevalence of incidental findings in the CT component.

Methods

Retrospective study of 117 WB-SPECT/CT scans for oncological bone assessment over a 4-month-period. Scan analysis was performed by two independent experienced radionuclide radiologists.

Results

The male:female ratio was 71:46 and the mean patient age was 68 years. The primary malignancies were predominantly prostate 65/117 (55.6%) and breast 40/117 (34.2%). There were additional findings of malignancy above the clavicles in 16/116 scans (13.8%) and below the lesser trochanters in 16/117 scans (13.7%). Two cases in the ‘above the clavicles’ group were suspected solitary metastases, whereas four cases in the ‘below lesser trochanters’ group were bone metastases at risk of pathological fracture. Incidental findings of clinical significance included suspected new malignancy in 11/117 (9.4%).

Conclusion

A WB-SPECT/CT (from vertex to toes) oncological bone protocol is useful for the detection of additional findings of clinical significance above the clavicles and below the lesser trochanters. Reviewing and reporting the CT findings in SPECT/CT is important.
Mucosal Microbiota Associated With Eosinophilic Esophagitis and Eosinophilic Gastritis
Authors: Furuta Glenn T. , Fillon Sophie A. , Williamson Kayla M. , Robertson Charles E. , Stevens Mark J. , Aceves Seema S. , Arva Nicoleta C. , Chehade Mirna , Collins Margaret H. , Davis Carla M. , Dellon Evan S. , Falk Gary W. , Gonsalves Nirmala , Gupta Sandeep K. , Hirano Ikuo , Khoury Paneez , Leung John , Martin Lisa J. , Menard‐Katcher Paul , Mukkada Vincent A. , Peterson Kathryn , Spergel Jonathan M. , Wechsler Joshua B. , Yang Guang‐Yu , Rothenberg Marc E. , Harris J. Kirk
Published: December 2022

Objective:

The aim of the study was to determine the mucosal microbiota associated with eosinophilic esophagitis (EoE) and eosinophilic gastritis (EoG) in a geographically diverse cohort of patients compared to controls.

Methods:

We conducted a prospective study of individuals with eosinophilic gastrointestinal disease (EGID) in the Consortium of Eosinophilic Gastrointestinal Disease Researchers, including pediatric and adult tertiary care centers. Eligible individuals had clinical data, mucosal biopsies, and stool collected. Total bacterial load was determined from mucosal biopsy samples by quantitative polymerase chain reaction (PCR). Community composition was determined by small subunit rRNA gene amplicons.

Results:

One hundred thirty‐nine mucosal biopsies were evaluated corresponding to 93 EoE, 17 EoG, and 29 control specimens (18 esophageal) from 10 sites across the United States. Dominant community members across disease activity differed significantly. When comparing EoE and EoG with controls, the dominant taxa in individuals with EGIDs was increased (Streptococcus in esophagus; Prevotella in stomach). Specific taxa were associated with active disease for both EoE (Streptococcus, Gemella) and EoG (Leptotrichia), although highly individualized communities likely impacted statistical testing. Alpha diversity metrics were similar across groups, but with high variability among individuals. Stool analyses did not correlate with bacterial communities found in mucosal biopsy samples and was similar in patients and controls.

Conclusions:

Dominant community members (Streptococcus for EoE, Prevotella for EoG) were different in the mucosal biopsies but not stool of individuals with EGIDs compared to controls; taxa associated with EGIDs were highly variable across individuals. Further study is needed to determine if therapeutic interventions contribute to the observed community differences.
Wnt Family Member 9b (Wnt9b) Is a Sensitive and Specific Marker for Triple-negative Breast Carcinoma Including Metaplastic Carcinoma
Authors: Shaker Nada , Shafi Saba , Parkinson Bryce , Chen Wei , Parwani Anil V. , Ding Qingqing , Li Zaibo
Published: December 2022

Wnt9b was recently identified as a highly sensitive and specific marker for breast carcinomas. Due to the limited number of triple-negative breast carcinomas (TNBCs) in previous study, we further explored Wnt9b’s utility in breast carcinoma, especially in TNBCs including metaplastic carcinomas. We systematically evaluated Wnt9b expression on tissue microarrays (TMAs) from 413 breast carcinomas, 208 urothelial carcinomas, 102 endometrial carcinomas, 109 cholangiocarcinomas, 192 ovarian carcinomas, 48 lung adenocarcinomas, 69 colorectal adenocarcinomas, and 78 melanomas, and whole tissue section (WTS) from 20 human epidermal growth factor receptor 2–positive, 34 nonmetaplastic TNBCs, and 67 invasive metaplastic carcinomas. The results showed Wnt9b was highly expressed in breast carcinomas (91% on TMA and 98% on WTS) and in nonmetaplastic TNBCs (91% on TMA and 97% on WTS), but almost completely negative in other tested tumor types. Wnt9b was also highly expressed in metaplastic carcinomas (80%), significantly higher than GATA3 (56%) and SOX10 (48%), but slightly lower than TRPS1 (90%). In summary, our results demonstrate that Wnt9b is a highly sensitive marker for breast carcinomas, including TNBCs and metaplastic carcinomas. Further, we compared its utility with other breast markers including TRPS1, GATA3, and SOX10 in metaplastic carcinomas.
Accuracy of Nodule Volume and Airway Wall Thickness Measurement Using Low-Dose Chest CT on a Photon-Counting Detector CT Scanner
Authors: Dunning Chelsea A.S. , Marsh Jeffrey F. , Winfree Timothy , Rajendran Kishore , Leng Shuai , Levin David L. , Johnson Tucker F. , Fletcher Joel G. , McCollough Cynthia H. , Yu Lifeng
Published: December 2022

Objectives

A comparison of high-resolution photon-counting detector computed tomography (PCD-CT) versus energy-integrating detector (EID) CT via a phantom study using low-dose chest CT to evaluate nodule volume and airway wall thickness quantification.

Materials and Methods

Twelve solid and ground-glass lung nodule phantoms with 3 diameters (5 mm, 8 mm, and 10 mm) and 2 shapes (spherical and star-shaped) and 12 airway tube phantoms (wall thicknesses, 0.27–1.54 mm) were placed in an anthropomorphic chest phantom. The phantom was scanned with EID-CT and PCD-CT at 5 dose levels (CTDIvol = 0.1–0.8 mGy at Sn-100 kV, 7.35 mGy at 120 kV). All images were iteratively reconstructed using matched kernels for EID-CT and medium-sharp kernel (MK) PCD-CT and an ultra-sharp kernel (USK) PCD-CT kernel, and image noise at each dose level was quantified. Nodule volumes were measured using semiautomated segmentation software, and the accuracy was expressed as the percentage error between segmented and reference volumes. Airway wall thicknesses were measured, and the root-mean-square error across all tubes was evaluated.

Results

MK PCD-CT images had the lowest noise. At 0.1 mGy, the mean volume accuracy for the solid and ground-glass nodules was improved in USK PCD-CT (3.1% and 3.3% error) compared with MK PCD-CT (9.9% and 10.2% error) and EID-CT images (11.4% and 9.2% error), respectively. At 0.2 mGy and 0.8 mGy, the wall thickness root-mean-square error values were 0.42 mm and 0.41 mm for EID-CT, 0.54 mm and 0.49 mm for MK PCD-CT, and 0.23 mm and 0.16 mm for USK PCD-CT.

Conclusions

USK PCD-CT provided more accurate lung nodule volume and airway wall thickness quantification at lower radiation dose compared with MK PCD-CT and EID-CT.
Utility of Banff Human Organ Transplant Gene Panel in Human Kidney Transplant Biopsies
Authors: Smith Rex N. , Rosales Ivy A. , Tomaszewski Kristen T. , Mahowald Grace T. , Araujo-Medina Milagros , Acheampong Ellen , Bruce Amy , Rios Andrea , Otsuka Takuya , Tsuji Takahiro , Hotta Kiyohiko , Colvin Robert
Published: December 2022

Background.

Microarray transcript analysis of human renal transplantation biopsies has successfully identified the many patterns of graft rejection. To evaluate an alternative, this report tests whether gene expression from the Banff Human Organ Transplant (B-HOT) probe set panel, derived from validated microarrays, can identify the relevant allograft diagnoses directly from archival human renal transplant formalin-fixed paraffin-embedded biopsies. To test this hypothesis, principal components (PCs) of gene expressions were used to identify allograft diagnoses, to classify diagnoses, and to determine whether the PC data were rich enough to identify diagnostic subtypes by clustering, which are all needed if the B-HOT panel can substitute for microarrays.

Methods.

RNA was isolated from routine, archival formalin-fixed paraffin-embedded tissue renal biopsy cores with both rejection and nonrejection diagnoses. The B-HOT panel expression of 770 genes was analyzed by PCs, which were then tested to determine their ability to identify diagnoses.

Results.

PCs of microarray gene sets identified the Banff categories of renal allograft diagnoses, modeled well the aggregate diagnoses, showing a similar correspondence with the pathologic diagnoses as microarrays. Clustering of the PCs identified diagnostic subtypes including non-chronic antibody-mediated rejection with high endothelial expression. PCs of cell types and pathways identified new mechanistic patterns including differential expression of B and plasma cells.

Conclusions.

Using PCs of gene expression from the B-Hot panel confirms the utility of the B-HOT panel to identify allograft diagnoses and is similar to microarrays. The B-HOT panel will accelerate and expand transcript analysis and will be useful for longitudinal and outcome studies.
Is Exclusion of Coronary Artery Disease in the Kidney Allocation System Preventing Optimal Longevity Matching?
Authors: Tandukar Srijan
Published: December 2022

Background.

Coronary artery disease (CAD) in a kidney transplant candidate is an important predictor of posttransplant mortality. It is not known how the exclusion of CAD in the kidney allocation system has impacted its goal of longevity matching.

Methods.

This is an observational study on adult deceased donor kidney transplant alone recipients between December 4, 2014, and December 31, 2018, with Medicare fee for service (FFS) insurance. Patients were categorized on the basis of Kidney Donor Profile Index (KDPI), Estimated Posttransplant Survival (EPTS), and CAD. Outcomes studied were mortality, death with a functioning graft, overall graft loss, and death-censored graft loss.

Results.

Among 21 151 patients with Medicare FFS coverage for >1 y before transplant, there were 2869 and 18 282 patients with and without CAD, respectively. On Kaplan-Meier analysis, there was higher risk of mortality, death with a functioning graft, overall graft loss, and death-censored graft loss with CAD (P < 0.05 for all). Mortality was higher for CAD group within each category of KDPI and among patients with Estimated Posttransplant Survival 0% to 20% receiving kidneys with KDPI <20% (P < 0.001 for all). On Cox multivariate analysis, the hazard ratios (HRs) of mortality and graft loss were higher with CAD diagnosis without intervention (HR 1.38 [1.25-1.52] and 1.29 [1.18-1.4]), CAD with stents (HR 2.76 [1.68-4.53] and 2.36 [1.46-3.81]), and CAD with bypass surgery (HR 1.56 [1.29-1.89] and 1.39 [1.17-1.65]). Posttransplant CAD events were higher in patients with preexisting CAD (P < 0.001).

Conclusions.

The exclusion of a candidate’s history of CAD in the kidney allocation system adversely impacts its goal of optimal longevity matching.
Descriptions of Micromonospora grosourdyae nom. nov., Micromonospora sonchi comb. nov. and Micromonospora thawaii sp. nov. to resolve problems with the taxonomy and nomenclature of strains named Micromonospora endophytica
Authors: Carro Lorena , Oren Aharon
Published: December 2022

The name

Micromonospora endophytica

has been used for three different organisms. The first organism with this name is the species represented by strain DCWR9-8-2T, a species published in 2015 but whose name was never validated. In 2019 the type species of the genus

Jishengella

was reclassified into the genus

Micromonospora

, while maintaining its original epithet, thus establishing the second group of organisms known as

M. endophytica

, but the first for which the name was validated. Additionally, in 2018 the reclassification of the genus

Verrucosispora

into the genus

Micromonospora

was proposed, but a new epithet has not been specified for the species named

Verrucosispora endophytica

, which remains an orphaned species. Therefore, it is necessary to propose new names that can unequivocally identify these taxa. We have analysed the taxonomic position of the strains, comparing them with the species with valid published names of the genus

Micromonospora

. We here propose Micromonospora thawaii sp. nov. for the species represented by strain DCWR9-8-2T, and Micromonospora grosourdyae nom. nov. and Micromonospora sonchi comb. nov. for the two orphaned species of

Verrucosispora

,

V. endophytica

and

Verrucosispora sonchi

, respectively. Genomic analysis also showed that

M. trujilloniae

is a later heterotypic synonym of

M. andamanensis

.
JMM Profile: Rift Valley fever: a zoonotic viral haemorrhagic disease
Authors: Lean Fabian Z. X. , Johnson Nicholas
Published: December 2022

Rift Valley fever (RVF) is caused by infection with Rift Valley fever virus (RVFV), a mosquito-borne RNA virus that affects both humans and livestock species. Humans can also acquire infection from contact with infected animals and contaminated bodily fluid. Veterinary vaccines are available for use in livestock, but no vaccines have been approved for humans to date. The virus is currently endemic in most sub-Saharan regions of Africa but numerous incursions into Middle Eastern countries and islands in the Indian Ocean, such as Mayotte (an overseas Department of France), have occurred in the past decade. The risk of further geographical expansion is high and therefore additional investigation is warranted to better understand disease transmission and pathogenic mechanisms to develop threat mitigation strategies.
Human serum induces daptomycin tolerance in Enterococcus faecalis and viridans group streptococci
Authors: Tickle Alicia R. H. , Ledger Elizabeth V. K. , Edwards Andrew M.
Published: December 2022

Daptomycin is a membrane-targeting lipopeptide antibiotic used in the treatment of infective endocarditis caused by multidrug-resistant Gram-positive bacteria such as

Staphylococcus aureus

, enterococci and viridans group streptococci. Despite demonstrating excellent in vitro activity and a low prevalence of resistant isolates, treatment failure is a significant concern, particularly for enterococcal infection. We have shown recently that human serum triggers daptomycin tolerance in

S. aureus

, but it was not clear if a similar phenotype occurred in other major infective endocarditis pathogens. We found that

Enterococcus faecalis

,

Streptococcus gordonii

or

Streptococcus mutans

grown under standard laboratory conditions were efficiently killed by daptomycin, whereas bacteria pre-incubated in human serum survived exposure to the antibiotic, with >99 % cells remaining viable. Incubation of enterococci or streptococci in serum led to peptidoglycan accumulation, as shown by increased incorporation of the fluorescent d-amino acid analogue HADA. Inhibition of peptidoglycan accumulation using the antibiotic fosfomycin resulted in a >tenfold reduction in serum-induced daptomycin tolerance, demonstrating the important contribution of the cell wall to the phenotype. We also identified a small contribution to daptomycin tolerance in

E. faecalis

from cardiolipin synthases, although this may reflect the inherent increased susceptibility of cardiolipin-deficient mutants. In summary, serum-induced daptomycin tolerance is a consistent phenomenon between Gram-positive infective endocarditis pathogens, but it may be mitigated using currently available antibiotic combination therapy.
Influence of the mutation load on the genomic composition of hybrids between outcrossing and self-fertilizing species
Authors: Fyon Fréderic , Berbel-Filho Waldir M.
Published: December 2022

Hybridization is a natural process whereby two diverging evolutionary lineages reproduce and create offspring of mixed ancestry. Differences in mating systems (e.g., self-fertilization and outcrossing) are expected to affect the direction and extent of hybridization and introgression in hybrid zones. Among other factors, selfers and outcrossers are expected to differ in their mutation loads. This has been studied both theoretically and empirically; however, conflicting predictions have been made on the effects mutation loads of parental species with different mating systems can have on the genomic composition of hybrids. Here we develop a multi-locus, selective model to study how the different mutation load built up in selfers and outcrossers as a result of selective interference and homozygosity impact the long-term genetic composition of hybrid populations. Notably, our results emphasize that genes from the parental population with lesser mutation load get rapidly over-represented in hybrid genomes, regardless of the hybrids own mating system. When recombination tends to be more important than mutation, outcrossers’ genomes tend to be of higher quality and prevail. When recombination is small, however, selfers’ genomes may reach higher quality than outcrossers’ genomes and prevail. Taken together these results provide concrete insights into one of the multiple factors influencing hybrid genome composition and introgression patterns in hybrid zones with species containing species with different mating systems.
CluSA: Clustering-based Spatial Analysis framework through Graph Neural Network for Chronic Kidney Disease Prediction using Histopathology Images
Authors: Lee Joonsang , Warner Elisa , Shaikhouni Salma , Bitzer Markus , Kretzler Matthias , Gipson Debbie , Pennathur Subramaniam , Bellovich Keith , Bhat Zeenat , Gadegbeku Crystal , Massengill Susan , Perumal Kalyani , Saha Jharna , Yang Yingbao , Luo Jinghui , Zhang Xin , Mariani Laura , Hodgin Jeffrey B. , Rao Arvind
Published: December 2022

Machine learning applied to digital pathology has been increasingly used to assess kidney function and diagnose the underlying cause of chronic kidney disease (CKD). We developed a novel computational framework, Clustering-based Spatial Analysis (CluSA), that leverages unsupervised learning to learn spatial relationships between local visual patterns in kidney tissue. This framework minimizes the need for time-consuming and impractical expert annotations. To incorporate spatial information over the clustered image patterns on the biopsy sample, we spatially encoded clustered patterns with colors and performed spatial analysis through graph neural network. A random forest classifier with various groups of features were used to predict CKD. For predicting high/low eGFR at the biopsy, we achieved a sensitivity of 0.97, specificity of 0.90, and accuracy of 0.95. AUC was 0.96. For predicting eGFR changes in one-year, we achieved a sensitivity of 0.83, specificity of 0.85, and accuracy of 0.84. AUC was 0.85. This study presents the first spatial analysis based on unsupervised machine learning algorithms. Without expert annotation, CluSA framework can not only accurately classify and predict the degree of kidney function at the biopsy and in one year, but also identify novel predictors of kidney function and renal prognosis.
Integrative analysis of blood cells DNA methylation, transcriptomics and genomics identifies novel epigenetic regulatory mechanisms of insulin resistance during puberty in children with obesity
Authors: Anguita-Ruiz A , Torres-Martos A , Ruiz-Ojeda FJ , Alcalá-Fdez J , Bueno G , Gil-Campos M , Roa-Rivas J , Moreno LA , Gil A , Leis R , Aguilera CM
Published: December 2022

Background

Puberty is a time of considerable metabolic and hormonal changes associated with a physiological increase in peripheral tissue insulin resistance (IR). There is evidence that physiological IR does not resolve in youth who are obese, which may result in increased cardio-metabolic risk. Understanding the molecular and biological processes underlying the development of IR in puberty and the additional impact of obesity on these processes is crucial to prevent type 2 diabetes.

Methods

This is a longitudinal study based on the follow-up until puberty of a cohort of prepubertal Spanish boys and girls. The study population was composed of 139 children organized in a longitudinal approach of 90 subjects (47 females) and two cross-sectional approaches of 99 (52 females) and 130 (71 females) subjects for prepubertal and pubertal stages, respectively. Children were allocated into experimental groups according to their obesity and IR status before and after the onset of puberty. All participants presented blood DNA samples for GWAS and EWAS analyses. In 44 children of the pubertal stage, we counted on blood RNA samples for RNA-seq analysis.

Results

Our large-scale integrative molecular analysis identified novel blood multi-omics signatures (mapping the lociABCG1, ESR1andVASN, among others) significantly associated with IR longitudinal trajectories in children with obesity during pubertal maturation. Functional enrichment analysis revealed that identified loci participate in systemic metabolic pathways and sexual maturation processes relevant to the pathogenesis of IR in the context of puberty. Additional analyses on cardiometabolic and inflammatory phenotypes showed that blood DNAm patterns of some of the identified loci are further associated, beyond IR, with an overall risky-cardiometabolic profile in children. Serum protein levels of vasorin (VASN), one of the most promising novel biomarkers identified in this study, were further associated with IR in the pubertal stage.

Conclusions

To our knowledge, this is the first longitudinal multi-omics approach characterizing molecular blood alterations for IR and obesity during the metabolically critical period of puberty. Our results shed light on the molecular mechanisms underlying epigenetic alterations in obesity and propose novel and promising biomarkers for IR and metabolic alterations in children.
Unbiased serology reveals autoimmunity and HIV antibody signatures in HIV CNS Escape
Authors: Hawes I.A. , Alvarenga B.D. , Browne W. , Wapniarski A. , Dandekar R. , Bartley C.M. , Sowa G.M. , DeRisi J.L. , Cinque P. , Dravid A.N. , Pleasure S.J. , Gisslen M. , Price R.W. , Wilson M.R.
Published: December 2022

Background

Antiretroviral therapy (ART) suppresses plasma and cerebrospinal fluid (CSF) HIV replication with occasional asymptomatic episodes of detectable HIV RNA known as asymptomatic (AS) escape. Neurosymptomatic (NS) CSF escape is a rare exception in which CNS HIV replication occurs in the setting of neurologic impairment. The origins of NS escape are not fully understood.

Methods

Using a large cohort of PLWH (n=111), including elite controllers (n=4), viral controllers (n=4), ART untreated subjects (n=18), HIV-associated dementia (n=4), ART suppressed (n=16), AS escape (n=19), NS escape (n=35), secondary escape (n=5) subjects, and HIV-negative controls (n=6), we investigated immunoreactivity to self-antigens in the CSF of NS escape by employing neuroanatomic CSF immunostaining and massively multiplexed self-antigen serology (PhIP-Seq). Additionally, we utilized pan-viral serology (VirScan) to deeply profile the CSF anti-viral antibody response and metagenomic next-generation sequencing (mNGS) for pathogen detection.

Results

We detected Epstein-Barr virus (EBV) DNA more frequently in the CSF of NS escape subjects than in AS escape controls. Based on immunostaining and PhIP-Seq, there was evidence for increased immunoreactivity against self-antigens in NS escape CSF. Finally, VirScan revealed several immunodominant epitopes that map to the HIV env and gag proteins in the CSF of PLWH.

Discussion

We deployed agnostic tools to study whether there was evidence for a neuroinvasive co-infection and/or autoimmunity in HIV escape syndromes. We more frequently detected EBV DNA and immunoreactivity to self-antigens in NS escape. Whether these additional inflammatory markers are byproducts of an HIV-driven inflammatory process or whether they independently contribute to the neuropathogenesis of NS escape will require further study.
Multifunctional properties of mycorrhizal helper bacteria: improve mycorrhizal colonization and increase phosphate uptake in Banana
Authors: Shah Chandni , Mali Himanshu , Kamble Vijay , Mandavgane Shachi , Subramanian R B
Published: December 2022

Using mycorrhizal fungi with their helper bacteria (MHB) to alleviate phosphate deficiency improve plant growth and rejuvenate the soil is the newer safer and most promising environment-friendly approach to limiting synthetic agrochemicals. Here 65 MHBs were isolated from the mycorrhizosphere of the Banana plant and 12 were screened based on their biofilm formation protease and N-acyl homoserine lactones production. A newly reported MHBEnterobactersp. was identified through the 16S ribotyping method and posed plant growth-promoting properties i.e solubilized phosphate produced indole acetic acid ammonia and hydrogen sulfide. The biocompatibility experiment showed a 4-fold increased mycorrhizal proliferation in MHB added plate compared to the control. Further field experiments suggested the banana plants 10-4-fold increment in plant height (216.54 cm) and stem diameter (10.66 cm). At the same time10-fold significant improvements were noted in leaf carbohydrate (639.9 mg g-1) protein (432.76 mg g-1) chlorophyll (268.66 mg g-1) phenol (1.9 mg g-1) and proline (uMole g-1) content of experimental plant compared to control. The study also showed a 5-fold increase in phosphate content (12.84 mg g-1) than the control (2.4 mg g-1). The isolates increased the mycorrhizal colonization and spore number by 79.33 % and 14.31 g-1in the rhizospheric soil. Total organic carbon and nitrogen (0.68 %) total phosphorus (55 kg ha-1) and potassium (499.66 kg ha-1) content of soil were positively affected by MHB and AMF. Further-more principal component analysis (PCA) and Pearsons correlation analysis of all the obtained results clearly showed the positive insights of inoculated MHB and AMF on the growth of the banana plant and soil restoration.
Offspring overcome poor parenting by being better parents
Authors: Potticary Ahva L. , Cunningham Christopher B. , Moore Allen J.
Published: December 2022

The evolutionary repercussions of parental effects are often discussed as static effects that can have negative influences on offspring fitness that may even persist across generations. However, individuals are not passive recipients and may mitigate the persistence of parental effects through their behaviour. Here, we tested how the burying beetleNicrophorus orbicollis, a species with complex parental care, responded to poor parenting. We manipulated the duration of parental care received and measured the impact on traits of both F1 and F2 offspring. As expected, reducing parental care negatively affected traits that are ecologically important for burying beetles, including F1 offspring development time and body size. However, F1 parents that received reduced care as larvae spent more time feeding F2 offspring than parents that received full care as larvae. As a result, both the number and mass of F2 offspring were unaffected by the developmental experience of their parents. Our results show that flexible parental care may be able to overcome poor developmental environments and limit negative parental effects to a single generation.
Merging short and stranded long reads improves transcript assembly
Authors: Kainth Amoldeep S. , Haddad Gabriela A. , Hall Johnathon M. , Ruthenburg Alexander J.
Published: December 2022

Long-read RNA sequencing has arisen as a counterpart to short-read sequencing, with the potential to capture full-length isoforms, albeit at the cost of lower depth. Yet this potential is not fully realized due to inherent limitations of current long-read assembly methods and underdeveloped approaches to integrate short-read data. Here, we critically compare the existing methods and develop a new integrative approach to characterize a particularly challenging pool of low-abundance long noncoding RNA (lncRNA) transcripts from short- and long-read sequencing in two distinct cell lines. Our analysis reveals severe limitations in each of the sequencing platforms. For short-read assemblies, coverage declines at transcript termini resulting in ambiguous ends, and uneven low-coverage results in segmentation of a single transcript into multiple transcripts. Conversely, long-read transcript assembly lacks strand-of-origin information and depth, culminating in erroneous assembly and quantitation of transcripts. We also discover a cDNA synthesis artifact in long-read datasets that markedly impacts the identity and quantitation of assembled transcripts. Towards remediating these problems, we develop a computational pipeline to “strand” long-read cDNA libraries that rectifies inaccurate mapping and assembly of long-read transcripts. Leveraging the strengths of each platform and our computational stranding, we present and benchmark a hybrid assembly approach that drastically increases the sensitivity and accuracy of full-length transcript assembly on the correct strand and improves detection of biological features of the transcriptome. When applied to a challenging set of under-annotated and cell-type variable lncRNA, our method resolves the segmentation problem of short-read sequencing and the depth problem of long-read sequencing, resulting in the assembly of coherent transcripts with precise 5’ and 3’ ends. Our workflow can be applied to existing datasets for superior demarcation of transcript ends and refined isoform structure, which can enable better differential gene expression analyses and molecular manipulations of transcripts.
Free and interfacial boundaries in individual-based models of multicellular biological systems
Authors: Germano Domenic P. J. , Zanca Adriana , Johnston Stuart T. , Flegg Jennifer A. , Osborne James M.
Published: December 2022

Coordination of cell behaviour is key to a myriad of biological processes including tissue morphogenesis, wound healing, and tumour growth. As such, individual-based computational models, which explicitly describe inter-cellular interactions, are commonly used to model collective cell dynamics. However, when using individual-based models, it is unclear how descriptions of cell boundaries affect overall population dynamics. In order to investigate this we define three cell boundary descriptions of varying complexities for each of three widely used off-lattice individual-based models: overlapping spheres, Voronoi tessellation, and vertex models. We apply our models to multiple biological scenarios to investigate how cell boundary description can influence tissue-scale behaviour. We find that the Voronoi tessellation model is most sensitive to changes in the cell boundary description with basic models being inappropriate in many cases. The timescale of tissue evolution when using an overlapping spheres model is coupled to the boundary description. The vertex model is demonstrated to be the most stable to changes in boundary description, though still exhibits timescale sensitivity. When using individual-based computational models one should carefully consider how cell boundaries are defined. To inform future work, we provide an exploration of common individual-based models and cell boundary descriptions in frequently studied biological scenarios and discuss their benefits and disadvantages.
Highly defended nudibranchs ‘escape’ to visually distinct background habitats
Authors: van den Berg Cedric P. , Santon Matteo , Endler John A. , Cheney Karen L.
Published: December 2022

The ‘escape and radiate’ hypothesis predicts that once species have evolved aposematism, defended species can utilise more visually diverse visual backgrounds as they ‘escape’ the need to be well camouflaged. This enables species to explore new ecological niches, resulting in increased diversification rates. To test this hypothesis’ ‘escape’ component, we examined whether the background habitats of 12 nudibranch mollusc species differed among species depending on the presence and strength of chemical defences. We obtained a rich array of colour pattern statistics using Quantitative Colour Pattern Analysis (QCPA) to analyse backgrounds viewed through the eyes of a potential predator (triggerfish,Rhinecanthus aculeatus). Colour pattern analysis was done at viewing distances simulating an escalating predation sequence. We identified four latent factors comprising 17 non-correlated colour pattern parameters, which captured the among-species variability associated with differences in chemical defences. We found that chemically defended species, indeed, were found on visually distinct backgrounds with increased colour and luminance contrast, independent of viewing distance. However, we found no evidence for increased among-species background diversity coinciding with the presence and strength of chemical defences. Our results agree with the ‘escape and radiate’ hypothesis, suggesting that potent chemical defences in Dorid nudibranchs coincide with spatiochromatic differences of visual background habitats perceived by potential predators.

Lay Summary

According to the ‘escape and radiate’ hypothesis, the ability to store potent chemical defences as protection from predators enables animals to be minimally dependent on matching visual backgrounds for camouflage. We found evidence supporting this hypothesis in 12 species of nudibranch molluscs. Aposematic species were found on visual backgrounds that differed consistently in appearance from the visual background of undefended cryptic species. However, we found no difference in the variability of visual backgrounds between species with or without chemical defences. This suggests that warning colouration in eastern Australian Dorid nudibranchs coincides with broadly generalisable spatiochromatic properties of visual backgrounds.
Multi-Response Phylogenetic Mixed Models: Concepts and Application
Authors: Halliwell Ben , Holland Barbara R. , Yates Luke A.
Published: December 2022

The scale and resolution of trait databases and molecular phylogenies is increasing rapidly. These resources permit many open questions in comparative biology to be addressed with the right statistical tools. Multi-response (MR) phylogenetic mixed models (PMM) offer great potential for multivariate analyses of trait evolution. While flexible and powerful, these methods are not often employed by researchers in ecology and evolution, reflecting a specialised and technical literature that creates barriers to usage for many biologists. Here we present a practical and accessible guide to MR-PMM. We begin with a review of single-response (SR) PMM to introduce key concepts and outline the limitations of this approach for characterizing patterns of trait co-evolution. We emphasise MR-PMM as a preferable approach to analyses involving multiple species traits, due to the explicit decomposition of trait covariance across levels in the model hierarchy. We discuss multilevel distributional models, meta-analyses, multivariate models of evolution, and extensions to non-Gaussian response traits. We highlight techniques for causal inference using precision matrices, as well as advanced topics including prior specification and latent factor models. Using simulated data and visual examples, we discuss interpretation, prediction, and model validation. We implement many of the techniques discussed in example analyses of plant functional traits to demonstrate the general utility of MR-PMM in handling complex real world datasets. Finally, we discuss the emerging synthesis of comparative techniques made possible by MR-PMM, highlight strengths and weaknesses, and offer practical recommendations to analysts. To complement this material, we provide extensive online tutorials including side-by-side model implementations in two popular R packages,MCMCglmmandbrms.