IntroductionAntimicrobial prophylaxis, involving short antibiotic courses preceding surgical procedures, is recommended to minimize postoperative infections. Paediatric cardiac surgeries are classified as clean procedures, though infection challenges persist due to illness severity and extended ICU stays. Antimicrobial prophylaxis varies, ranging from single doses to extended administration until catheters are removed. Typically lasting 24 to 48 hours, it has proven infection-reduction benefits. Despite these practices, uncertainties surround the optimal nature, timing, and duration of administration. This concern is amplified by escalating antimicrobial resistance driven by antibiotic overuse. Vulnerable paediatric populations bear heightened consequences of irrational antimicrobial use, contributing to global resistance trends. Yet, a defined optimal prophylaxis schedule for paediatric cardiac surgery is lacking. Importing adult guidelines may be inadequate due to paediatric research complexities and population diversity. Developing effective prophylaxis protocols is crucial for children undergoing cardiac surgery, given global antibiotic overuse and evolving drug resistance. Establishing an optimal prophylactic strategy remains a challenge, necessitating further research for evidence-based protocols to mitigate infections in this vulnerable patient cohort.MethodsThis study investigates antibiotic use in paediatric cardiac surgery. A retrospective analysis of 100 patients from a rural Indian hospital (2017-2018) assesses antibiotic patterns, including type, dose, duration, and adherence to prophylaxis protocols.ResultsIn the studied cohort of paediatric cardiac surgery patients, complete compliance (100%) with antibiotic prophylaxis was observed. However, deviations were identified: 30% received antibiotics prematurely, and 30% did not align with institutional protocol criteria. Concerning antibiotic selection, 87% followed hospital policy with the recommended cefoperazone and sulbactam combination plus amikacin, while 9% received piperacillin/tazobactam + amikacin due to sepsis. Irregular use (22%) based on clinical records occurred. Furthermore, 4% received piperacillin/tazobactam + teicoplanin, with one instance of inappropriate higher antibiotic use. Regarding prophylaxis duration, only 27% adhered to the appropriate timeline, with 40% exceeding 48 hours, indicating extended use. Upon discharge, a notable proportion (45 patients) received antibiotic prescriptions. Among them, 73% were prescribed rationally, while 27% exhibited irrational antibiotic use.ConclusionThe findings of this study shed a significant light on the issue of antibiotic misuse within the context of paediatric cardiac surgery. It underscores the pressing need for more stringent measures to regulate and address this concerning trend. The study underscores the pivotal importance of adhering rigorously to established protocols and guidelines for antibiotic prophylaxis. This adherence not only holds the potential to elevate the overall quality of patient care but also plays a critical role in combating the escalating challenge of antibiotic resistance. Through a concerted effort to optimize antibiotic usage, we can simultaneously enhance patient outcomes and contribute to the ongoing fight against the emergence of antibiotic-resistant strains, thus preserving the efficacy of these vital medications for future generations. Antimicrobial prophylaxis, a very brief course of antibiotics initiated just before the start of surgical procedures, is recommended to reduce postoperative infection .As a clean procedure, paediatric cardiac surgeries should have a lower risk for infection; however, given the severity of illness and prolonged ICU stays, infections remain an ongoing challenge. Antimicrobial prophylaxis in paediatric cardiac surgery takes numerous forms. Regimens vary greatly, from single-dose prophylaxis to continuing antibiotics until all chest tubes and central venous catheters have been removed. Antimicrobial prophylaxis varies usually in cardiac surgery from 24 hours to 48 hours antimicrobial prophylaxis. Antibiotic use in the perioperative period is a well-established adjunct to reducing the incidence of infection [However, the nature, timing, and duration of administration remain undetermined. Further, in the context of increasing attention to antimicrobial resistance predicated upon the overuse of antibiotics, addressing this issue is timely. Paediatric populations are vulnerable to the majority of illnesses and the adverse effect of irrational use of antimicrobials is more serious among children than adults. If antibiotics are used inappropriately, it leads to the emergence and worrying of national and global trends of antimicrobial resistance. However, in paediatric cardiac surgery, an optimal schedule has not been defined. Paediatric recommendations follow the guidelines for adults, which might be improper because of the inherent challenges in paediatric research and the heterogeneity of the population. Implementation of an effective prophylaxis protocol is needed for children undergoing cardiac surgery, especially in view of worldwide antibiotic overuse and the development of drug resistance .Children's metabolic immaturity poses significant challenges in the medical field, making it arduous for healthcare professionals to accurately determine the suitable dosage of antimicrobial drugs and reliably predict their pharmacokinetics and pharmacodynamics . CardiacCardiac surgery and cardiopulmonary bypass result in an immunoparalyzed state in children making them susceptible to sepsis and other hospital-acquired infections . PotentiDespite the importance of antibiotic prophylaxis during open chest management, no specific recommendations exist . FindingStudy designThis research presents a comprehensive retrospective observational study conducted at the Bhanubhai and Madhuben Patel Cardiac Center, Shree Krishna Hospital, Karamsad, a prominent teaching hospital located in rural India. The study is aimed at evaluating the efficacy and rationality of antibiotic prophylaxis in paediatric cardiac surgery, which holds significant implications for patient care and outcomes in this vulnerable population. As a standard practice, ethical approval was obtained from the Institutional Ethics Committee (IEC) before the study's initiation, emphasizing the commitment to upholding ethical principles and ensuring patient privacy and safety.The investigation encompasses a well-defined cohort of 100 paediatric patients (aged <14 years) who underwent cardiac surgery within a specific period, spanning from January 2017 to February 2018. This selection ensures a diverse representation of paediatric cardiac surgical cases, ranging from various congenital heart defects to acquired heart diseases. By including a wide range of patients, the study aims to capture the complexity and diversity of cardiac surgery in children, contributing to more robust and applicable findings.Patient data were meticulously collected from the hospital's medical record department, employing a standardized case report form. This form was thoughtfully designed to capture essential parameters, such as patient demographics, intricate surgical details, antibiotic usage patterns, and infection-related parameters. By utilizing a comprehensive data collection approach, the study ensures that all critical factors influencing the antibiotic prophylaxis protocol's efficacy are thoroughly examined and considered.The study's results are anticipated to provide valuable insights into the effectiveness of antibiotic prophylaxis in paediatric cardiac surgery, specifically focusing on its impact on reducing the incidence of SSIs and associated postoperative complications. By identifying potential areas for improvement, this research seeks to inform evidence-based practices and guide further efforts to optimize antibiotic prophylaxis strategies in paediatric cardiac surgery, thereby contributing to improved patient outcomes and enhancing the quality of care in this unique patient population.Study populationThe study population was defined based on specific inclusion criteria to ensure a well-defined and representative sample for analysis. Inclusion criteria encompassed paediatric patients aged up to 14 years who had undergone cardiac surgery at the esteemed cardiac department of Shree Krishna Hospital during a predetermined period, specifically spanning from January 2017 to February 2018. By focusing on paediatric patients within this age range, the study aimed to assess the impact of antibiotic prophylaxis in a vulnerable and distinct subgroup of the population, known for its unique physiological and clinical considerations.The choice of the cardiac department at Shree Krishna Hospital as the study setting was deliberate, considering the hospital's reputation as a prominent teaching and tertiary care facility for paediatric cardiac services in rural India. This selection ensured access to a diverse and comprehensive patient pool, encompassing a wide range of congenital heart defects and acquired heart diseases that required cardiac surgery.In contrast, to maintain the study's specificity and to ensure homogeneity in the data analysis, exclusion criteria were strictly applied. Patients above 14 years of age were excluded from the study to establish a clear focus on the paediatric population. This strategic exclusion aimed to eliminate potential confounding factors associated with age-related variations in surgical outcomes and antibiotic responses.Furthermore, non-cardiac surgical cases were excluded from the study to ensure that the analysis remained relevant and targeted to the research question's scope. By limiting the study to paediatric cardiac surgery cases alone, the investigation could concentrate on the efficacy and rationality of antibiotic prophylaxis solely within this specific surgical context.Collectively, the meticulous selection of the study population through well-defined inclusion and exclusion criteria ensured the integrity of the research findings, allowing for a comprehensive examination of the antibiotic prophylaxis protocol's impact on paediatric cardiac surgery outcomes. The resulting data would provide valuable insights for healthcare providers, researchers, and policymakers to optimize antibiotic prophylaxis strategies, ultimately leading to improved patient care and reduced healthcare burdens associated with surgical site infections in this vulnerable patient population.Hospital's policy for antibiotic prophylaxis in paediatric cardiac surgeryThe hospital's policy for antibiotic prophylaxis in paediatric cardiac surgery is as follows: Cefoperazone and sulbactam + amikacin are administered intravenously within 60 minutes before the start of surgery. Additionally, antibiotic treatment is continued for 48 hours after the surgery is completed.This prophylaxis protocol has been carefully designed to minimize the risk of SSIs and promote optimal postoperative recovery for paediatric cardiac surgery patients. The timely preoperative administration of cefoperazone and sulbactam + amikacin aims to achieve therapeutic drug concentrations at the surgical site, effectively providing a protective barrier against potential microbial contamination during the procedure. By ensuring the presence of these antibiotics before the start of surgery, the hospital aims to prevent the occurrence of SSIs, which can lead to increased morbidity, prolonged hospital stays, and additional healthcare costs.Equally crucial is the continuation of antibiotic treatment for 48 hours post-surgery. This extended prophylaxis period is essential during the early recovery phase when patients are at a heightened risk of infection. By maintaining antibiotic coverage in the immediate postoperative period, the hospital aims to support wound healing, minimize inflammation, and reduce the likelihood of SSIs. This approach aligns with best practices, as extended prophylaxis has been shown to significantly decrease the incidence of SSIs in paediatric cardiac surgery.The selection of cefoperazone and sulbactam + amikacin as the preferred antibiotics is based on their broad-spectrum coverage against common pathogens encountered in cardiac surgical settings. The combination targets a wide range of gram-positive, gram-negative, and anaerobic bacteria, providing comprehensive protection against potential sources of infection. The choice of intravenous administration ensures rapid drug delivery and optimal bioavailability, making these antibiotics well-suited for preoperative prophylaxis.To maintain the policy's effectiveness and evidence-based approach, the hospital adopts a multidisciplinary approach. The formulation and implementation of the antibiotic prophylaxis policy involve collaboration among cardiac surgeons, paediatricians, infectious disease specialists, and pharmacists. The hospital's dedication to patient safety and the proactive approach to infection prevention demonstrated through this antibiotic prophylaxis policy highlights its commitment to providing exceptional care to young cardiac surgery patients. By adhering to this well-structured protocol, the hospital aims to optimize patient outcomes, enhance postoperative recovery, and reduce the burden of SSIs on young patients and their families.In summary, the hospital's policy for antibiotic prophylaxis in paediatric cardiac surgery, involving the administration of cefoperazone and sulbactam + amikacin intravenously before and after surgery, is meticulously designed to protect patients from SSIs and contribute to better overall outcomes in this vulnerable patient population.Demographic and surgical characteristics of the study group are presented in Table In our study group, 30% of patients were administered antibiotics preoperatively, before the day of surgery. Among these patients, 30% did not have a justified reason for antibiotic use according to the institute's protocol (refer to Table All patients received intraoperative antibiotics. The most common antibiotic prophylaxis regimen was cefoperazone and sulbactam + amikacin, administered to 87% of the patients. The next most frequently used prophylaxis was piperacillin/tazobactam + amikacin, given to 9% of the patients, while piperacillin/tazobactam + teicoplanin was used in 4% of cases Table .In 13% of cases, deviation from the institute's protocol was observed due to suspected or proven ongoing sepsis. However, upon evaluating the medical records, it was found that 23% of these cases did not actually require alternate antibiotics. It is likely that these patients were clinically unwell but did not have a bacterial infection.In Table Additionally, out of the 27 patients who received prophylaxis for less than 48 hours, six of them developed an infection at the surgical wound. Furthermore, Table In our study group, a total of 73 patients received prolonged antibiotic prophylaxis, lasting more than 48 hours. Among these, 40 patients had no infection, indicating an irrational reason for the prolonged need, contrary to the institute's protocol. This group constitutes 40% of the study population Table .Regarding postoperative antibiotic utilization, meropenem was administered to 21 patients, vancomycin to two patients, colistin to 10 patients, and teicoplanin to eight patients. These antibiotics were given based on culture reports or clinical suspicion of sepsis, as determined by the treating intensivist. Among the positive culture results, eight patients showed multi-drug resistance, indicating a high proportion of multi-drug resistant variants.In the study group, there were two reported cases of mortality. One patient succumbed to septic shock with multi-organ dysfunction, leading to the unfortunate outcome.Out of the 100 patients in the study, 45 patients were prescribed antibiotics at the time of hospital discharge, indicating a considerable number of prescriptions. Among these 45 patients, 73% received antibiotics rationally, while 27% received antibiotics irrationally. Once again, fluoroquinolones were used in a high proportion (Table Additionally, there was one patient who chose to leave the hospital against medical advice and transferred to a district hospital. This patient was advised to continue parenteral broad-spectrum antibiotics despite leaving the hospital early.The results of this study demonstrate that antibiotic prophylaxis in paediatric cardiac surgery for the study group was 100% in adherence to the institution's protocol. However, when comparing our study with other published studies, we found that the misuse of antibiotics in paediatric cardiac surgery is still prevalent. Apostolopoulou Eleni et al.  evaluateNairooz H. Al-Momany et al.  assessedHarbarth et al.  comparedBased on a systematic review, the Society of Thoracic Surgeons recommends not continuing antibiotic prophylaxis for more than 48 hours postoperatively . In our Despite some discrepancies in data due to the retrospective nature of the study using hospital records, the study revealed that all patients received the appropriate dose of antibiotics based on their weight and creatinine clearance. Moreover, all patients received prophylactic antibiotics within 60 minutes before the skin incision, in line with the institution's guidelines.It is concerning that 45% of patients were prescribed antibiotics at the time of hospital discharge, with 27% of them not having justification for the continuation of antibiotics on discharge. Additionally, the use of fluoroquinolones at discharge is not justified in paediatric patients .The study findings highlight the need for better adherence to antibiotic prophylaxis guidelines in paediatric cardiac surgery. Similar observations of inadequate adherence to antibiotic prophylaxis for surgery have been reported from India, but there are no published Indian studies specifically addressing adherence to antibiotic prophylaxis protocols for paediatric cardiac surgery.As this study was retrospective and conducted at a single centre, caution must be exercised when generalizing the findings to other health centres. Moreover, the cost implications of irrational antibiotic use were not part of the study's scope. The one-year duration of the study limits insights into the long-term utilization of antibiotics in this context. A more extended study could provide a better understanding of antibiotic usage patterns.In this study, we observed that antibiotic prophylaxis was consistently employed in all cases of paediatric cardiac surgery. However, a concerning pattern of significant misuse and overuse of antibiotics was evident. While similar observations have been documented in studies conducted abroad, there remains a notable gap in published research from India regarding this issue. Our study underscores the urgent need for more stringent implementation of antibiotics prophylaxis protocols in paediatric cardiac surgery to optimize patient care and safety.The widespread misuse of antibiotics in this vulnerable patient population necessitates immediate action to mitigate the emergence of antibiotic resistance and safeguard the effectiveness of these essential medications. To achieve this, regular audits and constant reinforcement of standardized protocols are vital. By closely monitoring antibiotic utilization and adherence to established guidelines, healthcare providers can identify and address areas of concern, ensuring that antibiotics are used judiciously and in accordance with best practices.Furthermore, this study highlights the significance of conducting more comprehensive research and multi-centric studies in India to gain deeper insights into antibiotic prophylaxis practices specific to paediatric cardiac surgery. Such efforts can yield valuable data to support the formulation of evidence-based guidelines tailored to the unique needs of the Indian patient population.In conclusion, optimizing antibiotic prophylaxis in paediatric cardiac surgery demands a collaborative approach involving healthcare professionals, policy-makers, and researchers. By implementing robust protocols, conducting regular audits, and fostering a culture of responsible antibiotic use, we can effectively preserve the sensitivity of antibiotics and safeguard the health of young cardiac patients in India.


Adherence to antibiotic recommendations and safety aspects of restrictive use are important components when combating antibiotic resistance. The primary aim of this study was to assess the impact of national guidelines on antibiotic prescriptions for bone augmentation procedures among dentists working at three specialized clinics. The secondary aim was to assess the occurrence of postoperative infections.Medical charts of 400 patients treated with bone augmentation were reviewed: 200 in the years 2010–2011 and 200 in 2014–2015. The Swedish national recommendations for antibiotic prophylaxis were published in 2012.P < 0.001). The administration of a 3-7-days antibiotic prescription increased significantly from 25.5% in 2010–2011 to 35% in 2014–2015. The postoperative infection rates (4.5% and 6.5%) were without difference between the studied periods. Smoking and omitted antibiotic prophylaxis significantly increased the risk of postoperative infection. Logistic regression analyses showed that patient male gender and suffering from a disease were predictive factors for the clinician to adhere to the guidelines.There was a wide variation in antibiotic regiments prescribed throughout the study. The number of patients treated with antibiotic prophylaxis in a single dose of 2 g amoxicillin, and treated as advocated in the national recommendations, was low and decreasing between the two time periods from 25% (n = 50/200) in 2010–2011 to 18.5% (n = 37/200) in 2014–2015. The number of patients not given any antibiotics either as a prophylactic single dose or during the postoperative phase increased (After introduction of national recommendations for antibiotic prophylaxis before bone augmentation procedures, the patient group receiving a single preoperative dose decreased while the group not given antibiotic prophylaxis increased. There was no difference in occurrence of postoperative infections between the two time periods. The results indicate a need for educational efforts and strategies for implementation of antibiotic prudence and awareness among surgeons performing bone augmentation procedures. Antimicrobial resistance is an alarming and increasing problem world-wide seriously threatening modern health care where many treatment options are dependent on the availability of effective antibiotics , 2. The Patients’ expectations on the treatment with fixed prosthetic replacements are very high. Anatomic defects and lack of bone volume makes bone-grafting procedures frequently necessary. In jaws resorbed after trauma, or infection, it may be necessary to augment the alveolar bone to enable dental implant rehabilitation. In general, there are a variety of techniques to augment jawbone with arbitrary recommendations for the duration of post-extraction healing. Autografts are harvested and transferred within an individual from e.g. mandibular ramus, chin, or iliac crest, and commonly collected with a bone-scraper, mini-saw, or drill. Commercially available bone substitutes may be from cadaver bone, human and animal origin, or synthetically produced. Generally cadaver bone is the most used bone substitute today and mineralized freeze-dried bone allografts and xenografts functions well where the anatomical shape must be restored since the substitutes do not resorb. Many different synthetic bone substitute materials are tailor-made and available with different chemical and physical properties to meet market demands regarding resorption rate, chemical composition, granule size and degree of porosity. In addition, thin resorbable or non-resorbable synthetic or xenograft membranes are sometimes used to cover the augmented bone site under the mucosa to keep the bone in place and prevent ingrowth of soft tissue into the area.Although it is well known that the addition of a foreign or grafted material into a surgical site increases the risk of postoperative infection, reports regarding postoperative infections after these interventions are essentially lacking –7. EmpirSince the development of antibiotic resistance is considered the greatest threat to modern health care any effort to reduce unnecessary utilization, such as identifying areas of improvement, is of outmost importance. The aims of the current study were primarily to investigate antibiotic prescription pattern among Swedish dentists during bone augmentation procedures and to study the effect of published guidelines on the antibiotic prescription pattern. A secondary aim was to investigate the effect of antibiotic prophylaxis use on occurrence of post-operative infection after bone augmentation procedures.https://www.strobe-statment.org).A retrospective cross-sectional patient record study, to review the utilization of antibiotic prophylaxis, was performed at four different Swedish clinics performing bone augmentation procedures in conjunction to dental implant treatment. Two time periods were studied, before and after the publication of the Swedish national recommendations on antibiotic prophylaxis in 2012, in order to scrutinize the influence of the recommendations on the prescription behavior. The four specialized clinics performing implant surgery included were the Department of Periodontology at the Odontology Institution in Jönköping, the Department of Oral and Maxillofacial Surgery at the Odontology Institution in Jönköping, the Department of Oral and Maxillofacial Surgery at the Eastman Institute, Stockholm, and the Department of Oral and Maxillofacial Surgery at South Älvsborgs Hospital, Borås. A power calculation based on the assumption that 80% of the patients received prolonged antibiotic prophylaxis before the publication of the recommendations and 60% afterwards, gave a total required sample size of 200 patients at power 80% and alfa 0.05. Since the sample size calculation was based on a crude estimation, it was decided to double the number of included cases. Prior to onset, the study was approved by the Regional Ethics Committee, Stockholm (Ref no 2016/609 − 31). The study was performed in compliance with the STROBE statement checklist . The demographic data of patients is summarized in Table From a total of 200 patient records included in 2010–2011, there were 55.0% (n = 110) males and 45.0% (n = 90) females, and in 2014–2015 there were 51.5% (n = 103) males and 48.5% (n = 97) females. In 2010–2011, 51% (n = 102) and 51.5% (n = 103) in 2014–2015 of the total patients were healthy with no medication. The rest of the patients were diagnosed with various diseases, most commonly high blood pressure, asthma, depression, hypothyroidism, or migraine. In 2010–2011 there was no entry in 30% (n = 60) of the patient records regarding smoking habits, the corresponding figure for 2014–2015 was 37.5% (n = 75). 23.5% (n = 47) of the patients were stated to be smokers in 2010–2011 and 16% (n = 32) in 2014–2015. Two patients were on bisphosphonate treatment in 2010–2011 and one in 2014–2015. No patient exposed to radiation therapy was treated with bone augmentation in neither time periods. There were no significant differences between the two time periods regarding gender, health status and smoking habits. The number of patients in the category 17–30 years old decreased between the two time periods while the distribution of other age groups was unchanged , or after a healing period, i.e. not on the day of the bone graft procedure . The Chi-2 test was used to determine the differences between the two time periods . Logistic regression analyses were performed for the prediction of adherence to national guidelines regarding antibiotic prophylaxis, or decision to either prolong the prophylaxis or refrain from its use. A The results show wide variation in antibiotic prescription pattern regarding type of compound, dose, and duration across the two time periods. However, there was no difference in the dentists’ postgraduate education level between the two time periods.P = < 0.001) , 81.5% (n = 163/200), respectively, and the number of patients treated according to the national recommendation decreased between the two time periods. It was also found that there was an increase in the number of patients not receiving antibiotic prophylaxis from 11.5% (n = 23) in 2010–2011 to 27% (n = 54) in 2014–2015 (P = 0.026). Amoxicillin prescription was reduced slightly from 29.5% (n = 59) in 2010–2011 to 24.5% (n = 49) in the period of 2014–2015. A decrease (P = 0.0115) in usage of clindamycin was seen from 9% (n = 18) to 3.5% (n = 7) but an increase (P = 0.0435) in prescribing other antibiotic combinations from 9.5% (n = 19) to 15% (n = 30). The most common combination of compounds used was amoxicillin and phenoxymethylpenicillin  in 2010–2011 to 30% (n = 60) in 2014–2015 ( in 2010–P = 0.0001) in numbers in 2014–2015 with only 31% (n = 45) of the patients receiving antibiotics on the day of surgery. Meanwhile there were increase (P = 0.038) in 3-7-days antibiotic prescriptions with 25.5% (n = 51) (2010–2011), and 35% (n = 70) in 2014–2015. Antibiotic prescription for a duration of 10–14 days decreased between the two time periods  of patients received antibiotics on the day of surgery, and there was a decrease . From the nine patients who developed post-operative infections in 2010–2011, two were not given preoperative antibiotics, two received 2 g amoxicillin prophylaxis preoperatively, while five patients received other types of antibiotic prophylaxis. In 2014–2015, 11 patients were not prescribed antibiotics, one was treated with single dose 2 g amoxicillin prophylaxis according to the recommendation, and one patient received phenoxymethylpenicillin for seven days. The regression analysis shows a relationship between no antibiotic prescription, and the development of post-operative infection (P = 0.001). The twenty-two patients who developed post-operative infections were treated either locally by irrigation (n = 1), removal of the membrane (n = 1), or by removal of grafted bone or placed implant (n = 2). Systematic antibiotics were prescribed for most cases who developed an infection (8 cases in 2010–2011 and 13 cases in 2014–2015), with no difference regarding type and duration of prescribed antibiotic between the two time periods. Four patients were given a repeated antibiotic treatment.The total rate of postoperative infection was 5.5% (22/400), 9 patients in 2010–2011 and 13 patients in 2014–2015 developed post-operative infections. All these complications were diagnosed within the first month after surgery. There was no difference between the two time periods for developing an infection  had a 10–15% risk of infection where the risk is reduced to 1% with proper surgical technique and the use of prophylactic antibiotics , 20. SinThe present study constitutes the first step for a drug utilization review concerning antibiotic prescribing in patients who have undergone bone augmentation procedures in conjunction with dental implant treatment in Sweden. Stricter implementation efforts in this area are mandatory. Guidelines for antibiotic selection should be modified according to local factors, such as local resistant bacteria status and professional realities . Post- aThe results call for further nationwide studies on knowledge and attitudes towards the use of antibiotic prophylaxis in bone augmentation procedures. Randomized clinical trials are needed to provide guidelines based on solid scientific evidence.According to the present study the introduction of national recommendation of a preoperative single dose antibiotic prophylaxis before bone augmentation procedures led to an increase in the number of patients not receiving antibiotic prophylaxis and decrease of the group prescribed a single dose. Misuse or overuse of antibiotics seems to be common during bone augmentation procedures. Decision to adhere to guidelines regarding antibiotic use for these procedures does not seem to show gender equality. The results indicate a need for educational efforts and strategies for implementation of antibiotic prudence and awareness among surgeons.


Antibiotic time-outs (ATOs) are an evolving stewardship strategy capable of widespread impact with relatively low perceived personnel effort. ATO-based interventions have been shown to improve the rates of antibiotic de-escalation and increase the likelihood of antibiotic optimization. In August 2022, Hartford HealthCare implemented a 72-hour ATO best practice alert (BPA) within the electronic medical record (EMR). Herein, we evaluated the impact of this intervention on antibiotic use and describe behaviors associated with alert prompting.> 72 hours. An ATO alert was designed and embedded within the EMR and set to fire between the hours of 0700 and 1630. On BPA firing, prescribers were prompted to assess for antibiotic modification – a composite including discontinuation, de-escalation, inclusion of stop-date, and transition to oral therapies. Differences in the rate of antibiotic modification and overall antibiotic prescribing patterns for the 10 most frequently utilized antibiotics were compared between a pre-implementation control period (10/1/21 – 10/31/21) and a post-implementation period (10/1/22 – 10/31/22).This is a multi-center, quasi-experimental, retrospective chart review of admitted patients receiving empiric antibiotics for A total of 800 patients were included for analysis. There was no significant difference in the rate of antibiotic modification when comparing the pre- and post-implementation cohort ; however, there was a numerically lower rate of antibiotic escalation in the post-cohort . The duration of antibiotic therapy was longer in the post-implementation cohort .Despite ATO implementation, rates of antibiotic modification were similar between the pre- and post-cohort. Further work to understand the optimal approach to implementing an ATO will be required to improve the impact on antimicrobial therapy.Joseph L. Kuti, PharmD, bioMeriuex Inc.: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Merck & Co, Inc: Grant/Research Support|Shionogi Inc: Advisor/Consultant|Shionogi Inc: Grant/Research Support|Shionogi Inc: Honoraria


This testing protocol showed promising results for evaluating concrete damage due to ASRs based on mechanical and microscopical testing protocols, specifically the stiffness damage test (SDT) and the damage rating index (DRI). Concrete specimens that incorporated the aforementioned SPs and distinct reactive aggregates (coarse and fine) were manufactured and then stored in conditions that enabled ASR development and were monitored over time. Upon reaching the desired expansion levels of this study, the concrete specimens were prepared for the multilevel assessment. The results show that the SP-incorporated concrete specimens with lower and higher alkali content yielded lower and higher deterioration results, respectively. This clearly confirms that while SP-incorporated concrete that contains SPs with a higher alkali content could increase the risk of ASR deterioration, those SPs with a very low amount of alkali content could act as a mitigation strategy against ASRs. Finally, an investigation into the influence of distinct SPs on the chemical composition of an ASR gel was conducted, which confirmed that the SP with a higher alkali content had the highest potential for further deterioration.The effect of two superplasticizers (SPs) with various equivalent (eq.) alkali contents (i.e., with 0.00009% and 4.1% of Na Superplasticizers (SPs) are crucial in today’s concrete industry for the production of modern concrete . Their p+, K+, and OH−) from the concrete’s pore solution, producing a type of alkali-calcium-silica-rich gel (known as the ASR gel) that expands upon water intake, thus cracking the concrete [Alkali-silica reaction (ASR) is a deleterious reaction where certain reactive silicates that are found in the aggregates react with the alkali hydroxides  of naphthalene-, melamine- or ligno-based SPs is approximately 2–6%, while the polycarboxylate-based SP contains 0.1–1% of Na2Oeq. The organic fraction of the SPs is separated from the pore solution of the concrete within the first few minutes of hydration as the SPs are applied to the mixing water during concrete manufacturing [SPs are normally used in concrete to improve the workability  of concrete mixtures, as well as to facilitate the production of low water-to-cement concrete ,34. Theracturing , whereasacturing ,39,40,41acturing ,34,42 reacturing .Accordingly, specimens incorporating a naphthalene-based SP led to an increase in the hydroxide concentration in the pore solution, resulting in an increase in ASR-induced expansion , while tRecently, a number of testing procedures have been developed to assess the condition of damaged concrete and demonstrate the cause and extent of damage  and potential for further deterioration  of ASR-affected concrete. Among the various tools, a comprehensive multilevel protocol, which consists of mechanical  and microscopic  testing procedures, has been validated as a reliable testing protocol to evaluate the condition of damaged concrete ,7,12.The stiffness damage test (SDT) is a loading/unloading cyclical method in compression that is used as a test protocol to assess the degree of damage in concrete specimens affected by internal swelling reactions (ISRs), such as ASRs ,7,8. Thi2 area, resulting in the DRI number, which is used for comparative purposes, where a higher DRI number corresponds to a higher degree of damage in affected concrete [2 should be appraised per member for real structures in order to provide a statistically significant DRI result and, thus, a more reliable appraisal of the extent of the damage.Grattan-Bellew and Danay ,49 develconcrete . MoreoveSuperplasticizers (SPs) are mainly used to enhance the performance of concrete in its fresh and hardened states, yet their influence on ASR-induced development remains unknown in terms of damage, as captured through the multilevel assessment. This study, therefore, aims to perform a multilevel assessment of concrete by incorporating distinct reactive coarse and fine aggregates  while varying the type of SPs used via low–high alkali content. The specimens were manufactured in the laboratory and were monitored over time until the desired expansion level  was achieved . The ASR-induced expansion and kinetics of conventional and SP-incorporated concrete were compared, followed by damage development, in terms of mechanical degradation and crack generation and propagation.2Oeq) of 0.88%. Additionally, to accelerate ASR development, the total alkali content of both mixtures was increased to 1.25 percent Na2Oeq by cement mass. Moreover, two different superplasticizers with low to high alkali content  were selected for this study; their chemical compositions are presented in A total of one hundred concrete cylinders, 100 mm in diameter and 200 mm in length, were fabricated in the laboratory with a design compressive strength of 45 MPa. Highly reactive fine and coarse aggregates  were combined with nonreactive fine  and coarse aggregates , and these were used for concrete fabrication. The various aggregates used in this work, along with their lithological composition, are listed in According to ASTM C 192 , all conThe loading level for conducting the SDT was initially determined through the designed compressive strength test, which was performed on two undamaged specimens . As ASRs may develop in the control specimens using the same mixture proportions , the con2, which represents the DRI number.For each expansion level, two concrete cylinders were cut in half lengthwise with a masonry saw equipped with a diamond blade and were polished with the aid of a mechanical hand polisher with grits/abrasives of 30 (coarse), 60, 140, 280 (80–100 microns), 600 (20–40 microns), 1200 (10–20 microns), and 3000 (4–8 microns) prior to the microscopic assessment. Grids of 1 cm by 1 cm were drawn on the surface of the polished concrete specimens, representing the field of view at 15–16× magnification while using a stereomicroscope. The damage features  down to 1 mm in size were counted in each grid. The weighted counts  were thThe average expansion levels as a function of time in the ASR-affected concrete specimens made with a reactive coarse aggregate  and reactive sand  are illustrated in Generally, the New Mexico (NM + Lav) concrete mixtures follow a parallel trend, where the conventional concrete (CC) and Admixture 1-incorporated concrete mixtures reached 0.11% and 0.10% at 63 and 69 days, respectively. Later, the Admixture 1-incorporated concrete was followed by a decrease in the expansion rate, reaching 0.25% of expansion at 288 days, while 197 days were required for the conventional NM + Lav concrete to achieve the same level of expansion. On the other hand, the Texas (TX + Dia) concrete mixtures present faster kinetics when compared to the reactive coarse aggregate. A parallel trend is observed for the Admixture 2 and CC-incorporated concrete mixtures, both reaching 0.30% of expansion after 70 and 78 days, respectively, while 101 days were required for the Admixture 1-incorporated concrete, thus presenting a lower rate of expansion. This clearly shows that both mixtures incorporating Admixture 1 presented lower expansion levels when compared to CC, while Admixture 2 increased the expansion level of the Texas concrete specimens.The maximum load used for the SDT was 18.8 MPa for a compressive strength of 47 MPa. The SDI values  from an undamaged/sound CC incorporating NM  and TX  is presented in Overall, each concrete mixture presented an increase in expansion with time, yet differences were indeed observed with regard to the induced expansion and kinetics at the same given time. Evidently, the kinetics were different for concrete made with a reactive fine or coarse aggregate , as previously observed by ,61. Howe2Oeq compared to Admixture 2 with a 4.1% alkali content; the higher the alkali content, the greater the expansion. In this regard, Esfahani et al. [2Oeq provided by Admixture 2 and the cement paste is around 200 gr and 3800 gr, respectively, as per this study), the instant availability of sodium and potassium released by SP can impact the hydroxide concentration of a pore solution at an early age, resulting in an increase in ASR-induced expansion [Indeed, the difference in the alkali content in the admixtures might have contributed to the expansion levels observed, where Admixture 1 had a significantly low alkali content of 0.00009% Nai et al.  and Gilli et al.  have prei et al.  and somei et al. ). On thei et al. , the higi et al. ,63. As pi et al. ,43. It ixpansion ,37.Distinct superplasticizers can considerably affect ASR-induced damage development  ,40,41,42Microscopic AssessmentThe microscopic assessment carried out on various concrete samples in this work  demonstrIn order to better demonstrate the above differences, Mechanical Property LossesWhen analyzing the graphs in 2Oeq) could slightly reduce the development of ASR damage, those admixtures with a high alkali content  could increase the mechanical property losses in ASR-affected concrete.Similar to the microscopic assessment regarding the SDT outputs  displayed in p values” being lower than 0.05. This, therefore, attests to the “diagnostic” nature of the SDT to appraise the mechanical property losses in the distinct superplasticizer-incorporated concrete specimens used in this work.Moreover, A two-way analysis of variance (ANOVA with a confidence level of 95%) was conducted as a function of ASR-induced expansion against SDT outcome  to evaluate the statistical significance of these results. According to Summary2Oeq, respectively . As was thoroughly discussed in the previous section, these differences among the various superplasticizers used in this study could be directly attributable to the alkali chemical composition of those admixtures, as per Leeman et al.  and Flavectively .x-axis) with the data gathered through the multilevel assessment: (a) SDI, demonstrating the extent of the physical integrity of concrete [y-axis), (b) DRI number/1000, addressing the level of microscopic deterioration [y-axis), and (c) damage variable “δ”, representing the given mechanical property loss of the damaged concrete [x-axis). Furthermore, the results gathered in this work are also summarized in By compiling the data obtained through the use of a comprehensive multilevel assessment , a four-quadrant chart could be drawn, as proposed by Sanchez et al.  Figure . The chaconcrete   and energy-dispersive X-ray spectroscopy (EDS). Thus, by following the DRI procedure, the concrete specimens with the highest expansion levels in this study  and with large cracks filled with ASR products  on ASR development in concrete specimens made with different aggregate types  via the use of a multilevel assessment. The latter contains a series of mechanical and microscopic techniques, mainly the stiffness damage test (SDT) and the damage rating index (DRI), which have previously been used as reliable techniques in condition assessments of alkali-silica reaction (ASR)-affected concrete. Thus, the main results gathered throughout this study are summarized hereafter:2Oeq) demonstrated faster ASR-induced expansion, while those made with Admixture 1  displayed slower ASR kinetics when compared to the conventional concrete samples. This is likely due to the chemical composition  of the incorporated superplasticizers; the higher the alkali content of the SP used in the mixture, the higher the alkalinity of the pore solution, likely resulting in higher ASR kinetics;The concrete specimens that incorporated Admixture 2  on the development of ASR-induced damage; the higher the alkali content of the SP used in the concrete mixture, the higher the ASR development. Moreover, very low alkali content in an SP used in a concrete mixture can act as a mitigation strategy against ASR development. Nevertheless, the multilevel assessment used in this study proved to be a suitable diagnostic approach that is able to capture the differences in the damage induced by ASR;An investigation into the chemical composition of the ASR gel found in the aggregate particles of the distinct concrete specimens showed that the specimens manufactured with Admixture 2 had the highest Na and Ca content, while those incorporating Admixture 1 had the lowest Na and Ca content. This could be a clear sign that the ASR gel analyzed in the aggregate particles of the specimens made with Admixture 2 had the highest ASR deterioration potential. Likewise, the significantly higher Ca content in the ASR gel obtained from the cement paste of the Admix 2 concrete specimens, once again, attests to the higher risk of ASR damage when using the Admixture 2 samples;A comparison of the distinct atomic ratios of the various ASR gels  gathered from the aggregate particles of the distinct concrete specimens showed that those made with Admixture 2 had the highest Na/Si and Ca/Si ratios, while those incorporating Admixture 1 had the lowest Na/Si and Ca/Si ratios. According to the previous works, this observation clearly attests to the mitigation potential of SP admixtures with very low alkali content against ASR deterioration, while those superplasticizers with high alkali content increase the likelihood of ASR damage.This work intended to investigate the impact of distinct SPs with various alkali content (i.e., Admixtures 1 and 2: 0.00009% and 4.1% Na


Some patients develop immunoglobulin G4 (IgG4)-related hypophysitis associated with systemic diseases. More than 30 cases of IgG4-related hypophysitis have been reported. However, biopsy has rarely been performed in these patients, and none have had an associated pituitary neuroendocrine tumor (PitNET). We present a case of concurrent IgG4-related hypophysitis and PitNET.A 56-year-old Japanese man arrived at the hospital with visual impairment, bitemporal hemianopia, and right abducens nerve palsy. Magnetic resonance imaging revealed pituitary body and stalk swelling as well as a small poorly enhanced right anterior lobe mass. Laboratory and loading test results suggested hypopituitarism. Because IgG4 level was elevated, a systemic examination was performed; multiple nodules were found in both lung fields. The diagnosis was based on an endoscopic transnasal biopsy of the pituitary gland. A histopathological examination revealed a marked infiltration of plasma cells into the pituitary gland, which was strongly positive for IgG4. The histological features of the resected tumor were consistent with those of gonadotroph PitNET, which was immunohistochemically positive for follicle-stimulating hormone-β and steroidogenic factor-1, and no plasma cell infiltration was observed. Based on the histopathological examination results, steroid therapy was initiated, which reduced pituitary gland size and serum IgG4 levels.This is the first reported case of IgG4-related hypophysitis with PitNET. Although no pathological findings indicating a relationship between the two conditions were found, we were able to preoperatively differentiate multiple lesions via detailed diagnostic imaging. Immunoglobulin G4 (IgG4)-related disease is a systemic chronic inflammatory condition characterized by elevated IgG4 levels and a marked infiltration of IgG4-positive plasma cells into affected organs. This disease was first reported in 2001 in a study on autoimmune pancreatitis associated with high serum IgG4 levels [The patient was a 56-year-old man with bitemporal hemianopia and left labial numbness. Magnetic resonance imaging (MRI) performed in another hospital showed a tumorous lesion in the pituitary aspect, and the patient was referred to our hospital. On the first hospital visit, the patient had visual impairment, bitemporal hemianopia, and right abducens nerve palsy. The results of the laboratory tests were as follows: thyroid-stimulating hormone (TSH), 0.658 μU/mL; free thyroxine, 0.41 ng/dL; growth hormone (GH), 0.62 ng/mL; luteinizing hormone, < 0.2 mIU/mL; follicle-stimulating hormone (FSH), < 1.0 mIU/mL; prolactin, 19.7 ng/mL; cortisol, 0.5 μg/dL; adrenocorticotropic hormone, 16.4 pg/mL; testosterone, < 5.0 ng/dL; and insulin-like growth factor-1, 119 ng/mL (− 0.73 standard deviation score). These findings suggested hypopituitarism. Corticotrophin-releasing hormone, GH-releasing hormone, gonadotropin-releasing hormone, and TSH loading tests showed gonadotropin, TSH, and hypothalamic–pituitary–adrenal axis deficiency . This was a finding that suggested masked diabetes insipidus. On MRI, the pituitary gland was found to be reduced in size Fig. e. Based In 2011, Leporati proposed five criteria for diagnosing IgG4-related hypophysitis . AlthougWhether the occurrence of PitNET is associated with IgG4-related hypophysitis remains unclear. Recently, many studies have been conducted on the relationship between IgG4-related disease and malignant neoplasms. IgG4-related disease is diagnosed using imaging, blood tests, and pathological examinations. However, patients with pancreatic cancer have elevated serum IgG4 levels and IgG4-positive plasma cell infiltration in tumor tissue . MoreoveSeveral mechanisms have been proposed to explain the relationship between IgG4-related disease and malignant neoplasms. Regulatory T cells (Tregs) are significantly elevated in patients with IgG4-related disease , and Th2Furthermore, tumor lesions often occur incidentally in the pituitary gland. Some types of incidental lesions were found in 17.8% of 1,000 cases of pituitary gland autopsy, and when restricted to lesions of ≥ 2 mm (the minimum size that can be identified on MRI), the incidence rate is 6.1%. Of those, PitNET accounted for 2% and Rathke’s cleft cyst for 3.7%, indicating that when treating pituitary lesions , these tHerein, we described the case of a patient with IgG4-related hypophysitis complicated and continuous with gonadotroph PitNET. Although no pathological findings indicated a relationship between the two conditions, we were able to preoperatively differentiate multiple lesions using detailed diagnostic imaging. Incidental lesions in the pituitary gland are occasionally observed, and because multiple lesions are possible, detailed preoperative diagnosis is required when treating pituitary lesions.


This paper analyzes Wikipedia’s representation of the Nobel Prize winning CRISPR/Cas9 technology, a method for gene editing. We propose and evaluate different heuristics to match publications from several publication corpora against Wikipedia’s central article on CRISPR and against the complete Wikipedia revision history in order to retrieve further Wikipedia articles relevant to the topic and to analyze Wikipedia’s referencing patterns. We explore to what extent the selection of referenced literature of Wikipedia’s central article on CRISPR adheres to scientific standards and inner-scientific perspectives by assessing its overlap with (1) the Web of Science (WoS) database, (2) a WoS-based field-delineated corpus, (3) highly-cited publications within this corpus, and (4) publications referenced by field-specific reviews. We develop a diachronic perspective on citation latency and compare the delays with which publications are cited in relevant Wikipedia articles to the citation dynamics of these publications over time. Our results confirm that a combination of verbatim searches by title, DOI, and PMID is sufficient and cannot be improved significantly by more elaborate search heuristics. We show that Wikipedia references a substantial amount of publications that are recognized by experts and highly cited, but that Wikipedia also cites less visible literature, and, to a certain degree, even not strictly scientific literature. Delays in occurrence on Wikipedia compared to the publication years show  a dependence on the dynamics of both the field and the editor’s reaction to it in terms of activity. For some time now, the bibliometric community has been increasingly engaging with new data sources, often involving new databases or, as in the case of Altmetrics, social media such as Twitter. Wikipedia, however, receives less attention as a format of science communication and knowledge transfer. Yet Wikipedia is one of the most widely used internet sources and strongly connected to the scientific publication system: According to Wikipedia's own guidelines, all science-based claims must be supported by scientific references, preferably secondary over primary sources.This raises the question to what extent Wikipedia, with its specific governance structures, produces output that in fact resembles familiar formats of scientific publication—and where it differs significantly. Our aim is to explore Wikipedia as a format of science communication, focusing on the analysis of the referenced literature in Wikipedia articles.Our first methodical decision is to base our research setting on a case study, which facilitates an explorative approach in terms of methods as well as content, as the distinct subject matter makes it easier to look at details where appropriate. For this purpose we chose the scientific innovation of CRISPR/Cas9 . Since innovation processes are characterized by the fact that they transfer scientific knowledge into application contexts and thus connect further areas of society and public perception, Wikipedia is an interesting format in this regard. Innovation processes are also often characterized by a temporary acceleration of dynamics, which makes an interesting case for Wikipedia’s promise of timeliness and constant updating. The chosen innovation, a new gene editing technology based upon an adaptive immune system of e.g. bacteria, for which Jennifer Doudna and Emmanuelle Charpentier received the Nobel Prize for Chemistry 2020, began more than twenty years ago and has left a long paper trail of scientific publications. It provides the necessary material as well as temporal scope for our endeavor.Quality dimensions applicable to the coverage (or selection) of referenced literature are comprehensiveness and relevance. Both dimensions are currently not straightforward to operationalize. What would comprehensiveness mean given the size and internal differentiation of the knowledge body on CRISPR? Relevance reflects the publications’ significance and importance for audiences, potentially dependent on further contextual factors. Coverage policies of databases as well as secondary publication formats can be understood as relevance decisions. This quality dimension is often exchanged with impact, resulting in models with high impact journals as predictor variables for Wikipedia references  to prohibit our analysis from being affected by assumptions about the coherence of reference formatting styles on Wikipedia, and (2) to prohibit the exclusion of references cited solely in the text. Finally, the case study format, with still manageable publication and data numbers, allows us to delve deeper into certain phenomena and issues related to data quality and referencing patterns on Wikipedia. We expect that the findings obtained will also be instructive for macro studies.Lancet, BMJ) as well as mega journals  in his recent study on COVID-19, besides citation counts and Altmetrics. Jemielniak et al.  and that publications can also be cited in the text instead of in the article's reference list. While recent revisions of articles usually apply Vancouver style for the formatting of references, Wikipedia does not have a single house style but expects the editors to use a consistent style within articles, which results in citation styles changing over the course of an article's history. To avoid limiting ourselves to the extraction of references, we focus on the development of heuristics for matching external publications against Wikipedia. In a first step we created two small corpora—highly cited publications and references of a selection of review papers—to be matched with the central Wikipedia article on CRISPR in order to evaluate different matching methods (Study (a)). Having found that DOI and PMID are quite effective, we collected additional Wikipedia candidate articles by comparing the DOIs and PMIDs of all publications in a larger, field-delineated input corpus with all revisions of all articles in the English Wikipedia (Study (b)). From all potentially suited Wikipedia articles we select the most relevant ones and extend the first study by matching all publications in the large field-delineated corpus against the selected articles (Study (c)) and evaluate all heuristics. Fig. Accounts Corpus comprises publications referenced in predominantly secondary literature formats, such as reviews and short communications. These accounts present and discuss the development of CRISPR, providing experts’ and stakeholders’ perspectives on which publications were relevant for the innovation process. To create this corpus, we searched Google Scholar for the terms "crispr history", "crispr development", and "crispr discovery" and, based on Google's relevance ranking, reviewed the search results pages until no relevant publications were found in a series of consecutive pages. 13 publications that contain history sections were discarded because they did not focus on the history of CRISPR. The resulting sources were supplemented by three CRISPR timeline web resources, obtained by searching for "crispr timeline" on Google and reviewing the search results pages accordingly. We extracted the references from the 29 resulting sources via WoS or extracted the references manually in the case of the timeline documents, and supplemented this copus by the sources themselves.The Field Corpus amounts to 20,585.WoS Highly Cited (HC) Corpus. To provide an impact perspective, especially in contrast to the historically oriented accounts, we sort this corpus by absolute citation counts and cut off at 500 publications. This number corresponds to the volume of references in the central article . The reason for not using citation windows here is due to the particular dynamics of our 'innovation setting', where early publications are not necessarily highly cited from the start but typically contribute a considerable number of citations over time. We also decided against standard field-normalization based on WoS subject categories because of the volume of publications in high-impact multidisciplinary journals. The corpora of 1183 Accounts and 500 HC publications overlap: The deduplicated number of publications is 1340, 343 publications are contained in both corpora. 309 publications of the historical Accounts Corpus are not part of the field delineation. Both corpora are exploratory, and, to some extent, pragmatically defined, as we do not yet know much about what determines reference structures in Wikipedia, especially in case of innovations.In order to represent a topical perspective, publications containing "crispr"—as a highly distinctive term—in the title are searched in WoS and are defined as the core field. As a second layer, we add publications that contain "crispr" in their abstracts. For a third layer, representing influences and effects, we delineate publications where the proportion of references or citations to the core field compared to the total references or citations is higher than 30 percent and thus forms a substantial connection. The number of publications in this References, Further Reading), and additional metadata.All revisions of the CRISPR article were downloaded using the MediaWiki API, collecting the HTML versions of each revision’s page (2123 revisions as of 31 May 2021). Each revision has a unique revision timestamp, text sections , the reference sections  we developed heuristics for literal and fuzzy reference matching with varying degrees of precision. Verbatim heuristics match titles, DOIs, and PMIDs of the publications against the entire article text including all references. All strings are converted to lowercase ASCII, alphanumeric normalization is additionally used for title matching. The fuzzy matching heuristics match the publications’ titles with extracted references and allow for normalized edit distances of 0.2, 0.3, and 0.4. In particular, they consider author matching strategies such as the publication-to-reference-author ratio, the Jaccard Index of publication and reference authors, and a new author order score. In the new score, each author of the publication is assigned a gain equal to its position in the inverted list of authors divided by its actual position, with the sum of all values being the ideal score. Then, the authors of a given reference are evaluated in turn, receiving the same value if they match the author of the publication in the respective position and losing that value if not. The author order score is normalized by the ideal score. Figures The computation of the exact precision and recall values for the heuristics requires a manual analysis of the 2123 revisions and had to be omitted. Instead, we use an approximate value for the total number of correct items based on an analysis of references extracted from the central CRISPR article, which is primarily intended for the relative assessment of the heuristics. We also need to assess whether and to which extent we have missed referenced publications and hence analyze the references that are not in the input corpora. To this end, we manually checked and deduplicated all titles, DOIs, and PMIDs extracted from all references throughout the article’s entire revision history, resulting in 327 DOIs, 308 PMIDs, and 455 titles. We examined this data using a reverse matching to WoS and Scopus: Titles are again matched in alpha-numerical lowercase ASCII, DOIs and PMIDs verbatim, ambiguous results (mostly involving meeting abstracts and articles) are manually resolved. The respective Scopus item IDs are mapped to WoS, and the remaining title strings are manually searched on the Internet and in WoS, resulting in 333 unique WoS items, including one false positive. The comparison of matching and reverse matching does not show false negatives, and only one publication was missed by the reverse matching. Although this is almost completely consistent with our matching, it must be taken into account that the reverse matching is based on the extraction of titles, DOIs and PMIDs and is therefore not completely independent of the original matching.In a second step, we select, in addition to the central article, a set of ten CRISPR articles that are also highly relevant to the topic. This selection is based on knowledge about the matching heuristics plus further analytical steps.From the pilot study we learn that the number of matched publications can hardly be improved when applying the heuristics DOI, PMID, and title in a combined fashion; in fact, DOI and PMID are already very effective. We hence perform a search of the complete Field Corpus across the entire Wikipedia revision history to find further articles relevant to CRISPR with these two identifiers. The analysis of the revision history dump (about 678 million revisions) from June 2021 for 20,585 publications represented by 18,283 DOIs and 16,973 PMIDs resulted in 849 candidate articles.From this set we discard Wikipedia articles with less than six hits and articles about persons and visualize the hit frequency and its dynamics for the remaining Wikipedia articles candidates see Fig. . In an aThe initial matching procedures based on verbatim and fuzzy heuristics are repeated, but now using the complete Field Corpus as well as the central CRISPR article and the 10 additional articles.Table d), (e), and (f) identify more publications than the verbatim ones but come at the price of precision. The comparably smaller number of matches of the fuzzy heuristics (g), (h), and (i) result from the fact that author lists in Wikipedia articles are less well-maintained than identifiers and titles. However, the combined author and title heuristics performs better in terms of precision. The verbatim matching of publications based on titles only can lead to false positives if the title of a publication is a substring of the title of another publication (applies to one publication in the Accounts Corpus).A revision cites a publication if any of the matching heuristics correctly identifies the publication in the revision. The number of unambiguous, correctly matched publications from both corpora (Accounts and HC) is 199. The fuzzy matching heuristics , (e), and (f) match more publications than the verbatim heuristics at the price of precision; heuristics (g), (h), and (i) cannot identify more publications than the verbatim heuristics. In general, a heuristic that relies only on the publications’ titles tends to identify more publications. This is because we match titles not only in the references but also in text segments, and treat matches of conference abstracts and corrections to articles as false positives.Table d), and one by heuristic (f). Counting at the level of distinct publications and pooling the results, 459 unique publications out of 20,585 in our corpus were correctly matched from all matching heuristics, with 458 publications found using the exact methods and 451 found using the two identifiers PMID and DOI only. By matching with title only we found 432 publications, with DOI only 444 publications, and with PMID alone 429 publications.Summarizing the results at the level of individual matches, i.e., counting a publication that was correctly found in more than one of the 11 articles multiple times, we could identify 516 out of 670 matches by their exact title, 52 by their DOI, 91 by their PMID, 10 by heuristic , (e), and (f)) are able to identify publications earlier than the PMID-based approach in 25%, and earlier than the DOI-based approach in about 12% of all cases where the respective heuristics correctly match a publication. When looking at the mean delays  in Table To assess potential benefits of the relaxed matching heuristics in terms of delays, we also calculated the mean delay in days between each pair. Table d)–(f)) are able to find publications in "Genome-wide CRISPR-Cas9 knockout screens" earlier than the DOI- and PMID-based heuristics in about 90 percent of all cases. For all other articles, the fuzzy title heuristic is better than the DOI heuristic in less than 10% of the cases. For eight articles, fuzzy title heuristics succeed in finding a publication earlier than PMID in 25% or less of the time, and for two articles in about one third of the time. If wording heuristics are used exclusively, almost all publications are found no later than three days later.There is considerable variance between articles. For example, the fuzzy title heuristics  evidence presented by Benjakob and Aviram  regardinCaution is advised when titles are matched against the entire text of an article (as was done here): Some publication titles are exact substrings of other publications, others are so short that they can literally appear in the article. On the other hand, individual publications are referred to in the text of the Wikipedia article rather than in the reference section, which can be found only by a full-text search for the titles.With the extensive validations and mutual comparisons of the heuristics, we have achieved a high confidence in the correctness of matching publications as well as of the date of their first occurrence. In the following assessment of the central CRISPR article and the related Wikipedia articles in terms of the structure of references and the timeliness of citations, we refer to the first occurrence as the earliest date on which a reference was correctly identified, regardless of the applied heuristic.We first focus on the reference structure of the central CRISPR article. By reverse matching all extracted references from this article, we are able to correctly identify 332 WoS publications across all revisions. 199 of those match one or both of the initial corpora, the Accounts Corpus, and the HC Corpus: 183 with the Accounts Corpus versus 139 with the HC Corpus. In total, 294 of the 332 referenced WoS publications (excluding one that was missing from the reverse procedure) are part of our bibliometric field delineation of 20,585 publications. 99 of these are neither part of the HC nor the Accounts Corpus. Most of these publications belong to the core of the Field Corpus (the term CRISPR appears in the title) and belong to the time segment from 2015 onwards.38 referenced publications are WoS source items but not part of the Field Corpus, although four of this subset belong to the Accounts Corpus. 14 are at least loosely connected to the Field Corpus.Of the 332 WoS publications, 224 have the WoS document type 'Article' and 64 'Review', others are Editorials, News Items, and Letters.Of the remaining non-WoS references, about 110 could be identified through manual search as contributions to popular science or technical journals (such as "Technology Review"), technical blogs, and news sites. There are also references to clinical trials and patents as well as to other web resources. Although we have not deepened our analysis here, based on manual inspection it is likely that these references also support CRISPR-specific content claims in a narrower sense and not other areas . This does also fit our observation that (in single cases) references to scientific publications do not follow the standard format but refer to recommendation sites,It can be concluded that, on the one hand, the Wikipedia article reflects a broader discourse than a regular scientific review since it covers popular science and journalistic media, even if these sources are still relatively marginal. Our observation confirms the tendency of the findings of Benjakob and Aviram, who also report a minority of other, non-published sources, in their case books and websites.On the other hand, of the 60 publications referenced in more than five of our 32 historical accounts, 48 are referenced in both the central and related Wikipedia articles. Similarly, in the HC Corpus, 46 of the 60 most cited publications are referenced in at least one of the selected Wikipedia articles. This suggests that the opinion of Wikipedia editors on the relevance of publications is broadly in line with the scientific community and the metric perspective. The number of references of the central Wikipedia article, for example, is in the same order of magnitude as that of a scientific review. Nevertheless, the selected historical accounts also differ from each other to a certain extent as they are from different years and slightly different emphases are likely. Against this background, the fact that 183 of 332 WoS publications (55%) referenced by the central CRISPR article match the Accounts Corpus is a convincing sign that Wikipedia editors largely adhere to strictly scientific formats.Figure These temporal dynamics also emerge from a broader quantitative perspective, which results from the CRISPR article’s character and reference numbers:Figure Both graphs show the first substantial step in 2010 and another larger increase from 2014 onwards, demonstrating that text and references are added in a substantial manner. In 2019, the application-related section is moved to a new article on CRISPR gene editing, leading to a decrease of text and references. Thus, the late recognition of publications may to some extent be consistent with the general dynamics of the article’s edition.Figure We observe that four CRISPR-related articles were newly created between 2010 and 2014 : (1) "CRISPR interference" was created in 2010 and is the first that describes the biological mechanism in bacteria, while the technique was introduced in 2013.  "CRISPR/Cas Tools" and "Cas9" are both from February 2013, with the former being the first application-oriented article. Cas9 refers to a protein that is relevant for the immunological defense of bacteria and is crucial for the CRISPR/Cas gene-editing technique. (4) "Protospacer adjacent motif", which is based on the biological principles of the CRISPR/Cas mechanism, was created in September 2014. The oldest article, "Restriction Enzyme", about the enzyme essential for the bacterial immune system underlying the technique, is from 2001.The five newer articles are more application-oriented. While the five older articles show different patterns of delayed and instant recognition, the dynamics of referencing in case of the five newer articles in the second row are largely dominated by back-referencing to publications published before the time the Wikipedia articles were written. Thus, on the one hand, the number of specialized Wikipedia articles grows as the innovation and its application potential unfolds. On the other hand, new idiosyncratic dynamics are emerging to a certain extent: In the case of the article "Cas9", we see that a number of publications is retro-indexed in 2019.Of the total 459 distinct correctly matched WoS publications based on the 11 articles, 162 occur in more than one Wikipedia article. Of these 162, 49 distinct publications (30%) occur with at least one delay in the publication’s first occurrence between Wikipedia articles, not including delays caused solely by a later creation date of the respective article. In the majority of cases, publications occur either on the same day as the first occurrence (within our set) or on the creation date of the respective article.Table How does the speed with which Wikipedia recognizes publications relate to the speed in which the scientific community picks up publications? Figure We have analyzed the use of scientific literature in the Wikipedia article on CRISPR and the timeliness of the reference patterns of this central article as well as related articles. Our goal is to assess Wikipedia’s relevance and adequacy as a medium for the representation of scientific contents and, in particular, the tracing of scientific innovations. We tested different matching procedures to map from publication corpora to all revisions of Wikipedia’s central article and related articles on CRISPR. Methodically we demonstrated that a combination of verbatim matching heuristics yields sufficient accuracy to make Wikipedia a valuable object for analyses of science communication in addition to standard bibliometric sources. With that said, there is some variance between the analyzed Wikipedia articles.Our results are also promising on an empirical level: There is evidence that much of the CRISPR/Cas9 literature referenced in Wikipedia is highly cited or has been acknowledged by experts in the field. The majority of referenced publications is covered by WoS and part of our WoS field delineation; however, the concordance is not complete. News, magazine pieces, and other web resources are also referenced to some extent, which is contrary to the practices in regular scientific secondary or tertiary sources, at least in STEM subjects.We observe that the timeliness of referencing improves over time in the sense that major gaps in the recognition of older literature are filled quite early (in 2010 and 2014), while delays of one to a few years also occur later on. In the innovation’s earlier phase, timeliness depends to a certain degree on the general level of Wikipedia’s editors’ activity regarding the article and the topic. We conclude that delays in Wikipedia should be viewed less as a fixed quantity and more as dependent on the respective circumstances. However, unlike databases such as WoS, whose coverage policies are based on journals rather than individual publications, Wikipedia’s reference patterns represent a degree of article-level expert recognition. In the course of innovation, the representation of the topic in Wikipedia grows both in terms of the amount of text and the number of references of the central CRISPR article, but also in terms of the number of related, more specialized Wikipedia articles. It should be considered that the 29 historical accounts—apart from two exceptionsBenjakob and Aviram  relied oWe are working with print publication dates. While in our case spot-checks found very few preprint-versions of publications referenced in the central Wikipedia article, this may be different in other fields and with more recent data. Comparing Wikipedia occurrence data with these and online advance dates can make the analysis of latency more precise and nuanced.Another limitation of our research is that, as a case study, it focuses on the specific context of a novel-prize winning innovation from a STEM subject. It is not unlikely that the high profile of the innovation attracts a considerable number of editors, which could affect the dynamics of editing and latency of references. Similarly, the fact that the innovation and the related debates were so widely discussed in non-scientific sources such as newspapers and technology magazines could have impacted the extent to which these sources also occur as references. Given this limitation of a high-profile case and our finding that citation latency in this case is influenced by the specific interaction of a subfield's development and editor activity, future research could investigate whether (a) there is high profile research with low coverage in Wikipedia, (b) there is low profile research with high coverage in Wikipedia, and (c) there are different trends in STEM, humanities, etc.Within the framework of our explorative, descriptive design, we also did not specifically investigate the question of whether the representation of the field in Wikipedia in this case leads to feedback effects on intra-scientific communication, i.e., whether the early occurrence of some publications in Wikipedia leads to more attention and more citations within the scientific community. One may interpret Fig.


MET is a notable driver gene in the diversity of aberrations with clinical relevance, including exon 14 skipping, copy number gain, point mutations, and gene fusions. Compared with the former two, MET fusions are severely under‐reported, leaving a series of unanswered questions. In this study, we addressed this gap by characterizing MET fusions in a large, real‐world Chinese cancer population.MET fusion‐positive (MET+) patients were subsequently selected for clinical and molecular characterization.We retrospectively included patients with solid tumors who had DNA‐based genome profiles acquired through targeted sequencing from August 2015 to May 2021. MET fusions from 122 patients, resulting in an overall prevalence of 0.15%. Lung cancer comprised the majority of MET+ patients . Prevalence was markedly higher in liver cancer, biliary tract cancer, and renal cancer (range 0.52%–0.60%). It was lower in ovarian cancer (0.06%). A substantial proportion  of unique partners were reported for the first time. High heterogeneity was observed for partners, with ST7, HLA‐DRB1, and KIF5B as the three most common partners. Mutational landscape analysis of lung adenocarcinoma (n = 32) revealed a high prevalence of TP53 in MET+ alterations, EGFR L858R, EGFR L861Q, and MET amplification.We screened 79,803 patients across 27 tumor types and detected 155 putative MET fusions. Our findings warrant that further clinical validation and mechanistic study may translate into therapeutic avenues for MET+ cancer patients.To our knowledge, this is currently the largest study in characterizing  MET fusions are clinically relevant in that it results in constitutive MET activation, thereby promoting oncogenesis or therapeutic resistance.MET fusions is mostly derived from three studies, which identified 2  MET fusions in lung adenocarcinoma,MET fusions.MET fusions, which involved 58 unique partners, 48 of which reported for the first time. Subsequent characterization revealed the genomic landscape of these fusions and MET fusion‐positive lung adenocarcinoma cases. We also highlight the therapeutic relevance of MET fusions for targeted therapy with select LC cases.Herein, we report a retrospective study that screened 79,803 patients and identified 155 putative 22.1MET fusions and analyzed the clinical and molecular characteristics of the MET fusion‐positive patients. The study was approved by the institutional review board of Tianjin Medical University Cancer Hospital and Institute. Patients with solid tumors who had available genome profiles acquired through targeted sequencing from August 2015 to May 2021 were retrospectively included. There was no preselection based on tumor type, histologic subtype, age, sex, clinical stage, or sample type. A total of 79,803 patients were screened, corresponding to 41,404 tumor tissue samples, 35,770 plasma, 2,242 pleural effusion, and 387 cerebrospinal fluid. In this work, only one sample of each patient was included. After we reviewed the sample records, several patients had two or more types of samples or had more than two specimens with the same sample type . For those who had two or more types of samples, only the tissue sample was included. For those who had more than two specimens with the same sample type, only the sample detected the first time was included. Genomic profiling was performed with hybrid capture‐based next‐generation sequencing (NGS) using panels targeting 8, 41, 68, 108, 168, or 520 cancer‐related genes (Burning Rock Biotech). These panels were designed and validated for the identification of base substitutions, insertions, deletions, copy number variations (CNV), and gene fusions.This study screened the genomic profiles of patients with solid tumors for 2.2All wet‐lab procedures were performed at a College of American Pathologists (CAP)‐ and Clinical Laboratory Improvement Amendments (CLIA)‐certified clinical diagnostic laboratory (Burning Rock Biotech). Briefly, DNA from tumor tissues was extracted with a QIAamp DNA tissue kit, and cell‐free DNA from liquid biopsies was extracted with a QIAamp Circulating Nucleic Acid kit (Qiagen). DNA library construction and targeted sequencing with a commercial panel of 8, 41, 68, 108, 168, or 520 genes (Burning Rock Biotech) were performed as previously described.2.3MET fusions were investigated in 27 MET fusion‐positive lung adenocarcinoma (LUAD) patients who underwent targeted sequencing using a 168‐ or 520‐gene panel. In addition, the concurrent lung cancer driver alterations with MET fusions were also investigated in 32 MET+ LUAD patients who underwent targeted sequencing using panels targeting 8, 41, 68, 108, 168, or 520 cancer‐related genes. These panels included eight identical genes, also known as classic lung cancer oncogenes, including EGFR, KRAS, BRAF, ALK, ROS1, MET, RET, and ERBB2.All the reads were mapped to the human genome (hg19) with Burrows–Wheeler Aligner (BWA).2.4MET fusion‐positive patients. Wilcoxon signed‐rank test was used to compare the central tendency of a continuous variable, such as TMB, between two groups. All tests were two‐sided with a significance level set at p < 0.05.All statistical analyses were performed using the R programming language. Chi‐square or Fisher's exact test was used to compare between two groups in the proportions of values of a nominal variable, such as percentage of 33.1MET fusions events were identified in 122 patients (151 samples), resulting in an overall prevalence of 0.15% (122/79803).In this study, we retrospectively screened 79,803 patients with solid tumors who had DNA‐based genomic profiles acquired with panel‐based targeted sequencing. A total of 155 putative MET fusions (hereafter referred to as MET+) across cancer types. LC represents the largest subset , followed by colorectal cancer . These two cancer types showed similar prevalence rates of MET fusions (0.16% and 0.19%), which were comparable with overall prevalence. Although liver cancer (n = 3), biliary tract cancer , and renal cancer (n = 2) patients showed higher prevalence ranging from 0.52% to 0.60%, ovarian cancer  showed a markedly lower rate at 0.06%, these results may be artifacts due to the small number of MET+ patients. Pairwise comparison between different tumor types revealed no significant difference in prevalence levels  were women. Gender information was not documented for the remaining six cases (n = 1.2%). Median age was 58 years with a range of 27–87 years. More than half had stage III disease , followed by stage IV disease .Figure s Figure . Other cCRC, n = 1, 9.0%. 3.2MET+ patient is provided in Table MET was the 3' partner, among whom 21 (17.2%) carried multiple MET fusions, including 12 (9.8%) cases in which MET was also found as a 5' partner, and the remaining 9 patients had >1 (range 2–5) fusions, all of which with MET as the 3' partners. In terms of fusion events, MET was the 3' partner in 99 (63.9%) events and the 5' partner in the remaining 56 , these novel fusions were also identified in CRC (n = 7), BTC (n = 2), liver cancer (n = 2), gastroesophageal cancer , breast cancer (n = 1), pancreatic cancer (1 event), and other cancers (n = 1). A considerable proportion of MET fusions were intergenic . Precise 59 partners were found in nonintergenic fusions, with 76.3% of partners (n = 45) identified only once and 86.4% of partners (n = 51) identified ≤2 times. ST7 stood out as the most common partner occurring in 7 events, followed by HLA‐DRB1 and KIF5B (5 events each), and CAPZA2 and CFTR (4 events each). Notably, all nonintergenic fusions with HLA‐DRB or CAPZA2 had MET at the 3' end and occurred in LC. Fusions with KIF5B were also all detected in LC and had MET as the 3' partner except for one occasion. Besides LC (4 events), ST7‐MET was also present in CRC, OC, and other cancer types (1 event for each). Interestingly, apart from LC (2 events), fusions with CFTR were detected in 1 GEC and 1 breast cancer case in the forms of MET‐CFTR and CFTR‐MET, respectively. Analysis of breakpoint distribution indicated exon 15 as the most common exon  harbored MET exon 14 while most  had intact encoding sequences for MET KD. In addition, we found that 41.7% (50/122) of MET+ patients harbored concurrent MET amplification. The details are summarized in Table The majority  of the n Figure . Figure 3.3MET fusions, we then focused on the 32 MET+ LUAD cases for further characterization  had stage III or IV disease.LUAD was the predominant histologic subtype with n Figure . These pn Figure . SimilarKIF5B, CAPZA2, DOCK4, KCND2, LINC01392, and ST7  harbored MET KD or lacked exon 14  fusions. Excluding 25 intergenic ones, the remaining corresponded to 22 partners, including 15 novel ones. Most partners occurred only once except for 7 Figure . Figure TP53 (74%) and EGFR (63%) had high frequencies, while other drivers, such as ERBB2 (11%), RET (11%), and BRAF (7%), had relatively lower alteration rates. The most common concurrent MET alteration was MET amplification . TP53 aberrations were predominantly point mutations, including 13 (48.1%) missense, 3 (11.1%) nonsense, and 2 (7.4%) frameshift mutations. EGFR alterations included equal numbers of missense mutations and amplification (7 for each) as well as 3 indels and 1 fusion. The alteration frequencies of 8 LC‐associated driver genes were investigated in 32 MET+ LUAD patients who underwent a panel of 8, 41, 68, 108, 168, or 520 genes. KRAS (3%), ALK (3%), and ROS1 (0%) presented with low alteration frequencies  and achieved rapid partial response (PR) but developed brain metastasis 1 year later. Afterward, cabozantinib was started but the patient manifested intracranial progression within 1 month. She then received alectinib and crizotinib plus anlotinib. The patient achieved respective progression‐free survival (PFS) of 3 and 7 months. Genomic profiling 5 months later identified acquired MET Y1230C and Y1230H mutations in addition to HLA–DRB1–MET fusion, suggesting one or both point mutations as a potential mechanism of acquired resistance to crizotinib plus anlotinib.Next, we describe three cases that highlight the diverse therapeutic implications of different y Figure . She begEGFR L858R mutation (abundance: 1.9%). Plasma‐based genome profiling also identified low‐grade MET amplification (copy number: 2.4) and LINC01392‐MET (L2:M15) when the patient was on fourth‐line treatment with osimertinib plus anlotinib  and newly emerged IMMP2L‐MET (I4:M3) at low abundance. The patient progressed another 3 months later with the best response of PR. Whether one or both of the fusions were resistant to crizotinib and contribute to disease progression was unclear.The second patient was a 49‐year‐old woman (P13) with stage III LUAD positive for b Figure . She recKIF5B‐MET (K24:M15)‐positive LUAD resistant to second‐line crizotinib, as indicated by rapid progression within 2 months, which contrasted with previous report of durable response (10 months) to crizotinib in a patient with stage IV LUAD harboring KIF5B‐MET (K24:M14). Together, these cases demonstrated heterogeneity in the response to multi‐kinase and selective MET‐TKIs among carriers of different MET fusions.In the third highlighted case, a 62‐year‐old woman (P107) had a 4MET was first identified as part of an oncogenic gene arrangement with TRP,MET fusions and their therapeutic implications have been largely ignored. In this study, we addressed this challenge with a large‐scale screening of 79,803 patients across 27 tumor types, which led to the detection of 155 putative MET fusions from DNA‐based genomic profiles of 122 patients. Subsequent analyses answered fundamental questions such as prevalence rates in different tumor types, whether the fusions were enriched in any of these tumors, percentage of MET as the 3' partner and carriers of multiple fusions, location of the MET sequence, and breakpoints and partners. Notably, this study also identified 48 novel partners, which provided candidates for preclinical research into their biology and potential as drug targets. In terms of cancer types, LC patients represented the largest MET+ population  and LUAD as the largest histologic subtype . Analysis of the mutational landscape of MET+ LUAD revealed a prevalence of altered TP53 or EGFR much higher than those of other genes and found MET amplification, EGFR L858R, and EGFR L861Q as frequently concurrent aberrations.Although MET amplification and exon 14 skipping alterations are well‐known oncogenic drivers in multiple cancer types. A number of previous studies on the prevalence and clinicopathological characteristics of MET amplification/exon 14 skipping alterations in solid cancers across countries have been documented.MET fusions are poorly defined. To our knowledge, studies on MET fusions in large cohorts of tumors are scarce. Pekova et al. have reported EML4‐MET occuring in a pediatric papillary thyroid carcinoma patient  from a large cohort.EML4‐MET was detected in a stage IV CRC patient . A recent study by Yang et al. has revealed MET fusions in solid tumors from a multicenter study in China, indicating its incidence with 0.34% (37/10882) across cancer types and 0.07% (4/5835) in LC,MET fusions, including COMETT (LINC01510)‐MET, PRKAR1A‐MET, and SEMA3D‐MET, detected in LC and validated by RNA‐sequencing in Yang's work,MET fusions (COMETT (LINC01510)‐MET and PRKAR1A‐MET) were also detected in LC in the present work.MET fusions in various cancer types. Prevalence was 0.15% overall and ranged from 0.06% to 1.38% across tumor types. LC, CRC, breast cancer, and GEC each had more than 2,000 screened patients and showed similar, relatively low rates. In contrast, BTC, liver cancer, and renal cancer, all with <500 screened patients, showed markedly higher rates, which may or may not be an artifact due to the small sample size and warrants further investigation. Pairwise Fisher's exact test showed no significant difference among the tumor‐specific prevalence rates  events. In stark contrast, in a study of NSCLC patients confirmed to be ALK‐positive via immunohistochemistry and fluorescence in situ hybridization, those carrying fusions with one of the three most common partners  constituted 86.1% of (136/158) cases.RET‐positive cancer patients showed that 74% of fusions involved KIF5B, CCDC6, or NCOA4.MET was similar to NTRK in that both fusions were rare  and demonstrated no marked partner preference. In a similar study of NTRK fusions in cancer patients, those harboring fusions with any of the 3 most frequent partners ETV6, TPM3, and LMNA comprised 22.3% (198/889) of all NTRK‐positive cases, a percentage closer to our observation with MET .Our analysis revealed substantial heterogeneity in TP53 alterations in MET+ LUAD, which amounted to 74.1% (20/27). In comparison, TP53 has altered in 52.3% of (296/566) LUAD cases in The Cancer Genome Atlas databaseMET+ LUAD cases. This finding warrants further validation and may provide alternative therapeutic targets for MET+ LUAD patients. MET fusions are prohibitively rare for clinical trials of a MET‐altered cohort and as a result, no such trial has been reported to date.One interesting observation was the high frequency of MET as the 3' partner, involving 5' partners actionable targets such as protein kinase A (PRKAR1A),TLK2),LRIGDOCK4,DIXDC1YEATS2 .MET+ cancers. Also noteworthy were the fusions with MET as the 5' partner. The putative protein products may not undergo dimerization and subsequent MET transactivation and yet still be clinically relevant, as suggested by an interesting case report of MET‐UBE2H as a mechanism of acquired EGFR resistance in LC.Our findings also provided candidates for a mechanistic study that may translate into therapeutic inventions. Of the 58 unique fusion partners identified in our study, 48 were novel. Importantly, among the corresponding fusions, 13 were in‐frame with KD‐intact MET exon 14 may result in elevated oncogenic activity of the chimeric protein. For instance, our third highlighted case and a previously reported oneKIF5B), and regimen, although the former lacked MET exon 14. Nonetheless, the two cases showed vastly different responses to crizotinib as the former had a PFS of 2 months with best response of stable disease, while the response lasted for 10 months for the patient whose KIF5B‐MET included exon 14. This contrast was consistent with the observation that the prognosis for patients with MET exon 14 skipping was generally worse compared with MET‐amplified NSCLC.In addition to partners, breakpoints that result in the inclusion of MET fusions and heterogeneity of partners and breakpoint require large cohort sizes for high‐confidence characterization. Second, although this study is to date the largest effort in this field, MET+ patients were still scarce except in LC, which limited the depth of insights gained from the remaining tumor types. Third, MET fusions were identified from DNA‐based genomic profiles and were not validated on the mRNA or protein level. Therefore, the putative fused genes reported in our study will need further validation on the RNA and/or protein level. Fourth, the therapeutic data of most enrolled patients were not available. Therefore, it is challenging to determine whether the MET fusion is a primary or acquired event. The study could benefit from more detailed clinical information, especially those regarding treatment and response/progression, which could have led to the characterization of drug efficacy for different MET fusions and potential resistance mechanisms of MET+ patients.This study was limited by several factors. First, the low prevalence of 5MET fusions. Our findings provide insights into the structure, partner distribution, and concurrent genomic alterations of MET fusions. This study warrants further clinical validation and mechanistic investigations that may translate into therapeutic avenues for MET+ cancer patients.To our knowledge, this study is currently the largest in characterizing Hui Xia: Conceptualization ; data curation ; formal analysis ; writing – original draft ; writing – review and editing . Junhua Zhang: Conceptualization ; data curation ; formal analysis ; writing – original draft ; writing – review and editing . Tong Chen: Data curation . Mingzhao Wang: Data curation . Dongna Chen: Data curation . Tongguo si: Data curation ; project administration ; writing – review and editing . Yutao Liu: Data curation ; project administration ; writing – review and editing .This study was supported by the Translational research project of the Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS‐MOTRP2022002) and the Beijing Medical Award Foundation (YXJL‐2020‐0785‐1174).The authors have no conflict of interest to declare.All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board of Tianjin Medical University Cancer Hospital and Institute and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.All patients had provided written informed consent for participating in the study.Figure S1.Click here for additional data file.Table S1.Click here for additional data file.Table S2.Click here for additional data file.Data S1.Click here for additional data file.