bluuebunny/crossref_metadata_2025 huggingface dataset:
OUTCOMES OF TOTAL PROCTOCOLECTOMY (TPC) WITH ILEAL POUCH ANAL ANASTOMOSIS (IPAA)
Authors: Petrov Jessica , Al-Bawardy Badr , Gaidos Jill , Proctor Deborah
Published: January 2022

BACKGROUND

Total proctocolectomy (TPC) followed by ileal pouch anal anastomosis (IPAA) is the surgery of choice for eligible ulcerative colitis patients who are refractory to medical therapy or develop complications such as adenocarcinoma or dysplasia. Although associated with excellent quality of life, IPAA can lead to complications including chronic antibiotic-refractory pouchitis, anatomical complications, and development of Crohn’s disease. These outcomes remain a clinical challenge. The aim of this study was to evaluate the rate of complications and their treatment following TPC with IPAA to assess for predictors of adverse postoperative outcomes.

METHODS

This was a single center, retrospective study from January 1,2010 to December 31, 2020. We included patients who underwent TPC with IPAA and reported at least one episode of pouchitis, some of whom also had additional complications. Chronic pouchitis was defined as recurrent episodes of biopsy-proven inflammation or as reported in the patient record based on clinical presentation and responsiveness to treatment. Crohn’s disease of the pouch was defined as pre-pouch ileitis or development of a fistula more than 6 months post-operatively. Data is presented as number of cases and proportions.

RESULTS

A total of 44 subjects who underwent IPAA (52% female, mean age 46.4 ± 11.3 years) were included. The rate of acute pouchitis was 9%, the rate of chronic pouchitis was 75%. In the chronic pouchitis group, 45% were antibiotic-dependent and 7% were antibiotic-refractory.

We found that 70% of subjects required the initiation of medical therapy to treat symptoms of pouchitis, with the majority requiring chronic antibiotics (73%) (Table). A total of 10 subjects (23%) required biologics and 10 subjects (23%) required chronic steroid therapy. Anatomic complications were noted in 23 subjects (52%), the most common being abscess/fistula formation (30%), followed by stricture formation (27%). Anatomic complications appeared more likely to occur when more time had elapsed since the original surgery. 10 subjects (23%) needed repeat surgery and 9 subjects (20%) developed Crohn’s disease of the pouch.

CONCLUSIONS

In our cohort, we found that nearly two thirds of subjects required medical therapy to treat pouchitis following IPAA including 25% requiring treatment biologic/immunosuppressant therapy. In addition, one quarter required repeat surgery for treatment of complications. Limitations of this study include a tertiary patient population and small sample size. We found a lack of standardized characterization of pouchitis with respect to symptoms and lab abnormalities. In future work, we plan to use this data to develop a prospective, multi-center study to establish a standardized database of patients who underwent IPAA. This will help better understand factors that influence outcomes and guide management.
EFFECTS OF DELAYED ENDOSCOPIES IN INFLAMMATORY BOWEL DISEASE PATIENTS DURING THE COVID-19 PANDEMIC
Authors: Young Karen , Hargunani Devesh , Poylin Vitaliy
Published: January 2022

OBJECTIVES

Care for many chronic conditions was altered during the COVID-19 pandemic. For patients with Inflammatory Bowel Disease (IBD), routine maintenance including endoscopies were postponed. The effects of delaying endoscopies on IBD outcomes are currently unknown. This study aimed to evaluate effects of delays of maintenance endoscopies on patients with IBD during the COVID-19 pandemic.

METHODS

This was a retrospective review of all IBD patients scheduled for routine endoscopy at Northwestern Memorial Hospital March 13, 2020 through May 31, 2020. All endoscopic examinations were canceled in this period due to COVID-19. Patients were divided between those whose endoscopies were rescheduled promptly (on-time) or postponed (delayed) after August 31, 2020. Patient outcomes were examined one year after cancellation. Primary outcomes included hospital and emergency room admissions. Secondary outcomes included need for surgery and medication changes.

RESULTS

100 patients were included in the delayed group and 150 in the on-time group, with a mean age of 47.5 and 42.8 years respectively. 59.2% had Crohn’s disease (CD), 39.2% had Ulcerative Colitis (UC) and 1.2% had indeterminate colitis. Both groups had similar initial severity scores as measured by the Harvey-Bradshaw Index in CD and the Simple Clinical Colitis Activity Index in UC. On average, the on-time group endoscopy was re-scheduled 2.8 months after closure compared to 9.1 months for the delayed group. There was no difference in the number of emergency room visits or hospital admissions during the delay. At one-year post-endoscopy, there was no difference in the number of emergency room visits between the on-time group (n=10, 6.7%) and the delayed group (n=3, 3%), p= 0.17. One-year post-endoscopy there were significantly more hospitalizations in the on-time group (n=14, 9.3%) compared to the delayed group (n=3, 3%), p=0.03. There was one malignancy in the on-time group and two in the delayed group which did not reach statistical significance. Although clinical severity scores were similar at 1 year, there were more IBD related surgeries in the on-time group (16) compared to the delayed group (4), p=0.03.

DISCUSSION

Patients with delayed endoscopies due to COVID-19 did not experience worse outcomes compared to patients whose endoscopies remained on-time. There was a trend towards increased malignancies in the delayed group, but higher number of admissions and operations in the on-time group despite similar degree of inflammation on endoscopy. Retrospective nature of this review did not allow us to evaluate all factors that may have influenced the decision for admission and surgery.

CONCLUSIONS

Controlled delay in endoscopies in patients with IBD with closely monitored re-scheduling efforts is safe and can be utilized in times of emergencies without compromising patient outcomes.
SELF-RATED HEALTH IN INFLAMMATORY BOWEL DISEASE CORRELATES WITH ANXIETY, DEPRESSION, CATASTROPHIC THINKING, AND DISEASE SEVERITY
Authors: Palmer Brooke , Petrik Megan , Tomasino Kathryn
Published: January 2022

BACKGROUND

The construct of self-rated health (SRH) has been found to be strongly associated with objective markers of health status (e.g., disease progression, healthcare utilization, mortality) in both general and disease-specific populations. For individuals with inflammatory bowel disease (IBD), SRH correlates with symptom severity and health-related quality of life. SRH is typically influenced by one’s disease activity, functional status, and coping style, but there is scant research investigating how specific psychological constructs are related to SRH in patients with IBD. This study aimed to examine how SRH correlates with anxiety, depression, and catastrophic thinking patterns. If clarified, results can inform assessment and intervention efforts to improve quality of life in IBD.

METHODS

Participants were recruited from a gastroenterology clinic in a midwestern academic medical center. Questionnaires included: Hospital Anxiety and Depression Scale (HADS), GI-Cognitions Questionnaire, and the 36-Item Short Form Survey (SF-36). SRH was measured from SF-36 item 1, which asked participants to rate their health on a five-point scale ranging from excellent to poor. Physicians also completed a clinician rating of IBD activity (Partial Mayo Index [PMI] for ulcerative colitis and Harvey Bradshaw Index [HBI] for Crohn’s disease). Pearson correlation analyses were conducted comparing SRH ratings to psychological variables and IBD activity.

RESULTS

A total of 117 adults participated (mean age = 38.5 years, 59% female; see Table 1 for demographics). Higher ratings of anxiety, depression, somatization, and catastrophic thinking patterns about GI symptoms were significantly correlated with poorer SRH. There was a significant negative correlation between SRH and IBD activity for patients with Crohn’s disease, but not ulcerative colitis. This is likely due to a restricted range of possible scores on the PMI. Table 2 displays correlation analyses.

DISCUSSION

Results highlight the potential utility of SRH to identify other patient concerns (e.g., anxiety, depression) and allow an additional avenue for medical providers to consider when assessing patients’ illness experience. Assessing SRH could be part of a step-wise screening and referral process in GI clinics. For example, it may be fruitful to assess SRH in a standardized manner such as using the SF-36 item 1, and when poor SRH is detected, additional screening may be warranted such as using the PHQ-9 or GAD-7. If scores are elevated, a referral to a mental health provider with training in psychogastroenterology may help identify psychological factors that could be targeted via behavioral interventions to improve quality of life and coping with illness. Additional clinical recommendations will be discussed.
PREDICTIVE PERFORMANCE OF DIFFERENT POPULATION PHARMACOKINETIC MODELS IN A REAL-WORLD COHORT OF CROHN’S DISEASE PATIENTS
Authors: Samuels Abigail , Punt Nieko , Reifenberg Jack , Mizuno Tomoyuki , Colman Ruben , Menke Frank , Vogt Aaron , Vinks Alexander , Minar Phillip
Published: January 2022

INTRODUCTION

We have previously published the results of an infliximab (IFX) population PK model in children and young adults with Crohn’s disease (CD). We found that prediction accuracy was improved with less unexplained variability when the five covariates of drug clearance were included. We also developed a clinical decision support tool (RoadMABTM) to promote physician driven model-informed precision dosing. As IFX has a relatively long half-life, it is currently unknown under what conditions (Bayesian posterior) model performance would be improved. In this study, the aim is to evaluate the precision and bias of three population PK models in a real-world cohort of CD patients.

METHODS

We investigated CD subjects who were anti-TNF naïve and started IFX induction between 2019-2020 at Cincinnati Children’s Hospital Medical Center. All subjects had a minimum of four IFX doses and a minimum of two IFX concentrations measured with a drug-tolerant assay (Esoterix, LabCorp specialty lab, Calabasas, CA) as a part of their clinical care. We measured the mean predictive error (MPE) and the root mean squared error (RMSE) for describing the bias and precision, respectively, of the prediction of the most recent IFX level (which was excluded from the Bayesian estimation). Predictions were based on the selected PK mode, the available covariates of drug clearance (weight, serum albumin, erythrocyte sedimentation rate, neutrophil CD64 expression and antibody to IFX concentration) and prior IFX levels. Two modes were used to compare model performance. In RoadMABTM, the poly-exponential (POLY-1) mode enables last known covariates (if <182 days) and last known IFX level. The ordinary differential equations (ODE-N) mode enables all covariates within the last 182 days and the last N (-1, -2, -3) IFX levels (Figure 1).

RESULTS

We identified 105 subjects who met study criteria. The median (IQR) age at first IFX infusion was 14.6 years (11.8-16.8). The median (IQR) starting dose was 8.6 mg/kg (5.4-10) and 47% were female. For all 3 PK models, we found minimal bias and improved precision in the ODE-1 mode (Table1). While there was little difference in the precision (RMSE) when the POLY-1 mode was used, we found an improvement in bias (MPE) in this mode. In a smaller subset (n=36), we also compared model performance to predict an infusion5 or infusion6 level when an infusion4 (week14) level was known. All three models performed equally well in the POLY-1 mode with the Xiong et al. model showing superior precision with ODE-1. Finally, we compared model performance to predict an infusion3 (week6) level from the start of IFX (n=38) based on the covariates of drug clearance alone.

CONCLUSION

Based on our data, in CD patients, precision dosing for IFX should be largely based on the last known IFX concentration and the most recent covariates of drug clearance.
COMBINATION BIOLOGIC AND SMALL MOLECULE THERAPY FOR REFRACTORY ULCERATIVE COLITIS
Authors: Hickman Kaitlyn , Jordan Ronald , Sonnier William
Published: January 2022

INTRODUCTION

Some inflammatory bowel disease (IBD) patients do not achieve remission with maximal medical therapy. We present a case of refractory UC who achieved clinical, endoscopic, and histologic remission after combining biologic and small molecule therapy.

CASE DESCRIPTION

A 25-year-old Caucasian male was referred to our clinic for refractory UC. Since diagnosis four years prior, he failed mesalamine, azathioprine (intolerant), adalimumab (secondary nonresponse), vedolizumab (secondary nonresponse) with inability to taper prednisone. Upon presentation to our clinic he was at week 14 of infliximab therapy without clinical improvement. Therapeutic drug monitoring revealed adequate infliximab levels without antibodies. Colonoscopy revealed mayo 2-3 disease with discrete ulcerations (Figure 1). Due to primary non-response, he was initiated on ustekinumab (UST). He remained clinically active despite dose escalation up to evey four weeks and prednisone use. Tofacitinib was initiated with initial clinical improvement, then worsening after 3 months. The Tofacitinib dosing was increased from twice daily to three times daily and repeat colonoscopy revealed pan-colitis with Mayo 2 disease. Due to refractory disease the patient was started on combined therapy of tofacitinib twice daily with UST. On dual therapy the patient experienced progressive clinical improvement. After a year of dual treatment colonoscopy showed no disease activity, and biopsies showed no evidence of cryptitis, or crypt abscesses or active inflammatory infiltrate (Figure 2).

DISCUSSION

This case highlights the benefit of combination biologic therapy with small molecule therapy in medically refractory IBD. There are limited prospective data to endorse the widespread implementation of combination therapy. A meta-analysis of thirty studies, involving 279 patients, reported 59% were able to achieve clinical remission and 34% achieved endoscopic remission with treatment of dual biologic or small molecule therapy1. Concerns involving safety of combination biologic and small molecule therapy continue to be evaluated. In our case, the patient achieved clinical, endoscopic, and histologic remission with tofacitinib and UST without adverse effects. We present this case to support the safety and efficacy of combination therapy in medically refractory patients.

REFERENCES

Ahmed W, Galati J, Kumar A et al. Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2021. https://doi.org/10.1016/j.cgh.2021.03.034.
Do Birds of a Feather Flock Together? Rebel Constituencies and Civil War Alliances
Authors: Balcells Laia , Chen Chong , Pischedda Costantino
Published: January 2022

Challenging influential perspectives that downplay the role of shared rebel constituencies, we argue that they represent important causes of rebel alliances. Yet, we theorize distinct effects for different types of constituency. While compatible political aspirations push both organizations with a common ideological constituency and those with a common ethnic constituency to ally, for co-ethnic organizations this cooperation-inducing effect is offset by a cooperation-suppressing effect due to their higher risk of inter-rebel war. Leveraging a novel dataset of alliances in multiparty civil wars (1946–2015), we find support for our theoretical expectations. Shared ideological constituencies have a larger and more robust positive effect on the probability of alliances than shared ethnic constituencies. Furthermore, we find that co-ethnic rebel organizations tend to establish informal alliances only, while organizations sharing an ideological constituency are drawn to formal alliances.
Biology and Transmission Dynamics of Aedes flavivirus
Authors: Peinado Stephen A , Aliota Matthew T , Blitvich Bradley J , Bartholomay Lyric C
Published: January 2022

Aedes albopictus (Skuse) and Aedes aegypti (Linnaeus) (Diptera: Culicidae) mosquitoes transmit pathogenic arthropod-borne viruses, including dengue, chikungunya, and Zika viruses, with significant global health consequences. Both Ae. albopictus and Ae. aegypti also are susceptible to Aedes flavivirus (AEFV), an insect-specific flavivirus (ISF) first isolated in Japan from Ae. albopictus and Ae. flavopictus. ISFs infect only insect hosts and evidence suggests that they are maintained by vertical transmission. In some cases, ISFs interfere with pathogenic flavivirus infection, and may have potential use in disease control. We explored the host range of AEFV in 4 genera of mosquitoes after intrathoracic injection and observed greater than 95% prevalence in the species of Aedes and Toxorhynchites tested. Anopheles and Culex species were less permissive to infection. Vertical transmission studies revealed 100% transovarial transmission and a filial infection rate of 100% for AEFV in a persistently-infected colony of Ae. albopictus. Horizontal transmission potential was assessed for adult and larval mosquitoes following per os exposures and in venereal transmission experiments. No mosquitoes tested positive for AEFV infection after blood feeding, and infection with AEFV after sucrose feeding was rare. Similarly, 2% of adult mosquitoes tested positive for AEFV after feeding on infected cells in culture as larvae. Venereal transmission of AEFV was most frequently observed from infected males to uninfected females as compared with transmission from infected females to uninfected males. These results reveal new information on the infection potential of AEFV in mosquitoes and expand our understanding of both vertical and horizontal transmission of ISFs.
Development of a Simple Trap That Captures Ticks (Acari) on Their Dorsal Surface
Authors: Yans Matthew W , Branca Alyssa S , Hahn Noel G , Crawley Sydney E , Figurskey Anastasia C , Hobson Kenneth R , Banfield Michael G , Borden John H
Published: January 2022

We tested two versions of a trap that captures climbing ticks on their dorsum. A prototype based on a decades old model had three components, a truncated pyramidal base with steep sloping walls, downward facing sticky-tape extending beyond and spanning the boundary of the flat upper surface, on which ticks become dorsally immobilized, and a reservoir for gaseous CO2 emission from dry ice that rests on the flat upper surface. A preoperational trap was made of thermoformed plastic and differed from the prototype by its circular structure, a central depression suitable for future housing of a biotic CO2 generator and supplemental volatile lures and a transparent sticky ceiling that enables ticks to exhibit a phototactic response and allows users to see captured ticks without disturbing the traps. Field testing of the prototype in Florida and both trap types in Oklahoma and North Carolina achieved high catches of lone star ticks, Amblyomma americanum (L.) (Acari: Ixodidae), e.g. mean catches of >70 ticks (adults plus nymphs) in 4 h in both the prototype and preoperational traps in North Carolina, and significantly higher yields of ticks than on dry ice baited 1 m2 white sheets.
The rapid identification and diagnosis of meniscus tear by Magnetic Resonance Imaging using a deep learning model
Authors: Li Jie , Qian Kun , Liu Jinyong , Huang Zhijun , Zhang Yuchen , Zhao Guoqian , Wang Huifen , Li Meng , Liang Xiaohan , Zhou Fang , Yu Xiuying , Li Lan , Wang Xingsong , Yang Xianfeng , Jiang Qing
Published: January 2022

Objective

The meniscus tear is a common problem in sports trauma. The imaging diagnosis mainly depends on the MRI. To improve the diagnostic accuracy and efficiency, a deep learning model was employed in this study and the identification efficiency has been evaluated.

Methods

The standard knee MRI images of 924 individual patients were used to complete the training, validation, and testing process. The Mask R-CNN was considered as the deep learning network structure, and the ResNet50 was considered as the backbone network. The deep learning model was trained and validated with a dataset containing 504 and 220 patients, respectively. The accuracy testing was performed on a dataset of 200 patients and reviewed by an experienced radiologist and a sports medicine physician.

Results

After training and validation, the deep learning model effectively recognized the healthy and injured meniscus. The overall average precision of the bounding box and pixel mask was more than 88% when the IoU threshold value was 0.75. The detailed average precision of three types of menisci (healthy, torn, and degenerated) was ranged from 68% to 80%. The overall sensitivity of the bounding box and pixel mask was more than 74% at the IoU threshold from 0.50 to 0.95. The diagnosis accuracy for the healthy, torn, and degenerated meniscus was 87.50%, 86.96%, and 84.78%, respectively.

Conclusion

The Mask R-CNN recognized effectively and predicted the meniscus injury, especially for the tears that occurred at different parts of the meniscus. The recognition accuracy was admirable. The diagnostic accuracy can be further improved with the increase of the training sample size. Therefore, this tool has great potential in the application for the diagnosis of meniscus injury.

The translational potential of this article

Deep learning model has unique effect in reducing doctors’ workload and improving diagnosis accuracy. It can identify and classify injured and healthy meniscus more accurately after training and learning datasets. The torn and degenerated meniscus can also be distinguished by this model. This technology could serve as an effective tool for clinical MRI-assisted diagnostics in meniscus injury.
Safety Profile of Sinopharm COVID-19 Vaccine and Breakthrough Infections in Pakistan
Authors: Rizwan Wajiha , Qureshi Ahmad Uzair , Rana Muhammad Nasir , Duggal Mubeen Nazar , Sohaib Muhammad , Sadiq Masood
Published: January 2022

Background

To determine the safety profile of Sinopharm COVID-19 vaccine and identify breakthrough infections.

Method

The study design was analytical cross sectional. An online questionnaire was filled by 1033 respondentsbetween 16th and 22nd April 2021. Adults who had received both doses of Sinopharm COVID-19 vaccine more than a week ago or only a single dose with serious side effect were included in the study. The frequency and severity of vaccination related side effects were assessed and breakthrough infection identified.

Results

The mean age of participants was 36.7 ± 12.91(18 – 92) years. Ninety one percent of participants (n=946) were health care professionals. One fifth (n=225/1033, 21.8%) had suffered from COVID-19 infection prior to vaccination, confirmed using the nasal RT-PCR test. None of the participants reported serious (grade III) or life threatening (grade IV) adverse reactions after either of the two doses. The most common side effects after the first dose were pain at injection site (20.3%), fatigue (20.3%), headache (13.9%), myalgia (12.5%) and fever (9.3%) whereas after the second dose were fatigue (16.8%), pain at injection site (15.8%), myalgia (14%) and fever (6.7%). The side effects were more common in participants who had previous history of COVID-19 infection. Of 225 previously infected participants, 97(43.1%) (p value=0.020) and 90 (40%) (p value=0.001) participants had side effects after 1st and 2nd dose respectively. 16 participants (1.55%) developed PCR positive COVID-19 infection two weeks after the second dose while 3(0.29%) participants had a re-infection. There was one case of probable severe COVID-19 infection, 2 weeks after the second dose and recovered completely with treatment.

Conclusion

Our study shows that Sinopharm COVID-19 vaccine is generally safe with no serious side effects. The side effects were however, more common in inviduals who already had COVID-19 infection. The COVID-19 breakthrough infection and reinfection could occur after the vaccination.
Effectiveness of the EPA-based ‘Toolbox Family Medicine’ on students’ learning satisfaction: study protocol for a controlled trial
Authors: Amarell Nicola , Wehner Maximilian , Schroeder Johanna , Wild Dorothea , Welchowski Thomas , Weltermann Birgitta
Published: January 2022

Background

Family practices constitute an important learning environment for medical students. However, teaching situations markedly vary between practices, and students frequently find rotations underwhelming. Especially, students’ active participation in patient care varies profoundly, although it has a significant impact on students’ interest in primary care careers. To standardize and improve learning situations in practices, we developed the so-called ‘Toolbox Family Medicine (TFM)’ using the concept of entrustable professional activities. It provides standardized learning content appropriate for students’ levels and allows teaching adaptable to actual practice conditions.

Methods

Using a controlled trial with a waiting list control arm, we will evaluate the effectiveness of the toolbox on students’ learning satisfaction. A total of 94 students will be allocated 1:1 to intervention and control practices. The teaching concept ‘Toolbox Family Medicine (TFM)’ comprises a didactic workshop for supervising physicians and a toolbox with practice-specific tasks for medical students. The primary outcome is students’ overall satisfaction with their learning progress after the rotation. Secondary outcomes include the kind and number of tasks performed, the entrusted level per task, the feasibility of implementing the toolbox in actual practice settings, and students’ motivation to pursue a career in primary care.

Discussion

We assume an improvement in learning satisfaction with the intervention. The study will begin with the next practice rotations.

Administrative information
Effect of removing race correction factor in glomerular filtration rate estimation on predicting acute kidney injury after percutaneous coronary intervention
Authors: Huang Chenxi , Murugiah Karthik , Li Xumin , Masoudi Frederick A. , Messenger John C. , Mortazavi Bobak J. , Krumholz Harlan M
Published: January 2022

Background

Race is a social and not a biological construct. Major societies have recommended removing a race correction factor when estimating glomerular filtration rate (eGFR). eGFR is a strong predictor for acute kidney injury (AKI) after percutaneous coronary intervention (PCI). We assessed the effect of removal of the race correction factor in eGFR calculation on the predictive ability of contemporary models for AKI after PCI.

Methods

We used data from the American College of Cardiology’s National Cardiovascular Data Registry (NCDR) CathPCI registry to assess the effect of removing a race correction in eGFR calculation on two previously published AKI models developed using NCDR data – a logistic regression-based model and a gradient boosting machine learning (ML) model. We first assessed the calibration and discrimination of these models with and without race correction and subsequently included race as an independent predictor in a model without race-corrected eGFR. We assessed model performance overall, and stratified by Black and non-Black subgroups. The models were trained on the same cohort used to develop the NCDR models and validated with a contemporaneous validation data set.

Results

We included 947,091 PCI procedures in 915,223 patients (mean age 64.8 years; 7.9% were Black and 32.8% women) with an AKI rate of 7.4%. In the NCDR model, inclusion of race correction in eGFR significantly underestimated AKI risk among Black patients (predicted 7.6% vs observed 10.2%) while slightly overestimating risk among non-Black patients (predicted 7.4% vs observed 7.1%). Removing the race correction partially corrected the underestimation among Black patients (predicted 8.2%). Including race as an independent predictor and introducing interaction terms further reduced the underestimation (predicted 10.1%). The receiver-operating-characteristic curve (AUC) was similar among these models, but was consistently lower in Black patients. Compared with the logistic model, the ML model had better calibration in Black patients (with race correction predicted 8.6% and without 8.7%) but still underestimated AKI risk. With race included as a predictor, the ML model achieved similarly good calibration in Black patients (predicted 10.1%). The AUCs of ML models were better than the logistic models but did not differ based on the inclusion of the race correction.

Conclusion

Removing the race correction in eGFR calculation has a positive effect of reducing the underestimation of the risk of AKI following PCI for Black patients. However, despite the reduction in underestimation, Black patients remain at elevated risk for AKI compared to non-Black patients. There is a need to better capture the determinants of this higher AKI risk through richer data and advanced modeling techniques.
Investigating sensitivity of nasal or throat (ISNOT): A combination of both swabs increases sensitivity of SARS-CoV-2 rapid antigen tests
Authors: Goodall Barbara L , LeBlanc Jason J , Hatchette Todd F , Barrett Lisa , Patriquin Glenn
Published: January 2022

The COVID-19 pandemic has been hallmarked by several waves of variants of concern (VoCs), each with novel challenges. Currently, the highly transmissible Omicron VOC is predominant worldwide, and sore throat is common among other cold-like symptoms. Anecdotes on social media suggested sampling one’s throat can increase sensitivity for Omicron detection by antigen-based rapid testing devices (Ag-RDTs). This work determines whether the sensitivity of Ag-RDTs designed for nasal sampling is altered with use of self-administered throat swabs in self-perceived asymptomatic individuals. This investigation compared results of a common Ag-RDT (i.e. Abbott Panbio COVID-19 Ag Rapid Test Device) using three sampling sites: nasal swab; throat swab and; combined nasal/throat. All Ag-RDT results were confirmed with molecular testing. Compared to RT-PCR, samples from nasal or throat swabs each detected 64.5% of SARS-CoV-2 cases; however, combining the contributions of each swab increased sensitivity to 88.7%. This trend was also evident with the Rapid Response Ag-RDT (BTNX), which uses a more flexible swabs than Panbio. When nasal swab collection was compared to paired sampling of the nasal/throat using a single swab with the Panbio Ag-RDT, the sensitivity of each was 68.4% and 81.6%, respectively. No false-positive results were observed with nasal, throat, or combined nasal/throat sampling. Self-administered throat and nasal/throat swabs both had >90% acceptability. These findings support the use of self-collected combined nasal/throat sampling for Ag-RDT based SARS-CoV-2 detection in self perceived asymptomatic individuals.
Seroprevalence of anti-SARS coronavirus 2 antibodies in Thai adults during the first three epidemic waves
Authors: Lerdsamran Hatairat , Mungaomklang Anek , Iamsirithaworn Sopon , Prasertsopon Jarunee , Wiriyarat Witthawat , Saritsiri Suthee , Anusorntanawat Ratikorn , Siriyakorn Nirada , Intalapaporn Poj , Sirikhetkon Somrak , Sangsiriwut Kantima , Dangsakul Worawat , Sawadpongpan Suteema , Thinpan Nattakan , Okada Pilailuk , Techasuwanna Ranida , Mongkalangoon Noparat , Prasert Kriengkrai , Puthavathana Pilaipan
Published: January 2022

This study sought to determine the anti-SARS-CoV-2 antibody status of 4111 Thai people from May 2020 to April 2021, a period which spanned the first two and part of the third epidemic wave of the COVID-19 in Thailand. Participants comprised 142 COVID-19 patients, 2113 individuals at risk due to their occupations [health personnel, airport officers, public transport drivers, and workers in entertainment venues (pubs, bars and massage parlors)], 1856 individuals at risk due to sharing workplaces or living communities with COVID-19 patients, and 553 Thai citizens returning after extended periods in countries with a high disease prevalence. All sera were tested in a microneutralization assay and a chemiluminescence immunoassay (CLIA) for IgG against the N protein. Furthermore, we performed an immunofluorescence assay to resolve discordant results between the two assays. Antibody responses developed in 88% (15 of 17) of COVID-19 patients at 8 days and in 94-100% between 15 and 60 days after disease onset. Neutralizing antibodies persisted for at least 8 months, longer than the IgG did, against the N protein. None of the health providers, airport officers, and public transport drivers were seropositive, while the antibodies were present in 0.44% of entertainment workers. This study showed the seropositivity of 1.9, 1.5, and 7.5% during the 3 epidemic waves, respectively, in Bangkok residents who were at risk due to sharing workplaces or communities with COVID-19 patients. Also, antibody prevalence was 1.3% in Chiang Mai people during the first epidemic wave, and varied between 6.5 and 47.0% in Thais returning from high-risk countries. This serosurveillance study found a low infection rate of SARS-CoV-2 in Thailand before the emergence of the Delta variant in late May 2021. The findings support the Ministry of Public Health’s data, which are based on numbers of patients and contact tracing.
Microenvironmental Sensing by Fibroblasts Controls Macrophage Population Size
Authors: Zhou Xu , Franklin Ruth A. , Adler Miri , Carter Trevor S. , Condiff Emily , Adams Taylor S. , Pope Scott D. , Philip Naomi H. , Meizlish Matthew L. , Kaminski Naftali , Medzhitov Ruslan
Published: January 2022

Animal tissues are comprised of diverse cell types. However, the mechanisms controlling the number of each cell type within tissue compartments remain poorly understood. Here, we report that different cell types utilize distinct strategies to control population numbers. Proliferation of fibroblasts, stromal cells important for tissue integrity, is limited by space availability. In contrast, proliferation of macrophages, innate immune cells involved in defense, repair, and homeostasis, is constrained by growth factor availability. Examination of density-dependent gene expression in fibroblasts revealed that Hippo and TGF-β target genes are both regulated by cell density. We found YAP1, the transcriptional co-activator of the Hippo signaling pathway, directly regulates expression of Csf1, the lineage-specific growth factor for macrophages, through an enhancer of Csf1 that is specifically active in fibroblasts. Activation of YAP1 in fibroblasts elevates Csf1 expression and is sufficient to increase the number of macrophages at steady state. Our data also suggest that expression programs in fibroblasts that change with density may result from sensing of mechanical force through actin-dependent mechanisms. Altogether, we demonstrate that two different modes of population control are connected and coordinated to regulate cell numbers of distinct cell types. Sensing of the tissue environment may serve as a general strategy to control tissue composition.

Significance Statement

Collections of distinct cell types constitute animal tissues. To perform their unique functions, each cell type must exist in the correct number and proportion in a given tissue compartment. However, many of the mechanisms regulating and coordinating cell population sizes remain enigmatic. Our study characterizes two different modes of population size control, utilized by two ubiquitous cell types, macrophages and fibroblasts. Macrophage populations are more sensitive to the presence of growth factors in the environment and fibroblasts are more sensitive to space limitations. Intriguingly, space-sensing mechanisms in fibroblasts directly control the production of growth factor for macrophages and thus macrophage numbers. This link suggests a mechanism by which macrophage compartment size is controlled by stromal cells according to the microenvironment.
Virtual Epileptic Patient (VEP): Data-driven probabilistic personalized brain modeling in drug-resistant epilepsy
Authors: Wang Huifang E , Woodman Marmaduke , Triebkorn Paul , Lemarechal Jean-Didier , Jha Jayant , Dollomaja Borana , Vattikonda Anirudh Nihalani , Sip Viktor , Villalon Samuel Medina , Hashemi Meysam , Guye Maxime , Scholly Julia , Bartolomei Fabrice , Jirsa Viktor
Published: January 2022

One-third of 50 million epilepsy patients worldwide suffer from drug resistant epilepsy and are candidates for surgery. Precise estimates of the epileptogenic zone networks (EZNs) are crucial for planning intervention strategies. Here, we present the Virtual Epileptic Patient (VEP), a multimodal probabilistic modeling framework for personalized end-to-end analysis of brain imaging data of drug resistant epilepsy patients. The VEP uses data-driven, personalized virtual brain models derived from patient-specific anatomical (such as T1-MRI, DW-MRI, and CT scan) and functional data (such as stereo-EEG). It employs Markov Chain Monte Carlo (MCMC) and optimization methods from Bayesian inference to estimate a patient’s EZN while considering robustness, convergence, sensor sensitivity, and identifiability diagnostics. We describe both high-resolution neural field simulations and a low-resolution neural mass model inversion. The VEP workflow was evaluated retrospectively with 53 epilepsy patients and is now being used in an ongoing clinical trial (EPINOV).
1-deoxysphingolipid biosynthesis compromises anchorage-independent growth and plasma membrane endocytosis in cancer cells
Authors: Cordes Thekla , Kuna Ramya S. , McGregor Grace H. , Khare Sanika V. , Gengatharan Jivani , Muthusamy Thangaselvam , Metallo Christian M.
Published: January 2022

Serine palmitoyltransferase (SPT) predominantly incorporates serine and fatty acyl-CoAs into diverse sphingolipids that serve as structural components of membranes and signaling molecules within or amongst cells. However, SPT also uses alanine as a substrate in the contexts of low serine availability, alanine accumulation, or disease-causing mutations in hereditary sensory neuropathy type I (HSAN1), resulting in the synthesis and accumulation of 1-deoxysphingolipids. These species promote cytotoxicity in neurons and impact diverse cellular phenotypes, including suppression of anchorage-independent cancer cell growth. While altered serine and alanine can promote 1-deoxysphingolipid synthesis, they impact numerous other metabolic pathways important for cancer cells. Here we combined isotope tracing, quantitative metabolomics, and functional studies to better understand the mechanistic drivers of 1-deoxysphingolipid toxicity in cancer cells. Both alanine treatment andSPTLC1C133Wexpression induce 1-deoxy(dihydro)ceramide synthesis and accumulation but fail to broadly impact intermediary metabolism, abundances of other lipids, or growth of adherent cells. However, spheroid culture and soft agar colony formation were compromised when endogenous 1-deoxysphingolipid synthesis was induced viaSPTLC1C133Wexpression. Consistent with these impacts on anchorage-independent cell growth, we observed that 1-deoxysphingolipid synthesis reduced plasma membrane endocytosis. These results highlight a potential role for SPT promiscuity in linking altered amino acid metabolism to plasma membrane endocytosis.
Development of Actionable Targets of Multi-kinase Inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells
Authors: Denisova Oxana V. , Merisaari Joni , Kaur Amanpreet , Yetukuri Laxman , Jumppanen Mikael , von Schantz-Fant Сarina , Ohlmeyer Michael , Wennerberg Krister , Aittokallio Tero , Taipale Mikko , Westermarck Jukka
Published: January 2022

Therapeutic resistance to kinase inhibitors constitutes a major unresolved clinical challenge in cancer and especially in glioblastoma. Multi-kinase inhibitors may be used for simultaneous targeting of multiple target kinase and thereby potentially overcome kinase inhibitor resistance. However, in most cases identification of the target kinases mediating therapeutic effects of multi-kinase inhibitors has been challenging. To tackle this important problem, we developed an Actionable Targets of Multi-kinase Inhibitors (AToMI) strategy and used it for characterization of glioblastoma target kinases of staurosporine derivatives displaying synergy with protein phosphatase 2A (PP2A) reactivation. AToMI consists of interchangeable modules combining drug-kinase interaction assay, siRNA high-throughput screening, bioinformatics analysis and validation screening with more selective target kinase inhibitors. As a result, AToMI analysis revealed AKT and mitochondrial pyruvate dehydrogenase kinase PDK1 and PDK4 as kinase targets of staurosporine derivatives UCN-01, CEP-701, and K252a that synergized with PP2A activation across heterogeneous glioblastoma cells. Based on these proof-of-principle results we propose that application and further development of AToMI for clinically applicable multi-kinase inhibitors could provide significant benefits in overcoming the challenge of lack of knowledge of target specificity of multi-kinase inhibitors.
ESCPE-1 Mediates Retrograde Endosomal Sorting of the SARS-CoV-2 Host Factor Neuropilin-1
Authors: Simonetti Boris , Daly James L. , Simón-Gracia Lorena , Klein Katja , Weeratunga Saroja , Antón-Plágaro Carlos , Tobi Allan , Hodgson Lorna , Lewis Phil , Heesom Kate J. , Shoemark Deborah K. , Davidson Andrew D. , Collins Brett M. , Teesalu Tambet , Yamauchi Yohei , Cullen Peter J.
Published: January 2022

Endosomal sorting maintains cellular homeostasis by recycling transmembrane proteins and associated proteins and lipids (termed ‘cargoes’) from the endosomal network to multiple subcellular destinations, including retrograde traffic to the trans-Golgi network (TGN). Viral and bacterial pathogens subvert retrograde trafficking machinery to facilitate infectivity. Here, we develop a proteomic screen to identify novel retrograde cargo proteins of the Endosomal SNX-BAR Sorting Complex Promoting Exit-1 (ESCPE-1). Using this methodology, we identify Neuropilin-1 (NRP1), a recently characterised host factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as a cargo directly bound and trafficked by ESCPE-1. ESCPE-1 mediates retrograde trafficking of engineered nanoparticles functionalised with the NRP1-interacting peptide of the SARS-CoV-2 Spike protein. ESCPE-1 sorting of NRP1 may therefore play a role in the intracellular membrane trafficking of NRP1-interacting viruses such as SARS-CoV-2.
PROTAC-mediated selective degradation of cytosolic soluble epoxide hydrolase enhances ER-stress reduction
Authors: Wang Yuxin , Morisseau Christophe , Takamura Akihiro , Wan Debin , Li Dongyang , Sidoli Simone , Yang Jun , Wolan Dennis W. , Hammock Bruce D. , Kitamura Seiya
Published: January 2022

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme responsible for lipid metabolism and is a promising drug target. Here, we report the first-in-class PROTACs small molecule degraders of sEH. Our optimized PROTAC selectively targets the degradation of cytosolic but not peroxisomal sEH, resulting in exquisite spatiotemporal control. Remarkably, our sEH PROTAC molecule has higher potency in cellular assays compared to the parent sEH inhibitor as measured by significantly reduced ER stress. Interestingly, our mechanistic data indicate that our PROTAC directs degradation of cytosolic sEH via the lysosome, not through the proteasome. The molecules presented here are useful chemical probes to study the biology of sEH with the potential for therapeutic development. Broadly, our results represent a proof-of-concept for the superior cellular potency of sEH degradation over sEH enzymatic inhibition, as well as subcellular compartment-selective modulation of a protein by PROTACs.

Highlights

First-in-class soluble epoxide hydrolase (sEH) small-molecule degraders.

Selective degradation of cytosolic but not peroxisomal sEH.

Significant and stable reduction in sEH protein levels, leading to enhanced cellular efficacy in ER stress reduction relative to the parent inhibitor.
A novel, NADH-dependent acrylate reductase in Vibrio harveyi
Authors: Bertsova Yulia V. , Serebryakova Marina V. , Baykov Alexander A. , Bogachev Alexander V.
Published: January 2022

Bacteria coping with oxygen deficiency use alternative terminal electron acceptors for NADH regeneration, particularly fumarate. Fumarate is reduced by the FAD_binding_2 domain of cytoplasmic fumarate reductase in many bacteria. The variability of the primary structure of this domain in homologous proteins suggests the existence of reducing activities with different specificities. Here we produced and characterized one such protein, Vibrio harveyi ARD, and found it to be a specific NADH:acrylate oxidoreductase. This previously unknown enzyme contains covalently bound FMN and non-covalently bound FAD and FMN in a ratio of 1:1:1. The covalently bound FMN is absolutely required for activity and is attached by the specific flavin transferase, ApbE, to a threonine residue in the auxiliary FMN_bind domain. RT-qPCR and activity measurements indicated dramatic stimulation of ARD biosynthesis by acrylate in the V. harveyi cells grown aerobically. In contrast, the ard gene expression in the cells grown anaerobically was high without acrylate and increased only twofold in its presence. These findings suggest that the principal role of ARD in Vibrio is energy-saving detoxification of acrylate coming from the environment.

Importance

The benefits of the massive genomic information accumulated in recent years for biological sciences have been limited by the lack of data on the function of most gene products. Approximately half of the known prokaryotic genes are annotated as “proteins with unknown functions,” and many other genes are annotated incorrectly. Thus, the functional and structural characterization of the products of such genes, including identification of all existing enzymatic activities, is a pressing issue in modern biochemistry. In this work, we have shown that the ard gene product of V. harveyi (GenBank ID: AIV07243) exhibits a yet undescribed NADH:acrylate oxidoreductase activity. This activity may allow acrylate detoxification and its use as a terminal electron acceptor in anaerobic or substrate in aerobic respiration of marine and other bacteria.