bluuebunny/crossref_metadata_2025 huggingface dataset:
Systemic glucocorticoids as an adjunct to treatment of postoperative pain after total hip and knee arthroplasty
Authors: Køppen Kasper S. , Gasbjerg Kasper S. , Andersen Jakob H. , Hägi-Pedersen Daniel , Lunn Troels H. , Mathiesen Ole
Published: November 2022

BACKGROUND

Postoperative analgesic effects of systemic glucocorticoids given as an adjunct to treatment are largely undetermined in alloplastic procedures.

OBJECTIVES

To investigate the beneficial and harmful effects of peri-operative systemic glucocorticoid treatment for pain after total hip arthroplasty (THA) or total knee arthroplasty (TKA).

DESIGN

A systematic review of randomised clinical trials (RCTs) with meta-analyses, trial sequential analyses and GRADE. Primary outcome was 24 h intravenous (i.v.) morphine (or equivalent) consumption with a predefined minimal important difference (MID) of 5 mg. Secondary outcomes included pain at rest and during mobilisation (MID, VAS 10 mm), adverse and serious adverse events (SAEs).

DATA SOURCES

We searched EMBASE, Cochrane CENTRAL, PubMed and Google Scholar up to October 2021.

ELIGIBILITY CRITERIA

RCTs investigating peri-operative systemic glucocorticoid versus placebo or no intervention, for analgesic pain management of patients at least 18 years undergoing planned THA or TKA, irrespective of publication date and language.

RESULTS

We included 32 RCTs with 3521 patients. Nine trials were at a low risk of bias. Meta-analyses showed evidence of a reduction in 24 h cumulative morphine consumption with glucocorticoids by 5.0 mg (95% CI 2.2 to 7.7; P = 0.0004). Pain at rest was reduced at 6 h by 7.8 mm (95% CI 5.5 to 10.2; P < 0.00001), and at 24 h by 6.3 mm (95% CI 3.8 to 8.8; P < 0.00001). Pain during mobilisation was reduced at 6 h by 9.8 mm (95% CI 6.9 to 12.8; P < 0.00001), and at 24 h by 9.0 mm (95% CI 5.5 to 12.4, P < 0.00001). Incidence of adverse events was generally lower in the glucocorticoid treatment group. SAEs were rarely reported. The GRADE rated quality of evidence was low to very low.

CONCLUSION

Peri-operative systemic glucocorticoid treatment reduced postoperative morphine consumption to an individually relevant level following hip and knee arthroplasty. Pain levels were reduced but were below the predefined MID. The quality of evidence was generally low.

REGISTRATION

PROSPERO ID: CRD42019135034
Complementary system vs. conventional trifocal intraocular lens: comparison of optical-quality metrics and unwanted-light distribution
Authors: Naujokaitis Tadas , Auffarth Gerd U. , Khoramnia Ramin , Łabuz Grzegorz
Published: November 2022

Purpose:

To evaluate the ARTIS Symbiose complementary intraocular lens (IOL) system, consisting of the MID and PLUS models, in comparison with a conventional trifocal IOL (AcrySof IQ PanOptix).

Setting:

The David J. Apple Center for Vision Research, Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany.

Design:

Laboratory investigation.

Methods:

Modulation and phase transfer functions were obtained in polychromatic light using an optical bench setup. Simulated visual acuity (VA) values were derived from optical-quality metrics weighted by neural contrast sensitivity. United States Air Force (USAF) chart images were acquired and processed. Furthermore, the light distribution beyond the center of a polychromatic point spread function was assessed.

Results:

The peak simulated VA values of ARTIS Symbiose MID were at 0D of defocus (-0.02 logMAR) and at -1.5D (0.00 logMAR); of ARTIS Symbiose PLUS, they were at 0D of defocus (-0.01 logMAR) and at -2.5D (0.01 logMAR). AcrySof IQ PanOptix demonstrated three peaks: at 0D of defocus (-0.02 logMAR), at -1.75D (0.03 logMAR) and at -2.5D (0.02 logMAR). The summation of USAF chart images in the simulated binocular IOL system produced a slightly better image quality at -1.0D and -1.5D than AcrySof IQ PanOptix. The IOLs yielded comparable light spread across the studied range except for a localized intensity spike of the ARTIS Symbiose IOLs.

Conclusions:

The complementary IOL system may yield better monocular intermediate VA compared to the conventional trifocal IOL. However, the effect of binocular summation in terms of VA and the perception of photic phenomena still needs to be investigated.
Higher Rates of Head Contacts, Body Checking, and Suspected Injuries in Ringette Than Female Ice Hockey: Time to Ring in Opportunities for Prevention
Authors: Heming Emily E. , Sobry Alexandra J. , Cairo Alexis L. , Williamson Rylen A. , Kolstad Ash T. , West Stephen W. , Goulet Claude , Russell Kelly , Emery Carolyn A.
Published: November 2022

Objective:

Ringette and female ice hockey are high participation sports in Canada. Despite policies disallowing body checking, both sports have high injury and concussion rates. This study aimed to compare physical contact (PC), head contact (HC), and suspected injury and concussion incidence rates (IRs) in female varsity ringette and ice hockey.

Design:

Cross-sectional.

Setting:

Canadian ice arenas.

Participants:

Eighteen Canadian female university ringette and ice hockey tournament/playoff games in the 2018-2019/2019-2020 seasons.

Assessment of Risk Factors:

Game video-recordings were analyzed using Dartfish video-analysis software to compare both sports.

Main Outcome Measures:

Univariate Poisson regression analyses (adjusted for cluster by team, offset by game-minutes) were used to estimate PC, HC, and suspected injury IRs and incidence rate ratios (IRRs) to compare rates across sports. Proportions of body checks (level 4-5 trunk PC) and direct HC (HC1) penalized were reported.

Results:

Analyses of 36 team-games (n = 18 ringette, n = 18 hockey) revealed a 19% lower rate of PCs in ringette than ice hockey {IRR = 0.81 [95% confidence interval (CI), 0.73-0.90]}, but a 98% higher rate of body checking [IRR = 1.98 (95% CI, 1.27-3.09)] compared to ice hockey. Ringette had a 40% higher rate of all HC1s [IRR = 1.40 (95% CI, 1.00-1.96)] and a 3-fold higher rate of suspected injury [IRR = 3.11 (95% CI, 1.13-8.60)] than ice hockey. The proportion of penalized body checks and HC1s were low across sports.

Conclusions:

Body checking and HC1 rates were significantly higher in ringette compared to ice hockey, despite rules disallowing both, and very few were penalized. These findings will inform future injury prevention research in ringette and female ice hockey.
Outcomes of Venovenous Extracorporeal Membrane Oxygenation in Viral Acute Respiratory Distress Syndrome
Authors: Kazui Toshinobu , Hsu Chiu-Hsieh , Lick Scott D. , Hypes Cameron D. , Natt Bhupinder , Malo Joshua , Mosier Jarrod M. , Bull David A.
Published: November 2022

Our study assessed the relationship between the duration of venovenous extracorporeal membrane oxygenation (V-V ECMO) and patient outcomes. We studied patients undergoing V-V ECMO support for acute respiratory distress syndrome (ARDS) between 2009 and 2017 who were reported to the Extracorporeal Life Support Organization registry. We evaluated survival, major bleeding, renal failure, pulmonary complications, mechanical complications, neurologic complications, infection, and duration of V-V ECMO support. Multivariable regression modeling assessed risk factors for adverse events. Of the 4,636 patients studied, the mean support duration was 12.2 ± 13.7 days. There was a progressive increase in survival after the initiation of V-VECMO, peaking at a survival rate of 73% at 10 days of support. However, a single-day increase in V-V ECMO duration was associated with increased bleeding events (odds ratio [OR] 1.038; 95% confidence interval [CI]: 1.029–1.047; p < 0.0001), renal failure (OR 1.018; 95% CI: 1.010–1.027; p < 0.0001), mechanical complications (OR 1.065; 95% CI: 1.053–1.076; p < 0.0001), pulmonary complications (OR 1.04; 95% CI: 1.03–1.05; p < 0.0001), and infection (OR 1.04; 95% CI: 1.03–1.05; p < 0.0001). V-V ECMO progressively increases survival for ARDS over the first 10 days of support. Thereafter, rising complications associated with prolonged durations of support result in a progressive decline in survival.
Impact of prior coronary artery bypass grafting on periprocedural and short-term outcomes of patients undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis
Authors: Machanahalli Balakrishna Akshay , Ismayl Mahmoud , Palicherla Anirudh , Aboeata Ahmed , Goldsweig Andrew M. , Zhao David X. , Vallabhajosyula Saraschandra
Published: November 2022

Background

The effect of prior coronary artery bypass graft (CABG) on the outcomes of transcatheter aortic valve replacement (TAVR) remains incompletely characterized. In this meta-analysis, we investigated the impact of prior CABG on TAVR outcomes.

Methods

A systematic search was conducted in PubMed, Google Scholar, and Cochrane databases from inception to 24 July 2022, using the search terms ‘TAVR’, ‘CABG’, ‘peri-procedural complications’, and ‘mortality’. The major outcomes were peri-procedural complications, intraprocedural mortality, 30-day mortality, and 30-day cardiac mortality. We used random-effects models to aggregate data and to calculate pooled incidence and risk ratios with 95% confidence intervals (CIs).

Results

Among 116 results from the systematic search, a total of 8 studies (5952 patients) were included. Compared to patients without previous CABG, patients with prior CABG undergoing TAVR were younger, predominantly male sex, had more comorbidities, higher rates of peri-procedural myocardial infarction (MI) [relative risk (RR) 1.93; 95% CI, 1.09–3.43; P = 0.03], but lower rates of stroke (RR 0.71; 95% CI, 0.51–0.99; P = 0.04), major vascular complications (RR 0.70; 95% CI, 0.51–0.95; P = 0.02), and major bleeding (RR 0.70; 95% CI, 0.56–0.88; P = 0.002). There were no significant differences between the two cohorts in rates of pacemaker implantation, cardiac tamponade, acute kidney injury, intra-procedural mortality, 30-day mortality, and 30-day cardiac mortality.

Conclusion

Among patients undergoing TAVR, a history of prior CABG was not associated with an increased risk of periprocedural complications (except for acute MI) or short-term mortality compared to those without CABG.
Dual-Energy Computed Tomography–Derived Iodine Density and Spectral Attenuation Analysis for Differentiation of Inverted Papilloma and Sinonasal Squamous Cell Carcinoma/Lymphoma
Authors: Tunlayadechanont Padcha , Tritanon Oranan , Chansakul Thanissara , Pureepatipat Supaporn
Published: November 2022

Objective

This study aimed to assess the value of dual-energy computed tomography for differentiation of inverted papilloma from squamous cell carcinoma (SCC)/lymphoma.

Methods

Twenty-eight patients with pathologically diagnosed inverted papilloma or SCC/lymphoma underwent contrast-enhanced dual-energy computed tomography. Qualitative features (laterality, location, enhancement pattern, border, necrosis, hemorrhage, calcification, bone destruction, pterygopalatine fossa extension, adjacent invasion, and perineural spreading) and quantitative features (iodine density and spectral attenuation curve slope) were analyzed. Optimal cutoff thresholds of diagnostic efficacy were generated.

Results

Fifteen patients had inverted papilloma, and 13 had malignancy (5 SCC and 8 lymphoma). Computed tomography findings of bilateral lesions, sphenoid sinus involvement, pterygopalatine fossa extension, and adjacent invasion were significantly associated with SCC/lymphoma. The iodine density was significantly higher in SCC/lymphoma (2.46 ± 0.22 mg/mL) than in inverted papilloma (1.42 ± 0.46 mg/mL; P = 0.001). An iodine density threshold of 1.74 mg/mL had a sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 92.3%, 86.7%, 92.9%, 85.7%, and 90.3%, respectively. The spectral attenuation curve slope was significantly higher in SCC/lymphoma (4.35 ± 0.27 HU/keV) than in inverted papilloma (2.72 ± 0.88 HU/keV; P = 0.001). A spectral attenuation curve slope threshold of 3.34 HU/keV had a sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 92.3%, 86.7%, 92.9%, 85.7%, and 90.8%, respectively.

Conclusions

Squamous cell carcinoma/lymphoma had a significantly higher iodine density and spectral attenuation curve slope than inverted papilloma. Using optimal quantitative measurement thresholds provides high diagnostic efficacy.
A Mixed-Methods Systematic Review on Syndemics in Rheumatology
Authors: Ramírez-Flores María F. , Cadena-Trejo Cinthya , Motte-García Emilio , Juárez-Cruz Isaac D. , Fernandez-García Maria V. , Gastelum-Strozzi Alfonso , Alpizar-Rodriguez Deshire , Hernandez-Garduño Adolfo , Peláez-Ballestas Ingris
Published: November 2022

A syndemic framework assesses the multidimensionality of the interrelationships of diseases and their circumstances. This approach has given important insights into other nonrheumatic diseases.

Objective

We aimed to assess the use of framework and corresponding methodology to document syndemics and its impact in rheumatic and musculoskeletal diseases (RMDs).

Methods

Using a mixed-methods systematic review, studies using the syndemic framework approach for RMDs were identified and published from January 2003 to January 2021. The Joanna Briggs Institute, Cochrane Collaboration, and PRISMA guidelines were followed to search, retrieve, revise, and analyze.

Results

A total of 658 potential articles were identified, but only 10 were initially eligible. After a full-text review, 4 were included. Following a full-text review, 2 quantitative, 1 qualitative, and 1 mixed-methods study were included. In the first, network analysis found that RMDs were associated with comorbidities, unhealthy habits, low educational level, living in rural areas, socioeconomic conditions, and health inequality in indigenous communities. In the second, SSEM and cluster analysis demonstrated an association between low back pain and factors, such as comorbidities and indigenous status, among others, in urban/rural communities. The qualitative study examined 3 fishing family generations and reported less syndemic vulnerability. The mixed-methods study focused on osteoarthritis with multimorbidities in African American population, where lack of education added to worsening outcomes.

Conclusions

Even though the insights syndemic studies have given to other areas, its use in rheumatology is scarce. The complexity of the clinical and social determinants related to RMDs makes it necessary to conduct further studies from a syndemic perspective.
Lateral Suspension Technique in Treatment of Lateral Crus Malposition Belada Technique
Authors: Belada Abdullah , Akcan Fatih Alper
Published: November 2022

Lateral crus malposition can cause health problems from both functional and esthetic perspectives. Recently many techniques are developed to solve this problem. One of the failures that can be seen in these surgical techniques is that the lateral crus placed in its new position is shifted to the cephalic and is dislocated. Our aim in this study is to introduce the technique authors developed to prevent complications. 16 patients (10 female and 6 male) with a lateral crus malposition during rhinoplasty surgery were included in the study to have a reposition. The suture placed on the caudal end of the lateral crural strut graft attached to the lateral crus, which authors freed from the vestibule skin for repositioning in our patients operated with an open technique, is fixed by taking it out from the skin through the newly created pocket. The lateral crus, which was fixed with a suture in its new pocket, did not dislocate, did not shift to cephalic and no infection developed in any of our patients. In 1 of our patients, a second surgery was planned because the inserted lateral crural strut graft caused a narrowing in the nasal cavity.
Antithrombin, protein C and protein S: Genome and transcriptome wide association studies identify 7 novel loci regulating plasma levels
Authors: Ji Yuekai , Temprano-Sagrera Gerard , Holle Lori A , Bebo Allison , Brody Jennifer , Le Ngoc-Quynh , Brown Michael R , Martinez-Perez Angel , Sitlani Colleen M , Suchon Pierre , Kleber Marcus E , Emmert David B , Ozel Ayse Bilge , A Dobson Dre’Von , Tang Weihong , Llobet Dolors , Tracy Russell P , Deleuze Jean-François , Delgado Graciela E , Gögele Martin , Wiggins Kerri L , Souto Juan Carlos , Pankow James S , Taylor Kent D , Trégouët David-Alexandre , Moissl Angela P , Fuchsberger Christian , Rosendaal Frits R , Morrison Alanna C , Soria Jose Manuel , Cushman Mary , Morange Pierre-Emmanuel , März Winfried , Hicks Andrew A , Desch Karl C , Johnson Andrew D , de Vries Paul S ,   CHARGE Consortium Hemostasis Working Group,   INVENT Consortium, Wolberg Alisa S , Smith Nicholas L , Sabater-Lleal Maria
Published: November 2022

Objective

Antithrombin, protein C (PC) and protein S (PS) are circulating natural-anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies (GWAS) of plasma levels of antithrombin, PC, PS free and PS total.

Approach and Results

Study participants were of European and African ancestries and genotype data were imputed to TOPMed, a dense multi-ancestry reference panel. Each of 10 studies conducted a GWAS for each phenotype and summary results were meta-analyzed, stratified by ancestry. We also conducted transcriptome-wide association analyses and multi-phenotype analysis to discover additional associations. Novel GWAS findings were validated byin vitrofunctional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes.

GWAS meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, andHP-TXNL4B) and 1 with PS levels (ORM1-ORM2). TWAS identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement ofGCKR, SNX17, andHPgenes in antithrombin regulation.

Conclusion

The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.
Multimodal profiling of term human decidua reveals tissue-specific immune adaptations with maternal obesity
Authors: Sureshchandra Suhas , Doratt Brianna M. , Mendoza Norma , Rincon Monica , Marshall Nicole E. , Messaoudi Ilhem
Published: November 2022

The leukocyte diversity of early maternal-fetal interface has been recently described, however, characterization of decidua at term is still pending. We, therefore, profiled the CD45+ compartment within human term decidua collected via cesarean section. Relative to the first trimester, our analyses revealed a shift from NK cells and macrophages to T-cells and enhanced activation of all immune cells. T-cells in the decidua were phenotypically distinct from their blood counterparts and demonstrated significant clonotype sharing. Using pseudo-temporal analyses of macrophages, we characterize previously undescribed diversity of bonafide tissue resident decidual macrophages. The frequency of this population correlated with high pregravid maternal body mass index but responded poorly to bacteria ligands. Collectively, these findings provide evidence of skewing of decidual myeloid cells towards immunoregulation representing a possible mechanism to safeguard the fetus. This immune cell atlas of term decidua is an asset for future studies investigating pathological conditions that compromise reproductive success.

One sentence summary

Human immune cell atlas of term decidua and observed alterations with pre-gravid obesity.
Multilevel human secondary lymphoid immune system compartmentalization revealed by complementary multiplexing and mass spectrometry imaging approaches
Authors: Oyler Benjamin L. , Valencia-Dávila Jeferson A. , Moysi Eirini , Molyvdas Adam , Ioannidou Kalliopi , March Kylie , Ambrozak David , de Leval Laurence , Fabozzi Giulia , Woods Amina S. , Koup Richard A. , Petrovas Constantinos
Published: November 2022

Secondary human lymphoid tissue immune reactions take place in a highly coordinated environment with compartmentalization representing a fundamental feature of this organization.In situprofiling methodologies are indispensable for the understanding of this compartmentalization. Here, we propose a complementary experimental approach aiming to reveal different aspects of this process. The analysis of human tonsils, using a combination of single cell phenotypic analysis based on flow cytometry and multiplex imaging and mass spectrometry-based methodologies, revealed a compartmentalized organization at cellular and molecular level. More specifically, the skewed distribution of highly specialized immune cell subsets and relevant soluble mediators was accompanied by a compartmentalized localization of several lipids across different anatomical areas of the tonsillar tissue. The performance of such combinatorial experimental approaches could lead to the identification of novelin situinteractions and molecular targets for thein vivomanipulation of lymphoid organ, particularly the germinal center, immune reactions.
Comparing the effects of host species richness on different metrics of disease
Authors: Cortez Michael H.
Published: November 2022

Changes in host species richness can alter infection risk and disease levels in communities. I review theoretical predictions for direct and environmental transmission pathogens about the effects of host additions (or removals) on three common disease metrics: the pathogen community reproduction number (ℛ0) and the proportion (i.e., infection prevalence) and density of infected individuals in a focal host. To help explain why predictions differ between studies and between metrics, I analyze an SIR-type model of an environmentally transmitted pathogen and multiple host species that compete for resources. I use local sensitivity analysis to explore and compare how variation in an added host’s ability to transmit a pathogen, its density, and the pathogen transmission mechanism affect each disease metric. I find that if an added host species is a weak interspecific competitor, then each metric typically increases or decreases, respectively, when the added host has a high or low ability to transmit the pathogen. However, if the added host species is a strong interspecific competitor, then the response of each metric can be strengthened, weakened, or reversed depending on how the competitive effects of the added host propagate through the community and alter the densities of all host species in the community. The three metrics often respond in the same direction, but the metrics can respond in different directions for three reasons: (1) strong density-mediated feedbacks driven by high disease-induced mortality; (2) host additions or removals cause large changes in focal host density via competition or disease-induced mortality; and (3) the metrics use different quantities to define a host’s ability to transmit disease: the quantities for infection prevalence and infected density depend on the instantaneous production rates of infectious propagules whereas the quantities for ℛ0depend on lifetime production of infectious propagules. This study provides a framework that unifies prior theoretical studies and identifies rules governing the context-dependent relationships between host species richness and the three metrics of disease.
Dynamic growth re-orientation orchestrates flatness in the Arabidopsis leaf
Authors: Harline Kate , Fruleux Antoine , Lane Brendan , Mosca Gabriella , Strauss Soeren , Tavakolian Nik , Satterlee James W. , Li Chun-Biu , Singh Abhyudai , Smith Richard S. , Boudaoud Arezki , Roeder Adrienne H.K.
Published: November 2022

The growth and division of cells in plant leaves is highly dynamic in time and space, all while the cells cannot move relative to their neighbors. Given these constraints, models predict that long range regulatory systems must exist to maintain flat forms. Juxtaposed microRNA (miR-NA) networks could serve as one of these regulatory systems. One of these miRNAs, miR319 is thought to be expressed from the base of leaves and to promote growth by degrading class II TCP transcription factor mRNAs. A miR319 overexpression mutant,jagged and wavy(jaw-D) exhibits rippling and undulating leaves, consistent with biomechanical predictions that without genetic spatial coordination, tissues will deform. It has been theorized thatjaw-Drippling results from overgrowth at the margins, however this does not fully address how miR319 expression from the base of wild-type (WT) leaves allows them to flatten. Here, we track the growth, cell division and cell maturation in live WT andjaw-Dleaves to ask how miR319 expression in WT promotes flattening. This data revealed the importance of spatially distinct growth, division and differentiation patterns in WT leaves, which are missing injaw-D.We propose that WT leaf cells respond to differentiation cues to dynamically re-orient growth in specific tissue locations and regulate flattening.
Racial/ethnic differences in pre-pregnancy conditions and adverse maternal outcomes in the nuMoM2b cohort: a population-based cohort study
Authors: Meredith Meghan E. , Steimle Lauren N. , Stanhope Kaitlyn K. , Platner Marissa H. , Boulet Sheree L.
Published: November 2022

Objective

To: (1) determine how pre-existing conditions contribute to racial disparities in adverse maternal outcomes; and (2) incorporate these conditions into models to improve risk prediction for racial minority subgroups.

Design

Secondary data analysis of a population-based cohort study.

Setting

Academic healthcare institutions in the United States.

Population

A cohort of 8,729 women included in the “Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b)”.

Methods

Poisson regression to estimate adjusted risk ratios, and mediation analysis to evaluate the contribution of multimorbidity to racial/ethnic disparities. Area under the receiver operating characteristic curve (AUC) to evaluate model performance.

Main Outcome Measures

Incidence of severe preeclampsia, postpartum readmission, and blood transfusion.

Results

In the nuMoM2b cohort (n=8729), accounting for pre-existing conditions attenuated the association between non-Hispanic Black race/ethnicity and risk of severe preeclampsia. Cardiovascular and kidney conditions were associated with risk for severe preeclampsia among all women (aRR, 1.77; CI, 1.61-1.96, and aRR, 1.27; CI, 1.03-1.56 respectively). The mediation analysis results were not statistically significant; however, cardiovascular conditions explained 36.6% of the association between severe preeclampsia and non-Hispanic Black race/ethnicity (p=0.07). The addition of pre-pregnancy conditions increased model performance for the prediction of blood transfusion and severe preeclampsia.

Conclusions

Pre-existing conditions may explain some of the association between severe preeclampsia and non-Hispanic Black race/ethnicity. Specific pre-pregnancy conditions were associated with adverse maternal outcomes and the incorporation of comorbidities improved the performance of most risk prediction models.

Funding

Research reported in this publication was supported in part by Imagine, Innovate and Impact (I3) from the Emory School of Medicine, Georgia Tech, and through the Georgia CTSA NIH award (UL1-TR002378) and by the National Science Foundation under grant number DGE-2039655 (Meredith); any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation.
Racial disparities in nephrectomy and mortality among patients with renal cell carcinoma: Findings from SEER
Authors: Ikuemonisan Joshua , Aremu Taiwo Opeyemi , Oyejinmi Isaac , Ajala Christopher , Anikpezie Nnabuchi , Akinso Oyindamola , Mtengwa Mutsa , David Adeyemo , Olokede Olugbenga , Adejoro Oluwakayode
Published: November 2022

Purpose

To assess racial differences in the receipt of nephrectomy in patients diagnosed RCC in the US.

Materials and Methods

2005 to 2015 data from the SEER database was analyzed and 70059 patients with RCC were identified. We compared demographic and tumor characteristics between Blacks and Whites. We applied logistic regression to assess the influence of race on the odds of the receipt of nephrectomy. We also applied Cox proportional hazards model to assess the impact of race on cancer-specific mortality (CSM) and all-cause mortality (ACM) in patients diagnosed with RCC in the US.

Results

Overall, there was a relative increase in the use of nephrectomy from 2007 (p<0.0001). However, Blacks had 18% lower odds of receiving nephrectomy compared to Whites (p < 0.0001). The odds of the receipt of nephrectomy also reduced with age at diagnosis. In addition, patients with T3 stage had the greatest odds of receiving nephrectomy when compared to T1 (p < 0.0001). There was no difference in the risk of cancer-specific mortality between Blacks and Whites, Blacks had 27% greater odds of all-cause mortality than Whites (p < 0.0001). Patients who did not receive nephrectomy had a 42% and 35% higher risk of CSM and ACM respectively, when compared to patients who received nephrectomy.

Conclusions

Blacks diagnosed with RCC in the US have a greater ACM risk and are less likely than Whites to receive nephrectomy. Systemic changes are needed to eliminate racial disparity in the treatment and outcomes of RCC in the US.
A Fast Solution for Automated Single-Molecule Force Spectroscopy Data Collection and Processing
Authors: Xu Shuai , Kang Yafeng , Liu Zhiqiang , Shi Hang
Published: November 2022

Force spectroscopy is a sophisticated technology for studying the physical chemistry of polymers at the single-molecule level. Its implication in biomolecules, e.g., proteins, DNA or RNA, yielded tremendous information on their structures, folding, and functions. In a routine procedure, an experimenter pulls the molecule of interest to generate the force-extension (FE) curve using technologies that include atomic force microscopy (AFM), magnetic force spectroscopy (MFS), optical tweezer and acoustic force spectroscopy (AFS), then extract parameters characteristic to the polymer. The latter step requires fitting the FE curve with mathematical models. Although several models have been widely applied for over 20 years, the fitting of the experimental data was not as straightforward. This step can be time-consuming, prone to mistakes, and sometimes cause debate. To lower the technical barriers for users and to reduce the time consumption and errors involved in force spectroscopy data processing, we optimized the fitting procedure for three classical worm-like chain (WLC) models into an automated software package named Single Molecule Force Spectroscopy Toolkit (SMFST). Our MATLAB-based software with a graphical user interface demonstrated robust fitting for three models in a wide range of forces and provided convenient tools for batch data processing to meet future requirements of high-throughput data collection.
Using evolutionary constraint to define novel candidate driver genes in medulloblastoma
Authors: Roy Ananya , Sakthikumar Sharadha , Kozyrev Sergey V. , Nordin Jessika , Pensch Raphaela , Pettersson Mats ,   Zoonomia Consortium, Karlsson Elinor , Lindblad-Toh Kerstin , Forsberg-Nilsson Karin
Published: November 2022

Current knowledge of cancer genomics is biased against non-coding mutations. Here, we use whole genome sequencing data from pediatric brain tumors, combined with evolutionary constraint inferred from 240 mammals to identify genes enriched in non-coding constraint mutations (NCCMs). We compare medulloblastoma (MB, malignant) to pilocytic astrocytoma (PA, benign) and find drastically different NCCM frequencies between the two. In PA, a high NCCM frequency only affects theBRAFlocus, while in MB, >500 genes have high levels of NCCMs. Intriguingly, many genes are associated with different age of onset, such asHOXB1in young patients andNUAK1in adult patients. Our analysis points to different molecular pathways in different patient groups. These novel candidate driver genes may assist patient stratification in MB and may be useful for treatment options.

One-Sentence Summary

Non-coding constraint mutations implicate novel candidate genes to stratify medulloblastoma by age and subgroups.
Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B
Authors: Mehlman Tamar (Skaist) , Biel Justin T. , Azeem Syeda Maryam , Nelson Elliot R. , Hossain Sakib , Dunnett Louise E. , Paterson Neil G. , Douangamath Alice , Talon Romain , Axford Danny , Orins Helen , von Delft Frank , Keedy Daniel A.
Published: November 2022

Much of our current understanding of how small-molecule ligands interact with proteins stems from X-ray crystal structures determined at cryogenic (cryo) temperature. For proteins alone, room-temperature (RT) crystallography can reveal previously hidden, biologically relevant alternate conformations. However, less is understood about how RT crystallography may impact the conformational landscapes of protein-ligand complexes. Previously we showed that small-molecule fragments cluster in putative allosteric sites using a cryo crystallographic screen of the therapeutic target PTP1B (Keedy*, Hill*, 2018). Here we have performed two RT crystallographic screens of PTP1B using many of the same fragments, representing the largest RT crystallographic screens of a diverse library of ligands to date, and enabling a direct interrogation of the effect of data collection temperature on protein-ligand interactions. We show that at RT, fewer ligands bind, and often more weakly -- but with a variety of temperature-dependent differences, including unique binding poses, changes in solvation, new binding sites, and distinct protein allosteric conformational responses. Overall, this work suggests that the vast body of existing cryogenic-temperature protein-ligand structures may provide an incomplete picture, and highlights the potential of RT crystallography to help complete this picture by revealing distinct conformational modes of protein-ligand systems. Our results may inspire future use of RT crystallography to interrogate the roles of protein-ligand conformational ensembles in biological function.
The biophysical nature and not only the size of protein aggregates determines the strength of the immune response against dengue ED3
Authors: Kibria Md. Golam , Shiwaku Yukari , Brindha Subbaian , Kuroda Yutaka
Published: November 2022

Here we used domain 3 of dengue virus serotype 3 envelope protein (D3ED3), a natively folded globular low-immunogenicity protein, to ask whether the biophysical nature of amorphous aggregates can affect immunogenicity. We prepared amorphous oligomers in five distinct ways. One oligomer type was produced using our SCP tag (Solubility Controlling Peptide) made of 5 Isoleucines (C5I). The others were prepared by miss-shuffling the SS bonds (Ms), heating (Ht), stirring (St), and freeze-thaw (FT). Dynamic light scattering showed that all five formulations contained oligomers of approximately identical sizes with hydrodynamic radii (Rh) between 30 and 55 nm. Circular dichroism (cd) indicated that the secondary structure content of oligomers formed by stirring and freeze-thaw was essentially identical to that of the native monomeric D3ED3. The secondary structure content of the Ms showed moderate changes, whereas the C5I and heat-induced (Ht) oligomers exhibited a significant change. Immunization in JcL:ICR mice showed that both C5I and Ms significantly increased the anti-D3ED3 IgG titer. Ht, St, and FT were barely immunogenic, similar to the monomeric D3ED3. Cell surface CD marker analysis by flow cytometry confirmed that immunization with Ms generated a strong central and effector T-cell memory. This result adds a new dimension to earlier studies where the strength of the immune response was associated solely with the presence and sizes of the oligomers. It also suggests that controlled oligomerization can provide a new, adjuvant-free method for increasing a protein’s immunogenicity, yielding a potentially powerful platform for protein-based vaccines.

Significance

Protein aggregation is suspected to increase the immunogenicity of proteins. Here we show that the strength of the immune response depends not merely on the size of the oligomers/aggregates but also on their biophysical properties. Dengue virus 3 envelop protein domain 3 (D3ED3) was oligomerized/aggregated in five different ways. All five formulations contained oligomers with hydrodynamic radii between 30 and 55 nm. Two formulations, where D3 ED3 was natively folded, were not or poorly immunogenic. On the other hand, two others, where D3ED 3 was in a molten globule-like state, were strongly immunogenic. This result adds a new dimension to earlier studies where the strength of the immune response was associated solely with the presence and sizes of the oligomers.
G protein-biased LPAR1 agonism promotes prototypic antidepressant effects
Authors: Kajitani Naoto , Okada-Tsuchioka Mami , Inoue Asuka , Miyano Kanako , Masuda Takeshi , Boku Shuken , Iwamoto Kazuya , Ohtsuki Sumio , Uezono Yasuhito , Aoki Junken , Takebayashi Minoru
Published: November 2022

Prototypic antidepressants, such as tricyclic/tetracyclic antidepressants (TCAs), have multiple pharmacological properties and have been considered to be more effective than newer antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), in treating severe depression. However, the molecular mechanisms underlying the high efficacy of TCAs have not been completely understood. Herein, we found that lysophosphatidic acid receptor 1 (LPAR1), a G protein-coupled receptor, mediates the antidepressant effects of amitriptyline, a typical TCA. Amitriptyline directly bound to LPAR1 and activated downstream G protein signaling without affecting β-arrestin signaling, which implied that amitriptyline could act as a G protein-biased agonist of LPAR1. This biased agonism is unique to TCAs and has not been observed in other antidepressants, such as SSRIs. Long-term infusion of mouse hippocampus with 1-oleoyl-2-O-methyl-glycerophosphothionate (OMPT), a potent G protein-biased LPAR1 agonist, induced behavior similar to that induced by antidepressants. In contrast, LPA, a non-biased agonist of LPAR1, induced anxious behavior, indicating that LPAR1 may regulate conflicting emotional behaviors because of the downstream signaling bias. Furthermore, RNA-seq analysis revealed that LPA and OMPT have opposite patterns of gene expression changes in hippocampus. Ingenuity pathway analysis indicated that chronic intrahippocampal administration of OMPT could activate LPAR1 downstream signaling (Rho and MAPK), whereas LPA suppressed LPAR1 signaling. The results reveal the unique antidepressant effects of TCAs and indicate the potential of G protein-biased agonists of LPAR1 as targets for novel antidepressants.
Molecular determinants of fibrillation in a viral amyloidogenic domain from combined biochemical and biophysical studies
Authors: Nilsson Juliet F. , Baroudi Hakima , Gondelaud Frank , Pesce Giulia , Bignon Christophe , Ptchelkine Denis , Chamieh Joseph , Cottet Hervé , Kajava Andrey V. , Longhi Sonia
Published: November 2022

The Nipah and Hendra viruses (NiV and HeV)are biosafety level 4 human pathogens classified within theHenipavirusgenus of theParamyxoviridaefamily. In both NiV and HeV, the gene encoding the Phosphoprotein (P protein), an essential polymerase cofactor, also encodes the V and W proteins. These three proteins, which share an intrinsically disordered N-terminal domain (NTD) and have unique C-terminal domains (CTD), are all known to counteract the host innate immune response, with V and W acting by either counteracting or inhibiting Interferon (IFN) signaling. Recently, using a combination of biophysical and structural approaches, the ability of a short region within the shared NTD (PNT3 region) to form amyloid-like structures was reported. Here, we evaluated the relevance of each of three contiguous tyrosine residues located in a previously identified amyloidogenic motif (EYYY) within HeV PNT3 to the fibrillation process. Our results indicate that removal of a single tyrosine in this motif significantly decreases the ability to form fibrils independently of position, mainly affecting the elongation phase. In addition, we show that the C-terminal half of PNT3 has an inhibitory effect on fibril formation that may act as a molecular shield and could thus be a key domain in the regulation of PNT3 fibrillation. Finally, the kinetics of fibril formation for the two PNT3 variants with highest and lowest fibrillation propensity were studied by Taylor Dispersion Analysis (TDA). The results herein presented shed light onto the molecular mechanisms involved in fibril formation. In addition, the PNT3 variants we generated represent valuable tools to further explore the functional impact of V/W fibrillation in transfected and infected cells.
Adipose triglyceride lipase is regulated by CAMKK2-AMPK signaling and drives advanced prostate cancer
Authors: Awad Dominik , Pulliam Thomas L. , Spradlin Meredith , Cao Pham Hong-Anh , Subramani Elavarasan , Tellman Tristen V. , Ribeiro Caroline F. , Pakula Hubert , Ackroyd Jeffrey J. , Murray Mollianne M. , Han Jenny J. , Piyarathna Badrajee , Drake Justin M. , Ittmann Michael M. , Coarfa Cristian , Farach-Carson Mary C. , Loda Massimo , Eberlin Livia S. , Frigo Daniel E.
Published: November 2022

Lipid metabolism plays a central role in prostate cancer. To date, the major focus on prostate cancer lipid metabolism has centered onde novolipogenesis and lipid uptake with little consideration for how cancer cells access these lipids once they are created or taken up and stored. Patient-derived phosphoproteomics identified adipose triglyceride lipase (ATGL), a previously suspected tumor suppressor, as a CAMKK2-AMPK signaling target that, conversely, promotes castration-resistant prostate cancer (CRPC) progression. Phosphorylation of ATGL increased its lipase activity, cancer cell proliferation, migration, and invasion. Shotgun lipidomics and mass spectrometry imaging demonstrated ATGL’s profound regulation of lipid metabolismin vitroandin vivo, remodeling membrane composition. Inhibition of ATGL induced metabolic plasticity, causing a glycolytic shift that could be exploited therapeutically by co-targeting both metabolic pathways. Together, these data nominate ATGL and intracellular lipolysis as potential therapeutic targets for the treatment of CRPC and provide insights for future combination therapies.
Triggered Release from Thermosensitive Liposomes Improves Tumor Targeting of Vinorelbine
Authors: Regenold Maximilian , Kaneko Kan , Wang Xuehan , Peng H. Benson , Evans James C. , Bannigan Pauric , Allen Christine
Published: November 2022

Triggered drug delivery strategies have been shown to enhance drug accumulation at target diseased sites in comparison to administration of free drug. In particular, many studies have demonstrated improved targetability of chemotherapeutics when delivered via thermosensitive liposomes. However, most studies continue to focus on encapsulating doxorubicin while many other drugs would benefit from this targeted and localized delivery approach. The proposed study explores the therapeutic potential of a thermosensitive liposome formulation of the commonly used chemotherapy drug vinorelbine in combination with mild hyperthermia (39-43 °C) in a murine model of rhabdomyosarcoma. Rhabdomyosarcoma, the most common soft tissue sarcoma in children, is largely treated using conventional chemotherapy which is associated with significant adverse long-term sequelae. In this study, mild hyperthermia was pursued as a non-invasive, non-toxic means to improve the efficacy and safety profiles of vinorelbine. Thorough assessment of the pharmacokinetics, biodistribution, efficacy and toxicity of vinorelbine administered in the thermosensitive liposome formulation was compared to administration in a traditional, non-thermosensitive liposome formulation. This study shows the potential of an advanced formulation technology in combination with mild hyperthermia as a means to target an untargeted therapeutic agent and result in a significant improvement in its therapeutic index.

Graphical abstract
X-ray diffraction and Mössbauer spectroscopy study of oxoborate azoproite (Mg,Fe2+)2(Fe3+,Ti,Mg,Al)O2(BO3): an in situ temperature-dependent investigation (5 ≤ T ≤ 1650 K)
Authors: Biryukov Yaroslav P. , Zinnatullin Almaz L. , Levashova Irina O. , Shablinskii Andrey P. , Cherosov Mikhail A. , Bubnova Rimma S. , Vagizov Farit G. , Krzhizhanovskaya Maria G. , Filatov Stanislav K. , Shilovskikh Vladimir V. , Pekov Igor V.
Published: November 2022

This work is devoted to an investigation of elemental composition, crystal structure and thermal expansion of natural oxoborate azoproite from the Tazheran massif (Siberia, Russia) in the temperature range 5–1650 K. Elemental composition was determined by energy-dispersive X-ray spectroscopy (EDX). Its empirical formula based on five oxygen atoms is (Mg1.81Fe2+
0.19)∑2.00(Fe3+
0.36Ti0.26Mg0.26Al0.12)∑1.00O2(BO3). Local environment, oxidation states and ratio of Fe atoms are determined using Mössbauer spectroscopy and compared with EDX and single-crystal X-ray diffraction (SCXRD) data. A refinement of the crystal structure from SCXRD data collected at 293 K was provided for the first time. The structure could be described both in terms of cation- and anion-centered polyhedra. It is composed of vertex- and edge-sharing metal–oxygen [MO6]
n

− octahedra that form extended zigzag chains along the a axis building up a framework with the [BO3]3− triangles located in its distorted trigonal channels. From the other point of view, there are double chains consisting of oxocentred [OM
4]
n

+ tetrahedra and [OM
5]
n

+ tetragonal pyramids forming six-membered rings with the triangles in its cavities. Four non-equivalent Mn

+ sites are occupied by cations as follows: M(1) (2a) and M(2) (2d) – Mg, M(3) (4g) – Mg and Fe2+, M(4) (4h) – Fe3+, Ti4+, Mg and Al3+. According to differential scanning calorimetry, low- and high-temperature powder X-ray diffraction (LT- and HT-XRD) data, Mössbauer spectroscopy and magnetometry data (5 ≤ T ≤ 1650 K), there are no phase transitions obtained in the temperature range investigated. However, some anomalies in temperature dependencies of unit-cell parameters caused by a partial Fe2+ → Fe3+ oxidation are found in the range 873–1173 K. Azoproite melts at a temperature higher than 1600 K. Eigenvalues of the thermal expansion tensor are calculated for the oxoborate and thermal expansion is described in comparison with its crystal structure.
Determination of the superlattice structure factor by X-ray diffraction using a temperature gradient
Authors: Levonyan Levon , Manukyan Hasmik
Published: November 2022

The influence of a temperature gradient directed perpendicular to the crystal surface on the diffraction focusing of a spherical X-ray wave in a superlattice is studied for the Laue geometry. It is shown that different satellites can be focused on the exit surface of the crystal by a smooth change in the gradient value, which can become the basis for the experimental determination of the structure factor of the superlattice.