Frontiers in Medicine

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ISSN / EISSN : 2296-858X / 2296-858X
Published by: Frontiers Media SA (10.3389)
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Vanessa Alexandra Buetler, Nada Agbariah, Deborah Pia Schild, Fabian D. Liechti, Anna Wieland, Nicola Andina, ,
Published: 17 May 2022
Frontiers in Medicine, Volume 9; https://doi.org/10.3389/fmed.2022.890661

Abstract:
Introduction: An increasing number of case reports have associated vaccinations against coronavirus disease 2019 (COVID-19) with immune-mediated thrombotic thrombocytopenic purpura (iTTP), a very rare but potentially life-threatening thrombotic microangiopathy, which leads to ischemic organ dysfunction. Thrombus formation in iTTP is related to a severe deficiency of the specific von Willebrand-factor-cleaving protease ADAMTS13 due to ADAMTS13 autoantibodies.Methods: We present a case of iTTP following exposure to the mRNA-based COVID-19 vaccine BNT162b2 (Comirnaty®, Pfizer-BioNTech). In addition, we review previously reported cases in the literature and assess current evidence.Results: Apart from our case, twenty cases of iTTP occurring after COVID-19 vaccination had been published until the end of November 2021. There were 11 male and 10 female cases; their median age at diagnosis was 50 years (range 14–84 years). Five patients (24%) had a preexisting history of iTTP. Recombinant adenoviral vector-based vaccines were involved in 19%, mRNA-based vaccines in 81%. The median onset of symptoms after vaccination was 12 days (range 5–37), with 20 cases presenting within 30 days. Treatment included therapeutic plasma exchange in all patients. Additional rituximab, caplacizumab, or both these treatments were given in 43% (9/21), 14% (3/21), and 24% (5/21) of cases, respectively. One patient died, despite a prolonged clinical course in one patient, all surviving patients were in clinical remission at the end of the observational period.Conclusion: Clinical features of iTTP following COVID-19 vaccination were in line with those of pre-pandemic iTTP. When timely initiated, an excellent response to standard treatment was seen in all cases. ADAMTS13 activity should be determined pre-vaccination in patients with a history of a previous iTTP episode. None of the reported cases met the WHO criteria for assessing an adverse event following immunization (AEFI) as a consistent causal association to immunization. Further surveillance of safety data and additional case-based assessment are needed.
Hyunmin Ahn, Ikhyun Jun, Kyoung Yul Seo, Eung Kweon Kim,
Published: 17 May 2022
Frontiers in Medicine, Volume 9; https://doi.org/10.3389/fmed.2022.871382

Abstract:
Purpose: To investigate an artificial intelligence (AI) model performance using multi-source anterior segment optical coherence tomographic (OCT) images in estimating the preoperative best-corrected visual acuity (BCVA) in patients with senile cataract.Design: Retrospective, cross-instrument validation study.Subjects: A total of 2,332 anterior segment images obtained using swept-source OCT, optical biometry for intraocular lens calculation, and a femtosecond laser platform in patients with senile cataract and postoperative BCVA ≥ 0.0 logMAR were included in the training/validation dataset. A total of 1,002 images obtained using optical biometry and another femtosecond laser platform in patients who underwent cataract surgery in 2021 were used for the test dataset.Methods: AI modeling was based on an ensemble model of Inception-v4 and ResNet. The BCVA training/validation dataset was used for model training. The model performance was evaluated using the test dataset. Analysis of absolute error (AE) was performed by comparing the difference between true preoperative BCVA and estimated preoperative BCVA, as ≥0.1 logMAR (AE≥0.1) or <0.1 logMAR (AE &lt;0.1). AE≥0.1 was classified into underestimation and overestimation groups based on the logMAR scale.Outcome Measurements: Mean absolute error (MAE), root mean square error (RMSE), mean percentage error (MPE), and correlation coefficient between true preoperative BCVA and estimated preoperative BCVA.Results: The test dataset MAE, RMSE, and MPE were 0.050 ± 0.130 logMAR, 0.140 ± 0.134 logMAR, and 1.3 ± 13.9%, respectively. The correlation coefficient was 0.969 (p < 0.001). The percentage of cases with AE≥0.1 was 8.4%. The incidence of postoperative BCVA > 0.1 was 21.4% in the AE≥0.1 group, of which 88.9% were in the underestimation group. The incidence of vision-impairing disease in the underestimation group was 95.7%. Preoperative corneal astigmatism and lens thickness were higher, and nucleus cataract was more severe (p < 0.001, 0.007, and 0.024, respectively) in AE≥0.1 than that in AE &lt;0.1. The longer the axial length and the more severe the cortical/posterior subcapsular opacity, the better the estimated BCVA than the true BCVA.Conclusions: The AI model achieved high-level visual acuity estimation in patients with senile cataract. This quantification method encompassed both visual acuity and cataract severity of OCT image, which are the main indications for cataract surgery, showing the potential to objectively evaluate cataract severity.
Ha Young Yoon, Heisook Lee, Jeong Yee,
Published: 17 May 2022
Frontiers in Medicine, Volume 9; https://doi.org/10.3389/fmed.2022.868040

Abstract:
This study aimed to assess the research on medical Artificial intelligence (AI) related to sex/gender and explore global research trends over the past 20 years. We searched the Web of Science (WoS) for gender-related medical AI publications from 2001 to 2020. We extracted the bibliometric data and calculated the annual growth of publications, Specialization Index, and Category Normalized Citation Impact. We also analyzed the publication distributions by institution, author, WoS subject category, and journal. A total of 3,110 papers were included in the bibliometric analysis. The number of publications continuously increased over time, with a steep increase between 2016 and 2020. The United States of America and Harvard University were the country and institution that had the largest number of publications. Surgery and urology nephrology were the most common subject categories of WoS. The most occurred keywords were machine learning, classification, risk, outcomes, diagnosis, and surgery. Despite increased interest, gender-related research is still low in medical AI field and further research is needed.
Published: 17 May 2022
Frontiers in Medicine, Volume 9; https://doi.org/10.3389/fmed.2022.870587

Abstract:
The use of medicines in healthcare is safer and more effective than it has ever been, with pharmacovigilance having been active in some form for over 150 years (1). Yet, in 2000, marking what is often thought of as the beginning of the modern patient safety era, two landmark reports appeared, one by the Institute of Medicine in the United States, and the other by the Department of Health in the United Kingdom, demonstrating that avoidable patient harm during healthcare remains extraordinarily expensive and unacceptably common (2, 3). Both reports identified that medication errors are a leading cause of patient harm, and called for a “systems” approach to error prevention. A systems approach promotes the redesign of faulty or error-prone aspects of work systems, environments and procedures, based on an understanding of human factors and ergonomics, rather than exhorting individuals to be more careful or blaming them when patient harm occurs. Employing such a systems approach, some high-profile successes have been achieved in the last 20 years (4, 5). However, medication errors remain a persistent and concerning source of patient harm throughout the world, prompting the World Health Organization (WHO) in 2017 to launch its third Global Patient Safety Challenge, namely Medication Without Harm (6). The WHO Challenge report makes it clear that medication errors typically do not occur because of negligence or carelessness, but because of poor quality or unsafe medication systems, and estimates the global cost of medication errors at $42 billion annually. The report calls for a global reduction in the level of avoidable harm related to medications by 50% over 5 years (6). The field of human factors has demonstrated that human beings have measurable physical and psychological limits within which individuals operate at their best (7). Once outside of these limits, sheer effort or exhortation to try harder will have little or no lasting effect, and performance will inevitably decline. In a study in the United States based on 5,888 h of direct observation, hospital interns working traditional shifts involving multiple work periods longer than 24 h each month, had a 21% greater chance of making serious medication errors than when working without extended-duration shifts (8). Fatigue levels, such as these, have been equated to blood-alcohol levels in terms of their detrimental effects on performance, suggesting that work shifts of 17 h or more are equivalent to being intoxicated over the legal limit to drive a car (9). No one would accept a clinician practicing while drunk, yet the expectation is often that equivalent fatigue levels should be worked through simply by sheer effort. A prominent recent reminder that blame is often the first course of action when patient harm occurs can be seen in the response to the tragic death of 6-year old Jack Adcock in 2011 while under the care of Dr. Bawa-Garba (10). Dr. Bawa-Garba did make mistakes during Jack's care, including with medications, but she was operating in a system where any doctor would be have been dangerously overstretched—she was a junior doctor with no senior assistance, in sole charge of six hospital wards, in which the computer system for laboratory results was not functioning at the time (11). Dr. Bawa-Garba was prosecuted for manslaughter, and she and a senior nurse involved in Jack's death, were removed from their professional registers. Such a blame reaction does little or nothing to improve patient safety, as it fails to address the obvious systemic problems underlying the fatal healthcare failure, hence leaving these conditions unaddressed to precipitate further failures in the future. To make matters worse, the legal proceedings against Dr. Bawa-Garba led to widespread concern in the United Kingdom that doctors should no longer record personal reflections on their practice for fear of these records being used against them in a court of law at a later date (12). Given that reflective practice is considered an important part of quality improvement for individual practitioners, it can only be concluded that patient safety in the United Kingdom is now substantially poorer than it was before the Bawa-Garba case. After a long and expensive legal process Dr. Bawa-Garba was reinstated as a medical practitioner in 2018, yet little attention has been given to the system problems that precipitated the tragedy (13). Unfortunately, criminal prosecutions of clinicians for simple human errors are not uncommon, and continue to occur, as demonstrated by the current high-profile case in the United States in which nurse, RaDonda Vaught, has been found guilty of criminally negligent homicide resulting from a medication error (14, 15). Despite policy level directives that the systems approach should be prioritized over exhortation and blame when aiming to reduce medication errors and patient harm, evidence would suggest that this is often not the case during everyday clinical work (16). For example, in 2020, a 10-year multisite study reported 4223 local corrective measures taken in response to 7072 patient safety incident reports made during perioperative and critical care (17). The study lists the five leading corrective measures as: (1) communication through mortality and morbidity meetings; (2) email alerts; (3) new or revised clinical protocols; (4) a change in material or supplier; and (5) more training. Note that four out of five of these corrective measures are exhortative in nature, and are consistent with the belief that patient safety is best achieved through greater effort on the part of clinicians (e.g., be more aware, follow the new protocol, get better trained). Only one corrective measure (a change in material or supplier), involves a minor change to the work system in which clinicians are expected to perform safely. The perioperative period is one of the most intensive phases of medication administration in...
Yi Wang, Lingling Tian, Lin Sun, Wenjing Zhou, Wenqiang Zhi, Jianbo Qing, Yasin Abdi Saed, Lina Dong, Xiadong Zhang,
Published: 17 May 2022
Frontiers in Medicine, Volume 9; https://doi.org/10.3389/fmed.2022.823267

Abstract:
Microbial ecosystem consists of a complex community of bacterial interactions and its host microenvironment (tissue, cell, metabolite). Because the interaction between gut microbiota and host involves many diseases and seriously affects human health, the study of the interaction mechanism between gut microbiota and host has attracted great attention. The gut microbiome is made up of 100 trillion bacteria that have both beneficial and adverse effects on human health. The development of IgA Nephropathy results in changes in the intestinal microbial ecosystem that affect host physiology and health. Similarly, changes in intestinal microbiota also affect the development of IgA Nephropathy. Thus, the gut microbiome represents a novel therapeutic target for improving the outcome of IgA Nephropathy, including hematuria symptoms and disease progression. In this review, we summarize the effect of intestinal microbiota on IgA Nephropathy in recent years and it has been clarified that the intestinal microbiota has a great influence on the pathogenesis and treatment of IgA Nephropathy.
Shiwei Wang, Guoxiang Liu, Tianyuan Jia, Changsheng Wang, Xiaoye Lu, Lei Tian, Qian Yang, Changqing Zhu
Published: 17 May 2022
Frontiers in Medicine, Volume 9; https://doi.org/10.3389/fmed.2022.848491

Abstract:
Background and Objective: Acute kidney injury (AKI), the common complication after cardiopulmonary resuscitation (CPR), seriously affects the prognosis of cardiac arrest (CA) patients. However, there are limited studies on post-resuscitation AKI. In addition, it has been demonstrated that N-acetylcysteine (N-AC) as an ROS scavenger, has multiorgan-protective effects on systemic and regional ischaemia-reperfusion injuries. However, no studies have reported its protective effects against post-resuscitation AKI and potential mechanisms. This study aimed to clarify the protective effects of N-AC on post-resuscitation AKI and investigate whether its potential mechanism was mediated by activating Nrf-2/HO-1 pathway in the kidney. Methods: We established cardiac arrest models in rats. All animals were divided into four groups: the sham, control, N-AC, and ZnPP groups. Animals in each group except for the ZnPP group were assigned into two subgroups based on the survival time: 6 and 48 h. The rats in the control, N-AC, and ZnPP groups underwent induction of ventricular fibrillation (VF), 8 min untreated VF and cardiopulmonary resuscitation. Renal function indicators, were detected using commercial kits. Renal pathologic changes were assessed by haematoxylin–eosin (HE) staining. Oxidative stress and inflammatory responses were measured using the corresponding indicators. Apoptosis was evaluated using terminal uridine nick-end labeling (TUNEL) staining, and expression of proteins associated with apoptosis and the Nrf-2/HO-1 pathway was measured by western blotting. Results: N-AC inhibited post-resuscitation AKI. We observed that N-AC reduced the levels of biomarkers of renal function derangement; improved renal pathological changes; and suppressed apoptosis, oxidative stress, and inflammatory response. Additionally, the production of ROS in the kidneys markedly decreased by N-AC. More importantly, compared with the control group, N-AC further upregulated the expression of nuclear Nrf2 and endogenous HO-1 in N-AC group. However, N-AC-determined protective effects on post-resuscitation AKI were markedly reversed after pretreatment of the HO-1 inhibitor zinc protoporphyrin (ZnPP). Conclusions: N-AC alleviated renal dysfunction and prolonged survival in animal models of CA. N-AC partially exerts beneficial renal protection via activation of the Nrf-2/HO-1 pathway. Altogether, all these findings indicated that N-AC as a common clinical agent, may have the potentially clinical utility to improve patients the outcomes in cardiac arrest.
Jiaqi Zhang, Ning Liang, Yan Cao, Min Li
Published: 16 May 2022
Frontiers in Medicine, Volume 9; https://doi.org/10.3389/fmed.2022.839066

Abstract:
Vitiligo is characterized by chronic skin depigmentation arising from the autoimmune destruction of epidermal melanocytes. Systemic corticosteroid therapy is an effective immunosuppressive treatment for progressive generalized vitiligo. Circular RNAs (circRNAs) play various roles in diseases. In systemic corticosteroid therapy, however, how circRNAs function to counter vitiligo is still unclear. In this article, we identified the differentially expressed circRNAs (DEcircRNAs) in vitiligo patients before and after the administration of methylprednisolone. Total RNA was extracted from the peripheral blood of patients with vitiligo, and samples were hybridized into a circRNA array. A total of 375 (51 upregulated and 324 downregulated) circRNAs were differentially expressed. Box, scatter, volcano, and heatmap plots were generated to classify the samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on DEcircRNAs. These DEcircRNAs were enriched in vitiligo-related biological processes, such as ferroptosis, organic substance transport, protein metabolic process, and cellular component organization or biogenesis. Two different databases, TargetScan and miRanda, were used to predict circRNA/miRNA interactions. Several circRNA/miRNA interactions were involved in ferroptosis. These circRNAs might serve as therapeutic targets in the treatment of vitiligo.
TianYue Zhang, Xiaoxiao Song, Jie Qiao, Ruiliang Zhu, Yuezhong Ren,
Published: 16 May 2022
Frontiers in Medicine, Volume 9; https://doi.org/10.3389/fmed.2022.856606

Abstract:
Background: The impact of hypoxia on ferroptosis is important in cancer proliferation, but no predictive model combining hypoxia and ferroptosis for adrenocortical carcinoma (ACC) has been reported. The purpose of this study was to construct a predictive model based on hypoxia- and ferroptosis-related gene expression in ACC. Methods: We assessed hypoxia- and ferroptosis-related gene expression using data from 79 patients with ACC in The Cancer Genome Atlas (TCGA). Then, a predictive model was constructed to stratify patient survival using least absolute contraction and selection operation regression. Gene expression profiles of patients with ACC in the Gene Expression Omnibus (GEO) database were used to verify the predictive model. Results: Based on hypoxia-related gene expression, 79 patients with ACC in the TCGA database were divided into three molecular subtypes (C1, C2, and C3) with different clinical outcomes. Patients with the C3 subtype had the shortest survival. Ferroptosis-related genes exhibited distinct expression patterns in the three subtypes. A predictive model combining hypoxia- and ferroptosis-related gene expression was constructed. A nomogram was constructed using age, sex, tumor stage, and the predictive gene model. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that the gene signature was mainly related to the cell cycle and organelle fission. Conclusion: This hypoxia-and ferroptosis-related gene signature displayed excellent predictive performance for ACC and could serve as an emerging source of novel therapeutic targets in ACC.
Ping Yang, Zhenchao Wu, Chao Liu, Jiajia Zheng, Nan Wu, Zhangli Wu, Juan Yi, Ming Lu, Ning Shen
Published: 16 May 2022
Frontiers in Medicine, Volume 9; https://doi.org/10.3389/fmed.2022.889020

Abstract:
Background: Sequence type 11 (ST11) Klebsiella pneumoniae (Kp) is highly prevalent in China and is a typical sequence type among KPC-producing isolates. This study aimed to evaluate the clinical outcomes and microbiological features of ST11 Kp infections.Methods: A retrospective cohort study was conducted at Peking University Third Hospital from January 2017 to March 2021. Clinical data were collected from medical records. Antimicrobial susceptibility testing and string tests were performed. Whole-genome sequencing was used to analyze the capsular serotypes, detect virulence-associated genes, and perform multilocus sequence typing. The risk of all-cause mortality in ST11 Kp-infected patients was compared to that in non-ST11 Kp-infected patients.Results: From 139 patients infected with Kp, 49 ST11 Kp (35.3%) strains were isolated. The Charlson comorbidity index in the ST11 group was higher than that in the non-ST11 group (3.94 ± 1.59 vs. 2.41 ± 1.54, P = 0.001). A greater number of ST11 Kp-infected patients required ICU admission (46.9 vs. 16.7%, P < 0.001) and mechanical ventilation (28.6 vs. 10.0%, P = 0.005). All ST11 isolates presented a multidrug-resistant (MDR) phenotype, and twenty-nine (59.2%) hypervirulent Kp (hvKp) were identified. Twenty-four ST11 strains presented with hypermucoviscosity. The presence of capsular types K47 and K64 was frequent in the ST11 Kp strains (P < 0.001). The key virulence-associated genes rmpA, rmpA2, iucA, iroB, and peg344 were present in 26.5, 42.9, 59.2, 0, and 26.5% of the isolates, respectively, in the ST11 group. Twenty-one ST11 isolates harbored the combination of iucA+rmpA2. The 30-day mortality rate and sequential organ failure assessment (SOFA) score were significantly higher in ST11 Kp-infected patients than in non-ST11 Kp-infected patients (P < 0.01). ST11 Kp infection appeared to be an independent risk factor for mortality in ST11 Kp-infected patients.Conclusions: A high prevalence of the ST11 clone was found in the hospital, which accounted for elevated antimicrobial resistance and exhibited great molecularly inferred virulence. Patients with ST11 Kp infection had a tendency toward increased 30-day mortality and SOFA scores. ST11 Kp infection was an independent risk factor for mortality, suggesting that enhanced surveillance and management are essential.
Chen Chen, Xia Liu, Xiaoyan Peng
Published: 16 May 2022
Frontiers in Medicine, Volume 9; https://doi.org/10.3389/fmed.2022.895208

Abstract:
Background: To date, various treatments for cystoid macular edema (CME) in retinitis pigmentosa (RP) have been reported. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of current treatments for RP-CME. Methods: PubMed, Embase and the Cochrane library were searched from inception to August 2021. ClinicalTrials.gov, WHO ICTRP and ISRCTN were also searched for relevant studies. Only studies published in English were included. The RoB 2 tool was used to evaluate the risk of bias of randomized controlled trials (RCTs), and the MINORS scale was used to assess the methodological quality of non-RCTs. Review manager (Revman) was used to pool the data. The primary outcomes included the change of central macular thickness (CMT) and best-corrected visual acuity (BCVA) from baseline. The secondary outcomes included fluorescein angiography (FA) leakage, rebound of CME and adverse effects. Results: Thirty-two studies were included in the current systematic review and 7 studies were used for meta-analysis. Treatments for RP-CME included oral and topical carbonic anhydrase inhibitors (CAIs), systematic and local steroids, anti-VEGF therapy, NSAIDS, grid LASER photocoagulation, subliminal micropulse LASER, vitrectomy, lutein supplement and oral minocycline. CAIs and local steroids were proved to be effective in reducing CMT. The effects of anti-VEGF reagents varied among studies. Regarding other treatments, only one study for each method fitted the inclusion criteria, so the evidence was very limited. Conclusion: Topical CAIs, oral CAIs and local steroids are effective in treating RP-CME. However, due to the overall inferior design and small patient number of the included studies, the quality of evidence was poor. Systematic steroids, LASER, NSAIDS and vitrectomy may also be effective, nevertheless, considering the limited number of studies, no conclusion could be drawn regarding these treatments. More well-designed and conducted studies are needed in this field. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021273979, identifier CRD42021273979.
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