Several fusion genes are directly involved in the initiation and progression of cancers. Numerous bioinformatics tools have been developed to detect fusion events, but they are mainly based on RNA-seq data. The whole-exome sequencing (WES) represents a powerful technology that is widely used for disease-related DNA variant detection. In this study, we build a novel analysis pipeline called Fuseq-WES to detect fusion genes at DNA level based on the WES data. The same method applies also for targeted panel sequencing data. We assess the method to real datasets of acute myeloid leukemia (AML) and prostate cancer patients. The result shows that two of the main AML fusion genes discovered in RNA-seq data, PML-RARA and CBFB-MYH11, are detected in the WES data in 36 and 63% of the available samples, respectively. For the targeted deep-sequencing of prostate cancer patients, detection of the TMPRSS2-ERG fusion, which is the most frequent chimeric alteration in prostate cancer, is 91% concordant with a manually curated procedure based on four other methods. In summary, the overall results indicate that it is challenging to detect fusion genes in WES data with a standard coverage of ∼ 15–30x, where fusion candidates discovered in the RNA-seq data are often not detected in the WES data and vice versa. A subsampling study of the prostate data suggests that a coverage of at least 75x is necessary to achieve high accuracy. Fusion genes represent an important class of genomic alteration contributing to the tumorigenesis for both solid and hematological cancers. The hybrid genes are often produced by recurrent chromosomal rearrangements, such as translocation, deletion and insertion . In the de novo assembly-first method  represents another primary type of sequencing application which has been frequently utilized in cancer studies . The expIn our previous study, we have developed a method named Fuseq to identify fusion genes from RNA-seq data, which provides an accurate and fast prediction of the fusion aberration . In thisReads mapping is the process to infer which region in the reference sequence that a read can originate from. In recent years, a wide range of computational tools have been developed and implemented for reads mapping, e.g., BWA, HISAT2 and Bowtie2 . The staAll the discordant and split reads are first annotated with the information of mapping position, chromosome, gene names and transcript names. In this step, a GTF  file recording the characteristics of genome/transcriptome structure is provided as input . In our According to the definition, split reads overlap with the fusion breakpoints, thus provide direct evidence supporting a potential fusion event . For eacIn this step, several statistical tests and filters are applied to exclude the false positives. For example, in terms of the general features, the chromosomes of fusion genes are limited to autosome 1–22 and chromosome X and Y. The constituent genes should be protein-coding genes and the distance between the two genes from the same chromosome must be large enough (10 kilo bases in this study). Also, we set the minimum number of supporting read pairs of a fusion event to be one. Apart from the filtering criteria regarding the general characteristics, another primary factor causing false positives is paralog genes with extremely similar sequences. To address this issue, we implement an RNA-seq simulation to detect paralogs genes/transcripts. The simulation scheme is similar with what we did in our previous study . We applIn this study, we employ our method to several real WES datasets including the BeatAML cohort, TCGA-AML cohort and the Prostate Biomarkers cohort . All of The BeatAML cohort includes a total of 672 tumor specimens representing 562 unique patients, which gives a comprehensive genomic landscape of AML. Specimens from bone marrow and peripheral blood were obtained from patients with informed consent . The exohttps://tcga-data.nci.nih.gov/tcga) for public access.The TCGA-AML cohort represents another primary project investigating the genomic and epigenomic landscape of AML . In thisProstate cancer is a genetically heterogeneous disease which remains the most common and deadliest malignancy among Swedish men . The metWe first apply the Fuseq-WES method to validate the fusion genes in BeatAML dataset. PML-RARA is a well characterized fusion gene in acute promyelocytic leukemia (APL), which is a clinically and biologically unique subtype of AML . The fusThe inversion involving p13 and q22 segment on chromosome 16 leads to the fusion of CBFB and MYH11. The CBFB-MYH11 is consistently observed in patients with AML subtype M4Eo . SeveralThe formation of RUNX1-RUNX1T1 fusion is due to the balanced translocation between chromosome 8 and 21, which can be identified in 5–12% of AML cases . In the We apply the same analysis scheme on the TCGA-AML data to validate the fusion genes. The PML-RARA fusion is detected in 16 samples from RNA-seq data. We obtain six samples with matched exome sequencing data and the fusion event is identified in three of them. For CBFB-MYH11, the RNA-seq data shows that a total of 11 samples carry the fusion and there are six of them having exome sequencing data. Surprisingly, unlike the high validation rate in BeatAML data, none of the six samples having CBFB-MYH11 detected. The RUNX1-RUNX1T1 is identified in seven samples using RNA-seq and is confirmed in two out of four samples with WES data available.The Prostate Biomarkers (ProBio) project implements a targeted deep-sequencing approach to characterize the genomic profile of selected genes. TMPRSS2-ERG (TE) is a predominant fusion gene with a 55% prevalence in prostate cancer patients. From the project we obtain 65 samples with targeted sequencing data. We first use four separate tools for fusion gene detection, which include SvABA , LUMPY , GRIDSS The IGV call identifies 37 patients to be carrying the TE fusion, while the remaining 28 are TE negative. Using the Fuseq-WES approach, the TE fusion is identified in 41 samples and absent in 24 samples. Overall, the results are concordant in 36 TE positive and 23 TE negative cases, indicating a 91% agreement between the two analyses. The detailed number of mapped and split reads supporting the TE fusion is given in We further investigate how sequencing depth impacts on the accuracy of Fuseq-WES. First, we randomly select 10 samples for which the TE fusion is validated manually. Then, for each sample we randomly subsample the reads from original data (1500X coverage) to generate five lower-coverage samples including 150x (10%), 75x (5%), 30x (2%), 15x (1%) and 7.5x (0.05%). Finally, we perform Fuseq-WES for all 10 samples and report in In this study, we aim to exploit the potential value of whole exome sequencing data in the context of fusion gene detection. We develop a new method named Fuseq-WES and apply it to several representative cancer datasets. In two of the most comprehensive cohorts of AML, i.e. BeatAML and TCGA-AML, we identify and validate three fusion genes, PML-RARA, CBFB-MYH11 and RUNX1-RUNX1T1, which play important roles in the development and progression of AML. In the Prostate Biomarker dataset, we validate the most recurrent fusion gene, TMPRSS2-ERG, and achieve a 91% concordance using two detection schemes.Compared with the identification results using RNA-seq data, we find that only a fraction of the fusion genes could be detected in the exome sequencing data. For example, from the BeatAML dataset, we obtain 11 samples with exome-seq data for PML-RARA, and four of them are successfully identified to carry this chimeric alteration. In the TCGA-AML cohort, there are six exome-seq samples and we validate three of them carrying the PML-RARA fusion. High-confidence detection of fusion genes mainly depends on split reads. Thus, we also summarize the number of split reads in the WES and RNA-seq data . In the An obvious limitation of WES is that only the exome region is targeted from genomic DNA for sequencing. In this case, if a fusion junction is located in an intronic region that is out of the targeted enrichment of exonic regions, the exome sequencing is unable to capture that break point. In contrast, the RNA-seq holds an inherent advantage over exome-seq, by which the non-coding regions are removed to produce mature messenger RNA (mRNA), so that the chimeric junction is detectable by subsequent sequencing. Therefore, a fusion gene can be identified using WES data only if the break point is located in or close to the exonic regions. Another limitation of WES is the short read length, especially the length of valid split reads covering the fusion junction. We have drawn a conceptual figure in We also find that the validation rate is highly associated with gene-exon structure and the read coverage in WES data. A gene with dense exon distribution and the sequencing data with high coverage could facilitate the fusion detection. For the CBFB-MYH11 fusion, in the BeatAML data we identify a total of 15 samples with the mutation among 24 WES cases. The high validation rate could be due to that the MYH11 has 43 exons with the gene length of ∼154,000 bp, which represents a high density covering the whole region of the gene. However, using the TCGA-AML data, we cannot validate the fusion gene in any of the six cases with WES data available. From the BAM file we notice that the median read-depth of TCGA-AML and BeatAML samples are 15x and 40x, respectively, which is lower than the 75x threshold as indicated in This observation is confirmed by the analysis using prostate cancer data. The ProBio project applies a targeted sequencing method including the exons and introns, and provides ultra-deep sequenced data with read-depth up to 1500x. We achieve an overall agreement in 91% of the 65 cancer patients. A subsampling study of the prostate data suggests that at least ∼75x is needed for Fuseq-WES to get high sensitivity and accurate results. We have summarized the coverage of WES data of 23 primary cancers in The Cancer Genome Atlas (TCGA) database, which is presented in


Worries associated with COVID-19 health consequences are well-justified. They may motivate people to take safety precautions, but may hinder if they become too intense. Current research examined mainly age and gender as potentially associated with worries. This study instead, focuses on self-perceptions of ageing (SPA) and perceived age discrimination as potential predictors of worry, in light of the ageism pandemic which co-occurred with the COVID-19 outbreak. The study is based on a national representative sample of 1,092 adults aged 50+ in Israel. Phone interviews were conducted between March – May 2020, when Israel gradually moved from strict to partial lockdown. Our findings show that SPA and age-based discrimination in the healthcare system were significant predictors of worries. The findings point to the potentially negative impact of the ageism pandemic in relation to worries. Interventions that address ageism directed by self or others might alleviate people's worries in the COVID-19 pandemic.


Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research. The development of acute kidney injury (AKI) after major non-cardiac surgery is associated with substantial long-term morbidity and mortality. This joint Consensus Statement from the Acute Disease Quality Initiative and the PeriOperative Quality Initiative provides recommendations for the definition, prevention and management of postoperative AKI. AKI can be considered a sentinel postoperative complication that is strongly associated with increased risk of death, co-occurrence of other postoperative complications, increased length of hospital stay and the development of progressive chronic kidney disease (CKD), which results in a considerable health-care and societal burden7.The development of postoperative complications after major non-cardiac surgery — particularly acute kidney injury (AKI) — has consistently been associated with substantial long-term morbidity and mortality8. However, the role of AKI after other forms of major surgery, particularly gastrointestinal surgery, has received less attention, even though such procedures are associated with higher 30-day mortality than many forms of cardiac surgery9. Despite the importance of AKI as a complication after all forms of major surgery, lack of consensus exists with regard to the definition, prevention and treatment of postoperative AKI (PO-AKI) and the pathophysiology of PO-AKI in the non-cardiac setting has not been well described. Furthermore, the understanding of and approach to this condition can differ between specialists in nephrology, anaesthesia and/or perioperative medicine.Considerable research and previous consensus meetings have focused on AKI after cardiac surgeryIn 2019, a joint meeting of the Acute Disease Quality Initiative (ADQI-24) and the PeriOperative Quality Initiative (POQI-7) was convened to address PO-AKI after major non-cardiac surgery. Here, we present our recommendations for clinical practice as well as for further research in this important area.10. The broad objective of ADQI 24 was to produce expert-based statements and a summary of current knowledge pertaining to the definition and management of PO-AKI in the setting of non-cardiac surgery for use by clinicians and researchers, based on review of evidence by and professional judgment of the faculty as well as to identify evidence gaps to establish research priorities.The Conference Chairs of the 24th ADQI/7th POQI consensus committee  convened a diverse panel of clinicians and researchers representing relevant disciplines  from Europe, North America and Australia, to discuss the issues relating to PO-AKI. The consensus meeting was held at Emmanuel College, Cambridge, UK, on 4–7 September 2019, and followed the established ADQI process and POQI protocols, including use of a modified Delphi method to achieve consensus11. A number of ungraded research recommendations were also identified in areas where high-quality evidence is lacking. Strength of recommendations and aggregated conclusions were established by consensus of all of the participants, who formally voted and approved the consensus recommendations.Conference participants were divided into five work groups: group 1 was tasked with the epidemiology and pathophysiology of PO-AKI. Group 2 was tasked with developing a definition for PO-AKI. Group 3 developed recommendations for the prevention of PO-AKI. Group 4 focused on treatment options for patients with PO-AKI, and group 5 explored outcomes after PO-AKI . Members13  is a clinical syndrome rather than a single disease. The majority of cases of PO-AKI are multifactorial in cause (ungraded).Consensus Statement 1bThe incidence of PO-AKI (defined by changes in serum creatinine) varies with the characteristics and urgency of surgery. The incidence of AKI after day or ambulatory surgery is uncertain (ungraded).Consensus Statement 1cAKI defined by transient oliguria is more common in the intraoperative and postoperative period than AKI defined by serum creatinine. Severe oliguria and anuria, even in the absence of changes in serum creatinine, are associated with increased long-term morbidity and mortality (ungraded).Consensus Statement 1dThe majority of observational studies focus on AKI in the immediate postoperative period. Little evidence is available regarding the epidemiology of acute kidney disease in the perioperative setting (ungraded).Consensus Statement 1e2, diabetes mellitus, heart failure, ascites, hypertension, emergency surgery, intraperitoneal surgery, number of medications, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), high American Society of Anesthesiology Physical Status classification score and albuminuria. Patients with chronic kidney disease (CKD) and/or diabetes are at a particularly high risk of AKI (ungraded).Risk factors for PO-AKI include age >50 years, male sex, glomerular filtration rate <60 ml/min/1.73 m22. Adoption of this consensus definition has resulted in a greater appreciation of the incidence, varied presentation and outcomes of PO-AKI  consensus criteria to define PO-AKI in clinical trials and epidemiological studies35. One study suggested that discrimination for subsequent adverse outcomes could be enhanced by testing for novel biomarkers. In this study, which included some patients with PO-AKI, the sum of the concentration of tissue inhibitor of metalloproteinases 2 (TIMP2) multiplied by that of insulin-like growth factor binding protein 7 (IGFBP7) added prognostic information to AKI defined by urine output alone ([TIMP2]×[IGFBP7] > 2 was associated with progression from stage 1 AKI)36.More is known about PO-AKI defined by change in serum creatinine than that defined by perioperative decrements in urine output. The prognostic implications of intraoperative transient oliguria are controversial, with some studies reporting a higher risk of subsequent adverse outcomes and others suggesting no increase in risk39. In a study of PO-AKI after non-cardiac surgery, the incidence of AKI increased from 8% to 64% if urine output was included in the definition37. Some postoperative oliguria is assumed to be an appropriate physiological response to decreased intravascular volume, vasodilatation or non-osmotic release of arginine vasopressin in response to tissue injury40; however, sustained decrements in urine output, even without accompanying changes in serum creatinine, have been associated with longer-term morbidity and mortality41.Many, but not all, of the available studies suggest that PO-AKI defined by oliguria alone is more common than PO-AKI defined by changes in serum creatinine levels42. A study that evaluated substantial decline in kidney function, defined as a 30% decrease in estimated glomerular filtration rate at 60 days after surgery, suggested that the incidence of this outcome was only 2% among patients without PO-AKI (defined by change in serum creatinine only), but 10%, 17% and 29% among patients who experienced PO-AKI stages 1, 2, and 3, respectively43. The incidence of AKD in the general population is likely lower than in the post-surgery population; in a study of Canadian electronic health records, 5.2% of patients in a given period had AKD with or without AKI44.The concept of acute kidney disease (AKD) is intended to bridge the gap between AKI, which refers to an acute alteration in kidney function over a 7-day period, and CKD, which refers to a sustained alteration in kidney function over a 3-month period. AKD therefore refers to AKI that persists for more than 7 days after the initial insult, or a progressive decline in kidney function that does not meet AKI criteria on a week-by-week basis. Few epidemiological data are available on the incidence and prognosis of postoperative AKD, despite its likely importance as a bridge to development of sustained kidney dysfunction and CKD40. The three validated risk scores for PO-AKI include male sex, age >50 years, diabetes mellitus, hypertension, ascites, heart failure, emergent surgery, intraperitoneal surgery, poly-pharmacy, use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), and increasing American Society of Anesthesiologists physical status classification score46. Albuminuria and hypoalbuminaemia have also been described as risk factors for PO-AKI50. Risk factors for PO-AKI occurring in patients in the ICU more than 48 h after surgery reflect risk factors for AKI in critical illness including the need for new nephrotoxic medication, sepsis and shock52. Whether targeting modifiable risk factors for early PO-AKI, for example, using perioperative haemodynamic interventions, will impact the incidence of AKI later in the postoperative period, >48 h after surgery, remains uncertain.Several patient-related, surgery-related, and anaesthetic-related risk factors for developing early PO-AKI during the first 48 h after surgery have been described53. However, existing validated risk scores for PO-AKI were developed using a variety of older (pre-KDIGO) definitions of AKI or were applied to select surgical settings46. More generalizable prognostic clinical tools are needed to accurately risk-stratify patients preoperatively, particularly to distinguish those patients at the highest levels of risk (e.g. >20–30%). In the absence of such tools, patients with CKD and those with diabetes can reasonably be considered to be at increased risk of PO-AKI. The KDIGO guideline for the diagnosis, evaluation and management of AKI suggests that age >60 years, emergency surgery, elevated American Society of Anesthesiologists physical status classification score and preoperative comorbid illnesses, including diabetes and any chronic disease of the heart, lung or liver, are risk factors for PO-AKI42.Use of a validated clinical risk score is a potentially useful approach to risk stratify patients for targeted interventions or to facilitate the conduct of randomized controlled trials (RCTs)Understanding the pathophysiology and epidemiology of PO-AKI is central to the identification and development of novel preventative therapies and treatments. This understanding may be improved by conducting prospective studies that include collection of biological samples for histological and biomarker examination as well as retrospective analyses that examine shared pathogenesis across a spectrum of perioperative complications. The incidence of PO-AKI in the day and ambulatory surgery settings is uncertain and should be investigated in epidemiological studies. Development of better risk prediction tools for PO-AKI could help to risk-stratify patients and set thresholds of predicted risk that merit adjustments in perioperative care.54 and is supported by evidence from numerous clinical studies57. Furthermore, within the 7-day window, different timing of AKI may be indicative of the nature of the kidney insult, that is, intra-operative events versus post-operative insults.Although the KDIGO definition of AKI is now widely employed in the perioperative literature, the exact implementation of this definition varies considerably in terms of timeframe of diagnosis. We recommend defining PO-AKI as occurring when existing KDIGO criteria for AKI are met within 7 days of an operative intervention Box . AKI occ51. Use of a KHA was previously recommended by ADQI in the context of quality improvement processes for monitoring patients at a high risk of AKI before surgery58. A KHA comprises a structured evaluation that includes previous history of AKI, current medications, cardiovascular health, haemodynamic status and markers of kidney function (i.e. serum creatinine) and kidney damage (i.e. urine dipstick). Use of a KHA in the perioperative period involves integrated assessment of patient-specific and procedure-specific risk factors, clinical context and resource setting.Notably, AKI could potentially be present before surgery , highlighting the importance of a risk-based kidney health assessment (KHA)Importantly, the KHA approach can be used to perform context-dependent evaluation both before and after surgery, when AKI is diagnosed and during follow-up Fig. . A perio59, which may spuriously increase or decrease measured values, as well as perioperative changes in creatinine production that alter serum creatinine levels independently of changes in GFR60. Urine output is also likely to be influenced by multiple physiological factors specific to the perioperative period, including intravascular volume status, relative or absolute hypotension and neurohormonal response to surgery. Data suggest that although intraoperative oliguria is associated with PO-AKI, the positive predictive value is low32. We therefore recommend that urine output is interpreted in the context of severity of oliguria, clinical setting and other corroborating evidence of PO-AKI. Thus, isolated perioperative oliguria meeting AKI stage 1 criteria in the context of transient hypotension should not be viewed as being the same as more severe or prolonged oligo-anuria unresponsive to haemodynamic interventions. The presence of new evidence of kidney tubular damage (e.g. on urine microscopy or from novel biomarkers) or evidence of evolving sepsis in the context of early oliguria would be suggestive of AKI; these factors can be identified and integrated within a timely postoperative KHA.Conventional diagnostic criteria for AKI might be influenced by multiple factors specific to the perioperative period, rendering their predictive utility for PO-AKI less certain. Serum creatinine concentration is subject to abrupt changes in total body waterBox 2 Definition of PO-AKIConsensus Statement 1aWe recommend defining postoperative acute kidney injury (PO-AKI) as occurring when existing Kidney Disease Improving Global Outcomes (KDIGO) criteria for AKI are met within 7 days of an operative intervention (ungraded).Consensus Statement 1b.We recommend performing a risk-based Kidney Health Assessment (KHA) preoperatively and postoperatively, with the specific methods and frequency of assessment determined by clinical judgement based on individual patient-specific and procedural-specific risk factors and the available resources Consensus Statement 1cWe recommend using the term postoperative acute kidney disease (PO-AKD) when KDIGO criteria for AKI are present after postoperative day 7 and objective evidence of injury initiation was present within the first 7 postoperative days (ungraded).54 or AKD61 without the postoperative prefix. With this proposed nomenclature  occurs in patients with PO-AKI who continue to meet KDIGO criteria for AKI >7 days after surgery. Patients whose rise in serum creatinine level begins before postoperative day 7 but whose serum creatinine level does not increase ≥50% above baseline until 7–90 days after surgery would also meet PO-AKD criteria based on a slow progressive deterioration in kidney function in the postoperative period Box . Howeverure Fig. , it sougLimited information exists regarding the prognostic implications of the nature and timing of the AKI diagnosis within 7 days after surgery, and these important aspects of the PO-AKI diagnostic criteria warrant better characterization. Furthermore, to what extent indices of kidney injury other than serum creatinine and urine output, such as urinary or plasma biomarkers, are important for prognostication in PO-AKI is unknown and should be the subject of further study. Whether or not important differences exist in the epidemiology and prognostic significance of PO-AKD that arises as persistent PO-AKI compared with PO-AKD that develops after a gradual rise in creatinine after day 7 is also unknown.The impact of routine, structured KHA on the detection of PO-AKI remains to be determined. An expanded perioperative urinalysis conducted as part of a detailed KHA might identify previously unknown pathology and could potentially lead to additional, potentially expensive and/or invasive investigations that could delay surgery. The presumed benefits and cost-effectiveness of a KHA therefore require confirmation. Finally, the optimal interpretation of intraoperative and postoperative oliguria remains unclear and should be the subject of further study.62. Although the avoidance of potential nephrotoxins is considered to be a cornerstone of AKI prevention, there is a relative paucity of data supporting this approach. However, routine use of gentamicin for surgical prophylaxis was associated with an increased risk of AKI following orthopaedic surgery63 and, in the paediatric setting, systematic screening for nephrotoxin use, with a focus on close monitoring in patients exposed to multiple nephrotoxins and nephrotoxin cessation, has been shown to reduce rates of AKI65.Surgery is sometimes performed in patients with established AKI; however, common perioperative interventions focus on prevention of PO-AKI Box . As neph66.At present, common practice is to discontinue use of ACE inhibitors and ARBs before surgery to avoid perioperative hypotension. This approach is assumed to reduce the risk of perioperative AKI based on physiological rationale. In line with this established practice, we recommend discontinuing ACE inhibitors and ARBs for a minimum of 24 h before surgery to minimize the risks of perioperative hypotension and/or postoperative AKI Box . This re24.NSAIDs are generally avoided in surgical patients at a high risk of AKI, but might be beneficial as opiate-sparing agents in patients who are at a low risk of AKI. Although NSAIDs are widely used in patients with normal kidney function, their impact on risk of AKI in the postoperative period is unclear67.To date, no preoperative pharmacological intervention has been shown to reduce the risk of PO-AKI in RCTs. However, attention should be paid to ensuring euvolaemia prior to surgery and addressing or avoiding preoperative fluid losses caused by excessive fasting, bowel preparation and/or acute illnessBox 3 Prevention of PO-AKI: preoperative strategiesConsensus Statement 3a.We recommend that when considering use of medications or interventions that are associated with an increased risk of acute kidney injury (AKI), the relative benefits and/or necessity of the medications or interventions should be balanced with the risk of postoperative AKI (PO-AKI). This recommendation applies to outpatient medications, new medications and exposures including contrast media Consensus Statement 3b.We recommend discontinuing angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for a minimum of 24 h before surgery, dependent on the specific medication, to minimize the risks of perioperative hypotension and/or PO-AKI Consensus Statement 3c.We recommend assessing the relative risks and benefits of use of NSAIDs (including COX2 inhibitors) in individual patients. In general, in patients at a high risk of PO-AKI, the risk of AKI associated with use of NSAIDs might outweigh the benefits with regard to opioid minimization, whereas in low-risk patients, the benefits of use of NSAIDs might outweigh the risks. The risk–benefit profile in patients at a moderate risk of AKI is particularly uncertain 68. Algorithms that use cardiac output monitoring to optimize cardiac stroke volume and/or increase global oxygen delivery, known as goal-directed therapy, have been the subject of multiple RCTs. A Cochrane review and meta-analysis suggested that goal-directed therapy can reduce the risk of PO-AKI70. Large observational studies have shown strong associations between intraoperative hypotension and PO-AKI with the risk of organ injury a function of the severity and duration of the hypotension73. Both absolute mean arterial blood pressure (MAP (e.g. 60–70 mmHg)) and relative MAP (e.g. <30% reduction from baseline) thresholds are associated with PO-AKI. The results of an interventional trial of use of a MAP target of >65 mmHg as part of a goal-directed strategy have added weight to these observational data, demonstrating fewer postoperative complications (including AKI) and shorter length of hospital stay with this approach74. Similar to other settings such as sepsis, a higher MAP target may be beneficial in reducing the incidence of AKI in patients with poorly controlled pre-existing hypertension75.Intravenous fluid and haemodynamic management in the intraoperative and early postoperative period has a major impact on the development of PO-AKI Box . The REL78 .We recommend not using restrictive or zero-balance perioperative fluid regimens in major elective surgery (except in specific circumstances). Such regimens are associated with increased risk of postoperative acute kidney injury (PO-AKI) Consensus Statement 4b.We recommend the use of goal-directed haemodynamic therapy in high-risk patients to optimize volume status, blood pressure and cardiac output and reduce the risk of PO-AKI Consensus Statement 4c.We recommend maintaining an intraoperative mean arterial blood pressure (MAP) >65 mmHg to reduce the risk of PO-AKI. The risk of AKI is a function of both the magnitude of hypotension and its duration. For selected patients, including those with pre-existing systemic hypertension, a higher MAP target should be considered Consensus Statement 4d.We recommend the perioperative use of balanced crystalloids rather than 0.9% saline to reduce the risk of PO-AKI Consensus Statement 4eIn the setting of elective surgery outside of the ICU, insufficient evidence exists to make a recommendation regarding the choice of crystalloids or colloids for volume expansion to modify the risk of PO-AKI (ungraded).84. These findings suggest that maintenance of fluid and haemodynamic status in the early postoperative phase is important to avoid organ injuries including AKI28. A trial that used stroke volume optimization and vasopressors to target a MAP within 10% of the preoperative baseline value during and for 4 h after surgery showed that this strategy was associated with a reduction in postoperative organ injury, but was not powered to assess kidney-specific outcomes85. Further research is warranted to evaluate postoperative monitoring strategies and ideal clinical settings to reduce the risk of PO-AKI in moderate- to high-risk patients.The early postoperative period has not been extensively studied in relation to kidney outcomes. However, therapeutic strategies used in the hours after surgery could likely modify the risk of AKI Box . Clinica86. Failure to restart chronic ACE inhibitor or ARB therapy that was suspended preoperatively is associated with increased 30-day mortality88. However, the optimal time point to restart these medications has not been clearly established. Given their effects on the kidney, a reasonable approach would be to conduct a focused KHA before restarting ACE inhibitors or ARBs.As postoperative hyperglycaemia is strongly associated with AKI, avoidance of perioperative hyperglycaemia (>180 mg/dl) is recommended89.Enhanced recovery after surgery pathways are typically multimodal, multidisciplinary interventions that have been promoted to facilitate recovery from surgery. Use of NSAIDs to minimize opiate analgesia requirements is a common component of such pathways, along with avoidance of markedly positive fluid balance. Accordingly, in some settings such as colorectal surgery, implementation of an enhanced recovery after surgery pathway could be associated with a higher, rather than lower, incidence of AKIBox 5 Prevention of PO-AKI: postoperative strategiesConsensus Statement 5a.We recommend maintenance of adequate organ perfusion, including attention to euvolaemia and treatment of hypotension in the early postoperative period, to reduce the risk of postoperative acute kidney injury (PO-AKI). Monitoring and targeting haemodynamic parameters may require enhanced levels of monitoring and/or care depending on the clinical context and patient risk profile Consensus Statement 5b.We recommend treatment of postoperative hyperglycaemia (target glucose <180 mg/dl [<10 mmol/l]) to reduce the risk of PO-AKI Consensus Statement 5c.We recommend considering restarting angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy within the first 48 h postoperatively in patients who are haemodynamically stable without evidence of PO-AKI. This decision should be individualized and context-specific Consensus Statement 5d.We recommend that enhanced recovery after surgery (ERAS) pathways  are individualized based on the baseline risk of PO-AKI. The impact of ERAS pathways on the incidence of PO-AKI is unclear owing to the potential for both beneficial and harmful effects As a general principal, treatment of AKI should be initiated as early as possible, including in patients with suspected AKI or who are at a substantially increased risk of AKI. Management of PO-AKI involves specific approaches, for example, avoidance of nephrotoxins, as well as general management principles that are common to all postoperative complications, such as haemodynamic optimization. Similarly, treatment of PO-AKI shares many features with the treatment of AKI in other settings Table . Treatme95. Nephrology or urology consultation should be sought if intrinsic causes of AKI or obstruction are suspected based on the KHA results. The frequency and duration of monitoring should be individualized based on patient risk, exposure and clinical course .We recommend that the underlying causes of postoperative acute kidney injury (PO-AKI) should be determined and treated whenever possible Consensus Statement 6b.In patients with PO-AKI, we recommend that criteria for implementation of kidney replacement therapy (KRT) should be based on directly anticipated or observed life-threatening AKI-related complications Consensus Statement 6c.We suggest that AKI phenotype is taken into account when deciding what type of treatment to implement 97. However, observational studies have shown that the severity of AKI correlates with short-term101 and longer-term102 adverse events, suggesting that interventions that reduce the severity of AKI could improve these outcomes.The treatment and prevention bundle outlined in the 2012 KDIGO clinical practice guideline for AKI consists of supportive measures, including volume management, maintenance of adequate blood pressure and judicious avoidance of nephrotoxins. Two RCTs demonstrated that implementation of this bundle in high-risk patients identified by biomarkers after surgery significantly reduced the occurrence of PO-AKI, but were not powered to demonstrate differences in longer-term patient outcomesKidney replacement therapy (KRT) may be required in patients with severe AKI who develop medically refractory fluid and/or metabolic complications. In the absence of conventional indications, the best timing for initiating KRT in PO-AKI is uncertain. Potential rationales for initiating KRT during PO-AKI are avoidance of fluid accumulation, maintenance of acid-base and electrolyte control, provision of space to accommodate nutritional and medication needs, and abrogation of the interaction between the kidney and other organs. Theoretically, early initiation of KRT could facilitate better fluid, electrolyte and acid–base homeostasis. However, KRT is associated with increased risk of complications, healthcare costs and clinical workload.104 have stimulated debate regarding the best timing for KRT in patients with established AKI and differences in study design, patient populations, definitions of early and late RRT initiation, and inclusion criteria make head-to-head comparisons difficult.The 2012 KDIGO guidelines recommend starting KRT “when life threatening changes in fluid, electrolyte, and acid-base balance exist” and considering the “broader clinical context, the presence of conditions that can be modified with [KRT], and trends of laboratory tests — rather than single BUN and creatinine thresholds alone — when making the decision to start [KRT]”. Contradictory trial results105. Importantly, STARRT-AKI included a large cohort of patients with PO-AKI (n = 965) and showed no evidence of a benefit of early commencement of KRT in this subgroup . Thus, decisions regarding timing of KRT initiation remain a complex issue that should be individualized based on the clinical state of the patient, in particular imminently anticipated or observed life-threatening complications of AKI.Following our consensus conference, the results of the STARRT-AKI study provided high-quality evidence that early commencement of KRT based on AKI criteria in the absence of conventional indications does not improve survival, may needlessly expose some patients to KRT and results in a higher risk of KRT dependence at 90 days compared with a conservative strategy for starting KRT106. Until these strategies are better embedded in clinical practice, the potential benefits of individualized therapy for AKI subtypes cannot be clearly established.AKI is a heterogeneous condition consisting of distinct endotypes and phenotypes based on its aetiology, prognosis and molecular pathways. Different subtypes might require and benefit from different therapeutic strategies. However, current AKI definitions based on serum creatinine and urine output provide no information on AKI subtypes. Studies using various damage and functional AKI biomarkers suggest that these new tools might overcome the limitations of current AKI definitions to improve AKI phenotypingWe recommend further trials to assess the optimal choice and volume of fluids for intravascular expansion and vasopressor therapy in patients with PO-AKI as well as the use of protocol-based management of haemodynamic and oxygenation parameters to prevent worsening of PO-AKI. Investigation of individual components of the KDIGO guideline to identify those that are the most effective in treating PO-AKI is important given that these were largely assembled based on expert opinion. Better understanding of AKI phenotypes is required to enable further trials to assess the response to implementation of the KDIGO bundle and other treatment options according to different AKI endotypes and phenotypes.115 39.Patients with PO-AKI or AKD are at an increased risk of recurrent episodes of AKI and progressive deterioration of kidney function, including CKD and dialysis dependency108. Among 1,200 patients who underwent non-cardiac and non-vascular surgery, of whom 6.7% met the RIFLE criteria for AKI (2), the risk of non-cardiovascular complications (such as pneumonia and stroke) was similar in those with and without AKI over the first 2 weeks after surgery, but thereafter, patients with AKI experienced a significantly higher rate of cardiovascular events, including acute coronary syndrome, acute heart failure and arrhythmias107. Similarly, AKI after abdominal surgery has been associated with an increased risk of in-hospital complications, including perioperative acute myocardial infarction, pneumonia and sepsis (P < 0.001)29.Other postoperative complications, including infection, prolonged mechanical ventilation, tracheostomy and cardiovascular events are also more common in patients who develop AKI after surgery than in those who do not117. Furthermore, the risks of 30-day re-admission and discharge to a nursing facility or rehabilitation centre are increased31. PO-AKI has also been associated with important, but difficult to quantify adverse outcomes, including reduced quality of life and perceived well-being118 as well as with increased risk of malignancy, possibly due to interactions with the immune system119.Unsurprisingly, the development of PO-AKI is associated with substantial increases in hospital costs and resource utilization, as well as longer stays in the ICU and in hospital120 and limited evidence is available to support any specific monitoring paradigm. However, adverse outcomes are increased in patients with prolonged, more severe AKI, and in those whose kidney function does not recover to baseline levels, suggesting that use of these factors to inform the initial frequency and nature of follow-up would be a reasonable approach122.Given the increased risk of short- and long-term adverse outcomes following PO-AKI, appropriate monitoring and follow up of this cohort is a potential approach to improving patient outcomes. Although follow-up schemas for all-cause AKI have been proposed, the optimal timing of follow-up after a postoperative episode of AKI or AKD is unknown123. When available, further work-up and monitoring of kidney function with other diagnostics may be appropriate. Changes in management based on this monitoring should be communicated with the patient as well as with other treating physicians.Monitoring pathways should be developed in conjunction with nephrologists, but may be directly provided by perioperative physicians, primary care physicians or other specialists Fig. . As a mi58. A multi-disciplinary follow-up approach  combined with patient education is recommended but has not been formally studied. Undoubtedly, drug selection, dosing and monitoring are important and should be guided by personalized clinical decision making and regular assessment of kidney function. Both the use of nephrotoxic drugs and the inappropriate exclusion of potentially beneficial medications  need to be avoided125. In patients with AKD, in particular, a substantial risk exists of potential therapeutic failure caused by underdosing or avoidance of effective cardiovascular drugs. Close collaboration between the relevant clinical teams is paramount and future research efforts should clarify the ideal timing and method for providing post-AKI and AKD care .The incidence of kidney and non-kidney adverse events is increased following postoperative acute kidney injury (PO-AKI) or postoperative acute kidney disease (PO-AKD). In particular, patients with surgery-associated AKI or AKD are at an increased risk of new or worsening chronic kidney disease (CKD), which is associated with increased long-term mortality Consensus Statement 7b.The prevention of new or worsening CKD following an episode PO-AKI or PO-AKD is a public health priority. We recommend that all patients undergo at least one kidney health assessment once the acute phase of AKI or AKD is complete. This approach will require optimal communication and AKI education between health-care professionals and the patient or caregiver A need exists for epidemiological research to describe the frequency, nature and severity of PO-AKI and PO-AKD progression to CKD. The effectiveness and cost-effectiveness of supplementing a simple KHA with enhanced kidney health care in the prevention of CKD progression after surgery-associated AKI or AKD should be evaluated in appropriately selected patients. Finally, research is needed to explore a possible common aetiology between surgery-associated AKI or AKD and other chronic organ injuries as the longer-term effects of AKI do not only involve the kidney.PO-AKI is a sentinel postoperative event that is strongly associated with both short-term surgical complications and long-term adverse outcomes. In this Consensus Statement, we provide an overview of PO-AKI and management. However, PO-AKI is a heterogeneous syndrome with a variable clinical course. In many areas the strength of evidence is poor and accordingly our recommendations are weak. We provide research recommendations for these areas to enable greater clarity to be achieved in the future. Overall, we believe that an integrated approach to PO-AKI management requires serial evaluations of AKI risk, diagnosis, progress and outcomes throughout the perioperative period, which can be constructed as a series of focused KHAs.Supplementary Information


Using a generalized linear model accounting for confounding variables, we found that median PRS was significantly associated (p < 2 x 10−16) with COVID-19 mortality in each district corresponding to the population studied and had the largest effect on mortality (regression coefficient = 10.25). As a control we repeated our analysis on randomly selected 100 non-associated SNPs several times and did not find significant association. Therefore, we conclude that genetic susceptibility may play a major role in determining the differences in COVID-19 outcomes and mortality across the Indian sub-continent. We suggest that combining PRS with other observed risk-factors in a Bayesian framework may provide a better prediction model for ascertaining high COVID-19 risk groups and to design more effective public health resource allocation and vaccine distribution schemes.Host genetic variants can determine their susceptibility to COVID-19 infection and severity as noted in a recent Genome-wide Association Study (GWAS). Given the prominent genetic differences in Indian sub-populations as well as differential prevalence of COVID-19, here, we compute genetic risk scores in diverse Indian sub-populations that may predict differences in the severity of COVID-19 outcomes. We utilized the top 100 most significantly associated single-nucleotide polymorphisms (SNPs) from a GWAS by Pairo-Castineira et al Pairo-Castineira et al., 2021), two SNPs, namely, rs10735079 and rs2109069 are also present in the Indian Genome Variation Consortium (IGVC). The IGVC was a large-scale comprehensive study of the Indian sub-populations that was conducted to shed light on the genetic diversity among geographically and ethnically diverse Indian sub-populations. This study had identified a high degree of genetic distinctness, with respect to SNPs, in different Indian sub-populations . PRS provides an estimate of the genetic propensity of an individual to develop a disease and/or a trait . TransetHere, with prior information from the data of stratified Indian sub-populations, we calculated the PRSs with an aim to explore and identify Indian sub-populations that could be at a higher risk for COVID-19-mediated mortality. Considering the challenges associated with the transferability of the effect sizes, we also analyzed the differences in the patterns of LD, and used the SNPs with similar LD patterns in the discovery population and Indian population to ensure good prediction accuracy of the PRS. Based on these PRSs, we evaluated the population-wise susceptibility that can be of potential utility in more effective vaccine distribution schemes among Indian sub-populations.Pairo-Castineira et al., 2021). The study had identified genetic signals related to host antiviral defense pathways and those mediating inflammatory organ damage in critical COVID-19 patients using Mendelian randomization, GWAS and transcriptome-wide association studies. DNA samples were genotyped using Illumina Global Screening Array v.3.0 + multi-disease bead chips (GSAMD-24v3-0-EA) and Infinium chemistry . Further, genotype data of 390 samples across 25 populations from the IGVC (Phase 3) were used for analyzing the Indian sub-populations. Briefly, they represent diverse ethno-linguistic and geographical regions of India, and house information about genome-wide SNPs across Indian populations. The data span four major linguistic lineages - Indo-European (IE), Dravidian (DR), Austro-Asiatic (AA), and Tibeto Burman (TB) from different geographic locations  from contrasting ethnic backgrounds and ethnicity sub-categorized as caste groups (LP), religious groups (SP), and tribal isolated populations (IP) , ∼11% of South Asian, 8% African and 7% of East Asian ancestries (ons (IP) . Clusterdia.org/ .-values (below the genome-wide threshold p < 10−06). The top 100 such SNPs from the study represented in the IGVC data were analysed for and ascertained to have similar LD patterns (for applicability of effect sizes from non-SAS ancestry) across the Indian sub-populations and the GWAS discovery population and were used for polygenic score analysis. The effect sizes of 30 SNPs were derived from Europeans, 40 from South Asian, 21 from East-Asian and seven from African ancestries. PRS of each individual was calculated using PLINKv1.9 .While applying effect sizes derived from one ancestral population to another to calculate PRS, the accuracy is better when SNPs with similar LD patterns or allele frequencies between the discovery (majority of Europeans) and target (Indian) populations are used. Directly comparing LD patterns between Europeans (CEU) and IGVC populations was not possible because of the smaller number of SNPs represented in the OMNI array of the IGVC. So we first overlapped the GWAS results with the IGVC SNP data, from which the top 100 significant SNPs  were selected and verified for LD conservation. The genetic closeness of individuals of the IGVC to the SAS populations of the 1,000 Genomes has been shown in a recent study . AnotherThe LD pattern 5 MB around the top 100 most significantly associated SNPs were compared between each of these non-Indian ancestral populations with ITU using the varLD (v1.0) tool–a tool to compare the extent of LD differentiation at loci between pairwise populations, to assess LD structure across the discovery GWAS population and the target Indian population. . The minhttps://censusindia.gov.in). A similar model was constructed for the data with the IENLP1 population removed as this was seen as an outlier due to a very high value for deaths/million. The pseudo R2 values were calculated as (model$null.deviance-model$deviance)/model$null.deviance  was fit for deaths per million population of each district due to COVID-19 and PRS of the corresponding district. To account for potential confounders, we added percentage of population above 45 years of age, and sex ratio  to the GLM. Poisson distribution was used with the respective population of each district as an offset to control for overdispersion. The data were collected from the census records of India , and applied on 25 geographically and ethnically diverse sub-populations of the Indian sub-continent (p = 2.95 ✕ 10−06). Based on the PRS for each district, the susceptible population, i.e., the number of individuals in a population at risk for developing severe illness when infected with SARS-CoV-2 was also evaluated  on mortality while the potential confounders considered had significant (p < 2 x 10−16) but negligible effects. The same trend was observed on removing an outlier population, IENLP1 and the coefficient estimate for PRS had improved two-fold and the fit improved (pseudo R2 = 0.46)  . Based o = 0.46) ; Table 12) and the other closely located districts within Maharashtra have also been severely affected that could have promoted higher viral spread, and given the high PRS, they may present higher susceptibility to COVID-19 infection and associated inflammatory responses.No significant association of PRS derived from non-risk SNPs with the COVID-19 mortality was observed in the GLMs as shown in Previous observation of genetic differences in the individuals from different regions of India, and the strong association between genetic variants and COVID-19 illness led us to evaluate the genetics risk for SARS-CoV-2 mediated illness in Indian sub-populations. In this report, we have calculated the PRSs of SNPs in different Indian sub-populations, followed by a regression analysis with COVID-19 related mortality in different districts of India. Our results indicate a significant association between the number of COVID-19-related deaths with the PRS, and thereby can provide support for population specific prioritization in COVID-19 vaccination program.Pairo-Castineira et al., 2021). It has also been noted that the individuals belonging to different linguistic lineages in different geographic locations of India exhibit genetic distinctness (In a recent GWAS, these SNPs have been robustly associated with critical illness in patients with COVID-19 (inctness . Here, oinctness . Our resinctness . In the There are certain limitations of the present study. The GWAS was not directly conducted in the individuals of the Indian sub-populations, and the PRSs were based on effect sizes from different ancestral groups with COVID-19 infection. The mortality may also be affected by comorbidities like diabetes, hypertension, cardiovascular diseases , environIn this study, we provide a methodological framework for predicting Indian sub-populations that could be at a higher risk for developing COVID-19 mediated critical illness but not any clinical evidence. These scores in conjunction with the commonly noted comorbidities could provide a good prediction in ascertaining high COVID-19 risk groups. Such accurate identification of vulnerable populations is crucial for the development of effective prevention and vaccination strategies. Such strategies applied to populations with defined genetic histories such as in the Indian subcontinent can be easily extended to model population level susceptibility to several other important diseases that strain the public health system in India, and provide a necessary use case justifying national scale projects such as GenomeIndia.


Friction and wear performance of an un-textured surface and two types of widely used micro-scale texture surfaces, grooves and circular dimples, were examined and compared. The results demonstrated that the effect of surface textures on friction and wear performance is influenced by texture parameters and the materials of friction pairs. The circular-dimple texture and the groove texture, with certain texture parameters, played a positive role in improving friction and wear performance under specific operating conditions used in this research for SiC–steel and SiC–Si3N4 friction pairs; however, there was no friction and wear improvement for the textured SiC–PTFE friction pair. The results of this study offer an understanding and a knowledge base to enhance the performance of bearing elements in complex interacting systems.This paper reports research on the frictional behavior of a textured surface against several materials under dry and lubricated conditions, and this is aimed to provide design guidelines on the surface texturing for wide-ranging industrial applications. Experiments were performed on a tribo-tester with the facility of simulating A ball-on-plate model in reciprocating motion under dry, oil-lubricated, and water-lubricated conditions. To study the frictional behavior of textured SiC against various materials, three types of ball-bearing –elements, 52100 steel, silicon nitride (Si For equipment which works under extreme conditions under extreme conditions, a poor lubrication state of the key parts severely restricts the service performance of the whole machine or system. For example, the contact wear of rough peaks on the friction pair surface caused by heavy load or by insufficient oil supply will affect the reliability and service life of the equipment. How to effectively reduce equipment failure caused by severe friction and wear under extreme conditions has become a common issue that needs to be resolved.In the past decades, as surface processing technology has developed, surface texture has become a subject of attention within the interacting systems and complex machine elements to reduce friction and wear, such as mechanical interacting components, elements, piston liners, and rings and cutting tools ,2,3,4,5.Previously, many studies have reported the effects of a textured surface on frictional performance. Etsion et al.  researchMost previous studies on surface texturing have focused on optimizing texture parameters for optimal frictional performance, such as the texture size, shape, depth, and arrangement ,21,22,23The frictional behavior of a textured silicon carbide (SiC) plate against several types of materials was tested on an experimental device named UMT-2  with a ball-on-plate modular simulator , as depicted in 3N4, and PTFE were used in the experiments, which were named Ball-1, Ball-2, and Ball-3. To investigate the frictional behavior of textured SiC against various types of materials, three types of ball-bearing elements of materials 52100 steel, Sid and the groove width ΔW were set to about 50 μm. The white arrows in To compare the frictional performance of the textured and un-textured SiC plates, picosecond laser with a wavelength of 532 nm and a pulse frequency of 100 kHZ was used to fabricate textures on the plate surfaces. In the texture-machining process, 0.3 W laser energy and 100 mm/s scanning speed were selected to ensure that processing quality and efficiency were sustained. After laser processing, no further processing was performed on the surface. To study the frictional performance of the textured SiC plate under dry, water-lubricated, and oil-lubricated conditions, distilled water and synthetic base oil PAO4 were used as lubricants. The parameters of PAO4 are shown in Before the experiments, the samples were cleaned in petroleum and then acetone and alcohol. After that, they were dried with compressed nitrogen. Under the lubrication condition, 500 μL of distilled water/PAO4 was dripped on the plate before the test to ensure sufficient lubricant supply. In contrast, under the dry-friction condition, no lubricant was supplied. 3N4 friction pair, and SiC–PTFE friction pair, were tested.As shown in 3N4 ball was used, the friction coefficient showed different trends compared to the steel ball, as seen in When a SiWhen the friction pair was SiC–PTFE, the friction coefficient of the circular-dimple-textured and groove-textured surfaces was larger than that of the un-textured surface finally. This means that when the ball was PTFE, the circular-dimple and groove textures with various depths showed no improvement in frictional performance.3N4, and SiC–PTFE, the friction behavior showed significantly dissimilar trends for textured SiC against various types of materials under dry conditions. The SiC–steel friction pair significantly reduced the friction coefficient when textured circular-dimple and groove textures were fabricated on the SiC plate. When the SiC–Si3N4 friction pair was used, only groove textures with a depth of 3 μm exhibited better performance. When the PTFE ball was used, the circular-dimple and groove textures with various depths showed absolutely no friction improvement at all.Comparing the friction pairs of SiC–steel, SiC–Si3N4 ball was used, the friction coefficient values showed different trends than those with the steel ball, as shown in 3N4, textures exacerbated the wear of the friction pair, so the friction coefficient increased.When the SiWhen the friction pair was SiC–PTFE, the friction coefficient of circular-dimple-textured and groove-textured surfaces was slightly larger than that of the un-textured surface, but the difference in the coefficient values was not large. This means that when the ball was PTFE, the circular-dimple and groove textures with various depths showed no improvement in frictional performance.3N4, and SiC–PTFE, it can be seen that the friction behavior showed quite different trends when textured SiC was used against several types of materials under oil-lubricated conditions. The SiC–steel friction pairs can significantly reduce the friction coefficient when a circular-dimple texture was fabricated on the SiC plate. However, the groove texture had no improvement as the circular-dimple texture. When the SiC–Si3N4 friction pair was used, none of the circular-dimple and groove textures showed better performance and even increased friction. When the PTFE ball was used, the circular-dimple and groove textures with various depths showed absolutely no friction improvement at all.By comparing the friction pairs of SiC–steel, SiC–SiSilicon carbide ceramic shows an extremely low friction coefficient under water-lubricated simulated conditions. However, the viscosity of water is lower as compared with oil, leading to a smaller load capacity and the surface is susceptible to wear. Surface textures have evidently demonstrated to be an efficient system for improving tribological properties. To further improve the tribological performance of SiC ceramics, this study presents the friction coefficient of textured SiC combined with three types of mating materials under water-lubricated conditions.When the friction pair was SiC-PTFE, the friction coefficient trend was different to SiC-steel friction pair, as shown in When the material of the ball was PTFE, the friction coefficient of the circular-dimple-textured and groove-textured surfaces were much larger than that of the un-textured surface, as is shown in 3N4, and SiC–PTFE, the friction behavior showed quite different trends when the textured SiC against several types of materials under water-lubricated conditions. The SiC–Si3N4 friction pairs can significantly reduce friction coefficient when the circular-dimple and groove textures were fabricated on the SiC plate. Whereas, when the SiC–steel friction pair was used, only circular-dimple textures with a depth of 3 μm showed better performance. The friction performance was deteriorated when the textured circular dimples and grooves were used as the friction pair was SiC–PTFE.Comparing the friction pairs of SiC–steel, SiC–SiExperimental results are presented in 3N4, and SiC–PTFE evidence significantly dissimilar trends. 3N4 ball were used as the interfacing friction materials. The wear scar width of circular-dimple-textured surfaces and groove-textured surfaces was larger than that of the un-textured surface when a steel ball was used, as shown in 3N4 ball-bearing element material, the friction coefficient and the wear scar width were similar to those of the un-textured surface when the depth of the circular-dimple texture was 3 μm and 5 μm. Both the coefficient of friction and the width of the wear scar were lower than those of the un-textured surface when the depth was 10 μm. Therefore, 10 μm circular-dimple textures played an important role in reducing friction and wear. When considering a groove-textured surface, although the friction coefficient showed an insignificant gradient as compared to the un-textured surface, the width of the wear scar was relatively shallow, especially in the middle of the severely worn area. This implies that when the interfacing pair was Si3N4, the groove textures had a significant effect on wear reduction. The wear depth of the textured surface with various groove depths was smaller than that of the non-textured surface, as shown in 3N4 friction pairs.The material characteristics of friction pairs also affect the friction and wear performance of the textured surface. Experimental results in this research demonstrated that the friction and wear behavior of friction pairs SiC–steel, SiC–Si3N4 as the bearing material, the wear scar width of both circular-dimple-textured and groove-textured surfaces were larger than those of the un-textured surface. The wear scar width of the circular-dimple texture was smaller than that of the groove texture. At the same time, it can be seen from 3N4 ball-bearing element, the contact pressure was relatively higher, and the positive effect of the textures could not have offset the adverse effects, which were caused by the increased pressure; therefore, the friction coefficient and wear were enhanced compared to the non-textured surface.The wear scars and cross-sectional profiles of the test plates subjected to oil-lubricated conditions are shown in 3N4 ball-bearing element, the wear scar width of the circular-dimple-textured surface and groove-textured surface with various depths was smaller than that of the un-textured surface, except for 3-μm-deep grooves. For the wear scar depth, the values for circular-dimple-textured surface were almost the same as those for the un-textured surface, but for the groove-textured surface, the values were larger than those for un-textured surface. When the groove depth was 3 μm, the texture wear was more severe compared to other groove textures; therefore, the friction coefficient significantly fluctuated.3N4 as the ball-bearing element material, there was evidence of wear scar on the surface. However, for PTFE as the interfacial element material, no wear scar was observed after the plate was cleaned. The PTFE ball was worn at the beginning of the test, and the material was transferred to the SiC surface due to the relatively soft PTFE property. Friction and wear therefore occurred between the PTFE ball and the PTFE material transferred to the SiC surface, in turn resulting in a lower friction coefficient. On the textured SiC surface, no wear scar was observed after cleaning, as observed on the un-textured surface when a PTFE ball was used. The PTFE ball was the first to be worn, and then texture filling occurred, leading to severe wear and larger friction coefficient values between the textured surface and the PTFE ball-bearing element.As shown in 1.Texture depth and texture shape affected the friction and wear performance of textured surfaces. However, the influence varied under dry, oil-lubricated, and water-lubricated conditions. This is due to the different effects textures played under various lubricant conditions. The impact of texture was a comprehensive result of the positive role of enhancing the fluid hydrodynamic effect, storing the lubricant, and accommodating abrasive grains and the negative effect of increasing contact pressure.2.3N4, and SiC–PTFE show various trends. The circular-dimple texture and the groove texture played a positive role in improving friction and wear performance under certain operating conditions used in this research for SiC–steel and SiC–Si3N4 friction pairs, but there was absolutely no friction and wear improvement for the textured SiC–PTFE friction pair.The material of the mated friction pair affected the friction and wear performance of the textured surface. The experimental results in this research showed that the friction and wear behavior of friction pairs SiC–steel, SiC–SiThe frictional and wear performance of a textured surface against several types of materials under dry, oil-lubricated, and water-lubricated conditions were experimentally studied in this paper. The friction coefficient and wear scar width and depth of un-textured, circular-dimple-textured, and groove-textured surfaces were examined and compared. Considering the experimental results, the following conclusions can be drawn:


The triggers of initial onset of yips symptoms can be broadly divided into psychological and non-psychological factors; however, a trigger-based classification of yips has not been established. This study aims to obtain insight into the prevention of yips by clarifying whether there are differences in symptoms and personality traits according to a trigger-based classification of yips in baseball players. A total of 107 college baseball players responded to a questionnaire assessing the presence or absence of yips and its symptoms. They were classified into the psychologically triggered yips group, the non-psychologically triggered yips group, and the non-yips group based on the presence or absence of yips and the triggers of its initial onset. Additionally, we compared whether personality traits examined by the NEO Five-Factor Inventory differed across these three groups. The psychologically triggered yips group had significantly higher agreeableness scores compared with the non-yips group, whereas the non-psychologically triggered yips group had significantly higher neuroticism scores compared with the psychologically triggered yips group. In the non-psychologically triggered yips group, there was a significantly higher frequency of throwing errors than in the psychologically triggered yips group, with a tendency to develop yips symptoms gradually. Since the trigger-based classification of yips is closely related to the strength of the yips symptoms and the players' personality traits, the results of this study contribute to a better understanding of the symptoms of yips and establishment of the prevention of yips. Large prospective studies are necessary to determine the causal relationship between a trigger-based classification of yips and the personality traits and symptoms of athletes with yips. The “yips” phenomenon is a psycho-neuromuscular disorder characterized by involuntary movements that disrupt the execution of automatic fine motor behavior  age of 20.3 (1.3) years and an average of 12.5 (2.1) years of baseball experience. Based on the effect size obtained from a previous study using the NEO-FFI, the sample size was estimated by performing a power analysis using G*Power with a power of 0.8 and an alpha of 0.05 ; the tendency to seek out new experiences (openness); emotional instability, e.g., anxiety, depression, and self-consciousness (neuroticism); goal-directed behavior and organizations (conscientiousness); and social harmony and concern for cooperation (agreeableness)  to examine the effect of trigger-based classification of yips and throwing distance on the frequency of throwing errors, assuming a multinomial distribution of the dependent variable with a cumulative logit link function. Fixed effects included classification of yips and throwing distance, and the random effects included participants in the model. Sequential Bonferroni correction was used in post hoc comparisons. A Fisher-Freeman-Halton test was conducted to examine whether worsening of symptoms in psychologically stressful situations, such as games, differed between two yips groups. The five subscores of NEO-FFI were analyzed using multivariate analysis of variance (MANOVA) with one intersubject factor “group” . If an overall significant effect was obtained by MANOVA, a separate ANOVA was conducted. Tukey's post hoc tests were used for multiple comparisons. The effect size  was also calculated.We divided the participants into four groups based on their episodes that triggered the initial onset of yips symptoms: psychologically triggered yips group, non-psychologically triggered yips group, pain-triggered yips group, and non-yips group. Players were classified into psychologically triggered yips groups when episodes strongly associated with psychological factors such as “experience of throwing error,” “anxiety about throwing,” and “reprimands from others” triggered initial onset of yips. Players who were triggered by a change in throwing mechanics and who had no specific triggers for initial onset of yips, i.e., psychological factors did not trigger the initial onset of yips symptoms, were classified into the non-psychologically triggered yips group. Players who developed yips due to pain were not included in the statistical analysis because they could not be classified into either the psychological or non-psychological yips groups, and their numbers were small. All statistical analyses were performed using SPSS version 26 statistical software . The level of statistical significance was n = 19), the non-psychologically triggered yips group (n = 25), the pain-triggered yips group (n = 5), and the non-yips group (n = 55) based on the trigger of the initial onset of yips. The triggers of the psychologically triggered yips group included “experience of throwing error” (n = 11), “anxiety about throwing” (n = 5), “reprimand from others” (n = 2), and “fear-related throwing experience ” (n = 1). The non-psychologically triggered yips group consisted of 3 players triggered by a “change in throwing mechanics” and 22 players with no specific triggers.Participants were classified into the psychologically triggered yips group (H(2) = 1.193, p = 0.551] and baseball experience  among the psychologically triggered yips, non-psychologically triggered yips, and non-yips groups. The Fisher-Freeman-Halton test revealed no statistically significant difference in throwing arm among these three groups (p = 0.776). The Mann-Whitney U test showed that there were no significant differences in age at initial onset  and duration of yips  between the psychologically triggered yips and non-psychologically triggered yips groups. There was no significant difference between the two yips groups regarding whether yips symptoms were still present . In the psychologically triggered yips group, nine players displayed acute onset of symptoms while 10 players displayed a gradual onset of symptoms. Conversely, in the non-psychologically triggered yips group, 80% (20 out of 25 players) displayed a gradual onset. Although the p value did not reach statistical significance, the Chi-square test showed that the development of symptoms tended to differ between the psychologically triggered yips group and the non-psychologically triggered yips group [p = 0.054].The participants' characteristics are shown in F = 7.294, p < 0.001], and the interaction between the yips classification and throwing distance was not significant   = 5.591, p = 0.019]. The frequency of throwing error was significantly higher in the non-psychologically triggered yips group than in the psychologically triggered yips group. There was a significant fixed effect for the throwing distance . In addition, the multiple comparison test revealed that frequency of the throwing errors was significantly higher in short-distance throwing  compared with long distance (>50 m) throwing .The relationship between the frequency of throwing errors and throwing distance in both yips groups is shown in = 0.667] . There wp = 0.463, There was no significant difference between the two yips groups in the deterioration of throwing errors under stressful conditions such as games (p = 0.037). The separate ANOVA indicated that the agreeableness score and neuroticism score differed significantly among the three groups . The post hoc test showed that the agreeableness score was significantly higher in the psychologically triggered yips group compared with the non-yips group. Conversely, the neuroticism score was significantly higher in the non-psychologically triggered yips group compared with the psychologically triggered yips group. The other three dimensions did not differ significantly among the three groups .The results of MANOVA  revealedThe present study focused on triggers of the initial onset of throwing yips in baseball players and divided the triggers into psychological and non-psychological factors. The most striking finding of the present study was the difference in personality traits between the psychologically and non-psychologically triggered yips groups; i.e., the former had significantly higher agreeableness scores compared with the non-yips group, while the latter showed significantly higher neuroticism scores compared with the psychologically triggered yips group. Furthermore, the non-psychologically triggered yips group showed a significantly higher frequency of throwing errors and a tendency toward gradual development of yips symptoms compared with the psychologically-triggered yips group. Thus, the trigger-based classification of yips could potentially contribute to the prevention of yips because it is closely related to the symptoms and personality traits of the players.In 19 out of 49 (38.8%) yips-affected baseball players, psychological factors such as throwing errors, anxiety about throwing, and reprimand from others led to initial onset of yips. Conversely, 25 out of 49 (51.0%) yips-affected athletes developed yips due to non-psychological factors, including those who had no specific trigger for initial onset and those who developed yips after a change in throwing mechanics. A previous study reported that 75% of yips-affected golfers began to develop symptoms in a tournament in which psychological pressure was assumed to be high, suggesting that psychological factors account for a large proportion of the triggers of golfers' yips  and neuroticism have reported conflicting results. Enders et al.  reportedThe significantly higher agreeableness score in the psychologically triggered yips group and the higher neuroticism score in the non-psychologically triggered yips group suggest that there may be different triggers for the initial onset of the yips depending on players' personality traits. As mentioned above, yips are classified into Type I and Type II according to their subjective symptoms, which contributes to their treatment selection. However, classification based on the trigger of yips has not been reported thus far. The results of this study, which show for the first time an association between the trigger-based classification of yips and personality traits, have important implications from a preventive perspective because of their potential relevance to the mechanism of development of yips. However, it remains controversial whether these personality traits in yips-affected players are preexistent or a psychoreactive phenomenon  than for long-distance throwing (> 50 m). In yips-affected golfers, a previous study reported that the symptoms of yips are more likely to occur in short putts of ~1–4 feet  (Smith et al., In conclusion, we investigated whether the symptoms of yips and personality traits differed according to the trigger-based classification of yips. We obtained novel findings indicating that the psychologically triggered yips group showed significantly higher agreeableness scores compared with the non-yips group. Additionally, the non-psychologically triggered yips group showed significantly higher neuroticism scores and a higher frequency of throwing errors, particularly in long-distance throwing, compared with the psychologically triggered yips group. Since trigger-based classification of yips is closely related to yips symptom strength and the personality traits of players, the results of this study may contribute to a better understanding of symptoms of throwing yips and the establishment of prevention for yips. In the future, large prospective studies are necessary to investigate the causal relationship between personality traits and the trigger for the initial onset of yips.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Local ethics committee of the Ibaraki Prefectural University of Health Sciences. The patients/participants provided their written informed consent to participate in this study.TA, KA, HS, and TK designed the study. TA, KK, and TK collected the data. All authors contributed to data analysis, interpretation, and write the manuscript. All authors contributed to the article and approved the submitted version.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.