bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-dsDNA IgE induces IL-4 production from basophils, potentially involved in B-cell differentiation in systemic lupus erythematosus
Authors: Fujimoto Sho , Arinobu Yojiro , Miyawaki Kohta , Ayano Masahiro , Mitoma Hiroki , Kimoto Yasutaka , Ono Nobuyuki , Akashi Koichi , Horiuchi Takahiko , Niiro Hiroaki
Published: February 2023

Objectives

Recently, the involvement of basophils and IgE-type autoantibodies in the pathogenesis of SLE has been elucidated using mouse models; however, few studies have been conducted in humans. In this study, the role of basophils and anti-double-stranded DNA (dsDNA) IgE in SLE was examined using human samples.

Methods

The correlation between disease activity and serum levels of anti-dsDNA IgE in SLE was evaluated using enzyme-linked immunosorbent assay. Cytokines produced by IgE-stimulated basophils from healthy subjects were assessed using RNA sequences. The interaction of basophils and B cells to promote B cell differentiation was investigated using a co-culture system. The ability of basophils from patients with SLE with anti-dsDNA IgE to create cytokines that may be involved in B cell differentiation in response to dsDNA was examined using real-time PCR.

Results

Anti-dsDNA IgE levels in the serum of patients with SLE correlated with disease activity. Healthy donor basophils produced IL-3, IL-4 and TGF-β1 after anti-IgE stimulation. Co-culture of B cells with anti-IgE-stimulated basophils increased plasmablasts which were cancelled by neutralizing IL-4. After encountering the antigen, basophils released IL-4 more quickly than follicular helper T cells. Basophils isolated from patients with anti-dsDNA IgE promoted IL-4 expression by adding dsDNA.

Conclusions

These results suggest that basophils contribute to the pathogenesis of SLE by promoting B cell differentiation via dsDNA-specific IgE in patients similar to the process described in mouse models.
DETERMINATION OF RADON ACTIVITY CONCENTRATIONS IN SOME WELL WATERS NEAR THE AKŞEHIR-SIMAV FAULT SYSTEM AND ESTIMATION OF MEAN ANNUAL EFFECTIVE DOSES
Authors: Sandıkcıoğlu Gümüş Ayla
Published: February 2023

Radon concentrations were measured in four-well and spring water, which is used as drinking water, in the villages and districts of Afyonkarahisar province near Akşehir-Simav fault system for 24 month period, and the annual average effective dose amounts were calculated. In addition, the relationship between the average radon concentration results of potable water wells and the distance of the wells to the fault was examined for the first time in this region. Mean radon concentrations were measured between 1.9 ± 0.3 and 11.9 ± 0.5 Bql−1. The annual effective dose values were calculated between 11 ± 1.7 and 70.1 ± 2.8 μSvy−1 for infants, 4.0 ± 0.6 and 25.7 ± 1.0 μSvy−1 for children and 4.8 ± 0.7 and 30.5 ± 1.2 μSvy−1 for adults. In addition, the effect of the distance of the wells from the fault on the mean radon concentrations was also investigated. The regression coefficient (R2) was calculated as 0.85. The average radon concentration was observed higher in the water wells close to the fault. The highest mean radon concentration was measured in well no. 4, closest to the fault and 1.07 km away.
Seroprevalence of hepatitis E virus after pediatric liver transplantation
Authors: Getsuwan Songpon , Pasomsub Ekawat , Yutthanakarnwikom Pichet , Tongsook Chutatip , Butsriphum Napapat , Tanpowpong Pornthep , Janchompoo Pareena , Treepongkaruna Suporn , Lertudomphonwanit Chatmanee
Published: February 2023

Background

Southeast Asia is the endemic area of hepatitis E virus (HEV) infection. We aimed to determine the seroprevalence of the virus, its association, and the prevalence of chronic infection after pediatric liver transplantation (LT).

Methods

A cross-sectional study was performed in Bangkok, Thailand. Patients aged <18 years who had LT for >2 years underwent serologic and real-time polymerase chain reaction (rt-PCR) tests. Acute HEV infection was defined by the presence of positive anti-HEV immunoglobulin (Ig)M and HEV viremia from the rt-PCR. If the viremia persisted for >6 months, chronic HEV infection was diagnosed.

Results

A total of 101 patients had a median age of 8.4 years [interqartile range (IQR): 5.8–11.7]. The seroprevalence of anti-HEV IgG and IgM was 15% and 4%, respectively. Positive IgM and/or IgG were associated with a history of elevated transaminases with an unknown cause after LT (p = 0.04 and p = 0.01, respectively). The presence of HEV IgM was associated with a history of elevated transaminases with an unknown cause within 6 months (p = 0.01). The two patients (2%) diagnosed with chronic HEV infection did not fully respond to the reduction of immunosuppression but responded well to ribavirin treatment.

Conclusions

Seroprevalence of HEV among pediatric LT recipients was not rare in Southeast Asia. Since HEV seropositivity was associated with elevated transaminases of an unknown cause, investigation for the virus should be offered in LT children with hepatitis after excluding other etiologies. Pediatric LT recipients with chronic HEV infection may receive a benefit from a specific antiviral treatment.
Sharps Injuries Among Medical Trainees and Attending Physicians
Authors: Kasteler Stephen D. , Reid Michelle , Lee Peter C. , Sparer-Fine Emily , Laramie Angela K.
Published: February 2023

Purpose

Sharps injuries are a particularly concerning occupational hazard faced by physicians and are largely preventable. This study compared the proportion and rate of sharps injuries among medical trainees with those among attending physicians by sharps injury characteristics.

Method

The authors used data reported to the Massachusetts Sharps Injury Surveillance System from 2002–2018. Sharps injury characteristics examined were department where injury occurred, device, purpose or procedure for which device was used or intended, presence of sharps injury prevention feature, who was holding the device, and how and when the injury occurred. Global chi-square was used to assess differences in the percent distribution of sharps injury characteristics between physician groups. Joinpoint regression was used to evaluate trends in injury rates among trainees and attendings.

Results

From 2002–2018, 17,565 sharps injuries among physicians were reported to the surveillance system, 10,525 of which occurred among trainees. For attendings and trainees combined, sharps injuries occurred most in operating and procedure rooms and most often involved suture needles. Significant differences in sharps injuries were found between trainees and attendings with respect to department, device, and intended purpose or procedure. Sharps without engineered sharps injury protections accounted for approximately 4.4 times as many injuries (13,355, 76.0%) as those with protections (3,008, 17.1%). Among trainees, sharps injuries were highest in the first quarter of the academic year and decreased over time, while sharps injuries among attendings had a very slight, significant increase.

Conclusions

Sharps injuries are an ongoing occupational hazard faced by physicians, particularly during clinical training. Further research is needed to elucidate the etiology of the observed injury patterns during the academic year. Medical training programs need to implement a multipronged approach to prevent sharps injuries, including increased use of devices with sharps injury prevention features and robust training on safe handling of sharps.
Beyond Compliance: Growth as the Guiding Value in Undergraduate Medical Education
Authors: Woodruff James N. , Lee Wei Wei , Vela Monica , Davidson Arnold I.
Published: February 2023

Adhering to the paradigm of the natural sciences, much of undergraduate medical education (UME) in the United States remains committed to objectivity, compliance, and standardization in its approach to teaching, evaluation, student affairs, and accreditation practices. The authors argue that, while these simple and complicated problem solving (SCPS) approaches may be valid for some highly controlled environments of UME, they lack rigor in complex, real-world environments where optimal care and education is not standardized but is tailored to context and individual needs. This argument is supported by evidence that “systems” approaches, characterized by complex problem solving (CPS, differentiated from complicated problem solving), lead to better outcomes in patient care and student academic performance. Examples of interventions implemented at the University of Chicago Pritzker School of Medicine from 2011 to 2021 further illustrate this point.

Interventions in student well-being that emphasize personal and professional growth have led to student satisfaction that is 20% higher than the national average on the Association of American Medical Colleges Graduation Questionnaire (GQ). Career advising interventions that augment the use of adaptive behaviors in place of rules and guidelines have yielded 30% fewer residency applications per student than the national average while simultaneously yielding residency “unmatched” rates that are one-third of the national average. Regarding diversity, equity, and inclusion, an emphasis on civil discourse around real-world problems has been associated with student attitudes toward diversity that are 40% more favorable than the national average on the GQ. In addition, there has been an increase in the number of matriculating students who are underrepresented in medicine to 35% of the incoming class. The article concludes with a review of philosophic barriers to incorporating the CPS paradigm into UME and of notable pedagogic differences between CPS and SCPS approaches.
The University of Chicago Clinical Excellence Scholars Track: Aligning Dynamic Students With Innovative Programming in Early Medical Education at the Undergraduate Level
Authors: Milner Ross , Straus Christopher M. , Andrews Bree , Krapec Joni
Published: February 2023

The Clinical Excellence Scholars Track was developed in 2012 as a shared initiative between the Bucksbaum Institute for Clinical Excellence, the University of Chicago (UChicago) Careers in Healthcare office, and the UChicago Medicine Office of Community and External Affairs. The goal of the Clinical Excellence Scholars Track is to foster an understanding of the physician career and the doctor–patient relationship for a select group of undergraduate students. The Clinical Excellence Scholars Track achieves this goal through carefully tailored curricular requirements and direct mentoring experiences between Bucksbaum Institute Faculty Scholars and the student scholars. After participating in the Clinical Excellence Scholars Track program, student scholars report that their career understanding and preparation have benefitted as a result and that they meet with success in the medical school application process as well.
ESG Expands the View of Corporate Stewardship in Healthcare
Authors: Richardson Michele Baker
Published: February 2023

At Advocate Aurora Health, the board of directors established parameters for effectively executing the governance (G) function related to ESG activities while adopting a comprehensive approach to ESG that includes the corporate commitment to health equity. Establishing a board diversity, equity, and inclusion (DEI) committee with external experts served to integrate these efforts with the ESG strategy. This approach will continue to guide the board of directors of Advocate Health, formed in December 2022, by the combination of Advocate Aurora Health and Atrium Health. Our experience has demonstrated that empowering individual board committee members of not-for-profit healthcare organizations to embrace their unique responsibility for driving ESG requires collective efforts in the boardroom as well as a commitment to board refreshment and diversity.
Medical Disruptions During Center-Based Cardiac Rehabilitation
Authors: Khong Anthony , Liu Nina , Giancaterino Shaun , Junker Margaret , Labiak Rachel , Cortez-Toledo Elizabeth , Fausto Alejandra Galina Bernal , Andrade Humberto , Chen Christopher , López Javier E.
Published: February 2023

Purpose:

The purpose of this study is to show that with remote and virtual cardiac rehabilitation (CR) care models rapidly emerging, CR core components must be maintained to prioritize safety and effectiveness. Currently, there is a paucity of data on medical disruptions in phase 2 center-based CR (cCR). This study aimed to characterize the frequency and types of unplanned medical disruptions.

Methods:

We reviewed 5038 consecutive sessions from 251 patients enrolled in cCR program from October 2018 to September 2021. Quantification of events was normalized to sessions to control for multiple disruptions that occurred to a single patient. A multivariate logistical regression model was used to predict comorbid risk factors for disruptions.

Results:

Fifty percent of patients experienced one or more disruptions during cCR. Glycemic events (71%) and blood pressure (12%) abnormalities accounted for most of these while symptomatic arrhythmias (8%) and chest pain (7%) were less frequent. Sixty-six percent of events occurred within the first 12 wk. The regression model showed that a diagnosis of diabetes mellitus was the strongest predictor for disruptions (OR = 2.66: 95% CI, 1.57-4.52; P < .0001).

Conclusions:

Medical disruptions were frequent during cCR, with glycemic events being most common and occurring early. A diagnosis of diabetes mellitus was a strong independent risk factor for events. This appraisal suggests that patients living with diabetes mellitus, particularly those on insulin, need to be the highest priority for monitoring and planning and suggests that a hybrid care model may be beneficial in this population.
Preventing postoperative cognitive dysfunction using anesthetic drugs in elderly patients undergoing noncardiac surgery: a systematic review and meta-analysis
Authors: Zeng Kuan , Long Jingyi , Li Yi , Hu Jichang
Published: February 2023

Postoperative cognitive dysfunction (POCD) is a common neurological system disorder in surgical patients. The choice of anesthetic can potentially reduce POCD. The authors performed this network meta-analysis to compare different anesthetic drugs in reducing the incidence of POCD for elderly people undergoing noncardiac surgery. We searched MEDLINE, EMBASE, the Cochrane Library, and the Web of Science for randomized controlled trials comparing the different anesthetic drugs for noncardiac surgery in elderly from inception until July, 2022. The protocol was registered on the PROSPERO database (CRD#42020183014). A total of 34 trials involving 4314 patients undergoing noncardiac surgery in elderly were included. The incidence of POCD for each anesthetic drug was placebo (27.7%), dexmedetomidine (12.9%), ketamine (15.2%), propofol (16.8%), fentanyl (23.9%), midazolam (11.3%), sufentanil (6.3%), sevoflurane (24.0%), and desflurane (28.3%). Pairwise and network meta-analysis showed dexmedetomidine was significantly reducing the incidence of POCD when compared with placebo. Network meta-analysis also suggested dexmedetomidine was significantly reducing the incidence of POCD when compared with sevoflurane. Sufentanil and dexmedetomidine ranked the first and second in reducing the incidence of POCD with the surface under the cumulative ranking curve value of 87.4 and 81.5%. Sufentanil and dexmedetomidine had the greatest possibility to reduce the incidence of POCD for elderly people undergoing noncardiac surgery.
Biliary complications following split liver transplantation in adult recipients: a matched pair analysis on single-center experience
Authors: Matsushima Hajime , Fujiki Masato , Sasaki Kazunari , Raj Roma , D’Amico Giuseppe , Simioni Andrea , Aucejo Federico , Diago Uso Teresa , Kwon Choon Hyuck David , Eghtesad Bijan , Miller Charles , Quintini Cristiano , Eguchi Susumu , Hashimoto Koji
Published: February 2023

The utilization of split liver grafts can increase access to liver transplantation (LT) for adult patients, particularly when liver grafts are shared between 2 adult recipients. However, it is yet to be determined whether split liver transplantation (SLT) increases the risk of biliary complications (BCs) compared with whole liver transplantation (WLT) in adult recipients. This retrospective study enrolled 1441 adult patients who underwent deceased donor LT at a single-site between January 2004 and June 2018. Of those, 73 patients underwent SLTs. Graft type for SLT includes 27 right trisegment grafts, 16 left lobes, and 30 right lobes. A propensity score matching analysis selected 97 WLTs and 60 SLTs. Biliary leakage was more frequently seen in SLTs (13.3% vs. 0%; p <0.001), whereas the frequency of biliary anastomotic stricture was comparable between SLTs and WLTs (11.7% vs. 9.3%; p=0.63). Graft and patient survival rates of patients undergoing SLTs were comparable to those undergoing WLTs (p=0.42 and 0.57, respectively). In the analysis of the entire SLT cohort, BCs were seen in 15 patients (20.5%) including biliary leakage in 11 patients (15.1%) and biliary anastomotic stricture in 8 patients (11.0%) [both in 4 patients (5.5%)]. The survival rates of recipients who developed BCs were significantly inferior to those without BCs (p <0.01). By multivariate analysis, the split grafts without common bile duct increased the risk of BCs. In conclusion, SLT increases the risk of biliary leakage compared with WLT. Biliary leakage can still lead to fatal infection and thus should be managed appropriately in SLT.
Conundrums of choice of ‘normal’ kidney tissue for single cell studies
Authors: Jain Sanjay
Published: February 2023

Purpose of review

Defining molecular changes in key kidney cell types across lifespan and in disease states is essential to understand the pathogenetic basis of disease progression and targeted therapies. Various single cell approaches are being applied to define disease associated molecular signatures. Key considerations include the choice of reference tissue or ‘normal’ for comparison to diseased human specimens and a benchmark reference atlas. We provide an overview of select single cell technologies, key considerations for experimental design, quality control, choices and challenges associated with assay type and source for reference tissue.

Recent findings

Several initiatives including Kidney Precision Medicine Project, Human Biomolecular Molecular Atlas Project, Genitourinary Disease Molecular Anatomy Project, ReBuilding a Kidney consortium, Human Cell Atlas and Chan Zuckerburg Initiative are generating single cell atlases of ‘normal’ or disease kidney. Different sources of kidney tissue are used as reference. Signatures of injury, resident pathology and procurement associated biological and technical artifacts have been identified in human kidney reference tissue.

Committing to a particular reference or ‘normal’ tissue has significant implications in interpretation of data from disease samples or in ageing. Voluntarily donated kidney tissue from healthy individuals is generally unfeasible. Having reference datasets for different types of ‘normal’ tissue can aid in mitigating the confounds of choice of reference tissue and sampling biases.
The expanding spectrum and utility of antigens in membranous nephropathy
Authors: Miller Paul , Caza Tiffany
Published: February 2023

Purpose of review

Multiple antigenic targets were discovered in membranous nephropathy, representing distinct autoimmune diseases with a similar morphologic pattern of injury. An overview of recent developments, including antigen types, clinical associations, serologic monitoring, and advancements in understanding disease pathogenesis are provided.

Recent findings

Several new antigenic targets have defined subtypes of membranous nephropathy, including Neural epidermal growth factor-like 1, protocadherin 7, HTRA1, FAT1, SEMA3B, NTNG1, NCAM1, exostosin 1/2, transforming growth factor beta receptor 3, CNTN1, proprotein convertase subtilisin/kexin type 6, and neuron-derived neurotrophic factor. Autoantigens in membranous nephropathy may demonstrate unique clinical associations, assisting the nephrologist to identify potential disease etiologies and triggers, such as autoimmune disease, cancer, medications, and infections.

We are entering an exciting era for which an antigen-based approach will further define subtypes of membranous nephropathy, allow for development of noninvasive diagnostics, and improve care for patients.
Placental Histopathologic Findings of a Large Cohort of Patients With SARS-CoV-2 Infection During Pregnancy
Authors: Lin Ruby , Forquer Heather , Cviko-Pajt Aida , Schauer Galen M. , Abellar Rosanna G. , Hedderson Monique , Kuzniewicz Michael W. , Greenberg Mara B.
Published: February 2023

Pregnant individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at a higher risk for adverse pregnancy outcomes. Previous small cohort studies have shown increased frequency of placental lesions associated with maternal vascular malperfusion, fetal vascular malperfusion, and inflammation among patients with SARS-CoV-2, without controlling for cardiometabolic risk factors among many such patients. We aimed to evaluate whether SARS-CoV-2 infection during pregnancy is independently associated with placental abnormalities when controlling for risk factors that could affect placental histopathology. Retrospective cohort study of placentas from singleton pregnancies in Kaiser Permanente Northern California from March to December 2020. Pathologic findings were compared among those with confirmed cases of SARS-CoV-2 during pregnancy and those without. We examined the association between SARS-CoV-2 infection and categorical placental pathologies, controlling for maternal age, gestational age, prepregnancy body mass index, gestational hypertension, preeclampsia/eclampsia, preexisting diabetes, history of thrombosis, and stillbirth. A total of 2,989 singleton gestation placentas were analyzed, 416 (13%) from pregnancies with SARS-CoV-2 infection and 2,573 (86%) from those without infection. Among placentas from pregnancies with SARS-CoV-2, 54.8% had evidence of inflammation, 27.1% maternal malperfusion abnormality, 20.7% massive perivillous fibrin or chronic villitis, 17.3% villous capillary abnormality, and 15.1% fetal malperfusion. After controlling for risks factors and stratifying interval time between SARS-CoV-2 infection and delivery, no association was found between placental abnormalities and SARS-CoV-2 infection during pregnancy. SARS-CoV-2 infection was not associated with an increased risk of placentally mediated adverse outcomes during pregnancy, compared with placentas sent for other indications, in this large diverse cohort.
Risk Perceptions and Risk Thresholds Among Surgeons in the Management of Intraductal Papillary Mucinous Neoplasms
Authors: Sacks Greg D. , Shin Paul , Braithwaite R. Scott , Soares Kevin C. , Kingham T. Peter , D’Angelica Michael I. , Drebin Jeffrey A. , Jarnagin William R. , Wei Alice C.
Published: February 2023

Objectives:

We aimed to determine whether surgeon variation in management of intraductal papillary mucinous neoplasm (IPMN) is driven by differences in risk perception and quantify surgeons’ risk threshold for changing their recommendations.

Background:

Surgeons vary widely in management of IPMN.

Methods:

We conducted a survey of members of the Americas HepatoPancreatoBiliary Association, presented participants with 2 detailed clinical vignettes and asked them to choose between surgical resection and surveillance. We also asked them to judge the likelihood that the IPMN harbors cancer and that the patient would have a serious complication if surgery was performed. Finally, we asked surgeons to rate the level of cancer risk at which they would change their treatment recommendation. We examined the association between surgeons’ treatment recommendations and their risk perception and risk threshold.

Results:

One hundred fifty surgeons participated in the study. Surgeons varied in their recommendations for surgery [19% for vignette 1 (V1) and 12% for V2] and in their perception of the cancer risk (interquartile range: 2%–10% for V1 and V2) and risk of surgical complications (V1 interquartile range: 10%–20%, V2 20–30%). After adjusting for surgeon characteristics, surgeons who were above the median in cancer risk perception were 22 percentage points (27% vs 5%) more likely to recommend resection than those who were below the median (95% CI: 11%–4%; P<0.001). The median risk threshold at which surgeons would change their recommendation was 15% (V1 and V2). Surgeons who recommended surgery had a lower risk threshold for changing their recommendation than those who recommended surveillance (V1: 10.0 vs 15.0, P=0.06; V2: 7.0 vs 15.0, P=0.05).

Conclusions:

The treatment that patients receive for IPMNs depends greatly on how their surgeons perceive the risk of cancer in the lesion. Efforts to improve cancer risk prediction for IPMNs may lead to decreased variations in care.
Extremely low seasonal prey capture efficiency in a deep-diving whale, the narwhal
Authors: Chambault Philippine , Blackwell Susanna B. , Heide-Jørgensen Mads Peter
Published: February 2023

Successful foraging is essential for individuals to maintain the positive energy balance required for survival and reproduction. Yet, prey capture efficiency is poorly documented in marine apex predators, especially deep-diving mammals. We deployed acoustic tags and stomach temperature pills in summer to collect concurrent information on presumed foraging activity (through buzz detection) and successful prey captures (through drops in stomach temperature), providing estimates of feeding efficiency in narwhals. Compared to the daily number of buzzes (707 ± 368), the daily rate of feeding events was particularly low in summer (19.8 ± 8.9) and only 8–14% of the foraging dives were successful (i.e. with a detectable prey capture). This extremely low success rate resulted in a very low daily food consumption rate (less than 0.5% of body mass), suggesting that narwhals rely on body reserves accumulated in winter to sustain year-round activities. The expected changes or disappearance of their wintering habitats in response to climate change may therefore have severe fitness consequences for narwhal populations.
Collective rotational motion of freely expanding T84 epithelial cell colonies
Authors: Ascione Flora , Caserta Sergio , Esposito Speranza , Villella Valeria Rachela , Maiuri Luigi , Nejad Mehrana R. , Doostmohammadi Amin , Yeomans Julia M. , Guido Stefano
Published: February 2023

Coordinated rotational motion is an intriguing, yet still elusive mode of collective cell migration, which is relevant in pathological and morphogenetic processes. Most of the studies on this topic have been carried out on epithelial cells plated on micropatterned substrates, where cell motion is confined in regions of well-defined shapes coated with extracellular matrix adhesive proteins. The driver of collective rotation in such conditions has not been clearly elucidated, although it has been speculated that spatial confinement can play an essential role in triggering cell rotation. Here, we study the growth of epithelial cell colonies freely expanding (i.e. with no physical constraints) on the surface of cell culture plates and focus on collective cell rotation in such conditions, a case which has received scarce attention in the literature. One of the main findings of our work is that coordinated cell rotation spontaneously occurs in cell clusters in the free growth regime, thus implying that cell confinement is not necessary to elicit collective rotation as previously suggested. The extent of collective rotation was size and shape dependent: a highly coordinated disc-like rotation was found in small cell clusters with a round shape, while collective rotation was suppressed in large irregular cell clusters generated by merging of different clusters in the course of their growth. The angular motion was persistent in the same direction, although clockwise and anticlockwise rotations were equally likely to occur among different cell clusters. Radial cell velocity was quite low as compared to the angular velocity, in agreement with the free expansion regime where cluster growth is essentially governed by cell proliferation. A clear difference in morphology was observed between cells at the periphery and the ones in the core of the clusters, the former being more elongated and spread out as compared to the latter. Overall, our results, to our knowledge, provide the first quantitative and systematic evidence that coordinated cell rotation does not require a spatial confinement and occurs spontaneously in freely expanding epithelial cell colonies, possibly as a mechanism for the system.
Autocorrelated measurement processes and inference for ordinary differential equation models of biological systems
Authors: Lambert Ben , Lei Chon Lok , Robinson Martin , Clerx Michael , Creswell Richard , Ghosh Sanmitra , Tavener Simon , Gavaghan David J.
Published: February 2023

Ordinary differential equation models are used to describe dynamic processes across biology. To perform likelihood-based parameter inference on these models, it is necessary to specify a statistical process representing the contribution of factors not explicitly included in the mathematical model. For this, independent Gaussian noise is commonly chosen, with its use so widespread that researchers typically provide no explicit justification for this choice. This noise model assumes ‘random’ latent factors affect the system in the ephemeral fashion resulting in unsystematic deviation of observables from their modelled counterparts. However, like the deterministically modelled parts of a system, these latent factors can have persistent effects on observables. Here, we use experimental data from dynamical systems drawn from cardiac physiology and electrochemistry to demonstrate that highly persistent differences between observations and modelled quantities can occur. Considering the case when persistent noise arises owing only to measurement imperfections, we use the Fisher information matrix to quantify how uncertainty in parameter estimates is artificially reduced when erroneously assuming independent noise. We present a workflow to diagnose persistent noise from model fits and describe how to remodel accounting for correlated errors.
Analysis of the phosphoproteome of CK2
α
(–/–)
/Δ
α′
C2C12 myoblasts compared to the wild-type cells
Authors: Borgo Christian , Cesaro Luca , Hirota Tsuyoshi , Kuwata Keiko , D'Amore Claudio , Ruppert Thomas , Blatnik Renata , Salvi Mauro , Pinna Lorenzo A.
Published: February 2023

CK2 is a Ser/Thr protein kinase composed of two catalytic (
α
/
α
′) subunits and a non-catalytic β-subunit dimer, whose activity is often abnormally high in cancer cells. The concept that CK2 may be dispensable for cell survival has been challenged by the finding that viable CK2
α
/
α
′ knock-out myoblast clones still express small amounts of an N-terminally deleted
α
′ subunit generated during the CRISPR/Cas9 procedure. Here we show that, although the overall CK2 activity of these CK2
α
(–/–)
/Δ
α
′ (KO) cells is less than 10% compared to wild-type (WT) cells, the number of phosphosites with the CK2 consensus is comparable to that of WT cells. A more in-depth analysis, however, reveals that the two phosphoproteomes are not superimposable according to a number of criteria, notably a functional analysis of the phosphoproteome found in the two types of cells, and variable sensitivity of the phosphosites to two structurally unrelated CK2 inhibitors. These data support the idea that a minimal CK2 activity, as in KO cells, is sufficient to perform basic housekeeping functions essential for cell survival, but not to accomplish several specialized tasks required upon cell differentiation and transformation. From this standpoint, a controlled downregulation of CK2 would represent a safe and valuable anti-cancer strategy.
Pathways to global-change effects on biodiversity: new opportunities for dynamically forecasting demography and species interactions
Authors: Paniw Maria , García-Callejas David , Lloret Francisco , Bassar Ronald D. , Travis Joseph , Godoy Oscar
Published: February 2023

In structured populations, persistence under environmental change may be particularly threatened when abiotic factors simultaneously negatively affect survival and reproduction of several life cycle stages, as opposed to a single stage. Such effects can then be exacerbated when species interactions generate reciprocal feedbacks between the demographic rates of the different species. Despite the importance of such demographic feedbacks, forecasts that account for them are limited as individual-based data on interacting species are perceived to be essential for such mechanistic forecasting—but are rarely available. Here, we first review the current shortcomings in assessing demographic feedbacks in population and community dynamics. We then present an overview of advances in statistical tools that provide an opportunity to leverage population-level data on abundances of multiple species to infer stage-specific demography. Lastly, we showcase a state-of-the-art Bayesian method to infer and project stage-specific survival and reproduction for several interacting species in a Mediterranean shrub community. This case study shows that climate change threatens populations most strongly by changing the interaction effects of conspecific and heterospecific neighbours on both juvenile and adult survival. Thus, the repurposing of multi-species abundance data for mechanistic forecasting can substantially improve our understanding of emerging threats on biodiversity.
The involvement of CiaR and the CiaR-regulated serine protease HtrA in thermal adaptation of Streptococcus pneumoniae
Authors: Gazioglu Ozcan , Habtom Medhanie , Andrew Peter W. , Yesilkaya Hasan
Published: February 2023

The in vivo temperature can vary according to the host tissue and the response to infection.

Streptococcus pneumoniae

has evolved mechanisms to survive these temperature differences, but neither the consequences of different temperatures for pneumococcal phenotype nor the genetic basis of thermal adaptation are known in detail. In our previous study [], we found that CiaR, which is a part of two-component regulatory system CiaRH, as well as 17 genes known to be controlled by CiaRH, were identified to be differentially expressed with temperature. One of the CiaRH-regulated genes shown to be differentially regulated by temperature is for the high-temperature requirement protein (HtrA), coded by SPD_2068 (htrA). In this study, we hypothesized that the CiaRH system plays an important role in pneumococcal thermal adaptation through its control over htrA. This hypothesis was evaluated by testing strains mutated or overexpressing ciaR and/or htrA, in in vitro and in vivo assays. The results showed that in the absence of ciaR, the growth, haemolytic activity, amount of capsule and biofilm formation were considerably diminished at 40 °C only, while the cell size and virulence were affected at both 34 and 40 °C. The overexpression of htrA in the ∆ciaR background reconstituted the growth at all temperatures, and the haemolytic activity, biofilm formation and virulence of ∆ciaR partially at 40 °C. We also showed that overexpression of htrA in the wild-type promoted pneumococcal virulence at 40 °C, while the increase of capsule was observed at 34 °C, suggesting that the role of htrA changes at different temperatures. Our data suggest that CiaR and HtrA play an important role in pneumococcal thermal adaptation.
Characteristics for Machine Learning Detection of Large Vessel Occlusion on Computed Tomography Angiography
Authors: Lingam Sneha , Remedios Lucas W. , Remedios Samuel W. , Landman Bennett A. , Davis Larry T. , Clark Stephen W.
Published: February 2023

Detection of large vessel occlusion (LVO) using machine learning on computed tomography angiography (CTA) may help stroke triage, yet applicability across varied patient and image characteristics has not been examined. The study will examine which characteristics are important when using a convolutional neural network to identify LVO on CTA. A retrospective cohort study (November 2017–May 2019) at a comprehensive stroke center evaluated 677 stroke-alerted patients with an LVO of the internal carotid artery, M1, or M2 (n=150) and a matching number without LVO were included. An Inception module-based network was trained for binary classification of LVO presence. Results were examined by LVO location, window settings, non-LVO findings, demographics, risk factors, presentation status and times, interventions, and outcomes. Three hundred patients were included (48% women; median age 65). Mean±95% CI for cross-validation test and external validation, respectively, are area under precision-recall curve 0.871±0.094 and 0.742±0.018 and area under receiver operating characteristic curve 0.920±0.051 and 0.852±0.004. 145 true positive (TP), 5 false negative (FN), 39 false positive (FP), and 111 true negative (TN) patients were identified. Significant comparisons (P<0.05) identified: lower window settings for misclassifications, smoking history for all FN versus 33% TP (P=0.005), and tissue plasminogen activator treatment for 41% FP versus 20% TN (P=0.017). Our LVO detection tool had high performance across patient characteristics with few exceptions. FP had pathology warranting detection, including distal occlusions. Lower window settings among misclassifications highlight the need for image quality when using machine learning for decision support.
A Bayesian Perspective Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest
Authors: Brophy James M
Published: February 2023

Background

Whether extracorporeal CPR (eCPR) has survival benefits over conventional CPR (cCPR) in patients with refractory out-of-hospital cardiac arrest is an unresolved clinical question. Performing trials in this environment is exceedingly challenging and inferences need careful examination.

Objective

Determine if a Bayesian perspective provides additional inferential insights.

Methods

The INCEPTION trial of patients with refractory out-of-hospital cardiac arrest reported eCPR and cCPR had similar effects on the primary outcome, 30 day survival with a favorable neurologic outcome. Herein the probability of eCPR superiority, equivalence or inferiority to cCPR is re-evaluated with a Bayesian analysis using both vague and informative priors (from previously completed randomized clinical trials (RCTs)).

Results

Depending on the chosen prior, the Bayesian reanalysis of the INCEPTION intention-to-treat (ITT) data suggests an equivalence probability < 10% (defined as an absolute risk difference (RD) < 1%) but a clinical superiority probability of 66 - 99 % (defined as RD > 1.0). An INCEPTION per protocol (PP) analysis with a vague prior suggested a 1% probability of clinical benefit but this posterior probability increased to 86% when informative PP data from previous RCTs were considered.

Conclusion

Bayesian INCEPTION trial re-analyses provide additional quantative insights. The totality of the ITT evidence reveals a high probability for a clinically meaningful eCPR benefit over cCPR at 30 days. A PP analysis shows a less definitive probability of benefit. (Abstract word count 197, Manuscript word count 1477)
Association between aspirin dose and outcomes in patients with acute Kawasaki disease
Authors: Suzuki Takanori , Michihata Nobuaki , Hashimoto Yohei , Yoshikawa Tetsushi , Saito Kazuyoshi , Matsui Hiroki , Fushimi Kiyohide , Yasunaga Hideo
Published: February 2023

Background

The most effective dosage of aspirin to prevent coronary artery abnormalities in patients with acute Kawasaki disease remains unknown. Using a Japanese national inpatient database, this study aimed to identify the appropriate dose of aspirin to be prescribed to patients with acute Kawasaki disease.

Method

We used the Diagnostic Procedure Combination database to identify patients with Kawasaki disease treated with intravenous immunoglobulin between 2010 and 2021.The outcomes included the occurrence of coronary artery abnormalities and intravenous immunoglobulin resistance, length of stay, and medical costs. Restricted cubic spline functions were performed to examine the association between aspirin dose and the outcomes.

Results

Data of 82109 patients were extracted from the database. Non-linear associations were observed between aspirin dose and the outcomes. In comparison with an aspirin dose of 30 mg/kg/day, the odds ratio (95% confidence interval) for coronary artery abnormalities was 1.40 (1.13–1.75) at 5 mg/kg/day. An aspirin dose of ≥30 mg/kg/day did not significantly change the odds ratio for coronary artery abnormalities. Compared with a dose of 30 mg/kg/day, the odds ratio (95% confidence interval) for intravenous immunoglobulin resistance was 0.87 (0.76–1.00) at 5 mg/kg/day and 0.59 (0.36–0.98) at 80 mg/kg/day. An increase in aspirin dose was associated with a shorter length of stay and lower medical costs.

Conclusions

Low-dose aspirin may increase the risk of coronary artery abnormalities in patients with acute Kawasaki disease; however, increasing aspirin doses beyond the standard doses may not be associated with a reduction in coronary artery abnormalities. High-dose aspirin showed the potential to reduce hospital stay and medical costs without increasing complications.

Article Summary

The study showed by restricted cubic spline that the dose of aspirin was no significant association between aspirin escalation and CAAs in patients with acute KD.

What’s Known on This Subject

Aspirin is standard treatments used with IVIG of acute Kawasaki Disease (KD), Few studies have shown the most effective dosage of aspirin to to prevent CAAs.

What This Study Adds

The dose of aspirin was no significant association between aspirin escalation and CAAs in patients with acute KD.
Genetic variation supports a causal role for valproate in prevention of ischemic stroke
Authors: Mayerhofer Ernst , Parodi Livia , Narasimhalu Kaavya , Wolking Stefan , Harloff Andreas , Georgakis Marios K , Rosand Jonathan , Anderson Christopher D
Published: February 2023

Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. To overcome this limitation, we applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. Among 2,150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12-year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 µg/ml per one SD, 95% CI [3.45, 8.11]). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (HR per one SD 0.73, [0.58, 0.91]) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p-trend=0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per one SD 0.53, [0.32, 0.86]) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs. 13/71, 18.3%, p-trend=0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p=0.61), suggesting minimal pleiotropy. In an independent cohort of 1,241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per one SD 0.77, 95% CI: [0.61, 0.97]). These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention.
Neuroimaging-based analysis of DBS outcome in pediatric dystonia: Insights from the GEPESTIM registry
Authors: Al-Fatly Bassam , Giesler Sabina , Oxenford Simon , Li Ningfei , Achtzehn Johannes , Krause Patricia , Visser-Vandewalle Veerle , Krauss Joachim K. , Runge Joachim , Tadic Vera , Bäumer Tobias , Schnitzler Alfons , Vesper Jan , Wirths Jochen , Timmermann Lars , Kühn Andrea A. , Koy Anne
Published: February 2023

Introduction

Deep brain stimulation (DBS) is an established treatment in patients with pharmaco-resistant neurological disorders of different ages. Surgical targeting and postoperative programming of DBS depend on the spatial location of the stimulating electrodes in relation to the surrounding anatomical structures and on electrode connectivity to a specific distributed pattern of brain networks. Such information is usually collected using group-level analysis which relies on the availability normative imaging-resources (atlases and connectomes). To this end, analyzing DBS data of children with debilitating neurological disorders like dystonia would make benefit from such resources, especially given the developmental differences between adults and children neuroimaging data. We assembled pediatric, normative neuroimaging-resources from open-access neuroimaging datasets and illustrated their utility on a cohort of children with dystonia treated with pallidal DBS. We aimed to derive a local pallidal sweetspot and explore a connectivity fingerprint associated with pallidal stimulation to exemplify the utility of the assembled imaging resources.

Methods

A pediatric average brain template was implemented and used to localize DBS electrodes of twenty patients of the GEPESTIM registry cohort. Next, a pediatric subcortical atlas was also employed to highlight anatomical structures of interest. Local pallidal sweetspot was modeled and its degree of overlap with stimulation volumes was calculated as a correlate of individual clinical outcome. Additionally, a pediatric functional connectome of neurotypical subjects was built to allow network-based analyses and decipher a connectivity fingerprint responsible for clinical improvement in our cohort.

Results

We successfully implemented a pediatric neuroimaging dataset that will be made available to public use as a tool for DBS-analyses. Overlap of stimulation volumes with the identified DBS-sweetspot model correlated significantly with improvement on a local spatial level (R = 0.46,permuted p= 0.019). Functional connectivity fingerprint of DBS-outcome was determined as a network correlate of therapeutic pallidal stimulation in children with dystonia (R = 0.30,permuted p= 0.003).

Conclusions

Local sweetspot and distributed network models provide neuroanatomical substrates for DBS-associated clinical outcome in dystonia using pediatric neuroimaging surrogate data. The current implementation of pediatric neuroimaging dataset might help improving the practice of DBS-neuroimaging analyses in pediatric patients.