Poor oral health due to dental caries is one of the most prevalent non-communicable diseases worldwide. It has a significant impact on individuals across the lifespan and is a leading cause of preventable hospitalizations. The impacts of COVID-19 on oral health at the practice level are well documented, but gaps in understanding the impact on individual oral health remain. This review addresses this gap.Using a JBI scoping review process we mapped and summarized the evidence to identify the impact of COVID-19 on individual oral health. Key search terms were developed, and searches were undertaken by an experienced research librarian.The 85 included studies were conducted in 23 countries from 5 regions across the world classified using the United Nations Geoscheme system. The majority (82/85) were quantitative, 2 were reviews and there was one qualitative interview study. Cross-sectional surveys were the most common data collection approach followed by an analysis of clinical data, analysis of internet trends and other online methods. Five key areas were identified including changes to the provision of emergency dental services, provision of routine oral health services, oral hygiene maintenance at home, changes in dietary preferences, alternative models of dental provision and help-seeking and attitudes towards dental care in the future.This scoping review has demonstrated that the pandemic has impacted on oral health at the individual level. It is important that we are aware of these impacts and ensure that support systems are in place to overcome future periods where access to dental care might be compromised. The provision of preventive care remains a vital first step in ensuring good overall oral health as is paramount during periods where access to dental treatment might be limited.The online version contains supplementary material available at 10.1186/s12903-022-02463-0. Poor oral health is one of the most prevalent non-communicable diseases (NCDs) worldwide consuming one-fifth of out-of-pocket health expenditure –3. In 20The World Health Organization declared the global spread of coronavirus disease COVID-19) a pandemic on March 11th, 2020 . The imp a pandemThe immediate increase in stress and anxiety levels in response to the COVID-19 outbreak has impacted health-promoting behaviors, including oral hygiene , 26. DurUsing a scoping review process our purpose was to explore the breadth or depth of the literature, map and summarize the evidence and identify or address knowledge gaps concerning the impact of COVID-19 on individual oral health , 38. TheInclusion and exclusion criteria, consistent with our review purpose were developed and are outlined in Table A search strategy was developed in consultation with a specialist health librarian as recommended by the 2020 Methodology for JBI Scoping Reviews and peer-reviewed by using the Peer Review of Electronic Search Strategies (PRESS) checklist . A combiThe full search was conducted in Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), OVID, Proquest, Embase, Dentistry and Oral Health Sciences Source (DOSS) and Cochrane Database of Systematic Reviews. Search results were then saved and exported into EndNote, a bibliographic software program, to store, organize, and manage all results and then into Covidence , part ofA data extraction tool was developed within Covidence and used to extract key characteristics of each included study in tabular format  preregistrations to enhance transparency and replicability and to reduce any publication or reporting biases.A preliminary protocol for this review was published in the Open Science Framework . Table Our synthesis of the key findings of the included studies resulted in the development of the following themes: changes to the provision of emergency dental services, provision of routine oral health services, oral hygiene maintenance at home, changes in dietary preferences, alternative models of dental provision and help-seeking and attitudes to dental care in the future. These themes are reported below. The full dataset of the included studies is provided in Additional File Most studies concluded that there was an increase in the provision and utilisation of emergency oral health services –60. The Most studies reported that there was a decline in the provision and utilisation of routine oral health services , 71–91 wSelf-medication or using home remedies for oral health issues were reported  with oneThe included studies show mixed results regarding the changes in dietary habits of individuals during the pandemic. Three studies reported an increase in sugary food consumption and the number of meals , 97, 101There was increased use of and satisfaction with teledentistry among dental patients during the pandemic , 102–104There was also an increase reported in the use of online searches and social media to address/express oral health-related concerns during the pandemic , 105–109Most studies reported that there was a negative impact on the attitudes of individuals towards oral healthcare in the future , 111–118This scoping review aimed to undertake a comprehensive mapping and synthesis of key findings related to the impact of the COVID-19 pandemic on oral health at the individual level. Scoping reviews do not exclude studies based on study design or quality appraisals which enables a synthesis of findings that provides a useful starting point for future reviews and other research activity , 38.Government responses to the spread of COVID-19 varied across the world with many countries utilising lockdowns to stem the transmission. Service restrictions and lockdowns in many places resulted in limitation or cessation of essential services including dental services in some areas –20. Our Findings from this review were not surprising with many studies highlighting the impact that prolonged lockdowns had on dental treatment services (particularly emergency services) and routine oral health and preventive services. More recent studies have confirmed the impact that lockdowns had on dental service use by children, adults and older adults in the UK  with simRoutine oral health care and preventive practices are cornerstones of good oral health across the lifespan. Reduction in these services throughout the lockdowns may have increased in oral healthcare-related disparities for vulnerable groups , 87, 120Changes in dietary preferences were reported in some studies with both increases and decreases in the consumption of sugary foods , 101. HiThe results of this review highlight the role that the internet played throughout the pandemic with many people using it for advice and/or information regarding oral health. Interruptions to dental services throughout the pandemic were challenging however access to quality information and evidence-based materials to support oral health care routines should be readily available. Help-seeking via the internet is common with previous studies highlighting using social media and search engines to find information about oral health is popular in some countries , 125. HoThe use of teledentistry throughout the lockdown periods was reported within this review. Teledentistry may be useful to improve the ability to reach oral healthcare providers in times of crisis or to address service access issues , howeverPrevious studies have highlighted that the widening inequalities in oral health cannot simply be “treated away” (: p. 113)Many of the studies included in the review utilised cross-sectional, online, self-report surveys and existing datasets, with only one studyutilising qualitative methods. More qualitative studies could provide access to a deeper understanding of the factors that impact oral health at the individual level and could be used to inform the development of guidelines, policies and other information to improve oral health in the future , 129.The searches that formed the basis of this review were carried out from March 2020 to November 2021. These dates were chosen to capture the majority of studies published while countries across the globe were under the highest level of restrictions (including lockdowns in many places). With the emergence of Omicron in November 2021, many countries lifted lockdowns as part of their approach to living with COVID-19. Whilst the searches were comprehensive, we have only captured those studies that were published in the included databases in a specific period. There may have been other studies published outside of these periods. We also limited the search to studies published in English with full-text availability which may have meant that some other studies were excluded.As the emphasis of a scoping review is on comprehensive coverage and synthesis of the key findings, rather than on a particular standard of evidence we did not undertake a quality assessment of the included studies. This has resulted in the inclusion of a wide range of study designs and methodologies with small samples, cross-sectional designs using self-reported measures and internet-based research methods. The results of these studies provide valuable insights into the key issues faced by individuals throughout the pandemic however they must be interpreted with caution considering any specific methodological limitations.Future research in this area should focus on addressing some of these key limitations with more research exploring the direct impacts of COVID-19 on individual oral health required. This will enable the development of specific oral health prevention activities that support good oral health through times of crisis.COVID-19 has impacted the oral health of many people across the globe, however, there are few reviews that have explored these impacts at the individual level. This review addresses this gap. The findings demonstrate that the pandemic has impacted the provision of emergency dental services, provision of routine oral health services, oral hygiene maintenance at home, changes in dietary preferences and the use of online information and help-seeking. It is important that we are aware of these impacts and ensure that support systems are in place to overcome future periods where access to dental care might be compromised. This will include ensuring patients have access to good quality oral health services and information including preventive care. A shift in focus that ensures a coordinated interdisciplinary approach consisting of treatment, education and prevention will reduce the pressure on emergency health care systems in the future.Additional file 1. PRISMA-ScR checklistAdditional file 2. Extracted data


Mirror movements (MMs) are common abnormal motor performance in patients with poststroke hemiparesis. The study aimed to utilize the Electromyography (EMG) characterization of MMs in stroke patients and explore the relationship between MMs and the motor function of affected limbs.Sixty patients with stroke who had used to undergo clinical assessment and surface Electromyography (sEMG) were selected in this study. We investigated the standardized net excitation (SNE) and overflow percentage (OF) as a measure of mirror activities on bilateral muscles of stroke patients.In stroke patients, mirror activities occurred in both affected and unaffected muscles during maximal contractions. We found that OF at unilateral contraction on the affected side (UCA) was significantly greater than that at unilateral contraction on the unaffected side (UCU). Additionally, a negative correlation between OF at UCA and Brunnstrom stages on admission and discharge. However, there were no significant correlations between OF and disease duration, Barthel Index, or the degree of improvement in all clinical evaluations. We still found a positive correlation between SNE at UCA and the improvement of the Brunnstrom stage of the hand. But we could not find any significant correlation between SNE and other clinical evaluation scores.In conclusion, the study found mirror activities in both affected and unaffected muscles, confirming an asymmetry between them. Although the mechanisms are still unclear, we confirmed a significant correlation between MMs at UCA and the motor function of the affected upper extremity, which might provide further evidences for understanding MMs in stroke patients and a new research direction on evaluation for motor function and outcomes of stroke patients. Mirror movements (MMs) are involuntary movements occurring on one side of homologous muscles when unilateral voluntary movements are performed with the contralateral limb . This phThe evaluation of MMs is best achieved with surface Electromyography (sEMG). The EMG signals acquired by surface electrodes represent muscle activities in a region of interest. Importantly, previous studies showed that sEMG could be useful for assessing MMs after various neuropsychiatric disorders . DiffereConsidering that the proportion of bilateral muscle activities may better reflect the mutual influence between bilateral limbs , we hypoIn this retrospective study, we reviewed the sEMG records conducted at Sir Run Run Shaw Hospital from June 2021 to May 2022. Among patients who underwent sEMG, those with brain infarction confirmed by magnetic resonance imaging were selected. Of the 66 patients with brain infarction initially selected, 64 met the following inclusion criteria: Patients hospitalized for ischemic stroke, patients who have completed the sEMG assessment and functional scale assessment, including Brunnstrom Stages of Motor Recovery Scale (BR) and Barthel Index (BI), within 1 week after hospitalization. Regarding the exclusion criteria, patients with a history of other diseases affecting the motor function of the upper extremities were excluded. Likewise, patients with poor sEMG data or incomplete clinical data were excluded from the research. None of the patients had any limitations in the passive range of motion. Finally, there were 60 patients involved in our study. The medical history of all the patients was taken from the patient medical record. The motor recovery status was between stages I and VI in the BR.The experimental protocol was approved by the Ethics committee of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine (2022-534-01).All 60 patients had finished the BI of Activities of Daily Living (ADL) for independence in mobility and personal care (range 0–20) and a BR stage for motor recovery (range I–VI). Both were completed 1 week after hospitalization and on the day of discharge. Because of the higher patient compliance requirements, 41 patients had an arm motor score on the Fugl-Meyer Assessment Scale (FMA) 1 week after hospitalization, and only 24 patients had finished the same assessment before discharge. The same trained physical therapist performed all clinical assessments to avoid individual error. Furthermore, the evaluator was blinded to the content and purpose of the research.Subjects were asked to lay on a height-adjustable bed, with two legs straight and two feet close to the bed pedal. Both upper limbs were symmetrically close to the trunk, the shoulders and elbows were fully extended, and the forearms/wrists were maintained in a neutral position. Additional stabilization straps were applied to the distal forearms to prevent the flexion of the elbow joint, and a harness with a shoulder strap secured the trunk to the back support to avoid compensatory axial movement or shoulder protraction and retraction force generated by the joint’s movement during the task. Bipolar surface EMG electrodes  were placed over the muscle bellies of biceps brachii bilaterally, and a reference electrode was placed at the lateral humeral epicondyle on the left side see , as descThe sEMG was recorded using a medstra biomedical acquisition system . EMG signals were digitized at 1,000 Hz with a 12-bit A/D converter . High-and low-frequency filters were set at 500 Hz and 20 Hz. All the data was collected with custom LabVIEW software, processed by Megawin3.1 , and saved for offline analysis.The enrolled subjects were not aware of the focus of our research interests to avoid any participant bias or awareness that might affect the movements. They performed a set of voluntary isometric muscle contractions with visual feedback in a fixed order: (1) Unilateral contraction tasks on the affected side (UCA) and (2) unilateral contraction tasks on the unaffected side (UCU). During the task, the subject was asked to perform voluntary isometric muscle contractions with maximal force and relax the contralateral limb. In each set, three contractions should be completed, each contraction lasted 5 s, and the interval was 5 s. A root-mean-square (RMS) voltmeter provided visual feedback on EMG activity to enable subjects to maintain a steady muscle contraction . The redResting baseline EMG of the resting limb was obtained first before movement of the contralateral limb. Average amplitudes of EMG (AEMG) and RMS in the 3-s segment were calculated through the absolute values of EMG signals. The activity patterns of sEMG for the bilateral muscles (both active and resting limbs) were subsequently gained during two tasks. A period of 3 s of EMG signals was used due to stroke patients being too weak to maintain the steady force for a long time . AEMG anThe standardized net excitation (SNE) was defined as the irradiation of the resting muscle attributed to the contraction of the contralateral homologous muscle. As described in a recent study, the SNE of an irradiated muscle was defined by subtracting the value for irradiated EMG from its baseline activity and then normalizing the value of the baseline activity. The SNE was calculated in the following equations :The overflow of EMG activity recorded in the resting limb compared to the amount of EMG activity in the active limb was measured. An overflow percentage (OF) was calculated using the EMG value of the resting limb and the EMG value of the contracting limb following equation :U-test was applied to determine differences in sEMG parameters between the affected and unaffected muscles of patients with stroke. For the correlation of sEMG parameters with the clinical assessment and disease duration, the Spearman rank correlation coefficient was used. According to the BR score of the affected arm, the patients were divided into two groups, High Function Group  and Low Function Group , to further clarify the correlation between EMG parameters and clinical function. Furthermore, the Mann–Whitney U-test was used to determine differences in sEMG parameters between the two groups. All data are displayed as Means ± Standard deviation. The level of significance was set at 0.05. In order to show the difference more clearly, all the data used in the figures were logarithmically converted. Finally, all statistical analyses were completed using SPSS version 24.0 .The Chi-square test were used to compare male-to-female ratio and infarction side of the LFG and HFG. The Mann–Whitney p > 0.05). The disease duration of LFG is significantly longer than that of HFG (p < 0.05).Sixty stroke patients were included in this study. The average age, male-to-female ratio, infarction side, disease duration, and clinical assessment scores are summarized in AEMG and OFRMS during unilateral movement between the unaffected and affected extremities (p < 0.01). OF (including OFAEMG and OFRMS) was significantly greater during unilateral tasks of the affected limb than on the unaffected side (see AEMG or SNERMS (p > 0.05), although SNE (including SNEAEMG and SNERMS) at unilateral tasks of the affected limb was typically greater than that of the unaffected limb . As expected, the two groups had no significant difference in OF at UCU and SNE at both tasks.To confirm the correlation between sEMG parameters and clinical assessment, we divided the patients into HFG and LFG and compared the sEMG parameters between the two groups. In this study, stroke subjects performed voluntary isometric muscle contractions at maximal levels with the affected and unaffected limbs unilaterally. We chose two sEMG parameters, AEMG and RMS, to examine the electrical activity of the target muscles. We found no significant difference in results between the two parameters in all the analyses. Although the absolute values of RMS and AEMG were different, their results were completely consistent on the comparison between the affected and unaffected sides and the high and low function groups, as well as the correlation with motor function. Notably, both AEMG and RMS are important in estimating the change of sEMG signals . AdditioAs expected, we found mirror activities in both affected and unaffected muscles during maximal contractions with the help of sEMG techniques. Previously, it’s been believed that MMs always appeared predominantly in the distal upper limb muscles, especially the hands, and occurred on the unaffected side when patients move the paretic hand . NotablyWe also found a significant difference between sides in the electrical activity of muscles at two tasks. Notably, the OF at UCA was significantly higher than that at UCU. Although there was no significant difference in RE, an apparent trend was observed that SNE at UCA was higher than that at UCU. Therefore, we confirmed the asymmetry in motor overflow between affected and unaffected elbow flexion in stroke subjects, which was also observed by via ipsilateral corticospinal tracts.There are two possible explanations for the phenomena above. One is the reduction of interhemispheric inhibition (IHI). In healthy people, activating the motor area in one hemisphere causes inhibition of the homologous cortical area in the contralateral hemisphere, which is called IHI . After aMirror movements may reflect the motor function of patients with stroke. Conversely, people found that the location of MMs might be related to the motor function of the paretic hand. Notably, MMs in the unaffected hand had been associated with a significantly worse motor function . Hwang eThe explanation for the correlation between MMs and motor function is still unclear. In the IHI hypothesis, the increased inhibition from the contralesional hemisphere may play an important role in hindering the recovery of motor function for stroke patients . Notablyvia ipsilateral corticospinal tracts  for the publication of any potentially identifiable images or data included in this article.JD: conception, design, drafting of manuscript, analysis, and final approval of manuscript. FW: conception, design, interpretation of data, revision of manuscript, and final approval of manuscript. JL: conception, revision of manuscript, and final approval of manuscript. MY and CL: acquisition of data and final approval of manuscript. YS: concept, design, revision of manuscript, and final approval of manuscript. All authors contributed to the article and approved the submitted version.


The objective of this study was to perform a systematic review of the effectiveness of computer-driven technologies for treatment of patients suffering from BPD. A systematic literature review was conducted using the Pubmed, EMBASE, PsycNET (PsycINFO), CINAHL and Google Scholar electronic databases for the period from their inception dates until 2022. Thirty studies were selected for abstract screening. Seven studies were excluded for not meeting inclusion criteria. The remaining 23 studies were fully assessed, and 12 were excluded. Therefore, 11 studies were included in the analysis of the effectiveness of computer-driven technologies, which encompassed mobile applications, telehealth interventions, internet-based interventions, virtual reality MBT and dialogue-based integrated interventions. Computer-driven interventions are showing signs of effectiveness in the treatment of BPD symptoms. The limited number of articles found on the subject demonstrates a need for further exploration of this subject. Borderline personality disorder (BPD) is a widespread mental health disorder with a prevalence ranging from 0.5 to 1.4% in the general population . This diMany guidelines are readily available on the treatment of patients diagnosed with BDP. However, in the ways that the suggested guidelines can be applied to help these patients are unclear . PsychotComputer-driven technologies are used in different areas of medicine to personalize treatments and address accessibility and applicability problems . In psycThe objective of this study was to perform a systematic review of the effectiveness of computer-driven technologies for medical and psychological treatments of patients suffering from BPD. This would provide a broad overview of novel approaches for the treatment of BPD and could provide hints for future explorations of personalized medicine for patients diagnosed with this disorder. A systematic literature review was conducted using the Pubmed, EMBASE, PsycNET (PsycINFO), CINAHL and Google Scholar electronic databases for the period from their inception dates until 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used to guide the study design. Indexing (MeSH) terms and text words were used in the inquiries with the electronic databases for the key concepts of BPD  and computer-driven technologies . These conceptual entities were selected as they best encompass the modalities for computer-driven interventions in the treatment of BDP. Further studies were identified via cross-referencing. A complete research strategy can be found in The following criteria were used for the inclusion of studies in this review: (1) the study involved a computer-driven intervention for the treatment of patients suffering from BPD; (2) the study was conducted with the intent of addressing at least one symptom of BPD or general suffering from BPD; (3) the study included a qualitative or quantitative tool for the assessment of the effectiveness of an intervention on the symptoms of BPD; (4) the study was an original article; (5) the study included an engaging or immersive component involving the patient. Studies that used several different types of computer-driven technologies were included. Unpublished studies were excluded.Data were extracted with the help of a standardized Excel form and cross-validated by AH and CGM. The type of intervention, number of participants, outcome of interest, indicators of interest, effect size (if applicable) and general conclusion were collected. The methodological quality of the non-randomized and randomized controlled studies identified was analysed based on an adaptation of the Cochrane Collaboration Tool for Assessing the Risk of Bias . AH extrThe systematic review assessed studies that evaluated the effectiveness of computer-driven interventions on BPD symptoms. After the removal of duplicates, 30 studies were selected for abstract screening. This process eliminated seven studies, which were excluded for not meeting inclusion criteria, as they did not include a computer-driven intervention. The remaining 23 studies were fully assessed, and 12 studies were excluded  interventions).Therefore, 11 studies were included in the analysis. A flowchart for the inclusion of studies in this review is displayed in Five mobile applications were identified in this systematic review. The first mobile application assessed was the Rapid Intervention Guidelines using Health Technology for Borderline Personality (B-RIGHT) developed by Frias et al., which is a mobile application for self-management of emotional crises . This moThree mobile applications consisted of DBT integrations. Austin et al. assessed the overall experience and facilitation of therapeutic alliance (integration of DBT skills that are relevant to patients with BPD symptoms) among 24 outpatients diagnosed with BPD receiving DBT via a mobile application . This miThe last mobile application identified was EMOTEO. This mobile application was designed to monitor and reduce aversive tension in patients with BPD by suggesting targeted mindfulness-based exercises. Prada et al. designed a pilot study to assess the aversive tension of 16 patients suffering from BPD via a self-reported questionnaire . The autTwo studies reported the effectiveness of internet-based interventions for BPD symptoms in patients suffering from BPD.The first study, by Klein et al., reported a randomized controlled trial study that assessed the effectiveness and safety of internet-based self-management interventions . A groupZanarini et al. assessed the reduction in BPD symptoms in a randomized trial consisting of 80 women with BPD . A groupA comparative study designed by Zimmerman et al., conducted as part of the Rhode Island Hospital Adult Partial Hospital Program, compared the use of telehealth formats of ACT and evidence-based psychotherapy techniques, such as CBT and DBT, to their in-person counterparts . This stA single study on this topic was identified, designed by Falconer et al. . It consIn 2015, Fassbinder et al. designed a first case study on Priovi, which is an e-health, dialogue-based, integrated tool that uses the concepts of schema therapy . In thisAmong the 11 identified studies, various computer-driven technologies were assessed. There is still a lack of evidence regarding effectiveness for all the above modalities. The wide range of methodologies used to assess the effectiveness does not permit comparisons between the modalities. There is a greater body of evidence for mobile applications and internet-based interventions as compared to emerging interventions, such as telehealth, virtual reality MBT and dialogue-based integrated interventions. Meta-analysis could not be applied for this review as the identified studies were clinically diverse and because there was a mix of comparisons of a variety of treatments using different tools to assess BPD symptoms.In this systematic review study, we analyzed 11 studies that assessed the effectiveness of computer-driven technologies, such as mobile applications, telehealth interventions, internet-based interventions, virtual reality MBT and dialogue-based integrated interventions.Amongst the five reported mobile applications, four showed promising results regarding the improvement of BPD symptoms. However, it is difficult to state their effectiveness due to the numerous limitations in the identified studies, such as sample sizes, qualitative assessments and the various methodologies employed to assess BPD symptoms. The conclusions of these studies are consistent with a systematic literature review on the subject that assessed 16 mobile health applications for various mental health disorders . For patInternet-based interventions revolved around psychoeducation. While Zanarini et al.’s study reported a significant decline in BPD symptoms, the comparative study designed by Klein et al. did not report such improvements for their intention-to-treat protocol ,32. HoweTelehealth interventions have been gaining popularity, especially during the COVID-19 pandemic . For BPDAvatar-based MBT is still a novel avenue for the treatment of BPD symptoms. The major elements of MBT are used in this approach, which is why this format is hypothesized to be effective. The visual aspects of avatar-based MBT might help the patients in the process of mentalization thanks to its immersive component. BPD patients are reported to have difficulties mentalizing . The majWith regard to the dialogue-based integrated tool Priovi, the authors reported potential avenues for BPD symptoms. Priovi is based on Schema Therapy. The literature currently supports the effectiveness of Schema Therapy, ranging from assessments of it as a promising avenue to demonstrations of its effectiveness for the reduction of BPD symptoms ,48,49. TThis systematic review focused solely on the literature addressing the effectiveness of computer-driven interventions without limitations on the methodologies used for their assessments. Therefore, it was hard to establish comparisons between the identified modalities. The small number of studies identified reflects the novelty of this domain, which should expand with time. The search strategy was limited to medical databases to reflect the main objective. An approach targeting a wider range of practitioners could identify further interventions. Computer-driven interventions are showing signs of effectiveness in the treatment of BPD symptoms. This could yield potential novel avenues in the treatment of patients suffering from BPD. Using computer-driven interventions could be beneficial where accessibility to treatment as usual is not accessible or delayed, and this should be further studied. The promising effectiveness of these interventions demonstrates that they could also be employed as adjuncts to standard therapies and treatment plans. The limited number of articles found on the subject demonstrates a need for further exploration of this subject. Further studies, especially randomized controlled trials, should be conducted to better assess the effectiveness of these novel treatments for BPD symptoms.


To determine whether a multifaceted initiative resulted in maintained reduction in inappropriate treatment of asymptomatic pyuria (ASP) or bacteriuria (ASB) in the emergency department (ED).Single-center, retrospective study.Beginning in December 2015, a series of interventions were implemented to decrease the inappropriate treatment of ASP or ASB in the ED. Patients discharged from the ED from August to October 2015 (preintervention period), from December 2016 to February 2017 (postintervention period 1), and from November 2019 to January 2020 (postintervention period 2) were included if they had pyuria and/or bacteriuria without urinary symptoms. The primary outcome was the proportion of patients prescribed antibiotics within 72 hours of discharge from the ED. The secondary outcome was the number of patients returning to the ED with symptomatic UTI within 30 days of discharge.P < .001). This reduced frequency of inappropriate treatment was noted 3 years after the intervention, with 28% of patients receiving treatment for ASP or ASB in postintervention group 2. (P was not significant fin the comparison with postintervention group 1.) Among the 3 groups analyzed, we detected no difference in the numbers of patients returning to the ED with a symptomatic UTI within 30 days of ED discharge regardless of whether patients received antibiotics.We detected a significant decrease in the proportion of patients with ASP or ASB who were inappropriately treated when comparing the preintervention group and post-intervention group 1 (100% vs 32.4%; A multifaceted intervention resulted in a significant decrease in inappropriate use of antibiotics for ASP and/or ASB that was maintained 3 years after implementation. Symptoms of UTI include urinary urgency and frequency, suprapubic tenderness, costovertebral angle tenderness, and fever. Transient bacteriuria or colonization may result in asymptomatic bacteriuria (ASB), defined as the isolation of bacteria from an appropriately collected urine sample in a patient who lacks signs and symptoms of a UTI. Because ASB is not reflective of true infection, current Infectious Diseases Society of America (IDSA) guidelines recommend against the use of antibiotics to treat ASB except in the case of pregnancy or planned urologic procedure. Furthermore, it has been suggested that the use of antibiotics to treat ASB results in potentially avoidable adverse drug events including increased antibiotic resistance, increased rates of Clostridioides difficile infection, and increased rates of recurrent symptomatic UTI. Despite guideline recommendations against the use of antibiotics and the demonstrated risk of inappropriate antibiotic use, treatment of ASB remains common in clinical practice.Urinary tract infection (UTI) is one of the most common bacterial infections in the United States, resulting in an estimated 2 million visits to emergency departments (EDs) each year. Many studies have demonstrated an improvement in prescribing practices following educational intervention. Strategies for these interventions ranged from a single 1-hour educational session to the development of algorithms and pocket cards to assist prescribers and nursing staff in decision making. Not only have pharmacist-led educational interventions been shown to decrease the rate of inappropriate treatment of ASB, but some studies have also suggested a cost benefit associated with minimization of unnecessary treatment.In recent years, initiatives have been made to reduce the overprescribing of antibiotics in asymptomatic patients. Although ASB has gained recognition in recent years for promoting inappropriate antibiotic use, the impact of ASP on prescribing behavior and the impact antimicrobial stewardship initiatives have on those behaviors is not well characterized.Asymptomatic pyuria (ASP), defined as a urine specimen that contains increased numbers of leukocytes in an otherwise asymptomatic patient, represents the presence of inflammation that is not always due to true infection. However, it also commonly results in the inappropriate initiation of antibiotics.Several studies have demonstrated improvement in prescribing practices immediately following educational interventions, but few have characterized the sustained impact of such antimicrobial stewardship initiatives. Similarly, few studies have formally evaluated the influence of ASP on prescribing in the ED or the effects of initiatives to improve such prescribing. Therefore, the purpose of this study was to determine the sustained impact of a multifaceted intervention on the rate of inappropriate treatment of ASP or ASB in the ED at our institution.This single-center, retrospective study was conducted at the Wake Forest Baptist Medical Center (WFBMC) ED. The 45-bed adult ED at WFBMC receives ∼80,000 visits annually. The study was approved by the Wake Forest Baptist Health institutional review board.1), alerts embedded into order-entry software addressing the appropriate use of urine cultures , and elimination of reflex urine-culture orders for positive urinalyses  database . Results were filtered to identify patients who had urine study results meeting defined study criteria. Identified patients were then retrospectively screened for inclusion. Patients were reviewed consecutively in the chronological order in which they received care until the target sample size in each group was attained.3, history of stem-cell or solid-organ transplant, use of prednisone 20 mg equivalent of a glucocorticoid for at least 2 weeks, therapy with any medication used for prevention of organ rejection, or an absolute neutrophil count <1,000 cells/mm3.Patients were eligible for inclusion if they were at least 18 years of age and were discharged from the ED between August and October 2015 (preintervention group), between December 2016 and February 2017 (postintervention group 1), or between November 2019 and January 2020 (postintervention group 2)    were treated based on ASP in the absence of bacteriuria. This inappropriate antibiotic use in response to ASP was reduced in the months immediately following implementation of the intervention: 100% in the preintervention group versus 22% in postintervention group 1  was higher than predicted, emphasizing the importance of these interventions. Treatment rates decreased by approximately two-thirds in postintervention group 1, demonstrating an impact from the initiative that was both statistically and clinically significant. No other changes apart from the interventions could be identified as affecting this outcome. In contrast, an educational intervention in one nursing home demonstrated a reduction in the submission of inappropriate urine cultures and a reduction in ASB treatment up to 30 months after the intervention.The sustainability of various antibiotic stewardship initiatives has not been well described in the literature. A controlled crossover study evaluating the timing and duration of antimicrobial surgical prophylaxis demonstrated an improvement in appropriate prescribing practices immediately after education. However, such improvements were not sustained over the course of 12 months.The maintained reduction in inappropriate treatment seen in this study is likely to have been influenced by several factors. First, alerts embedded into order-entry software, and the elimination of reflex urine culture orders implemented as part of the initiative have remained in place since their implementation. Thus, any impact these interventions had immediately following their implementation was likely to be maintained. The antimicrobial stewardship program at the study institution is strong, which helped optimize the utilization of antimicrobial agents across the medical center, including in the ED. Furthermore, 24-hour pharmacist coverage in the ED may have contributed to day-to-day stewardship interventions that minimized inappropriate treatment throughout the study period.To our knowledge, this is the first study to demonstrate the impact of ASP on the inappropriate prescribing of antibiotics in the ED. Most patients meeting study inclusion criteria in all groups had ASP in the absence of confirmed ASB, suggesting that ASP may be a driver of inappropriate antibiotic usage. Although the high rate of ASP alone in the preintervention group was surprising, the rate of ASP in the absence of bacteriuria in the postintervention groups was not unexpected as the elimination of reflex urine cultures for positive urinalyses is suspected to have decreased the number of urine cultures overall. Notably, the sustained decrease in the primary outcome appears to have been driven by a sustained decrease in the treatment of ASP. Despite this, most patients treated for ASP did not have urine cultures obtained, suggesting that prescribers are making a presumptive diagnosis of UTI based only on a nonspecific inflammatory marker.The number of patients returning to the ED with signs or symptoms of UTI within 30 days of discharge was not significantly different among the 3 study groups. However, most of those who did return to the ED with a symptomatic UTI had received antibiotics for ASP and/or ASB. These results suggest that there is no apparent harm from refraining from treatment of asymptomatic patients.This study had several limitations. First, it was conducted at a single center and included a relatively small sample size. Due to the retrospective nature of the study, data capture was dependent upon accurate documentation in the medical record. Furthermore, exclusion criteria did not account for those with frequent UTIs or other comorbid conditions that may influence prescribing patterns. Finally, the data presented only represent snapshots of antibiotic utilization at various points over 4.5 years. As such, conclusions cannot be made as to the proportion of inappropriate treatment in the interim periods, and advances in medical trainee knowledge throughout the year may have influenced these results.In conclusion, a multifaceted stewardship initiative significantly decreased the proportion of inappropriate treatment of ASP or ASB in the ED in the months immediately following the interventions. The decreased proportion of inappropriate treatment of ASP and ASB was preserved when it was evaluated 3 years after the initial intervention.


To make full use of the regenerative value of waste cooking oil, and to solve the environmental pollution and food security issues caused by waste cooking oil, waste cooking oil was suggested for use in asphalt. Waste cooking oil was used to adjust the performance of virgin and aged asphalt. This review article summarizes research progress on the performance of asphalt and asphalt mixture with waste cooking oil. The results showed that a moderate dosage of waste cooking oil will improved the low-temperature performance and construction workability of petroleum asphalt and aged asphalt. The mixing and compaction temperature of asphalt mixture with waste cooking oil are reduced by up to 15 °C. The rutting resistance and fatigue resistance of modified asphalt and modified asphalt mixture with waste cooking oil are damaged. After the addition of waste cooking oil in aged asphalt, the high-temperature performance and shear rheologic property of aged asphalt will be recovered. The regeneration effect of waste cooking oil on aged asphalt and aged asphalt mixture is close to that of a traditional regeneration agent, and the partial performance of asphalt or asphalt mixture with waste cooking oil is better. There is no chemical reaction between waste cooking oil and asphalt, but the asphalt component and absorption peak intensity of partial functional groups are changed. The light components content of asphalt binder is usually increased. Further research regarding the engineering application of asphalt mixture with waste cooking oil should be conducted. The method for improving the performance of asphalt and asphalt mixture with waste cooking oil will be mainly researched.  The waste cooking oil is generated from the cooking and food production process. The waste edible vegetable oil and waste edible animal oil are classified as waste cooking oil. The waste cooking oil is mainly included the waste oil after repeatedly fried food, recycled waste oil from catering trade, gutter oil and condensate oil in smoke lampblack machine. According to the statistical results from the China National Grain & Oils Information Center, the human consumption of edible oil was 3545.0 million tonnes in 2020 in China, and an average of 500~700 million tonnes of waste cooking oil is produced every year. There are a lot of pathogenetic components and carcinogenic components in waste cooking oil, and the dosage of heavy metal, aflatoxin and benzopyrene exceeds the limit of standard scope. Once the waste cooking oil is flowed back to people’s dining table, the food security and human health will be seriously threatened . CurrentThe main component of waste cooking oil is fatty acid, which belongs to aromatic oil, and it is similar to the aromatic fraction in asphalt components. So, the waste cooking oil can be used to soften asphalt, restore the aged asphalt performance, and regulate the asphalt components and rheological property ,6,7. TheThe waste cooking oil is used as an asphalt-regenerating agent, which can realize the recycling of waste asphalt pavement materials and waste cooking oil. The partial performance of recycled asphalt with waste cooking oil is better than that with other waste oil. The asphalt regenerant prepared by waste cooking oil, waste bio oil and waste engine oil is added into 70# aged asphalt, when the dosage of asphalt regenerant is less than 13%, the penetration and softening point of recycled asphalt with waste cooking oil is higher than that of other recycled asphalt, but the ductility of recycled asphalt with waste cooking oil is the worst . The difwww.cnki.net. The published articles from 2010 to 2022 were chosen and analyzed in this paper, especially published articles in the last five years. Only the articles form core journals were included in the above published articles.However, the recoverability rate of waste cooking oil is relatively low in China, and the waste cooking oil is a potential environmental pollution source. If not be treated properly, it will give rise to soil pollution and environmental pollution. To increase the recycling utilization rate of waste cooking oil in the asphalt pavement, the application of waste cooking oil used as asphalt modifier, asphalt regenerant and biological binder is discussed basing on the domestic and abroad research. Articles discussing “waste cooking oil and modified asphalt” or “waste cooking oil and aged asphalt” or “waste cooking oil and asphalt mixture” were searched for in Web of Science and The ordinary performance and rheological properties of binder are analyzed, and the road performance of asphalt mixture is explained. The main factors influencing the performance of modified asphalt and asphalt mixture with waste cooking oil are discussed. The microscopic test, scanning electron microscopy and four fractions separation test are selected to measure the mechanism between waste cooking oil and asphalt binder, and the reaction between waste cooking oil and asphalt binder is illustrated. The existential problem in the current research and application field of waste cooking oil in asphalt pavement is proposed, which will provide reference for the widely application of waste cooking oil in asphalt pavement.The waste cooking oil is added into petroleum asphalt by the shearing process, after which the viscosity, stiffness, elastic recovery performance, temperature sensitivity, rutting resistance and resistance to fatigue cracking of modified asphalt with waste cooking oil are reduced. The above performance of modified asphalt with waste cooking oil is gradually declined with increasing the dosage of waste cooking oil. However, the low-temperature crack resistance, fatigue resistance and self-healing efficiency of modified asphalt with waste cooking oil are improved.Wen et al.  has studSun et al.  has studConsidering the overall performance of the asphalt binder, the dosage of waste cooking oil added into petroleum asphalt is generally lower than 10%. When the dosage of waste cooking oil is too high, the performance of the asphalt binder is damaged. Sun et al. ,26 prepaThe physical property of partial waste cooking oil is listed in 3 at °C; (3) The dosage of impurity in waste cooking oil is low; (4) The moisture content of waste cooking oil should be low; otherwise, the security of asphalt with waste cooking oil cannot be guaranteed.To achieve the obvious improvement effect of waste cooking oil on asphalt binder performance, the waste cooking oil should satisfy the following performance requirements ,21,23,27A mixture of modified asphalt with bio-oil derived from waste cooking oil or bio-asphalt derived from waste cooking oil is prepared, and the construction temperature of asphalt mixture is also decreased due to the reduction in viscosity of the binder . The conEriskin et al.  has founAfter the addition of waste cooking oil into an asphalt mixture, the temperature stability and strength of the asphalt mixture are markedly affected, but the influence of waste cooking oil on the moisture susceptibility of the asphalt mixture is relatively small. The partial performance of the asphalt mixture with waste cooking oil is damaged, and the waste cooking oil is not recommended to be added alone into asphalt mixture. To ensure the maximum performance of the asphalt mixture, the waste cooking oil and other modifiers  are blended into asphalt binder ,34.The function mechanism between waste cooking oil and petroleum asphalt or polymer is measured by a microscopic test. The physical blend between waste cooking oil and base asphalt occurs though a transform infrared spectroscopy test, and the almost no chemical reaction happens. The new absorption peaks appear in the modified asphalt with dosages of 4% and 8% waste cooking oil, but the above absorption peak position is corresponding with the infrared spectrum of waste cooking oil, and it shows that no new absorption peak has appeared . The infThe waste cooking oil as a low-viscosity material is used to regenerate aged asphalt, and the low-temperature crack resistance, fatigue performance, adhesion and construction workability of aged asphalt are improved. The ductility of aged asphalt is increased by the addition of waste cooking oil, but the rotational viscosity of rejuvenated asphalt binder with waste cooking oil is decreased.Yan et al.  found thZhao et al. ,52 pointThe construction safety, high-temperature stability and anti-aging property of aged asphalt are reduced by the addition of waste cooking oil. The performance of rejuvenated asphalt binder is closely related to the type of aged asphalt and waste cooking oil, aging degree of binder and waste oil. The influence of waste cooking oil on the performance of aged asphalt is summarized in The waste edible vegetable oil is added into different asphalt, AH-70# asphalt and AH-50# asphalt after spending time in a pressurized aging vessel, after which the increase in penetration for aged AH-70# asphalt, aged SBS-modified asphalt and aged AH-50# asphalt is gradually decreased. In addition, the influence of waste edible vegetable oil on the thermo-physical properties of the above aged asphalt is evidently different . Zheng  found thThe dosage of waste cooking oil in rejuvenated asphalt does not adhere to the concept: “the more the better”. The high-temperature performance and shear rheologic property of rejuvenated asphalt with an appropriate dosage of waste cooking oil can be equal to base asphalt, but the conclusion is not uniform whether the viscosity and low-temperature performance of the above rejuvenated asphalt can be recovered to the base asphalt level. There is a difference in the optimum dosage of waste cooking oil in aged asphalt determined by the conventional performance indexes or rheological property indexes, as listed in The low-temperature crack resistance of the aged asphalt mixture is improved with the increasing of waste cooking oil content. The maximum bending strain of the aged asphalt mixture with waste cooking oil contents of 0, 4%, 8% and 12% is 2633.32 µε, 2879.25 µε, 3087.44 µε and 3246.13µε . Yan et With the increasing dosage of waste cooking oil, the void ratio, Marshall stability, flow value, indirect tensile strength and fatigue life of a rejuvenated asphalt mixture with waste cooking oil are reduced. The permanent deformation resistance, freeze–thaw splitting strength ratio and residual stability of the above asphalt mixture are first increased and then decreased, and the moisture susceptibility of the above asphalt mixture is evidently improved ,74,77,78When the performance of a rejuvenated asphalt mixture with waste oil can meet specification requirements, the dosage of waste cooking oil in rejuvenated asphalt mixture is generally lower than that of waste engine oil. The density, Marshall stability, flow value, indirect tensile strength and freeze–thaw splitting strength ratio of a rejuvenated asphalt mixture with waste cooking oil are better than those with waste engine oil ,78. Howe3 at 15 °C, which can obtain better compatibility between aged asphalt and waste cooking oil; (3) Good aging resistance, heat stability and weather resistance; (4) Clean without impurities, and the impurities should be removed.The aged asphalt performance is closely related to the physical properties of waste cooking oil. To achieve good performance of rejuvenated-asphalt binder and mixture with waste cooking oil, the waste cooking oil used as rejuvenating agent should satisfy the following technical requirements ,62,64,65There is no chemical reaction between waste cooking oil and aged asphalt. The high polar sulfoxide group of aged asphalt is diluted by the addition of waste cooking oil, and the dosage of macromolecules and small molecules in aged asphalt are reduced, which helps to improve the dispersion of molecular weight for aged asphalt ,64,65,68−1 and 1030 cm−1 is different from that of the rejuvenated asphalt with waste cooking oil. This shows that the intensity of the above functional groups of rejuvenated asphalt with waste cooking oil is decreased markedly [The functional group of aged asphalt has a high similarity with rejuvenated asphalt with waste cooking oil though the infrared spectroscopy test, but the intensity of functional groups for aged asphalt at about 1600 cmmarkedly ,64,68, amarkedly , which iIn this paper, the waste cooking oil can be used as a modifier and regenerating agent applied in asphalt binder. The influence of waste cooking oil on asphalt and asphalt mixture performance is discussed, and the influence factor of asphalt with waste cooking oil is also analyzed. The performance of asphalt with waste cooking oil is related to the asphalt type, content and physical property of waste cooking oil. The low-temperature crack resistance, fatigue resistance, workability and self-healing efficiency of asphalt with waste cooking oil are improved, but the high-temperature performance of asphalt with waste cooking oil is reduced. The performance changes of asphalt mixture with waste cooking oil are similar to those of asphalt with waste cooking oil. Methods for improving the performance of asphalt and asphalt mixture with waste cooking oil are suggested as areas of further study, which can increase the applied range of asphalt with waste cooking oil.The regeneration efficiency of waste cooking oil used in aged asphalt is good. The performance of rejuvenated asphalt with waste cooking oil is nearly comparable to that of petroleum-based rejuvenator. The consumption of petroleum-based rejuvenator is reduced, which can accord with sustainable development. More waste cooking oil is encouraged to be collected and used to recover the performance of aged asphalt. Upon consideration of the influence of waste cooking oil on rejuvenated asphalt and asphalt mixture performance, the waste cooking oil should satisfy the technical requirements, such as viscosity, density and cleanliness.The method of distinguishing quality for waste cooking oil is proposed. After the waste cooking oil is collected, the waste cooking oil is distilled to remove moisture. The physical indicators of treated waste cooking oil are tested, and it is blended with virgin asphalt or aged asphalt according to the same preparation process. Based on the basic performance and compatibility of asphalt with waste cooking oil, such as the low-temperature performance, viscosity, adhesion and high-temperature performance, the waste cooking oil can be classified into different levels.The application feasibility of WCO into asphalt and asphalt mixture was analyzed in the above study, and the influence of WCO on the performance of asphalt and asphalt mixture was discussed, which was conducive to reveal the mechanism of WCO and asphalt binder. The following aspects will need to be further researched.The type and quality of WCO are not mentioned in the above study. Soybean oil, peanut oil and rapeseed oil are usually eaten, but the type and aging degree of WCO from the above oils are not explicitly discussed. This is may be the important reason for the performance differences of different rejuvenated asphalt and blends composed by WCO and binder, and the standardized application of WCO into asphalt and asphalt mixture will not be realized. Therefore, the influence of type and quality of WCO on asphalt and asphalt mixture performance will be studied; the performance difference of selected WCO is analyzed, and the quantitative quality control parameters of WCO will be proposed.The research on asphalt and asphalt mixture with WCO is still in a laboratorial testing stage at present, and the asphalt and asphalt mixture with WCO have not been applied in road projects. The influence of WCO on asphalt and asphalt mixture performance has not been uniform, and the modified asphalt with WCO or WCO rejuvenated asphalt binder performance may not work under the coupling effects of natural environment and vehicle load. Therefore, the improvement of composite technology on modified asphalt with WCO or WCO rejuvenated asphalt binder performance will be suggested to be conducted, which will improve the overall performance of the above asphalt, and the economy of different technologies will be also considered. Ultimately, the WCO will be realized with resourceful utilization into asphalt pavement.The low-temperature crack resistance and construction workability of modified asphalt with waste cooking oil are improved. However, the stiffness, elasticity recovery, temperature sensitivity, rutting resistance and resistance to fatigue cracking of modified asphalt with waste cooking oil are reduced. The type of base asphalt, dosage and quality of waste cooking oil have a significant influence on the modified asphalt performance. The dosage of waste cooking oil added into petroleum asphalt is generally lower than 10%. The compatibility between base asphalt and different polymer is improved by the addition of waste cooking oil, the storage stability of polymer-modified asphalt with waste cooking oil is enhanced, and the light components of polymer-modified asphalt are increased.The construction temperature, optimum asphalt content, indirect tensile strength, dynamic modulus, rut resistance and fatigue resistance of rejuvenated asphalt mixture with waste cooking oil are reduced, but the low-temperature crack resistance of rejuvenated asphalt mixture with waste cooking oil is improved. The construction temperature of waste cooking oil rejuvenated asphalt mixture is reduced by up to 15 °C, and the moisture susceptibility of rejuvenated asphalt mixture is less influenced by waste cooking oil.Performance of the rejuvenated asphalt mixture with waste cooking oil is closely related to the type and dosage of waste cooking oil, aged asphalt type, and aging degree of asphalt and waste cooking oil. However, the dosage of waste cooking oil in aged asphalt is not the more the better, and the optimum content of waste cooking oil is 1.0~15.0%.The high-temperature performance and shear rheologic property of aged asphalt with an appropriate dosage of waste cooking oil are recovered.The waste cooking oil is blended with base asphalt or aged asphalt; there is no chemical reaction between waste cooking oil and asphalt. However, there are differences in the absorption peak intensity of the individual functional group in modified asphalt with waste cooking oil. Meanwhile the structure of rejuvenated asphalt with waste cooking oil is the same as that of the aged asphalt, the asphaltene components of select asphalt are changed, and the content of saturated fraction is increased.


Cytoreductive surgery (CS) is performed to remove the primary tumor in the setting of metastatic disease. In metastatic renal cell carcinoma (mRCC), the role of cytoreductive nephrectomy (CN) in the treatment paradigm has evolved, adjusting to new changes in systemic therapy agents. In particular, immunotherapeutic agents, which utilize the body’s own immune system to attack cancerous cells, have improved over the past decade. Newer immunotherapy agents offer more effective treatments in mRCC, with the goal of more tolerable side effect profiles. However, now urologic and medical oncologists must reframe the role of CN in the context of these new systemic therapies. This review will discuss the current data on this topic as well as the historical context in which it is being studied.The role of CN in the treatment of metastatic renal cell carcinoma (mRCC) has been studied over the course of the past few decades. With the advent of immuno-oncologic (IO) agents, there has been a paradigm shift in the treatment of RCC. Within this new era of cancer care, the role of CN is unclear. There are several studies currently underway that aim to assess the role of CN in combination with these therapies. We reviewed articles examining CN, both historically and in the modern immunotherapy era. While immune-oncologic agents are relatively new and large clinical trials have yet to be completed, data thus far is promising that CN may provide clinical benefit. Multiple ongoing trials may clarify the role of CN in this new era of cancer care. Renal cell carcinoma (RCC) is the sixth most commonly diagnosed cancer in men and ninth in women, accounting for 5% and 3% of all cancers detected in these populations, respectively . Many paUsing Pubmed, Google Scholar, and Wiley Online Library, we performed a review of articles between 2000 and 2022. Search terms included a combination of terms including “cytoreductive nephrectomy”, “immunotherapy”, and “metastatic renal cell carcinoma”. Articles included were original articles published in English. Unpublished works, works not in English, and news articles were not included. Information on clinical trials was collected from clinicaltrials.gov, which was accessed in March 2022. p = 0.05) in the group that received surgery . Wit. Wit9]. Other ongoing studies, including the NORDIC-SUN and PROBE trials, are comparing patients who are receiving immune checkpoint inhibitors alone or in combination compared to patients receiving those medications in addition to cytoreductive surgery . In the The NORDIC SUN trial is evaluating the role of deferred CN in patients who have at least three IMDC high-risk features and are receiving combination nivolumab and ipilimumab . The ratCytoreductive surgery has been well studied and shows clinical benefit in the treatment of many non-genitourinary malignancies. The role of cytoreductive surgery in the setting of metastatic renal cell carcinoma has been studied at length with its role changing as the treatment paradigms shift. Cytoreductive surgery was first shown to be beneficial when used in conjunction with interferon therapy. While we no longer routinely use interferon therapy in the management of metastatic RCC, it proved that there may be a role for surgery in these patients. After the molecular basis of renal cell carcinoma was better understood and the targeted therapy era began, we again learned of the clinical utility of cytoreductive nephrectomy for these patients.The publication of the CARMENA trial and SURTIME trials, for a time, challenged the role of cytoreductive nephrectomies for patients receiving single-agent frontline VEGF inhibition. The limitations of these studies highlight the importance of appropriate patient selection and prospective publications with high levels of evidence in the contemporary treatment era. The SURTIME data did however highlight that the addition of sunitinib did not increase the morbidity of cytoreductive nephrectomies. Shortly after the SURTIME data, the analysis on the Registry for Metastatic Renal Cell Carcinoma registry showed that there was an inverse relationship between case volumes and morbidity, highlighting the importance of doing these highly complex procedures at institutions with experienced surgical teams and the appropriate resources to care for them both in the peri-operative setting as well as the post-operative setting. In terms of patient selection, patients with less IMDC risk factors were more likely to have favorable outcomes and if patients could decrease the amount of IMDC risk factors during treatment then they were more likely to have a favorable outcome. Finally, in the modern era of immune checkpoint inhibitors, the role of cytoreductive surgery remains largely uncertain. A recent NCDB study showed that it likely does have clinical benefit. Currently, there are multiple randomized trials investigating the role of cytoreductive nephrectomies with immune checkpoint inhibition.Within the exciting landscape that is the contemporary era of cancer care, there remain myriad new opportunities for cytoreductive surgical trials with systemic therapies. The question of whether these therapies should be given in the neoadjuvant setting, adjuvant setting, or both is yet to be clearly elucidated in the cytoreductive setting. The optimal combination and safety of these medications in conjunction with cytoreductive surgery is actively being studied, but results have yet to be published. Manipulation of the gut microbiome is also being studied with promising results as a possible mechanism to enhance the efficacy of immune checkpoint inhibitors in mRCC . The rolThe role of cytoreductive nephrectomies has evolved over the past few decades. As we await the results of the Cyto-KIK, NORDIC-SUN, and PROBE trials to help better elucidate the role of CN in the current landscape of immune-oncologic care, the current data indicate that there is a benefit in performing CN in select patients with mRCC.


In human rRNA, at least 104 specific uridine residues are modified to pseudouridine. Many of these pseudouridylation sites are located within functionally important ribosomal domains and can influence ribosomal functional features. Until recently, available methods failed to reliably quantify the level of modification at each specific rRNA site. Therefore, information obtained so far only partially explained the degree of regulation of pseudouridylation in different physiological and pathological conditions. In this focused review, we provide a summary of the methods that are now available for the study of rRNA pseudouridylation, discussing the perspectives that newly developed approaches are offering. Ribosome biogenesis is a highly complex process that requires the accomplishment of different steps. One of these fundamental steps is represented by the modification of ribosomal RNA (rRNA) at specific sites. These modifications are required for the proper maturation and folding of rRNA and impact its stability . It is aAlterations of pseudouridylation in rRNA are also known to play an active role in the development of human disorders such as cancer  and a raDespite its clear role in enabling proper ribosome function and its involvement in human pathology, the mechanism underlying the contribution of rRNA pseudouridylation in the development of human disorders remained underexplored for a long time. This relatively limited knowledge may be considered the consequence of the lack of proper reliable technical approaches. In fact, site-specific quantification of pseudouridine on a wide scale represented a major technical issue for a long time, but recent developments in high throughput sequencing approaches enabled us to obtain increasingly precise and reliable quantifications on a transcriptomic scale.This review aims to give an updated perspective of the available technical approaches that can be employed to fully characterize the role of altered rRNA pseudouridylation in the development of different human pathologies.Until recently, the study of pseudouridylation was hampered by biological and technical issues, because the isomeric form of pseudouridine possesses no distinguishable features nor mass changes. This limited the availability of methods for site-specific detection of pseudouridine, required a previous knowledge of the specific position of the pseudouridine in the sequence analyzed, and was suitable only for highly represented transcripts.Over the last few years, different approaches were developed for the quantitative and site-specific identification of the pseudouridine landscape in cellular models and tissue samples. They may be low throughput, for the identification or validation of specific pseudouridine sites, and high throughput for an overview of all sites of modification in a specific class of RNA or the whole transcriptome.The major features of the techniques reported for the detection of pseudouridines are summarized in in vivo deuterium labeling was successfully applied for direct determination of Ψs in cellular non coding RNA as rRNA and small nuclear RNA (and in such case at subpicomole amounts)  . Since pamounts) . This meamounts) . Using tamounts) . One of amounts) .More recently, using a mass spectrometry-based technology termed SILNAS , all ribosomal modifications of the 80S ribosome from yeast and subsequently from human were mapped . This meThe first discovered and most widely exploited method for the study of pseudouridylation was introduced by the use of the chemical reaction of N-cyclohexyl-N′-β-(4-methylmorpholinium) ethylcarbodiimide p-tosylate (CMC) to pseudouridine, which forms a stable adduct blocking reverse transcriptase and hence producing truncated complementary DNA (cDNA) . This mede novo identification of pseudouridine sites. These approaches combine RNA deep sequencing technologies together with selective chemical derivatization of pseudouridine by CMC. These CMC-based methods, namely Pseudo-Seq  was applied for the study of cellular ncRNAs and mRNAs . The PA-Other sequencing methods have been developed to overcome the many limitations of the CMC-RT approach. The first is based on bisulfite RNA treatment, termed RBS-Seq, which can detect transcriptome-wide at single-base resolution pseudouridine, in addition to m1A and m5C . RegardiThe second CMC-alternative high throughput method relies on RNA cleavage at uridine residues by hydrazine, followed by aniline treatment, and resistance of pseudouridine to chemical treatment . This meAll the described techniques have the great drawback of modifying RNA molecules and using customized protocols to map each specific modification individually. Furthermore, cluster sequencing involves an amplification step, experiencing potential bias and providing only an average picture of modifications in a population of RNA molecules  technology using nano wells  and nanopore sequencing  . The mai16S rRNA  and tRNA16S rRNA  were det samples . Among t samples  NanoPsu  samples  and Peng samples . However samples  for natiFinally, single-particle cryo-electron microscopy (cryo-EM) is a rapidly developing technique, which already depicted the structure of the 80S ribosome, together with rRNA modifications at an average of 3Å resolution . By thisGiven these recent developments, identifying the modifications in the chemical pattern of rRNA may well represent a new path towards formulating a true picture of the functional specialization of ribosomes. As described above, ribosome function and activity can be impacted by the composition in ribosomal proteins and the plasticity in rRNA which encompasses diversity in modifications and interaction with certain factors. Any changes in ribosomal function or activity may affect the regulation of gene expression in both normal and abnormal conditions. Although the exact mechanism through which an altered or oncogenic ribosome may affect tumor progression is not yet fully defined, a correlation between anomalies in ribosome biogenesis or function and cancer has been reported. This has helped in defining the link between alterations in translation apparatus and cancer etiology.As previously stated pseudouridylation is one of the most abundant chemical modifications affecting ribosome function. In general, these modifications can be driven by either stand-alone pseudouridine synthases or snoRNA H/ACA box guided pseudouridylation complexes. Pseudouridine synthases are classified into six families and are known to recognize the substrate and catalyze the conversion of uridine to pseudouridine without using any cofactors.On the other hand, RNA dependent pseudouridylation is carried out by H/ACA box snoRNA. H/ACA box snoRNAs, also known as SNORAs , possesIn numerous studies snoRNAs have also been directly related to cancer initiation and progression. Schulten and others explored the snoRNA expression in patients with breast cancer brain metastasis in comparison to non-metastatic breast cancers. The study revealed that 13 SNORAs were differentially expressed and possibly involved in supporting metastatic progression . Similarin vitro studies conducted on prostate cancer cells (However, despite the growing link of snoRNA with disease prognosis and progression very little is known about the method of action and the pathways adopted by these molecules to carry out the effect. Increased levels of DKC1 and H/ACA snoRNA together with elevated levels of pseudouridine were reported er cells . Anotherer cells . This deer cells .It would be worth mentioning here that the ribosomes can be targeted using drugs with different active molecules . ConsequTo sum up, we can expect that the recent advancement in the techniques that could identify the chemical modifications in rRNA molecules reported here could in perspective take us one step forward in better understanding the role played at the molecular level by altered rRNA pseudouridylation in disease development and sequentially in the development of strategies for better disease management and the development of targeted therapies snoRNA- or ribosome-centered .


Drosophila melanogaster as a model organism has been fundamental to understand the molecular and cellular mechanisms triggered by genotoxic stress. Here, we review the current knowledge regarding the cellular responses to ionizing radiation as the cause of DNA damage with special attention to apoptosis in Drosophila: how these responses are regulated and coordinated in different cellular contexts and in different tissues. The existence of intrinsic mechanisms that might attenuate the apoptotic pathway in response to this sort of DNA damage may well be informative for the differences in the clinical responsiveness of tumor cells after radiation therapy.Cells have evolved mechanisms that allow them to respond to DNA damage to preserve genomic integrity and maintain tissue homeostasis. These responses include the activation of the cell cycle checkpoints and the repair mechanisms or the induction of apoptosis that eventually will eliminate damaged cells. These “life” vs. “death” decisions differ depending on the cell type, stages of development, and the proliferation status of the cell. The apoptotic response after DNA damage is of special interest as defects in its induction could contribute to tumorigenesis or the resistance of cancer cells to therapeutic agents such as radiotherapy. Multiples studies have elucidated the molecular mechanisms that mediate the activation of the DNA damage response pathway (DDR) and specifically the role of p53. However, much less is known about how the different cellular responses such as cell proliferation control and apoptosis are coordinated to maintain tissue homeostasis. Another interesting question is how the differential apoptotic response to DNA damage is regulated in distinct cell types. The use of  Eukaryotic cells employ a diverse array of responses that include cell cycle arrest and DNA repair mechanisms to preserve genomic integrity after DNA damage. However, if the damage is too severe or it cannot be repaired, cells can activate the programed cell death pathway or apoptosis to prevent the transmission of defective DNA material to the daughter cells .In response to DNA damaging agents such as ionizing radiation (IR), cells trigger the DNA damage response (DDR) pathway that consists in an evolutionary conserved set of proteins that function as sensors, transducers and effectors of the genotoxic stress . MutatioDrosophila as a model organism to study the DNA damage pathway has been proven to be very valuable to decipher the cellular and molecular mechanisms that control and coordinate the different DNA damage induced responses such as cell cycle arrest, DNA repair, senescence, apoptosis and radioresistance  is detected by sensors of DNA lesions such as the MRE11–RAD50–NBS1 (MRN) protein complex. These proteins activate the upstream kinases ATM (ataxia-telangiectasia mutated or Telomere fusion in Drosophila (Tefu)), and ATR (ATM- and Rad3-Related or Meiotic-41 in Drosophila (Mei41))  has been identified in Drosophila, which makes its study easier (Drosophila p53 regulates apoptosis but not cell cycle arrest after irradiation (In (Mei41)) . Activat(Mei41)) . While tnduction   have been identified for both rpr and hid genes where p53 directly regulates their transcription   . Deletioadiation . From aladiation .Drosophila apoptosis protein 1 (Diap1). Diap1 functions as an inhibitor of the initiator caspase Dronc, an ortholog of caspase 9, and of the effector caspases Drice and Dcp1. Therefore, Diap1 degradation leads to Dronc activation, which promotes cell death [reviewed in When the levels of expression of the apoptotic factors have reached a threshold, they promote the inhibition of p53 and Chk2 mutant wing discs, IR-induced expression of the proapoptotic genes and cell death is still observed, although at lower levels and later time points when compared to the wild type controls , a JNK target gene that encodes for a phosphatase that acts in a negative feedback loop to limit JNK signaling. Downregulation of the JNK pathway by overexpressing puc, significantly reduces IR-induced cell death (rpr and hid (hid in response to ultraviolet (UV) irradiation  ligand identified in Drosophila, do not show a reduction in IR-induced apoptosis in the wing disc  family members Rbf1 and Rbf2  in the dorsal/ventral (D/V) boundary , as the absence of p53 or E2f1/Dp strongly suppressed DNA-damage induced apoptosis, both in the wing and the eye imaginal discs . Althoug and hid , only p5 and hid . While iosophila .Dp mutants, a condition that abolishes all E2f1 and E2f2 function, the apoptotic pathway must be blocked downstream of the expression of the proapoptotic genes rpr and hid, as both genes are strongly upregulated after irradiation, even though apoptosis is no detected  experiments have shown a direct regulation of mitochondria-associated genes by the E2f/Dp transcriptional factors   . As E2f1post-IR) . The oth mutants . These re of p53 . The reg2f sites . In the ll death . This rell death . It is pll death .puc, was observed in p53 mutant discs at later time points, suggesting that the JNK pathway is also active in a p53-independent manner , which contains the ansition  . As the JNK pathway is an important apoptotic trigger, it has been proposed that this cell cycle arrest protects cells from JNK-induced cell death while inducing proliferative signals to the surrounding tissue during wound healing . A similIn response to DNA damage, mammalian cells could also enter in a permanent cell cycle arrest known as senescence where the activation of p53 and the Cdk inhibitor p21 play prominent roles . RemarkaDrosophila tissues such as the salivary gland, the fat body, or the follicle cells and germ cells from the germarium enter a modified cell cycle known as the endocycle. During this process, G and S phases alternate without entering mitosis through the downregulation of Cdk1 activity  binding protein Fizzy-related (Fzr/Cdh1) . The APC mitosis . Therefo, fat body) are composed mainly for polyploid cells that undergo endocycles that, as we have described above, is a process that blocks the activation of the apoptotic pathway. However, cells that are actively proliferating and that form part of organs, such as the gut and the brain have been reported to be radioresistant. One important feature of these structures is that both contain stem cells. To maintain genomic stability after DNA damage and to avoid the transmission of mutations into progenitor cells, stem cells also activate a coordinate response, as we have described in wing discs . These cells are located at the anterior end of the germarium, adjacent to the niche cap cells (CpCs). The GSC divides asymmetrically generating a GSC and a transit-amplifying (TA) daughter cystoblast (CB). Cystoblasts divide four times with incomplete cytokinesis, forming cysts of 16 interconnected germline progenitors. In each cyst, only one cell will form the oocyte and will initiate meiosis, while the other 15 will enter the endocycle and will differentiate as polyploid nurse cells . The gerDrosophila male, the stem cell niche is located at the blind apical end of the testis. Post-mitotic somatic hub cells comprise a key component of this niche, supporting 10 to 12 GSCs  is highly expressed in GSCs and its function is required for maintenance of these cells  was identified as a cell survival factor in a screen searching for essential genes in stem cell self-renewal . As an E3 ligase that ubiquitinates proteins, Pie targets Foxo for degradation. Studies in larval eye discs showed that DNA damage-induced apoptosis in response to UV irradiation is mediated by JNK/Foxo signalling, in which Foxo and Kay/Fos transcriptionally activate the proapoptotic gene hid (pie induces high levels of Foxo that in turn increases the expression of hid triggering apoptosis of differentiating cells (pie (ban plays repressing hid in GSCs (see above). Importantly, in foxo mutants IR exposure causes a strong reduction in the number of GSCs, suggesting that the correct Foxo levels are critical for stem cell survival , enterocytes (ECs), and enteroendocrine (EE) cells  cells . The flyE) cells . Drosophrom ISCs . In resprom ISCs . The levrom ISCs . After econtrols . Surprisem cells . The fraem cells . Althougpie is specifically required for ISCs maintenance by Foxo control of cell division, but not through apoptotic cell death  was identified as one of the possible genes associated with changes in intestinal permeability upon radiation  for radiation-induced intestinal permeability in adiation . The funneration .Drosophila larval brain contains neural stem cells called neuroblasts (NBs). These cells are specified during the embryogenesis and divide asymmetrically to produce differentiated neurons and glial cells. Considering the lineage of brain NBs, it is possible to distinguish two different types: the NBs with a type I lineage, and neuroblasts with type II lineage. The NBs type I, that are the most abundant in the central brain (approximately 180 NBs), undergo stem cell-like asymmetric divisions, to self-renew and to generate two smaller daughter cells known as ganglion mother cells (GMCs). These cells divide only once to give rise to two post-mitotic neurons and/or glial cells. The NB type II are much less abundant (18 NBs), and divide asymmetrically to self-renew and generate intermediate neural progenitors (INPs). INPs have the capacity of undergoing up to 10 rounds of asymmetric division to self-renew and to generate GMCs and neurons throughout larval development. At the end of the late third instar larvae or early pupal stages, NBs stop proliferating and exit the cell cycle  and Stat92E (the sole STAT gene in Drosophila)  . Depletiand STAT  (Figure and STAT .hid and rpr, which antagonize Diap1 to allow caspase activation (Diap1 and hid are not different between the pouch and the frown in irradiated and non-irradiated discs, rpr expression shows a clear difference. While rpr expression, visualized by the activity of an 11-kb fragment upstream of the transcription start, is low in the frown in non-irradiated discs, it increases throughout the discs after irradiation, excepting in the frown (rpr in the frown, an effect, that is, consistent with the function of Wg blocking IR-induced apoptosis in this region (rpr expression, implying that the function of STAT preventing IR-induced apoptosis is likely through another target besides rpr (Diap1 by the transcriptional effector Stat92E (IR-induced apoptosis depends on the transcriptional activation of the proapoptotic genes, specifically of tivation  (Figure tivation . While the frown . This obs region . Howeverides rpr . This co Stat92E . The funInterestingly, it has been proposed that upon damage or IR-induced apoptosis, cells in the wing hinge acquire stem cell-like properties, such as the ability to change cell fate, and to translocate to another region of the disc .The transcription factor Zfh2 is an effector in the JAK/STAT pathway, and plays a key role in the induction of stem cell-like behaviour of the cells of the frown . During hid expression increases throughout the disc, whereas the expression of rpr is induced in the notum and the pouch, but not in the cells of the hinge, where it is repressed by Wg signalling. The co-expression of hid and rpr in the cells of the notum and the pouch results in increased apoptosis, while the expression of hid alone in the hinge cells is insufficient for activating caspase to induce apoptosis, but sufficient for promoting fate change and translocation. The activity in the frown of Zfh2 and STAT/Wg would maintain low level of effector caspase activity after irradiation in these cells, thereby allowing them to acquire new fate and relocate (The induction of the regenerative behavior of the cells of the frown in response to damage is mediated by caspase activity . Considerelocate .The existence of a subpopulation of epithelial cells that are intrinsically resistance to apoptosis has been linked to the regenerative ability shown by the wing discs . The apoDrosophila is a powerful model system for analyzing the mechanisms that control cell behavior in the context of the complex interactions that take place between the different cell types that constitute an organism. Importantly, the basic signalling pathways and their regulation are highly conserved between flies and humans. Here we have revised the current state of knowledge of the mechanisms that modulate and coordinate the DNA damage responses in different cellular contexts in Drosophila. The different studies carried out in this organism have shown that the sensibility to IR-induced apoptosis depends on the proliferation state of the cells. They also have provided new insights about the intrinsic mechanisms that attenuate the apoptotic pathway in response to DNA damage in different stem cells. This effect seems to be through joint efforts from multiple signalling pathways.Much is known about the activity of the components of the DDR pathway controlling the different cellular responses after DNA damage. However, how these responses are regulated in different cellular contexts is less explored. The mechanisms that control cell proliferation and apoptosis in response to genotoxic stress must be tightly coordinated to maintain genomic integrity and tissue homeostasis. The existence of in-built mechanisms that might attenuate or block DNA-damage induced apoptosis in different cell types and cell proliferation states may well be informative for the clinical responsiveness of tumor cells to radiation-therapy. The lack of knowledge about this issue, therefore represents a very substantial gap in our understanding of the underlying cellular mechanism implicated in radioresistance of tumor cells. The specific response triggered by IR exposition largely depends on the developmental context, the cell type and the proliferation status of the cell. The action of different signalling pathways in each cellular context can modulate the activity of the DDR pathway, which can lead to different outcomes. Therefore, it is not only important to characterize which members of the DDR pathway function in different cellular contexts and how they are coordinated, but also which signals can regulate its response. This is key to identify the mechanisms that modulate the sensibility to IR-induced apoptosis in distinct cellular contexts and therefore for understanding the underlying mechanism implicated in radioresistance of tumor cells.High-throughput sequencing techniques have revealed that each tumor type typically exhibits distinct constellations of genetic alterations that can affect signalling pathway activity related with different aspects of cancer behavior. An important challenge is to associate these genetic changes with the specific features show by different tumor cells.Drosophila provides a powerful in vivo model system for analyzing the signalling network that might be modulating the DDR in different cellular contexts and therefore the specific responses triggered by this pathway in each scenario. The knowledge generated in Drosophila can be used to gain new insight into the mechanisms that might be involved in modulating the DNA damage responses in different cellular contexts. These data can contribute to characterize the functional relationship between the genetic alteration exhibited by different tumor types, which have been defined through high-throughput technology, and the underlying cellular mechanisms implicated in radioresistance of tumor cells. The combination of multidisciplinary approaches might ultimately facilitate the development of personalized medicine.