The current burden of dyslipidemia, the pre-hospital application of statins and the association of pre-hospital statins with the severity of coronary artery disease (CAD) and in-hospital outcomes in Chinese patients with first acute coronary syndrome (ACS) are very significant and remain unclear.A total of 41,183 patients who underwent coronary angiography and were diagnosed with ACS for the first time from a nationwide registry study (CCC-ACS) were enrolled. The severity of CAD was assessed using the CAD prognostic index (CADPI). The patients were classified into statin and non-statin groups according to their pre-hospital statin treatment status. Clinical characteristics, CADPI and in-hospital outcomes were compared, and a logistic regression analysis was performed to determine whether pre-hospital statin therapy is associated with in-hospital outcomes and CADPI. A sensitivity analysis was used to further explore the issues above.P = 0.010). However, no association exists between statin pretreatment and in-hospital major adverse cardiovascular events (MACEs) or all-cause deaths in the entire population and subgroups . Surprisingly, statin pretreatment was associated with an 8.9% higher risk of severely obstructive CAD (CADPI ≥ 37) , and similar results were observed in subgroups of females, those aged 50 to 75 years, and patients with hypertension.The non-statin group had more in-hospital all-cause deaths (1.2 vs. 0.8%, Statin pretreatment was not related to MACEs or all-cause death during hospital stay, but it was associated with a higher risk of increased angiographic severity in patients with first ACS. Coronary artery disease (CAD) remains the leading cause of mortality worldwide , 2. MoraDyslipidemia is an independent risk factor for CAD, and statin therapy is well established for the primary and secondary prevention of cardiovascular diseases. Each 1 mmol/L reduction in low-density lipoprotein cholesterol (LDL-C) with statin therapy reduces the risk of major adverse cardiovascular events (MACEs) by approximately one-fifth –7. HenceSome studies have investigated the association of statin pretreatment with cardiovascular outcomes, but the results remain controversial. Ndrepepa et al. found that pretreatment of statins before percutaneous coronary intervention (PCI) was associated with a significant reduction of 1-year mortality in patients with stable angina . Two metIn the current study, we investigated the pre-hospital application of statins and the current burden of dyslipidemia and determined the relationship between pre-hospital statin treatment and angiographic severity [evaluated with the CAD prognostic index (CADPI)] and in-hospital outcomes in patients with first ACS in a nationwide registry study with ‘real-world’ settings: the Improving CCC (Care for Cardiovascular Disease in China) ACS project .CCC-ACS(NCT02306616), a national hospital-based quality improvement program, aims to increase adherence to ACS guidelines in China and to improve patient outcomes. Launched in 2014, the project had recruited 150 centers representing the diversity of care for ACS patients in tertiary hospitals across China at the time of the current study. For additional details, please refer to the published paper , non-ST-segment elevation myocardial infarction (NSTEMI) and STEMI. The exclusion criteria were as follows: without CAG (coronary angiography) check, renal failure, past AMI, past PCI or CABG, history of stroke and heart failure, and lack of clarity about the application of pre-hospital statins, myocardial injury markers, severe clinical conditions at admission and in-hospital outcomes. After exclusion, 41,183 of 63,641 inpatients with first ACS were registered between April 2014 and June 2017 from 150 hospitals. This study was approved by the ethics committee of Beijing Anzhen Hospital, Capital Medical University.The CADPI classification is hierarchical (0–100), and patients are assigned to the most severe category that applies to them. The CADPI cut-off point (≥37 versus <37) was selected to reflect > 70% stenosis in > 1 major epicardial coronary artery, which is a clinically actionable threshold for revascularization; this is also the cut-off point at which a survival benefit has been demonstrated previously for revascularization –17. DetaThe outcomes of this study included MACEs and all-cause deaths that occurred during hospitalization. MACEs were defined as a combination of cardiogenic death, recurrent myocardial infarction, stent thrombosis, and ischemic stroke.STEMI and NSTEMI are defined for study inclusion according to the recommended diagnostic criteria of the STEMI guidelines of 2010 and the non–ST-elevation ACS (NSTE-ACS) guidelines of 2012 issued by the CSC , 19. BecStatistical analyses were performed using SPSS 23.0 . Continuous variables were summarized using the mean ± standard deviation (SD) or median (IQR), and categorical variables were presented by counts and percentages. Continuous variables between two groups were compared by the two-sided t-test or the Mann–Whitney U test according to the normality of the distribution. Continuous variables between three or more groups were compared by an ANOVA or the Kruskal-Wallis test according to the normality of the distribution. Categorical variables were assessed with the Chi-square test. We used Cox regression analysis to calculate HRs and 95% confidence intervals (CIs) for in-hospital outcomes comparisons. Cox regression were constructed based on a 15-day observation. Hazard ratios (HRs) for different variables and corresponding 95% confidence intervals (CIs) were reported. A binary logistic regression was performed to examine the association between statin pretreatment and in-hospital outcomes or CADPI. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. Subgroup analyses of in-hospital outcomes and CADPI were then performed based on important characteristics, including age , sex , hypertension (no or yes), diabetes mellitus , PCI (no or yes), and Killip class (I-II or III-IV). Two-tailed p values of less than 0.05 were considered statistically significant.P = 0.876). The statin group contained a higher proportion of females than the non-statin group . Fewer patients in the statin group had five-fold elevated myocardial injury markers than in the non-statin group .A total of 5,224 (12.7%) patients with first ACS had a history of pre-hospital statin treatment. As showed in P < 0.001]. A total of 29,202 (89.9%) and 3,779 (80.6%) patients in the non-statin and statin groups (P < 0.001) did not meet the lipid-lowering treatment goals [LDL-C < 1.8 mmol/L (70 mg/dl)] for patients with arteriosclerotic cardiovascular disease (ASCVD), respectively. Similar to LDL-C, total cholesterol levels were also further decreased in the statin group compared with the non-statin group . However, pre-hospital statin treatment did not increase the HDL-C levels  and did not result in any differences in triglycerides between the 2 groups .As shown in P = 0.435). A total of 473 patients died during hospitalization . However, the rates of MACEs did not differ between the two groups .As shown in P = 0.955) and all-cause death  after controlling for confounders. Surprisingly, statin pretreatment was associated with an 8.9% higher risk of severely obstructive CAD (CADPI ≥ 37) . In addition, a Cox regression about MACE/all-cause death was employed based on the in-hospital stay (within 15 days) and statin pretreatment and the results showed no association with MACE/all-cause death  after controlling for confounders  in the entire population and in three subgroups . To the best of our knowledge, this study is the first to report about the relationship of the application of pre-hospital statins with angiographic severity in China based on a nationwide registry study with ‘real-world’ settings and a nationally representative sample of patients from tertiary hospitals.P < 0.001). Moreover, 89.9% and 80.6% of patients in the non-statin and statin groups did not meet the lipid-lowering treatment goals (LDL-C < 1.8 mmol/L) for patients with ASCVD, respectively, and similar results were observed in the subgroups, suggesting a huge burden of potential MACEs in the future. This is a significant challenge for Chinese cardiologists, and more attention should be paid to the lipid management of patients with ACS during long-term follow-up.The 2007–2008 China National Diabetes and Metabolic Disorders Study showed that the prevalence of dyslipidemia was 67.43% in males and 63.98% in females in Chinese people aged 20 and older . AnotherStatins are highly effective for the management of hyperlipidemia and CAD , 25. AsiA previous cross-sectional study showed that statin pretreatment is associated with reduced clinical severity in patients with acute ischemic cerebrovascular events . HoweverThe main mechanisms for ACS, especially fatal coronary events, is the rupture of the plaque’s protective fibrous cap. Superficial erosion, intraplaque hemorrhage, and the erosion of a calcified nodule also account for a minority . Thus, nIt has been demonstrated that plaque statin therapies attenuate progression and strengthen plaque stability and even achieve plaque regression and it may stabilize plaque by converting its components: The ESTABLISH study clarified for the first time that statin (atorvastatin 20 mg daily) significantly reduced plaque volume . The PROThis study involved the largest nationwide registry with ‘real-world’ settings (the Improving CCC-ACS project) to investigate the relationship of pre-hospital statin treatment with the severity of disease (CADPI) and in-hospital outcomes in patients with first ACS. Some limitations of the study cannot be neglected. First, larger prospective randomized clinical trials with long-term follow-up will be necessary in the future. Second, we did not precisely address the duration, dose and class of the statins, which might have affected the results. Last, a few individuals whose basic clinical data were seriously deficient were included in this study. Hence, we did not consider people with missing data and instead used a multiple interpolation method to interpolate the data.The initial ACS population in China has a huge burden of dyslipidemia with a low intervention rate. Pre-hospital statin intervention was not related to MACEs or all-cause death during hospital stay but was associated with a higher risk of increased angiographic severity in patients with first ACS. This is a significant challenge for Chinese cardiologists, and more attention should be paid to the lipid management of patients with ACS during long-term follow-up.The data analyzed in this study is subject to the following licenses/restrictions: The original data belongs to the improving CCC (Care for Cardiovascular Disease in China) ACS project. Requests to access these datasets should be directed to the improving Care for Cardiovascular Disease in China (CCC) project.www.clinicaltrials.gov (NCT02306616).Institutional Review Board approval was granted for the aggregate data set for research and quality improvement by the Ethics Committee of Beijing An Zhen Hospital, Capital Medical University. Participating sites were granted a waiver of patient consent under the common rule. This study was listed at LZ and ZY conceived and designed the study. JZ contributed to the design. LZ performed the study, analyzed the data, and drafted the manuscript. YZ, CC, and FD helped with the study. All authors read, critically revised, and approved the final manuscript.


Background: PARP inhibitors have shown significant improvement in progression-free survival, but their costs cast a considerable financial burden. In line with value-based oncology, it is important to evaluate whether drug prices justify the outcomes.Objectives: The aim of the study was to systematically evaluate PARP inhibitors on 1) cost-effectiveness against the standard care, 2) impact on cost-effectiveness upon stratification for genetic characteristics, and 3) identify factors determining their cost-effectiveness, in four cancer types.Methods: We systematically searched PubMed, EMBASE, Web of Science, and Cochrane Library using designated search terms, updated to 31 August 2021. Trial-based or modeling cost-effectiveness analyses of four FDA-approved PARP inhibitors were eligible. Other studies known to authors were included. Reference lists of selected articles were screened. Eligible studies were assessed for methodological and reporting quality before review.Results: A total of 20 original articles proceeded to final review. PARP inhibitors were not cost-effective as recurrence maintenance in advanced ovarian cancer despite improved performance upon genetic stratification. Cost-effectiveness was achieved when moved to upfront maintenance in a new diagnosis setting. Limited evidence indicated non–cost-effectiveness in metastatic breast cancer, mixed conclusions in metastatic pancreatic cancer, and cost-effectiveness in metastatic prostate cancer. Stratification by genetic testing displayed an effect on cost-effectiveness, given the plummeting ICER values when compared to the “treat-all” strategy. Drug cost was a strong determinant for cost-effectiveness in most models.Conclusions: In advanced ovarian cancer, drug use should be prioritized for upfront maintenance and for patients with BRCA mutation or BRCAness at recurrence. Additional economic evaluations are anticipated for novel indications. The development of poly (ADP-ribose) polymerase (PARP) inhibitors represents a breakthrough in first harnessing the “synthetic lethality” concept in clinical use  and kickAlthough efficacy as first-line monotherapy is as yet unproven, PARP inhibitors as maintenance therapy amplify the existing treatment effect. In advanced ovarian cancer, patients receive repeated courses of platinum-based chemotherapies with over 70% risk of recurrence until “platinum resistance” . In metaValue-based oncology is thus warranted to address the cost-effectiveness of novel drugs, for which acceptable prices should be tied to justifiable patient outcomes by cost-effectiveness analyses . IncremeGiven the recently approved multiple indications in a variety of cancer types and the inconsistent genetic prerequisites for BRCA mutation and HRD status across indications, it is also questionable whether the full biomarker-guided use of PARP inhibitors would improve cost-effectiveness as they acted more profoundly on patient stratification. In this systematic review, we aimed to evaluate PARP inhibitors on 1) the cost-effectiveness against the standard of care, 2) impact on cost-effectiveness upon stratification for genetic characteristics, and 3) to elucidate the key factors that determine cost-effectiveness in the management of ovarian, breast, pancreatic, and prostate cancers.This study was conducted according to the recommended checklist of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and benchmarked with the methodology of similar systematic reviews on medicinal cost-effectiveness .We systematically searched PubMed, EMBASE, Web of Science, and Cochrane Library, without language and date restriction, using the search terms:  and (“cost” OR “cost-effectiveness” OR “cost-utility” OR “economics”) in any field, updated to 31 August 2021. Reference lists of eligible articles were checked for additional relevant articles, and other studies known to the authors were included. Eligibility criteria were trial-based, or modeling cost-effectiveness analyses published in English or Chinese language related to any of the four FDA-approved PARP inhibitors, regardless of cancer types, lines of treatment, and comparator interventions. Non-comparative studies, reviews, responses, editorials, protocols, and abstract-only articles were excluded.Studies were assessed using the Quality of Health Economics Studies (QHES) instrument  and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist  . ArticleData were extracted based on a pre-defined extraction framework for bibliography, methods, results, and conclusion, including ICER at base-case analysis and model impact at sensitivity analyses. All presented monetary values were converted to U.S. dollars in the year of publication. The primary outcome of interest was the ICER of PARP inhibitors compared with observation (no maintenance treatment after standard treatment), alternative PARP inhibitors, and the standard of care.Two independent researchers (VKYC and RQY) performed literature screening and quality assessment. Data were extracted by one researcher (RQY) and cross-checked by another researcher (VKYC). All discrepancies were resolved in consensus meetings.A total of 22 original full-text studies passed the initial screening for eligibility . Among tn = 13), five in Asia, and two in Europe. Most studies targeted patients with advanced ovarian cancer (n = 15), with nine focusing on recurrence and six covering new diagnosis setting. The remaining studied metastatic pancreatic (n = 2), breast (n = 2), and prostate (n = 1) cancers. Five studies investigated the role of PARP inhibitors as active treatment, 16 studies as maintenance treatment, and one covered both categories. All studies used decision modeling. The most frequently adopted time horizon was a short-term between 1 and 5 years or until disease progression (n = 10). Ten studies were set out from the payer’s perspective, seven from a healthcare system perspective, and three from a societal perspective. Major comparison arms were observation (n = 15), followed by standard care (n = 5), and alternative biomarker-directed strategies (n = 2). All studies stratified patients based on BRCA mutation, but only three studies examined the effect of HRD status. Overall, the maintenance strategies with PARP inhibitors generated additional 0.07–4.41 QALYs compared with observation. As active treatment, PARP inhibitors gave 0.03–0.67 QALY compared with the standard care. Clinical benefits varied across types and lines of PARP inhibitors, comparison arms, genetic characteristics, time horizon, and simulation methods of survival data. Costs varied greatly between health systems and country contexts.PARP inhibitors were widely studied as maintenance treatment for patients with recurrent advanced ovarian cancer who were responsive to platinum-based chemotherapy. Eight studies compared PARP inhibitors against observation, with six of these concluding that they were not cost-effective. Specifically, In contrast to maintenance therapies, two studies evaluated the active role of PARP inhibitors in later lines in comparison with chemotherapies in the recurrence setting, with inconsistent results. In BRCAmut patients, the Institute for Clinical and Economic Review Report deemed olaparib cost-effective versus PLD + C  at $146,210 per QALY, in contrast to rucaparib, which was not cost-effective at $294,593 per QALY against PLD + C . HoweverSince 2018, PARP inhibitors have been approved for earlier use as upfront maintenance rather than waiting for relapse occurrence following successful response to first-line chemotherapy, based on genetic characteristics. Six studies investigated their value as upfront maintenance. Five studies compared PARP inhibitors against observation with four concluding them to be cost-effective. In particular, PARP inhibitors were approved for metastatic breast cancer with HER2-negative gBRCAmut patients who failed chemotherapy or for HR-positive gBRCAmut patients who failed or were ineligible for endocrine therapies. Two studies investigated the cost-effectiveness of PARP inhibitor versus standard chemotherapies in these patients, and both deemed the former not cost-effective. Saito’s group in Japan compared the strategy of olaparib monotherapy after positive BRCA mutation profiling to the use of capecitabine, eribulin, or vinorelbine without testing and discovered that the former costs $131,047 per QALY, which was hardly cost-effective at the WTP threshold of $89,286 . RegardiBRCAmut metastatic pancreatic cancer, a recent indication approved in 2019, was studied by two groups for its cost-effectiveness versus placebo, but the conclusions were mixed. In particular, Olaparib, as maintenance after first-line platinum-based chemotherapy for gOnly one study evaluated the cost-effectiveness in metastatic castration-resistant prostate cancer, owing to the recent approval in 2020. In the two scenarios modeled by Su et al. in the United States, compared with the standard care, olaparib was cost-effective when used among patients with at least one gene alteration in BRCA1, BRCA2, and ATM, with an ICER yielded at $116,903 per QALY. In the case of expanding the treatment group to patients who had alterations in any of all 15 pre-specified genes  after NGS testing, olaparib turned out to be a cost-effective option .In the studies that separated their analyses based on genetic characteristics, the ICERs using PARP inhibitors among only BRCAmut and/or HRD-positive patients were always lower than those among all patients, implying that the biomarker-directed treatment strategy was potentially cost-effective. Four studies directly compared the biomarker-directed strategy against “global PARP inhibitors,” an approach that offers the drug to all patients, regardless of their genetic characteristics. In recurrent advanced ovarian cancer, All the articles performed sensitivity analyses to assess the factors which potentially impacted the cost-effectiveness of PARP inhibitors. Out of 20 studies, 17 highlighted that the drug price was a significant driver of the ICER . In the PARP inhibitors marked a breakthrough in the burgeoning wave of precision oncology as they provide substantial progression-free survival benefit in a broad range of patients with actionable targets. The unbridled high costs may nonetheless hinder their presence in clinical routines; health economic studies are therefore warranted to assess priorities. This systematic review depicts several findings. First, the cost-effectiveness of PARP inhibitors varied with cancer types and lines of treatment. In most cases, they were not cost-effective as maintenance treatment for recurrent advanced ovarian cancer was compared with observation, but a stronger potential was attained when moved earlier to upfront maintenance in newly diagnosed advanced ovarian cancer. Limited evidence showed that PARP inhibitors were not cost-effective in metastatic breast cancer. The conclusions were mixed for metastatic pancreatic cancer, whilst olaparib in metastatic prostate cancer seemed to be cost-effective. Next, stratification by tumor genetic characteristics displayed an effect on ICERs, given the plummeting ICER values after confining treatment to BRCAmut- and/or HRD-only patients. Finally, drug cost was consistently highlighted in all models as a strong cost-effectiveness determinant, followed by the hazard ratio of PFS in some models. However, costs of comparator treatments, hospice care, general adverse event management, and molecular tests made minimal impact on all models.This review serves to inform payers of the overall cost-effectiveness pattern of PARP inhibitors and key areas to intervene for resource prioritization. Although all included studies utilized registrational randomized data, the overall conclusions in the analyses are logical. In platinum-sensitive BRCAmut ovarian cancer, olaparib maintenance offered significant PFS improvement with 19.1 versus 5.5 months of placebo upon first recurrence in the landmark trial, but when the drug was moved to upfront maintenance in newly diagnosed advanced ovarian cancer, the estimated median PFS difference was numerically extended to 36 months . DespiteUndeniably, the poor cost-effectiveness of PARP inhibitors in recurrent ovarian cancer and metastatic breast cancer remains an issue. The standard comparator in platinum-sensitive ovarian cases was wait-and-watch, which explains the tremendous incremental cost, following the introduction of an extra treatment. In the case of metastatic breast cancer, however, it was more attributed by the relatively minuscule incremental QALY as olaparib and talazoparib were compared against an effective treatment. Another contributor for both was the steep drug price, a strong determining factor identified in 85% of the studies. Taking the United States system as an example, the per month wholesale acquisition costs of PARP inhibitors for ovarian cancer ranged from $13,679 to 18,070 between 2017 and 2018 . In thisThere is a disproportionate distribution of economic evidence across different indications, countries, and health systems. The majority of studies were in the United States, and the remaining studies mostly originated from other developed countries, which signify an unmet need in developing countries where cost-effectiveness or even treatment access is questionable. Next, compared with advanced ovarian cancer, fewer studies evaluated the use of PARP inhibitors in metastatic breast, pancreatic, and prostate cancers, given that the latter indications were only approved recently. An assessment of cost-effectiveness consistency across systems was therefore less possible in these indications. Finally, owing to the lack of mature overall survival data, most studies either projected the overall survival impact based on the available PFS data or relied heavily on PF-QALY for interpretation. However, previous literature studies showed that a positive PFS correctly predicted a positive overall survival only 71% of the time . Since oPARP inhibitors were not cost-effective as maintenance treatment for recurrent ovarian cancer but could be cost-effective if used for newly diagnosed patients. PARP inhibitor use should be prioritized for upfront maintenance and for patients with BRCA mutation or BRCAness at recurrence. Economic evidence in metastatic breast, pancreatic, and prostate cancers was less and with mixed conclusions. Drug cost is the most important determinant for cost-effectiveness. Additional economic evaluations across the globe with mature overall survival data and novel indications are anticipated.


Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a destructive small vessel vasculitis affecting multiple organs. Renal involvement often leads to end-stage renal disease and increases mortality. Prompt diagnosis and initiation of adequate immunosuppressive therapy are critical for the best patient and kidney outcomes. However, considerable heterogeneity in symptoms and severity across the patients frequently hinder the diagnosis and management. The objective of this review is to emphasize the heterogeneity of the ANCA-associated vasculitis, facilitate the recognition and give guidance to the therapeutical possibilities. We present epidemiologic and risk factors, pathogenesis, and provide comprehensive clinical features of the disease. This article also focuses on the currently available therapeutic options and emerging cellular and molecular targets for the management of systemic and especially renal disease. We conducted extensive literature research published on PubMed and Google Scholar. We systematically reviewed, analyzed, and assembled databases, covering a broad spectrum of aspects of the disease. We compared and summarized the recommendations of two recent guidelines on ANCA-associated vasculitis. The incidence of ANCA-associated vasculitis, hence glomerulonephritis shows a steady increase. Familiarity with the presenting symptoms and laboratory abnormalities are necessary for rapid diagnosis. Early initiation of treatment is the key aspect for favorable patient and renal outcomes. A better understanding of the pathogenesis constantly leads to more targeted and therefore more efficient and less toxic treatment. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an inflammatory disorder of the small arteries, resulting in vascular destruction and tissue necrosis affecting various organs . The majGlomerulonephritis is a frequent manifestation of AAV, presenting in almost all cases of MPA and frequently in GPA , 3. RenaThe worldwide reported prevalence of AAV ranges from 4.6 to 21.8 cases per one million person-years –7. Most There is an obvious geographical difference between the distributions of MPA and GPA; MPA is more frequent in Southern Europe and Asia, while GPA is more prevalent in Northern Europe and Australia , 9, 12. Meta-analysis and genome-wide association studies (GWAS) confirm different genetic background for MPO- and PR3-AAV , 22.According to the current hypothesis, AAV occurs in genetically predisposed patients who were exposed to certain environmental factors. GWAS identified several human leukocyte antigen (HLA) and non-HLA regions associated with AAV. GPA is linked to HLA-DP1, α1-antitrypsin (SERPINA) and proteinase 3, MPA to HLA-DQ, and EGPA to HLA-DRB4. Single-nucleotide polymorphism in protein tyrosine phosphatase (PTPN22), cytotoxic T lymphocyte-associated antigen-4 (CTLA4), Toll-like receptor 9, Fc gamma receptors, interleukin-10 and 2 were also associated with higher occurrence of AAV , 24. EnvThe key concept in the pathogenesis is the priming of the neutrophil granulocytes. During priming, neutrophil responsiveness is amplified by an activating stimulus by prior exposure to an agent. Examples of priming agents include tumor necrosis alpha (TNFα), interleukin (IL)-1,−6, interferon-gamma (IFNγ), lipopolysaccharides, substance P, and granulocyte-macrophage colony-stimulating factor (GM-CSF) , 32. AddMPO rests in the azurophil granules, bound to neutrophil elastase (NE), cathepsin G, lactoferrin, PR3, and lysozyme, forming azurosomes. MPO aids the release of neutrophil elastase into the cytoplasm by oxidizing it. NE binds to F-actin and degrades the cytoskeleton, making its way to the nucleus. Cytoskeletal degradation inhibits concomitant phagocytosis, committing cells to NETosis. NE also cooperates with gasdermin D in the destruction of the nuclear envelope by forming pores and allowing water influx. Entering the nucleus, NE and MPO decondense chromatin by degrading histones . This prvia Toll-like receptor 9 (TLR9), enhancing antibody production (NET antigens are presented to naive T cells by dendritic cells that differentiate into CD4+ T helper (Th) cells. CD4+ T cells promote the differentiation of B-cells into ANCA-producing plasma cells. Cell-free DNA stimulates B-cells oduction . Activatoduction .sine qua non of granuloma formation. In the early phase of granuloma formation, neutrophil invasion and the release of lytic enzymes result in the formation of a necrotic core lesion. Over time, macrophages are recruited, primarily to phagocytose the apoptotic debris. This process is called efferocytosis. A defect in efferocytosis is postulated to be a key step in the formation and in the inability of resolution of the granulomas. Anti-PR3 antibodies halt the clearance of PR3-expressing or ANCA opsonized cells and increase pro-inflammatory cytokine and chemokine release, attracting further neutrophils and T-cells , with a marked decrease in glomerular filtration rate (GFR) over some weeks or months, sometimes accompanied by oliguria . AAV, hoConsidering the systemic nature of the disease, the involvement of various organs may complete the clinical picture, and the exclusion of alternative diagnoses, especially infections, is a crucial aspect of the evaluation. Extra-renal manifestations are also particularly important clues for the prompt diagnosis of ANCA-associated glomerulonephritis when rapid renal involvement is not present  2, 42, –74. FeveIn summary, considerable heterogeneity in symptoms and severity across the patients hinder the diagnosis and may delay proper treatment of the disease. The diagnosis of AAV starts with thinking of it.Since symptoms of vasculitis can be excessively overlapping, the Diagnostic and Classification Criteria in Vasculitis (DCVAS) study developed classification criteria to differentiate them. Results were published in 2022. These revised classification criteria were needed to increase sensitivity compared to the 1990 American College of Rheumatology (ACR) criteria. Since 1990, ANCA testing became widely available, as well as diagnostic imaging tools. On top of it, the recent classification included patients with MPA, which was not the case with the previous one. Another advantage is the shifting toward weighted criteria which enables a more discriminative classification –77.The diagnostic hallmarks of AAV are the anti-neutrophil antibodies. Their diagnostics are based on indirect immunofluorescence (IIF) of ethanol-fixed neutrophils or enzyme-linked immunosorbent assay (ELISA). IIF is more sensitive, while ELISA is more specific. Their use varies around the world and between laboratories. Based on IIF, there are two types of fluorescence patterns with ANCA positive sera: cytoplasmic (c-ANCA), and perinuclear (p-ANCA). The mixture of these antibodies is defined as atypical ANCA. Antigens are located in the granules. Cytoplasmic ANCA pattern can be detected throughout the cytoplasm, and it is most commonly directed against proteinase 3 (PR3). The perinuclear pattern is artifactual and results from alcohol fixation. After fixation, positively charged granular constitutes, especially myeloperoxidase (MPO), rearrange to the negatively charged nucleus membrane and can be stained with anti-myeloperoxidase antibodies , 78.ANCA antibodies are positive in 80–95% of ANCA-associated vasculitis patients. PR3- is strongly linked to GPA, while MPO-ANCA is to MPA and EGPA. Renal limited disease is usually MPO-ANCA positive as well . NonetheAtypical ANCA antibodies can be detected in drug-induced vasculitis, inflammatory bowel diseases, rheumatoid arthritis, and systemic lupus erythematosus . PerinucIn terms of complement levels, there is a controversy in the literature. Some authors declare that complement levels stay within the normal range, while others state that complement levels rise significantly in AAV, as a consequence of fulminant immune system activation , 95. MorThrombocytosis, normochromic normocytic anemia, and leukocytosis are common findings in complete blood count. EGPA manifests with eosinophilia, which is commonly >10% of the total leukocyte count and is frequently accompanied by elevated serum IgE levels. Although C-reactive protein (CRP) and erythrocyte sedimentation rate elevate, these markers have low specificity .Renal manifestation is evaluated by serum creatinine, blood urea nitrogen, and urine analysis. Proteinuria, hematuria, and urine sediment finding with dysmorphic erythrocytes and red blood cell casts aid the prompt diagnosis of the glomerular involvement.Since pathological features in the specimen do not alter the choice and the duration of the therapy currently, the need for renal biopsy in all AAV patients is controversial. The EULAR/ERA-EDTA  recommendations in 2016 supported the need for a renal biopsy to assist the diagnosis and prognosis  . In seleThe histopathological feature of ANCA-associated glomerulonephritis is pauci-immune small-vessel vasculitis. The term “pauci” refers to the scarcity of immunoglobulin and complement deposition detected by indirect immunofluorescence. In the earliest phase, light microscopy reveals neutrophil invasion occurring in the vessel walls, and it is gradually overtaken by mononuclear leukocytes. Leukocyte fragmentation (leukocytoclasia) can be observed.Segmental fibrinoid necrosis, with or without cellular and fibrocellular extracapillary crescents are common findings in early vascular lesions . AlthougGPA and EGPA patients rarely have necrotizing granulomatous lesions in the kidney biopsy specimens. Concomitant eosinophilic infiltration may be detected in GPA and it is prominent in EGPA .Repeat biopsies to monitor kidney function and the success of therapy are not performed routinely, however, they may have a role in assessing disease activity. Clinical biomarkers, such as hematuria and serum creatinine do not reflect disease activity specifically and sensitively enough, thus they can be mistaken for relapses. Approximately half of the patients who underwent rebiopsy had alteration in the Berden classification, up-or downstepping in the classification hierarchy , 106. ThAs discussed above, cutaneous manifestations can appear in a wide variability. Thus, diagnosis can be challenging, in which skin biopsy could aid the work. Lung biopsy is rare and only conducted in the absence of systemic manifestations or when serology cannot prove the diagnosis. It is to rule out alternative diagnoses since granulomas do not have a specific sign on imaging examinations, they can mimic tumors and infections as well .The chronic relapsing-remitting nature of AAV necessitates tight follow-up of disease activity to provide appropriate management. The Birmingham Vasculitis Activity Score V3.0 (BVAS) is an approved, easily available, and effective tool to evaluate disease severity in everyday clinical work. The scoring system scrutinizes 9 organ involvement, and 66 attributes altogether and assesses the symptoms according to their persistent or intermittent nature. Clinical features are weighted according to their clinical relevance , 108. ThOne of the main aims of this review is to summarize the recent recommendations for the management of ANCA-associated glomerulonephritis in light of two recent guidelines: KDIGO and the American College of Rheumatology/Vasculitis Foundation (ACR) guideline from 2021 , 113. AsThe treatment of AAV varies according to organ involvement and disease severity. ANCA-associated glomerulonephritis is considered an organ- or life-threatening disease, therefore, demands induction and maintenance immunosuppression .The standard induction immunosuppression therapy is glucocorticoids combined with cyclophosphamide (CYC) and/or rituximab (RTX) , Table 2Glucocorticoid (GC) treatment may include high dose (1–3 g) of intravenous (IV) methylprednisolone in patients presenting with RPGN, and daily oral glucocorticoids tapered over 5 months in all patients with organ-threatening disease. IV methylprednisolone is routinely administered in severe diseases; however, it has never been tested in randomized controlled trials. The recent ACR guideline recommends - as an ungraded position statement - either IV pulse or high-dose oral glucocorticoid treatment as a part of the initial therapy of active, severe GPA/MPA . As prolCyclophosphamide has been used for induction immunosuppression of AAV for almost 50 years now . The Eur−CD27− B cells, rituximab is likely to be more effective than cyclophosphamide, enabling earlier glucocorticoid tapering and better survival rates (The Rituximab for ANCA-Associated Vasculitis (RAVE) and the Rituximab versus Cyclophosphamide in ANCA-associated Renal Vasculitis (RITUXVAS) trials compared RTX- to CYC-based induction treatment. Remission rates, relapse rates, or adverse events , 120 weral rates . In seveal rates . The potal rates , while tal rates . Based o2. However, relapse rates were higher, mostly in PR3-ANCA positive patients  to pulse cyclophosphamide and found mycophenolate non-inferior for remission induction in patients with estimated GFR >15 ml/min/1.73 mpatients . This supatients . In factpatients  43). Ac. Ac2. Hopatients .2.Methotrexate (MTX) is the first choice combined with GC in active, non-severe GPA according to the ACR guideline . MTX is In refractory diseases, glucocorticoid dosage may be increased with the addition of CYC (if previously RTX was used) or with the addition of RTX (if previously CYC was used). Plasmapheresis may also be part of the treatment in poor responders , accordi2 nor in patients with lung hemorrhage  or RTX (without GC) .AZA proved to be a safe and efficient alternative to oral CYC for maintenance therapy in the Cyclophosphamide vs. Azathioprine for Early Remission Phase of Vasculitis (CYCAZAREM) trial. Severe adverse events and relapse rates did not differ between the groups, however, AZA treatment resulted in fewer cases of leukopenia .According to the Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trial, RTX-treated patients experience fewer major relapses than AZA-treated peers, and RTX was superior to AZA in PR3-ANCA positive patients . There a2). According to the WEGENT trial, MTX- and AZA-based maintenance therapies are equally effective in preventing relapse and provide similar long-term outcomes  . MTX, hooutcomes .While high doses of glucocorticoids and associated toxicity is a relevant concern in induction therapy, it must be noted that the prolonged administration of low-dose glucocorticoids seems to contribute to efficient maintenance therapy and also prevents relapses . AccordiThe recommendations regarding the first choice of maintenance therapy are slightly different according to the most recent guidelines. KDIGO recommends either RTX or AZA with low-dose GC for maintenance  while providing factors to consider choosing the best therapy for individual patients. RTX is preferred in relapsing disease, in PR3-ANCA disease, frail or older adults, when GC-sparing is important, or in AZA-allergy. AZA is preferred with hepatitis B exposure, low baseline immunoglobulin G (IgG < 300 mg/dl) level, or when RTX is not available . MMF proThe optimal duration of maintenance treatment is yet to be determined. Too early withdrawal of therapy increases the risk of relapse, while prolonged immunosuppression is associated with greater toxicity. The current KDIGO guideline suggests AZA to be administered for at least 18 months and therapy may extend to 4 years . RTX maiAlthough induction protocols are commonly effective in remission induction, maintenance regimens vary in efficacy. Depending on the treatment regimens, relapse rates range from 30 to 50% at 5 years .The rise in the ANCA titer is suggested as an early sign of the impending relapse. Doubling of ANCA-level in the previous 3 months provides an 11-times higher chance for relapse in the next 1.5 years . NeverthThe reason behind this observation is not entirely clear, but it might trace back to the pathogenicity of ANCA: epitope specificity and sialylation ratio which are thought to regulate ANCA reactivity , 143.Identifying clinical features and/or biomarkers to predict an imminent relapse reliably would be essential in the chronic care and follow-up in AAV patients and it remains a key research priority. Anti-PR3 positivity, granulomatous disease, lower serum creatinine at presentation, nasal Staphylococcus aureus colonization, ear-nose-throat involvement, and prior relapses convey a higher relapse risk . Though post hoc analysis of the RAVE trial, especially in PR3-ANCA positive patients  has immunomodulatory effects tibodies . IVIG istibodies . IVIG catibodies .To conclude, recognizing patients with a high risk of renal relapse would benefit clinical care and therapy optimization. Clinical relapse occurs mainly at the initiation of the maintenance therapies or during their tapering  which su2 at baseline have a substantially higher long-term ESRD-free survival rate, and their renal survival rate is approximately the same as in patients with mixed or crescentic pattern. Sclerotic histology with eGFR <15 ml/min/1.73 m2 however, is proposed to have a poor prognosis  should be prescribed if the patient has a history of hepatitis B or C infection . To avoiA severe but very rare infectious complication of rituximab treatment is progressive multifocal leukoencephalopathy (PML), caused by the JC polyoma virus. JC virus infects commonly and persistently the urinary tract of adults. The PML-associated neurotropic JC virus strain contains distinctive mutations in the surface loops of the major capsid protein, leading to escape from antibody-mediated neutralization. PML used to be the rare complication of HIV (human immunodeficiency virus) infected patients, but it has become more frequently related to immunosuppressive treatments with monoclonal antibodies. The cumulative reporting rates of confirmed PML in HIV-negative patients were at about two per 100 000 patients in the period 1998 to 2007, then increased to 7 to 8 per 100 000, which included patients with hematologic and oncologic diseases. The higher number of registered cases is partly due to the better awareness of the disease .Live attenuated vaccines are contraindicated during immunosuppressive therapies. Inactivated vaccines are recommended at least 2 weeks prior to the initiation of the treatment. In case of rituximab, vaccines should be given at least 5 months after the last dose and at least 4 weeks before the administration .Despite the evolution of immunosuppressive therapy in AAV, 20–25% of the patients develop ESRD and need renal replacement therapy . More AARenal transplantation provides better quality of life for patients with ESRD. Patients and transplant kidney survival is similar to nondiabetic patients . The relBortezomib is a proteasome inhibitor, which is implicated to inhibit NF-kB, halting cell proliferation, and committing B-cells to apoptosis . BortezoAdding hydroxychloroquine to standard therapy proved to be effective in reducing relapses, and steroid doses. It helped to improve symptoms and it was well tolerated as well . An ongoBelimumab, an anti-BAFF monoclonal antibody may inhibit the AAV-associated overexpression of BAFF  and promAn ongoing study (COMBIVAS) evaluates the efficacy of combined rituximab and belimumab (NCT03967925), and another one (BREVAS) belimumab combined with azathioprine .Abatacept is a fusion protein of the Fc region of human IgG1 and the extracellular domain of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4/CD152). CTLA-4 is a constitutively expressed receptor on regulatory T-cells, and it is homologous to the co-stimulatory T-cell protein, CD28. By binding to CD80 and CD86 on antigen-presenting cells with a higher affinity than CD28, abatacept prevents T-cell activation . A studyA case report of two patients demonstrated remission with the use of C5 inhibitor, eculizumab, but it has never been studied more thoroughly .A randomized study, Alemtuzumab for ANCA Associated Refractory Vasculitis (ALEVIATE), studied alemtuzumab, a monoclonal antibody against the CD52 on T-cells, targeting them to destruction . AlthougTocilizumab, a humanized interleukin-6 receptor antibody, could be a potential therapeutic drug in AAV. The efficacy of tocilizumab has already been proved for large-vessel vasculitis, and some studies also detected clinical remission in AAV . Large-sPromising results have recently been published from the European IXCHANGE study of an anti-C5a antibody, vilobelimab. Vilobelimab proved to be efficient in maintaining therapy in terms of remission with good safety and tolerability profile. Vilobelimab use is suspected to be able to lower glucocorticoid dosage and its toxicity (NCT03712345).in vivo and in vitro  in NET formation has been demonstrated. Correspondingly, PADI inhibitors reduce histone citrullination and NET release both in vitro . Selectiin vitro . Hence, Leflunomide is a dihydro-orotate-dehydrogenase inhibitor which is responsible for pyrimidine synthesis. By halting the synthetic pathway, it arrests the actively proliferating T-, and B-lymphocytes and proved efficient in a small number of patients . CurrentThe initially nonspecific, then heterogenic symptoms can mislead the diagnostic approach and cause substantial delay in the adequate treatment of ANCA-associated glomerulonephritis. In the absence of distinct symptoms, renal-limited and not rapidly progressive forms are also challenging to identify. The clinical features and laboratory parameters of ANCA-associated vasculitis can mimic infection, malignancy, and other autoimmune diseases. ANCA-negative and atypical ANCA cases can complicate the road to the diagnosis. The first but necessary step of the diagnostic approach is to think of it. Although the treatment options are continuing to improve, the prompt diagnosis and treatment initiation of ANCA-associated glomerulonephritis have remained crucial factors in patient and renal outcome.AM, PS, and NL participated in reviewing the literature and writing the manuscript. All authors agree to be accountable for the content of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Physical activity is essential to maintain physical and mental well-being. During the COVID-19 pandemic, in-person physical activity opportunities were limited. This paper describes a telephone-based physical activity support strategy among racially/ethnically diverse patients during the COVID-19 pandemic. Adult patients at a large, Federally Qualified Health Center with an on-site exercise facility referral were eligible to transition to telephone support with personal fitness advisors during the pandemic stay-at-home orders. Baseline surveys assessed physical activity and environmental characteristics; follow-up phone calls used motivational interviewing and physical activity goal setting strategies. From March 23-July 23, 2020, 72 patients participated in 270 phone calls, or 3.8 (±2.1) calls per participant. Participants were, on average, aged 51.3 (±11.6) years, 87.5% female, 31.9% Hispanic/Latino, and 47.2% non-Hispanic Black. Patients meeting physical activity guidelines pre-pandemic reported more planned exercise , exercise days at home , and accomplishment of personal physical activity goals  than patients not meeting guidelines pre-pandemic. Patients with a home treadmill participated in twice the rate of calls compared to those without , but no other home environmental characteristics predicted participation rate. Pre-pandemic physical activity behavior appeared to predict pandemic physical activity and telephone-based physical activity support was effective for maintaining physical activity for some participants. Long term applications of this work will support continuity of clinic-community partnerships for health behavior change and provide a model for patient physical activity support by community health centers without on-site exercise facilities. Although physical activity is important for everyone across the lifespan, physical activity is particularly essential to maintain physical and mental well-being during the COVID-19 pandemic. Physical activity enhances the circulation of immune cells, supports weight maintenance and can offset increased caloric consumption, reduces stress and anxiety, and improves sleep and quality of life . Yet, emIt is unclear how short-term changes in physical activity behavior and opportunities during 2020 may have affected long-term behavior and health outcomes. Accordingly, in a call to action for physical activity research to inform pandemic policies and practices, Sallis et al.  recommenOur study was conducted at a large, multi-site Federally Qualified Health Center (FQHC) in central Texas. The Heart of Texas Community Health Center has provided medical care in the community since 1970, operated as an FQHC since 1999, and does business as Waco Family Medicine. The Center provides medical, dental, and behavioral health care for almost 60 000 unique patients, or approximately 1 in every 5 county residents, each year. One-quarter (23%) of patients are non-Hispanic Black/African American, 48% are Hispanic/Latino, and 27% are non-Hispanic White. Approximately 1 in 6 patients do not have health insurance and are afforded care through a sliding scale discounted fee program that expands coverage to approximately one-quarter of self-pay patients.In 2017, Waco Family Medicine established the Wellness Center, an on-site exercise facility, to address limitations in accessible and affordable physical activity opportunities as part of a community-centered health home approach to wellness and health equity. The program has been described previously . BrieflyMeasures section below, prompts and questions on a survey instrument guided the data collection.In March 2020, the Wellness Center closed in accordance with local COVID-19 health and safety guidelines. Fitness advisors pivoted from facilitating one-on-one, in-person advising at the Wellness Center to telephone-based support for physical activity. Fitness advisors (n = 4) contacted patients via telephone. Eligible patients had completed ≥1 in-person exercise advising visit at the Wellness Center in the month prior to the facility closure. During the initial telephone call, patients were asked to recall information about typical physical activity prior to the current coronavirus situation, describe resources at home that could facilitate physical activity while the Wellness Center was closed, and discuss exercise goals. Fitness advisors received data collection and motivational interviewing training and then used motivational interviewing techniques to help the patient develop Specific, Measurable, Attainable, Realistic, and Time-bound–or “SMART”–exercise goals . PreviouFollowing the initial baseline telephone call, follow-up calls were made approximately every 2 weeks thereafter. Follow-up calls assessed physical activity behavior and helped patients set new or modified activity-related goals, once again with prompts and questions on a survey instrument for data collection. This report summarizes observational data from the telephone-based support for physical activity during the first 4 months of the telephone call program, from March 23, 2020 through July 23, 2020. The Baylor University Institutional Review Board defined Wellness Center surveys as program evaluation and therefore not meeting the definition of human subject research; however, verbal informed consent to participate in the program surveys was obtained from all participants.2), diabetes (yes/no), hypertension (yes/no), and any COVID-19 testing at Waco Family Medicine (yes/no).Patient sociodemographic and basic health characteristics were obtained from the electronic health record and included age (in years), sex , race/ethnicity , body mass index  per meters (m)Wellness Center utilization data were also obtained from electronic records. Previous utilization data included the date of exercise referral and a count of the total number of in-person visits to the Wellness Center. Date of initial intake visit less the date of Wellness Center closure was used to calculate duration of participation.Baseline telephone survey data included self-reported physical activity and related health behavior theoretical constructs from the social cognitive theory, including self-efficacy and self-regulation strategies. At baseline, patients were asked to think about a typical week, prior to the COVID-19 pandemic. Patients were asked about any planned physical activity or exercise (yes/no) and days in a typical week they usually exercised at home (0–7 days). Physical activity was measured using a modified Baecke survey instrument that asked about type (free response), number of days, and duration of the two most frequently performed activities . Open-ennot at all confident and 5 indicating extremely confident, level of confidence that they could exercise when at home, when the weather is bad, when they do not have a fitness advisor, and make time for at least 30 minutes each day for physical activity . Self-regulation strategies for exercise behavior change were measured using six questions  may involve intervention modalities including print materials, telephone counseling, text messaging, mobile apps, and web-based platforms” . A numbeexercise desert, a built environment with limited walkability, green space, and affordable fitness facilities [In our study, approximately 80% of patients who participated in ≥1 telephone call identified as Hispanic/Latino or non-Hispanic Black. This race/ethnic distribution is in keeping with the overall patient population of the clinic system, and over 90% of patients live at or below 200% of the federal poverty guidelines. In this study, we surveyed patients about home resources and their environments because we previously described the community served by our clinic as an cilities , 36–39. cilities –40, and Our study is subject to several limitations. First, we only used a telephone-based physical activity strategy. Although internet and mobile phone-based interventions that allow for audio-visual connections can improve physical activity, socioeconomic disparities in internet access limited the accessibility of interventions that required the internet . Also, aNevertheless, we believe this work has three primary applications. Internally and immediately, telephone-based support for physical activity facilitated support of health behaviors during COVID-19, which achieved continuity of fitness advisor-patient interactions. Second, the Wellness Center was originally envisioned as a temporary plan for patients to build exercise-related skills and confidence before transitioning to other community exercise facilities. The lessons learned here–for example, the availability and relative importance of home resources among our patient population–will allow us to develop best practices for telephone-based transitional support after Wellness Center “graduation” when patients move to other exercise facilities in our community in the future. We also plan to explore the utility of video-based support and messaging through the electronic health system  for transitional support. Third, our Community Health Center has a unique on-site exercise facility to support equitable health opportunities through a community-centered health home approach to population health. Even beyond COVID-19 and exercise facility closure, other health centers may wish to implement telephone-based support for physical activity in the absence of an on-site exercise facility. Clinic-community partnerships for physical activity support can build on these findings and our prior work  to suppoDuring the COVID-19 pandemic, low-income adults were disproportionately affected by the virus and related economic sequelae, including increased exposure to the virus due to “essential worker” working conditions, increased caregiver burden and decreased discretionary time, and increased burden of comorbidities , 44. AltS1 File(PDF)Click here for additional data file.


We longitudinally investigated KP colonization and its association with LRTI in a South African birth cohort.The role of We conducted a case-control study of infants who developed LRTI and age-matched controls, followed twice weekly through infancy. Nasopharyngeal swabs taken fortnightly and at LRTI for 33-multipex Quantitative multiplex real-time polymerase chain reaction were tested at LRTI and twice weekly from 90 days preceding LRTI. Controls were tested over the equivalent period. Multivariate models investigated the factors associated with LRTI or with KP-associated LRTI (KP-LRTI).P-value=0.009). Clinical features of KP and non-KP-LRTI were similar with 114 (26%) infants hospitalized. Prematurity , HIV exposure , lower birthweight , and shorter breastfeeding time  were associated with KP-LRTI versus non-LRTI. These factors and younger age were associated with KP-LRTI versus non-KP-LRTI.Among 885 infants, there were 439 LRTI episodes, of which 68 (15.5%) were KP-LRTI . Infants with KP-LRTI were younger than those without KP-LRTI (median [IQR] 3.7 [2.1–5.9] vs 4.7 [2.8–7.9] months, KP was associated with a substantial proportion of LRTI, particularly in premature or HIV-exposed infants in whom strategies for treatment and prevention should be strengthened. Haemophilus influenzae type b [Hib] vaccines), have reduced the burden of pneumonia and changed the etiological spectrum. After the widespread uptake of PCV and Hib vaccines, other bacteria and viruses have been associated with an increasing etiological fraction of pneumonia, with coinfections occurring especially in severe disease (The incidence and severity of childhood pneumonia or lower respiratory tract infection (LRTI) have declined substantially in the last decade, but LRTI remains a major cause of mortality in children under five years of age, particularly in low- and middle-income countries (LMICs) . Socioec disease .Klebsiella pneumoniae (KP) has been reported to be an important bacterial pathogen that causes neonatal sepsis and mortality, predominantly in southeast Asia , a South African birth cohort study . The aimWe conducted a case-control study of children enrolled in the DCHS, a birth cohort study situated in a periurban area in South Africa . This arLongitudinal measurement of risk factors for LRTI including immunizations, smoke exposure, HIV exposure, nutrition, home environment, and maternal factors was done at study visits and during illness. Maternal smoking was self-reported antenatally and postnatally. Maternal HIV status was ascertained during pregnancy and CD4 count and viral load were measured; combination antiretroviral therapy (ART) was provided for all women infected with HIV, according to national guidelines, as described . InfantsThe Revised World Health Organisation (WHO) criteria were used for pneumonia or LRTI, as described . PneumonTM, Copan Diagnostics, CA) were collected twice weekly for the first year of life in the intensive cohort and at the time of LRTI. Nasopharyngeal swabs were transferred into nucleic acid preservation medium , transported on ice, and frozen at –80°C for batch testing. Swabs were tested at the time of LRTI and twice weekly up to 90 days before LRTI with qPCR. Swabs from age-matched control children without LRTI in the cohort were also tested over the equivalent period. Nucleic acid was extracted using mechanical lysis on a Tissuelyzer LT , followed by extraction with the QIAsymphony® Virus/Bacteria mini kit . Quantitative multiplex real-time PCR (qPCR) was done using FTDResp33  to identify up to 33 potential respiratory pathogens including KP. Due to previous concerns regarding false-positive results for the K. pneumoniae target in this assay, we did careful manual review of all amplification curves  and were able to exclude results which were likely to represent false-positive tests on the basis of (i) nonexponential amplification  and (ii) application of a strict cycle of quantitation (Cq) -cutoff value of <35 cycles for a positive result. In the majority of cases, likely false-positive results were clearly apparent, with weak, nonexponential amplification curves. K. pneumoniae-LRTI was defined as any LRTI positive for KP on qPCR.Nasopharyngeal swabs  and age of presentation (within two weeks). NPs were used for identification of potential pathogens to enable a case-control analysis because lower respiratory tract samples could not be collected in healthy controls. LRTI episodes were stratified into those in whom the swab collected at LRTI was positive for K. pneumoniae and associated with LRTI (KP-LRTI) and those in whom the swab was negative but positive for other organisms (non-KP-LRTI). Controls were similarly stratified on the basis of whether the swab was positive or negative for K. pneumoniae (KP controls or non-KP controls).The case-control dataset was derived from all infants included in the intensive follow-up cohort. Cases were selected on the basis of an LRTI episode in the first year of life and a valid NP available at the time of LRTI, as well as having a matched control. Controls were selected from age-matched children in the cohort who had been followed up twice weekly with NP swab collection and who had a valid NP result at the corresponding time point to enable comparison with casesPrematurity was defined as birth <37 weeks gestation with late prematurity as a gestational age of 34 to 37 weeks. Weight-for-age at birth Z-scores were derived from Fenton's growth standards , while wa priori set of confounding factors, including: sex, household income, parent employment status, season of birth, HIV exposure, maternal smoking, prematurity, birth weight, and age at LRTI.Analysis was done on a per child basis. We used a longitudinal analysis technique, generalized estimating equation models specifying a binomial distribution, and logit link function, which allowed for repeated measures per child because a child could have multiple LRTI episodes, or could be used as a control multiple times, and/or could switch status. Because the outcome (in Model A) was case status, this longitudinal analysis allowed for the status to change or to be repeated multiple times per child. In subsequent models (Models B and C), the case status was stratified on the basis of KP status. There was at least a 28-day period on either side of the episode between which a second event could occur. We used these models to determine risk factors associated with LRTI versus non-LRTI (Model A), KP-LRTI versus non-LRTI (Model B), or KP-LRTI versus non-KP-LRTI (Model C) at the time of event. Multivariate models were adjusted for an From March 5, 2012–March 31,2015, 1137 mothers (median [IQR] age 26 [22–31] years) were enrolled, yielding 1143 live births . More than three quarters of mothers  chose to participate in two-weekly follow-up; among these, cohort retention at one year was 88.7% (n=780/879) . Most di3 ; 228 children had an LRTI episode/s only, 254 were controls only , and 45 children were used as a case and a control at different times in the first year. Cases excluded due to the absence of the valid PCR result or age-matched control were similar to those included except for a higher prevalence of maternal smoking, Supplementary Table 1. Amongst mothers, 144 (27.4%) were HIV-infected, 99% of whom took ART in pregnancy, with most having CD4 count >250 cells/mm3 . There w3 . The pop3 .Table 1MK. pneumoniae qPCR results, 116 results, which would have been initially regarded as positive, were reclassified as negative following recalibration of the Cq cutoff value (only results with Cq < 35 cycles were regarded as positive), and a further 10 results with Cq < 35 cycles were regarded as negative based on nonexponential amplification curves. Using a case-control analysis, detection of K. pneumoniae at the time of LRTI was significantly associated with LRTI   . Althougme point . Among Lme point . Clinicame point .Table 2OMultivariate modeling of risk factors associated with all-cause LRTI included male sex , prematurity , or lower birth weight  . For KP-S. pneumoniae were lower among infants with KP-LRTI than those with non-KP-LRTI adjusted for age, but there were no other differences in coinfections (There was a higher incidence of RSV, influenza, or parainfluenza virus detected in infants with all-cause LRTI than those without LRTI but no differences in other viruses or bacteria. However, the odds of detecting fections .Table 5RK. pneumoniae was associated with community-acquired LRTI in African infants, especially in those who had been born prematurely or who were HIV-exposed. The finding that KP was associated with LRTI in the context of a well-immunized infant population, including Hib and PCV13, almost no HIV infection in children and good nutrition is novel and important, with possible consequences for empiric treatment. Further, KP-LRTI occurred beyond the neonatal period, at a median age of 3.7 months. KP has previously been described as an important cause of neonatal sepsis or nosocomial pneumonia (This birth cohort study found that neumonia . The Chineumonia . A retroneumonia . Our datK. pneumoniae was significantly associated with LRTI. The multicentre PERCH study also used a case-control methodology to attribute etiology from NP sampling of children hospitalized with severe or very severe pneumonia using the same PCR platform (Although it may be difficult to distinguish causality from colonization, through the use of a case-control design and with controls age-matched and from the same cohort, we showed that platform . Althougplatform . More deplatform . Furtherplatform .Prematurity was the strongest risk factor for KP-LRTI despite that most premature infants being born after 34 weeks and not requiring admission to the ICU. This highlights a group of infants that have not been previously recognized to be at increased vulnerability to KP disease but who constitute around 11% of births worldwide . MechaniK. pneumoniae. Copathogens or interaction with other organisms, as has increasingly been recognized in pneumonia pathogenesis, may have contributed to development of LRTI and recovery in the absence of specific treatment; however, we did not identify any specific pattern of co-pathogen detection with KP on multiplex PCR testing. Further studies are needed to determine whether K. pneumoniae is a significant pathogen and contributes to poorer outcomes in HIV-exposed or premature infants who require hospitalization for LRTI in other settings. The CHAMPS data similarly indicate that a high proportion of infants have K. pneumoniae as a contributory cause of death (Although other causes of LRTI such as RSV predominated, KP-LRTI was an important, treatable cause of community-acquired LRTI. KP-LRTI occurred at a median of 3.7 months, when empiric antibiotic therapy is oral amoxicillin or intravenous ampicillin in those who cannot tolerate oral therapy as recommended by WHO and other guidelines . This reof death , adding S. pneumoniae in children with KP-LRTI, compared with those with non-KP-LRTI suggests the possibility of an interaction between these two species. Both species possess an anionic antiphagocytic capsule, which may plausibly mediate contact-dependent inhibition. Commensal oral streptococcal species have been shown to have bacteriostatic activity against K. pneumoniae;(S. pneumoniae.The reduced age-adjusted odds of detecting eumoniae;, althougLimitations include a relatively small sample of infants with KP-LRTI. However, this study is the only longitudinal study of KP-LRTI through infancy that carefully delineated that occurrence occurred at a median age of 3.7 months, which was younger than other causes of LRTI. A further limitation is follow-up from birth for only one year. However, the highest incidence of LRTI occurs in the first year of life, as we have previously described . A furthK. pneumoniae may be considered. Strengthened strategies to reduce the risk of prematurity and promote longer exclusive breastfeeding are needed. Further study of the impact of KP-associated LRTI on long-term health in children is warranted to investigate long-term morbidity from early life illness.In summary, this study provides important new information on the association of KP with LRTI and specific risk factors in infants. These data have important implications for understanding possible organism interactions in the etiology of LRTI in infants in the context of high immunization coverage for PCV and Hib and for antibiotic therapy. In premature or HIV-exposed infants with LRTI, antibiotic therapy with coverage for


Diabetic retinopathy (DR) is a leading cause of blindness in American adults. If detected, DR can be treated to prevent further damage causing blindness. There is an increasing interest in developing artificial intelligence (AI) technologies to help detect DR using electronic health records. The lesion-related information documented in fundus image reports is a valuable resource that could help diagnoses of DR in clinical decision support systems. However, most studies for AI-based DR diagnoses are mainly based on medical images; there is limited studies to explore the lesion-related information captured in the free text image reports.In this study, we examined two state-of-the-art transformer-based natural language processing (NLP) models, including BERT and RoBERTa, compared them with a recurrent neural network implemented using Long short-term memory (LSTM) to extract DR-related concepts from clinical narratives. We identified four different categories of DR-related clinical concepts including lesions, eye parts, laterality, and severity, developed annotation guidelines, annotated a DR-corpus of 536 image reports, and developed transformer-based NLP models for clinical concept extraction and relation extraction. We also examined the relation extraction under two settings including ‘gold-standard’ setting—where gold-standard concepts were used–and end-to-end setting.For concept extraction, the BERT model pretrained with the MIMIC III dataset achieve the best performance . For relation extraction, BERT model pretrained using general English text achieved the best strict/lenient F1-score of 0.9316. The end-to-end system, BERT_general_e2e, achieved the best strict/lenient F1-score of 0.8578 and 0.8881, respectively. Another end-to-end system based on the RoBERTa architecture, RoBERTa_general_e2e, also achieved the same performance as BERT_general_e2e in strict scores.This study demonstrated the efficiency of transformer-based NLP models for clinical concept extraction and relation extraction. Our results show that it’s necessary to pretrain transformer models using clinical text to optimize the performance for clinical concept extraction. Whereas, for relation extraction, transformers pretrained using general English text perform better. Diabetic Retinopathy (DR), a common complication of diabetes, is the leading cause of blindness in American adults and the fastest growing disease threatening nearly 415 million diabetic patients worldwide . This diElectronic Health Records (EHR) have been increasingly implemented at US hospitals. Huge amounts of longitudinal patient data have been accumulated and are available electronically in structured tables, narrative text, and images. There is an increasing need for multimodal learning methods to link different data sources for clinical and translational studies. Recent emerging AI technologies, especially deep learning (DL) algorithms, have greatly improved the performance of automated vision-disease diagnoses systems based on EHR data. These AI systems for vision-disease diagnoses are usually developed using supervised machine learning models with medical images. The supervised machine learning models require annotated images, where the annotator have to manually label the region with lesions from images. In fact, the physicians have reviewed these medical images and documented detailed diagnosis, symptoms, and other critical observations in image reports, which could be a valuable resource to help annotators label images or serve as independent text features for lesion detection from medical images. There are increasing numbers of clinical studies utilizing clinical narratives –7. As thNatural language processing (NLP) is the key technology to extract patient information from clinical narratives to support various downstream clinical studies. Many NLP methods and systems have been developed to extract various types of information from clinical narratives. The clinical NLP community has organized a number of open challenges to advance information extraction from clinical narratives. Most state-of-the-art NLP methods for information extraction are based on supervised machine learning methods. The supervised machine learning models approach the information extraction as a two-stage pipeline, which typically include a clinical concept extraction (or named entity recognition [NER]) module to identify critical concepts  and a relation extraction module to link attributes  to the concepts. For concept extraction, a number of NLP models have been developed to first identify clinical concepts and their attributes and then classify them into predefined semantic categories . Relation extraction aims to establish semantic connections between extracted concepts and their attributes. Recently, transformer-based NLP models, built solely with a self-attention mechanism, outperformed other models and became state-of-the-art solution for information extraction from clinical narratives. For example, Peng et al.  proposedIn this study, we identified patients diagnosed with DR at the University of Florida (UF) Health and collected their image reports, developed annotation guidelines and annotated a corpus for DR-related concept extraction, developed transformer-based NLP methods to extract DR-related clinical concepts that could help lesion detection from medical images. We systematically examined two state-of-the-art transformer-based NLP models for DR-related concept extraction and relation extraction from fundus image reports. We also developed end-to-end systems to detect DR-related concepts as well as their attributes in a unified system.We identified 155 patients diagnosed with diabetic retinopathy and collected a total number of 536 fundus image reports from them at the University of Florida (UF) Health. Then, we developed initial annotation guidelines through a collaboration of clinicians specialized in DR treatment, computer image experts , and NLP experts . Then, we recruited two annotators  and conducted training sessions to help annotators get familiar with guidelines. We further improved the initial guidelines using several training sessions. After the annotators achieved a good inter-annotator agreement score calculated using Cohen’s Kappa [There are many DR-related clinical concepts documented in the image reports such as diagnoses, treatments, and medications. As our goal is to extract DR concepts that can potentially help lesion detection from medical images, we identified five different categories of concepts, including lesions, eye parts, laterality, severity, and negation. By definition, a lesion is a region in an organ or tissue which has suffered damage through injury or disease. In this study, we are particularly interested in lesions only associated with diabetic retinopathy (lesion occurred within the eye). Lesions that occurred in other organs were not be annotated. We also referred to the existing vocabulary of lesions , 17, andWe used the brat rapid annotation tool  for annoWe adopted a standard two-stage NLP pipeline, including a clinical concept extraction module to detect DR-related concepts and their attributes and a relation extraction module to link the attributes to the corresponding concepts. Many studies have examined rule-based and machine learning-based methods for information extraction from clinical narratives and showed that the machine learning-based methods often have better performance and generalizability. When applying rule-based NLP systems to a new dataset, researchers often have to customize the rules according to the new patterns and documenting styles.  ThereforFor the LSTM-CRFs model, following previous study on clinical concept extraction , we explWe evaluated annotation agreement using Cohen’s Kappa, κ, coefficient, where higher κ denotes annotator agreement. We used both strict  and lenient precision, recall, and F1-score to evaluate our NLP systems for concept extraction. Precision is defined as (the number of predicted concepts correctly identified by the NLP system) / ; recall is defined as (the number of predicted concepts correctly identified by the NLP system) / ; F1-score is defined as “/”. We used the micro average to calculate the overall score. We used accuracy to evaluate negation detection, which is defined as (the number of concepts with negations correctly identified) / .Two annotators annotated a total number of 4,782 DR-related concepts from 536 reports. We calculated the inter-annotator agreement score using 40 overlapped reports. For concept extraction, two annotators achieved an F1-score of 0.8021(in concept-level) and a token-level kappa score of 0.74. For relation annotation, two annotators achieved an F1-score of 0.7542. We randomly divided the dataset into a training set and a test set with an 8:2 ratio. Table Table Table Table Identify DR-related concepts is a critical step to leverage clinical narratives for lesion detection from the medical image. In this study, we developed annotation guidelines to annotate DR-related concepts from fundus image reports, annotated a corpus of 536 image reports with four categories of clinical concepts and two state-of-the-art transformer-based NLP models for detecting DR-related concepts and relations. For negation detection, we customized an existing negation detection algorithm, NegEx, using the training set and improved the accuracy from 0.62 to 0.9265, indicating it’s necessary to customize the rule-based negation detection algorithms using local datasets. For concept extraction, three out of four transformer-based models achieved better performance than the baseline model, except for the BERT_general model. The BERT model pretrained with the MIMIC III dataset achieved the best lenient F1-score of 0.9645. From Table We further link the severity, laterality, and eye part concepts to the corresponding lesion concept using relation extraction. The BERT_general model achieved the best strict/lenient scores of 0.8578 and 0.8881 for both settings, respectively. The RoBERTa_general also achieved the same performance as BERT_general in the strict evaluation score as a tie. Overall, the performance difference between the two transformer-based models in the end-to-end setting is not that significant with the setting using gold-standard concepts. It’s not surprising to see that the performances for end-to-end systems are lower  than pure relation extraction using gold-standard concepts.This study has limitations. The dataset we developed in this study is relatively clean without complex situations for relation extraction. For example, most of the relations are located at the same sentence. As the ultimate goal is to leverage the clinical narratives to help lesion detection from medical images, we plan to develop multimodal visual-text learning models to combine clinical text and medical images for early detection of DR in future studies.


N- and O- glycosylated proteins. Recent studies have shown that both free glycans and glycan-containing molecules have antiviral characteristics based on different mechanisms such as signaling, microbiome modulation, natural decoy strategy, and immunomodulatory action. In this review, we discuss the recent clinical studies and potential mechanisms of free and conjugated glycans' role in the prevention, treatment, and recovery of COVID-19.Milk contains all essential macro and micro-nutrients for the development of the newborn. Its high therapeutic and antimicrobial content provides an important function for the prevention, treatment, and recovery of certain diseases throughout life. The bioactive components found in milk are mostly decorated with glycans, which provide proper formation and modulate the biological functions of glycosylated compounds. The glycome of milk consists of free glycans, glycolipids, and  Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a single-stranded enveloped RNA virus that belongs to the beta coronavirus family. It was initially identified in humans in late 2019, which immediately caused a serious outbreak all over the world. The World Health Organization (WHO) reported the SARS-CoV-2 outbreak in the city of Wuhan, China in January 2020. Subsequently, WHO named this novel disease COVID-19 . AccordiMammalian milk is recognized as the major source of immunity for newborns since it contains various bioactive components such as free and conjugated oligosaccharides . Glycocovia the conjugation of distinct sugar moieties to proteins. This modification results in a microheterogeneity of glycoproteins that influences a myriad of attributes ranging from cell-to-cell communication to immune recognition (N-glycosylation and O-glycosylation are two main types of glycosylation in eukaryotes. While N-linked glycans (N-glycans) covalently bind to proteins at the carboxamide group in asparagine (Asn) side chain residue of Asn-X-Ser/Thr sequons, O-linked glycans (O-glycans) attach to the -OH group at the side chain of serine (Ser) or threonine (Thr) amino acids  residues, as well as α-linked Man substituted at C-2 and−6  mediated neutralization of viruses and toxins  are also involved in antimicrobial mechanisms against infections. Studies demonstrated that milk immunoglobulins of raw milk from non-immunized bovines, cows, and camels exert specific antibodies against human rotavirus . In addid toxins .The casein accounts for a majority (about 80%) of the protein mass in milk and includes different forms . Casein fractions are the main precursors of a myriad of biopeptides including bioactive peptides . They haO-glycosylation sites which noticeably contribute to its antimicrobial activity  it does not include known glycosylation sites. κ-casein is the major glycosylated casein that accounts for about 25% of total casein and has seven activity . κ-casei the gut . Furthernfection . Casein nfection –61.MFGM, which is a component of human milk, derives from the apical plasma membrane of lactating epithelial cells. It contains glycoproteins such as mucins, lactadherin, and bile salt-stimulated lipase (BSSL). MFGM glycoproteins could be effective antiviral agents against several viruses such as HIV and rotavirus; besides, they strengthen immunity against infections , 62, 63.in-vitro. They are extracellularly located and include a membrane-bound region, a short cytoplasmic segment, as well as the highly O-glycan part. O-glycans of MFGM proteins act as decoy proteins to inhibit pathogen attachment to epithelial cells  cannot utilize these structures (in-vivo study has shown that 19 distinct N-glycan structures from lactoferrin and immunoglobulins enhance Bifidobacterium longum subsp. infantis (B. infantis) growth. The study has also indicated that an enzyme produced by B. infantis, endo-ß-N-acetylglucosaminidase (EndoBI-1), can release about 800 mg of N-glycans from ten grams of either bovine or human milk glycoproteins  like HMOs, which lowers the environment pH in the gut as well as creates a high resistance to pathogen colonization through mucin structures since they generally grow at pH 6-7. Some conjugated glycans such as sIgA and lactoferrin take the role of binding epitopes to inhibit pathogen adhesion in a similar way to soluble oligosaccharides , human milk (58 types), bovine colostrum (100 types), and bovine milk (98 types)  . One typectively . Similar periods . The pro periods . Human c periods –90. Thes periods . To dateolostrum 0 types,  periods .N-acetyllactoseamine units via glycosyltransferase enzymes in the mammary gland. D-glucose (Glc), D-galactose , GlcNAc, L-fucose (Fuc), and NeuAc are basic building blocks of HMOs (N-containing (non-fucosylated) (42–55%), neutral (fucosylated) (35–50%), as well as acidic  (12–14%)  which are named type 1 chains. Lacto-N-tetraose (LNT) as type 1 is the most prevalent HMO  is linked to the lactose. Both type 1 and 2 chains can be further elongated by adding fucosyl and sialyl residues in order to create more diverse and larger HMOs . Th. ThN-ace of HMOs , 99. Bas(12–14%) . The laclent HMO . A type ger HMOs . HMOs arger HMOs , 102. Thger HMOs , 104. HMin-vitro study demonstrated that A-type HBGA co-localized at the cell surface with transfected SARS-CoV spike proteins. There was less interaction between ACE2 and spike protein of SARS-CoV-2 when there were anti-A-bodies  and alter epithelial cell gene expression, which improves tight junction function, lung damage, maturation in intestinal cells, and tissue repair . The devGlycosylated proteins are one of the most important components of both mature milk and colostrum and they actively take significant roles in different biological functions ranging from immunity to antiviral mechanisms. The most considerable functions of glycoconjugates are attributed to their glycan parts found in a conjugated form on protein structures. As the conjugated glycans are similar to free oligosaccharides regarding their structure and monosaccharides, they can also act as free ones in distinct biological mechanisms against viruses. Conjugated glycans, for instance, can shape the gut microbiome by enhancing the growth of beneficial bacteria, even more they can inhibit pathogens including different viruses such as norovirus, adenovirus, HIV, etc. by using unique antiviral mechanisms. Both human and bovine milk include incredible glycoprotein content ranging from lactoferrin to lactoperoxidase which exerts antiviral effects against diverse types of viruses as well as SARS-CoV-2. To date, the epidemic of COVID-19 and other potential coming outbreaks have indicated that searching for novel treatments against pathogens is critical to deal with them. As for especially human milk glycoproteins and their milk conjugated glycans, they are considered potential therapeutics to combat serious outbreaks that human beings face because of their antiviral properties. The mechanism and effectiveness of human milk on SARS-CoV-2 will be better understood by increasing the number of research and clinical applications of human milk and its components including HMOs and glycoconjugates. Importantly, glycan-rich milk, particularly colostrum, which contains a higher concentration of conjugated glycans than mature milk, may be used as a natural alternative to conventional drugs to prevent and/or treat viral diseases such as COVID-19 threatening the health of the general human population.Regarding potential studies in the future, plant-based glycans which are highly complex and heterogeneous could be also another antiviral agent in addition to milk-based glycans. Furthermore, plants' glycoproteins and their highly variable plant-derived glycans may be used as therapeutic proteins in medicine. Consequently, the comprehension of the structures and biological functions of a variety of conjugated glycans produced from different hosts is a critical requirement to develop novel glycoprotein-based therapeutics for the treatment of viral diseases including COVID-19.SK organized the general content of the paper. MK was responsible for general editing and organizing the authors as well as the contribution for two sections. AS, SS, and HD contributed one section of the paper. AA and BP were responsible for editing and organizing the paper. All authors contributed to the article and approved the submitted version.SK has received funding from Uluova Süt Ticaret A.Ş. (Uluova Milk Trading Co.). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.