Objective: At the tissue level, disruption of the extracellular matrix network leads to irreversible cardiac fibrosis, which contributes to myocardial dysfunction. At the myocyte level, downregulation of beta-adrenoceptors (beta-AR) reduces adaptation to increased workload. The aim of our study was to analyse the correlation between myocardial fibrosis and beta-AR sensitivity in patients with aortic valve (AV) disease. Methods: A total of 92 consecutive patients who underwent elective AV surgery between 2017–2019 were included in our study (51 with aortic regurgitation (AR-group); 41 with aortic stenosis (AS-group) and left ventricular (LV) biopsies were obtained intraoperatively. In vitro force contractility testing was performed by measuring beta-AR sensitivity (−log EC50[ISO]). In parallel, a quantitative analysis of myocardial fibrosis burden was performed. Results: Mean age at the time of AV surgery was not statistically different in both groups . The LV end-diastolic diameter was significantly enlarged in the AR-group when compared to the AS-group . Analysis of beta-AR sensitivity  and myocardial fibrosis  showed no significant differences between patients with AS and AR. There was no correlation between myocardial fibrosis and beta-AR sensitivity in the whole study cohort  or in the AS-subgroup . However, significant correlation of fibrosis and beta-AR sensitivity was seen in AR-patients . Conclusion: More severe myocardial fibrosis was associated with reduced beta-AR sensitivity in patients presenting with AR but not with AS. Therefore, our results suggest that in patients with AR, cellular myocardial dysfunction is present and correlates with the extent of myocardial fibrosis in the myocardium. Aortic valve (AV) surgery is the treatment of choice in symptomatic patients with severe aortic valve stenosis (AS)/aortic valve regurgitation (AR), and in asymptomatic patients with impaired left ventricular function or enlarged left ventricular end-systolic diameter . Severe However, the reasons of postoperative LV deterioration are still unknown. Our study group was able to show that in the asymptomatic stage of AV disease with simultaneously enlarged LVEDD, a significant cellular myocardial dysfunction, measured by in vitro contractility, is already present . A decreTherefore, the aim of our study was to analyse whether a correlation between myocardial fibrosis and in vitro beta-AR sensitivity in patients with aortic valve disease may exist.The investigation conforms to the principles outlined in the Declaration of Helsinki and patients were included after written informed consent. Our local ethics committee of the “Ärztekammer Hamburg” approved the study protocol in 21 February 2016 (No. PV3759).The study group consists of previously described patient group which underwent elective AV surgery at our institution between February 2017 and November 2019 , which is the concentration of ISO required to reach 50% maximal ISO-induced increase in force. As a measure of maximum effect size of beta-AR mediated inotropy, we calculated the fraction of maximum inotropic response induced by 30 mmol ISO compared to the inotropic response in the presence of high calcium (8 mM), expressed as FISO/Ca (%)  and on FISO/Ca. Double-sided p-values smaller than 0.05 were considered statistically significant. All statistical analyses were accomplished with the IBM SPSS 23 software .Continuous variables are presented as mean ± standard deviation; categorical variables are expressed as absolute and relative frequencies. A univariate linear regressions model was used to analyse the impact of fibrosis on logECp = 0.116). AR-patients were more frequently male , had a significant larger LV end-diastolic diameter  and a significant lower LV ejection fraction . Congenital AV disease  was present in 54.9% of the AR patients compared to 48.8% of the AS patients (p = 0.559). Body mass index was significantly lower in the AR-group (p = 0.022). Further cardiovascular risk factors and comorbidities did not differ between both groups . NYHA class II or more was present 49% of the AR patients and in 75% of the AS patients (p = 0.002). More patients with AR received Betablocker compared to AS (45% vs. 29% p = 0.169) and ACE-inhibitors , yet both not with statistical difference) Patient characteristics are outlined in p = 0.284). In the whole study group, there was no significant correlation between myocardial fibrosis and age , LV ejection fraction , as well as all other clinical parameters. In the AR-group, significant correlations were identified between myocardial fibrosis and hyperlipidemia  and arterial hypertension , whereas in the AS-group, no significant correlation was seen .The mean incidence of myocardial fibrosis in the whole study group was 9.9% (range: 0.3–52.0%) without a statistical difference between aortic stenosis and regurgitation   showed no significant differences between patients with aortic stenosis and regurgitation (50[ISO]) in the whole study cohort   C.ISO/Ca was significantly higher in AR patients . No correlation of myocardial fibrosis with FISO/Ca was seen in the whole study group , or in the AS-  or AR-subgroups .Maximum inotropic response measured by FOur work demonstrated that in human myocardial tissue of patients with severe aortic valve disease, myocardial fibrosis is present but without a significant difference in AR and AS. However, a significant correlation of fibrosis and in vitro beta-AR sensitivity was seen in patients with AR.Overall, severe aortic valve disease results in morphological changes of the left ventricle  which often do not correlate with the clinical presentation of the patients ,7,8. DurMyocardial fibrosis in AS has been studied extensively. Azevedo was able to show an association between a high degree of fibrosis with an increased mortality risk after AV surgery in AS patients . Most reIn chronic AR, only limited data regarding myocardial fibrosis and contractility is available. A small group of patients (n = 28) with chronic AR showed a smaller percentage of myocardial fibrosis (3.5%) compared to our studied AR patients (8.9%). Furthermore, no correlation between fibrosis and left ventricular function measured by echocardiography was detected by Elias et al. . However2 BSA) [2 [The identification of in vitro myocardial dysfunction in mostly asymptomatic patients in our, and previous, studies  highligh2 BSA) . In case BSA) [2 . Such fiOur study analysed only cellular and tissue-related changes in patients with AV disease. This approach enables us only to describe the in vitro changes in valvular cardiomyopathy. However, pathological signal cascades have not been studied by our in vitro approach and future studies  might help to link the ventricular remodelling to a pathological cascade on the cellular level. Moreover, the results of our analysis might be biased by a potential sampling error. Some segments of the LV might have more pronounced remodelling than others. However, many other studies also primarily work with ventricular samples only obtained from one location of the myocardium. In addition, a follow-up of the study group has not been performed so that the clinical impact of our in vitro findings is not verified so far. However, the main goal of our study was to identify differences of in vitro contractility and fibrosis in patients with aortic valve disease and a follow-up study is planned in the future.Myocardial fibrosis exists in patients with aortic valve disease. In patients with aortic regurgitation especially, cellular myocardial dysfunction is present and correlates with the extent of fibrosis in the myocardium. Our findings could help to provide an additional decision-making aid in the timing of the surgery before reduced cardiac function persists.


Virtual reality (VR) and augmented reality (AR) have evolved since their introduction to medicine in the 1990s. More powerful software, the miniaturization of hardware, and greater accessibility and affordability enabled novel applications of such virtual tools in surgical practice. This scoping review aims to conduct a comprehensive analysis of the literature by including all articles between 2018 and 2021 pertaining to VR and AR and their use by plastic and craniofacial surgeons in a clinician-as-user, patient-specific manner. From the initial 1637 articles, 10 were eligible for final review. These discussed a variety of clinical applications: perforator flaps reconstruction, mastectomy reconstruction, lymphovenous anastomosis, metopic craniosynostosis, dermal filler injection, auricular reconstruction, facial vascularized composite allotransplantation, and facial artery mapping. More than half (60%) involved VR/AR use intraoperatively with the remainder (40%) examining preoperative use. The hardware used predominantly comprised HoloLens (40%) and smartphones (40%). In total, 9/10 Studies utilized an AR platform. This review found consensus that VR/AR in plastic and craniomaxillofacial surgery has been used to enhance surgeons’ knowledge of patient-specific anatomy and potentially facilitated decreased intraoperative time via preoperative planning. However, further outcome-focused research is required to better establish the usability of this technology in everyday practice. Recent advances in imaging technology have greatly benefitted the field of medicine by allowing a better 3D visualization of anatomy in settings such as medical education and surgical planning. In particular, virtual reality (VR) and augmented reality (AR) have been applied to the medical field since the 1990s, although their adoption was limited by the quality of experience ,3,4. TheEarly VR technology was hindered by the issue of latency—that is, the delay between when the user moves their head and when the virtual image is adjusted—provoking vestibulocochlear vertigo in the user. It was not until a series of technological developments in the early 2010s—many driven by the parallel development of smartphones—that AR/VR technology became more widespread. Amongst these improvements were the refinement of the “positional tracking” of a user’s eyes to direct camera orientation, the enhancement of high-definition screen capabilities, and rotational tracking maturation via magnetic and computer-based methods ,9,10,11.Novel VR and AR platforms have proven to be a boon in the medical field, particularly where anatomic visualization is desired, but fully accomplishing anatomic visualization in the operating room is difficult. Studies on the use of VR/AR in surgery have identified several potential benefits: intuitive viewing of patient-specific anatomy, estimation of outcomes via pre-surgical planning, reduced intraoperative time, and decreased complications when VR/AR is used for intraoperative navigation ,5. OtherExisting reviews have broadly surveyed the use of VR/AR in the field of medicine, including in the domains of surgical training, education, planning, and navigation ,22. To dInnovations in VR and AR software and hardware have broadened accessibility to these platforms and made them more widespread than ever. In addition to novel medical applications that have begun to utilize mainstream devices such as the HoloLens and software platforms based on major software templates, powerful new smartphones have arisen as a growing platform for AR both within and outside of the clinical setting ,28,29,30The intersection of these technological advances, commercial accessibility, investment capital, and the ability to integrate into current practices in the mid-2010s have made understanding the present scope of VR and AR more important than ever. The field of plastic and craniomaxillofacial surgery is well positioned to explore these benefits since the use of three-dimensional imaging and patient-specific planning to create customized cutting guides, and prosthetics is a well established adjunct to a variety of procedures. We therefore aimed to conduct a scoping review of the use of VR and AR in the specific contexts of preoperative surgical planning and intraoperative navigation in order to elucidate their impact on patient care and individualized surgical procedures.The literature search and writing of this scoping review were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. This is a scoping review, a relatively novel study design alternative to systematic reviews in clinical research. As Munn et al. 2018 described, a scoping review is used to “identify knowledge gaps, scope of a body of literature, clarify concepts or to investigate research conduct ”.Publications were included if they were (1) within the scope of plastic and craniomaxillofacial surgery, (2) published between 2015 and 2022, (3) written in English, (4) used AR or VR for a patient-specific application, involved human participants, and the “user” of the technology was the clinician performing or rehearsing the procedure .Exclusion criteria were (1) VR or AR utilization for medical education, training, or performance assessment; (2) non-English, non-full-text articles published before 2015; (3) articles out of scope of plastic and craniomaxillofacial surgery; (4) integrated AR-robot assisted applications ; (5) “patient-as-user” applications ; and (6) studies that generally did not implement AR/VR for a patient-specific purpose.A literature search was conducted on August 6 2021 by MG and repeated and updated on November 2 2022 by NK utilizing the PubMed, Embase, and Ovid Medline databases. The following keywords and associated Boolean operators were used:  AND  AND .Search results were uploaded to Covidence  and assessed by two independent authors  in a two-step process according to a priori screening standards as described in the eligibility criteria. Articles were first screened by title and abstract; if it was unclear whether the study should be included based on the title and abstract alone, the entire article was assessed. After an initial assessment, the eligible full-text articles were read by two independent authors. If the two authors disagreed about inclusion or exclusion, a third author read the article and ruled for a consensus.A data collection form within Covidence  was jointly developed by two reviewers  to determine which variables to extract. The two reviewers independently charted the data, discussed the results, and continuously updated the form.Data were extracted on demographics , specific aims and conclusions, technology characteristics , and software), surgical procedure, the timing of implementation, study design, and participant characteristics.The literature search identified 1637 studies, with 1029 citations remaining after duplicates were removed. Based on the titles and abstracts, 823 were excluded. In total, 196 of the remaining 206 full-text articles were excluded for the following reasons: 103 were not in the field of plastic surgery, 54 were either non-English or not full-text articles , 22 focused on robot-assisted surgery, 9 focused on medical training or education, 6 were not patient-specific, 1 was related to patient education, and 1 was a review article. The remaining 10 articles were considered eligible for this review. See The 10 included articles were distributed between 2018 and 2022. In total, one of these was published in 2018, two were published in 2019, three were published in 2020 and 2021, respectively, and one was published in 2022. All included studies described a workflow for the implementation of a distinct AR or VR platform in the context of a given surgical procedure in a clinician-as-user, patient-specific manner. Three studies elaborated on their workflow description by examining the application and/or outcomes in a case report. The actual implementation of VR/AR was split between preoperative and intraoperative use. In total, 6/10 of these used AR/VR intraoperatively, and the remaining used AR/VR preoperatively.VR and AR were used in the context of the following procedures: perforator flaps reconstruction, mastectomy reconstruction, lymphovenous anastomosis, metopic craniosynostosis, dermal filler injection, auricular reconstruction, facial vascularized composite allotransplantation, and facial artery mapping. Of these, AR was studied in the context of deep inferior epigastric perforator (DIEP) in two studies and metopic craniosynostosis repair in two more. Both DIEP papers involved the intraoperative use of AR, whereas metopic craniosynostosis articles were split between preoperative and intraoperative use. Of note, the investigation of AR use in facial artery mapping had a secondary aim of proving its capacity to be used in dermal filler injections; as a result, this review considers dermal filler injections as the relevant clinical context in Waked et al. for inclusion in this scoping review.In total, 4/10 studies involved Microsoft HoloLens, and another 4 used smartphones as the platform for the VR and AR applications. Smartphone-based applications used varying brands: Android only , iOS onlIn total, 3/10 studies did not report the software used for their VR or AR applications. For those that reported the software type, 6/10 used some version of the Unity Gaming platform  as a basis for their custom-built software. The remaining study used Medicalholodeck , a software for visualizing and manipulating 3D CT data in the form of DICOM files.Three-dimensional modeling has become the cornerstone for preoperative planning and the production of intraoperative surgical aids. Presurgical planning in particular has become an important tool for planning and executing intricate procedures within the scope of plastic and craniomaxillofacial surgery . Such moA variety of methodologies were implemented among the included studies, with an overarching pattern of the use of a VR or AR platform in a case or series of cases. Regardless of the procedure of use and time of implementation, 3D imaging was initially conducted for transference to AR/VR platforms. The only exception to this was Amini et al., who did not need to visualize participant anatomy as they instead projected the 3D presence of a breast implant for mastectomy reconstruction patients . The majPerhaps most importantly, VR/AR was noted as a tool to potentially improve surgical outcomes. VR and AR may facilitate different perspectives of patient anatomy while planning and operating. Patient-specific modeling can optimize intraoperative actions. For example, in the context of LVA, AR facilitated preoperative planning and thereby minimized iatrogenic damage and scarring . PreoperIntraoperative AR-guided procedures were also determined to be accurate by subsequent Doppler ultrasound comparisons . SimilarSterility was not seen as an issue during the intraoperative implementation of AR. Head-mounted devices function independently of computers and are self-contained—utilizing vocal inputs and hand gestures registered by sensors for interaction with holograms ,15,27. MUnfortunately, there is a scarcity of accurate data in the literature. While some studies have carried out preliminary accuracy analysis by comparing frontal and lateral cephalograms prior to and after surgery, they acknowledge the need for more complete accuracy analysis using tools such as 3D CT scans . As AR aThe technology behind VR and AR implementation is itself flexible, as evidenced by the wide variety of hardware interfaces employed by the studies described here. These varied implementations allow the technology to be effectively used both preoperatively and intraoperatively as the need arises. A benefit of the aforementioned flexibility has been demonstrated by the use of VR and AR in multiple other surgical specialties. One AR system as early as 1997 utilized a mirror at an angle to create a parallax view with overlaid patient CT data, assisting neurosurgeons in removing glioblastomas . AR has also been implemented in general surgery since as early as 2004, when a 3D rendering of an adrenal adenoma and surrounding abdominal organs was overlaid on the laparoscopic camera screen during adrenalectomy . The useBeyond clinical use, VR has been extensively studied in its role as a surgical training tool in multiple fields ,51,52,53Notable, in line with the results of this scoping review is the relative scarcity of validation data for VR and AR alike: Multiple systematic reviews spanning specialties such as ophthalmology, neurosurgery, and orthopedics found absent or weak quantitative evidence for the implementation of such devices into practice . One recBeyond the direct impact of assisting a surgeon in conducting an optimized procedure, patient-specific anatomic modeling via AR was observed to have more mixed impacts on operative time and costs. For example, one novel application of AR for orthognathic surgery extended operative times by one hour due to issues with registering the hologram to the patient and handling the device . HoweverSimilarly to mixed findings on the impact of VR and AR on time, different findings on the impact of the technology on cost were present. When considering the use of MRA to minimize risks in dermal filler injection, for example, a cost of approximately EUR 250 for an MRA in Western Europe was attributed to the methodology . Yet, MeOverall, further quantification of the savings enabled by implementing these technologies is needed. The majority of the articles included in this review primarily focused on the development and implementation of novel workflows using these technologies. As a result, they did not comprehensively delineate nor compare the effect of their platform on surgical costs and timing. There is a need for further evaluation of these variables.One limitation of this scoping review is the constrained timeline from Jan 1 2015 onwards. The innovations in both hardware and software, which occurred in late 2015 and 2016, were the impetus for selecting the search’s start date; however, this could have limited final results via the involuntary exclusion of any relevant studies published before 2015 . There iSeveral limitations were noted throughout our search of the literature on VR/AR use in plastic and craniomaxillofacial surgery. There is a learning curve with respect to adopting the technology: Physician users expressed a need for training prior to AR use in metopic craniosynostosis repair . SimilarThere is also a dearth of readily available software for VR/AR use in plastic surgery. Many included studies had to develop in-house applications albeit based on existing software platforms. This may not be feasible for everyone attempting to implement these technologies into practice. Furthermore, software, depending on availability and technological capability, can be expensive and potentially increase operating costs. Although they were noted to be less expensive than some 3D printers, the development of a custom software platform by Cho et al. still costed approximately USD 16,500 and took 2 months to complete . These cThe accuracy of hologram registration to patients was potentially decreased in low-light conditions, although the lighting was observed to be largely homogenous and a non-issue in the OR . SeveralA common limitation of many of the studies included in this review is a lack of quantitative comparative analysis between VR/AR methods and gold standard techniques and a lack of prospective controlled studies. Given this lack of quantitative data, we were unable to complete a systematic review or meta-analysis and instead structured this as a scoping review. This is primarily a result of the included studies presenting “proof of concept” workflows of their respective VR/AR platform. Although some of these platforms appear to be closer to widespread use than others, each one identified the need for further innovation and the quantification of their VR/AR tool’s benefits compared to current gold standards. The dearth of information quantifying VR/AR’s outcomes vs. traditional models was a key reason for this review to focus on what information was available and assess the current scope of VR/AR in its role as a clinician-as-user, patient-specific tool in plastic surgery. By determining the current scope of VR and AR in this function, aspiring adopters of similar technology might be better informed on current capacities.The studies included in this review display the current capability of AR and VR technology. These capabilities include allowing unprecedented access to the patients’ own anatomy for the purpose of preoperative or intraoperative planning and execution, synergizing with existing 3D printing and potentially saving time during operations. However, more extensive outcome studies involving larger patient numbers are still required. This scoping review highlights the fact that there are limitations in our current application of these technologies that need to be improved in order for AR and VR to become more widely integrated into craniomaxillofacial surgery practice. Plastic and craniomaxillofacial surgeons have begun to introduce novel solutions that allow these technologies to be implemented in a clinician-as-user, patient-specific manner. The further development of VR and AR technology, coupled with ongoing innovations on the part of surgeons, engineers, and software developers, will determine the role that these tools will play in plastic surgery in the years to come.


Previous systematic review and meta-analysis indicates that rehabilitation within a week of intensive care unit (ICU) admission benefits physical function in critically ill patients. This updated systematic review and meta-analysis aim to clarify effects of initiating rehabilitation within 72 h of ICU admission on long-term physical, cognitive, and mental health. We systematically searched the MEDLINE, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi for randomized controlled trials (RCTs) between April 2019 and November 2022 to add to the previous review. Two investigators independently selected and extracted data. Pooled effect estimates for muscle strength, cognitive function, mental health after discharge, and adverse events were calculated. Evidence certainty was assessed via Grading of Recommendations, Assessment, Development, and Evaluations. Eleven RCTs were included in the meta-analysis. Early rehabilitation may improve muscle strength  and cognitive function . Contrastingly, early mobilization showed limited impact on mental health or adverse events. In summary, initiating rehabilitation for critically ill patients within 72 h may improve physical and cognitive function to prevent post-intensive care syndrome without increasing adverse events. The effect on mental function remains uncertain. Post-intensive care syndrome (PICS) is a new or worsening physical, cognitive, or mental health disorder that occurs and persists after hospitalization for a critical illness, leading to a decreased quality of life (QOL) ,2. Its dPrevious systematic review and meta-analysis (SRMA) has demonstrated that initiating rehabilitation within one week of ICU admission among critically ill patients correlates with enhanced Medical Research Council (MRC) scale scores and a reduced incidence of muscle weakness during ICU stays. Essentially, these findings suggest that commencing rehabilitation within the first week of ICU admission primarily impacts the physical function aspect of PICS ,8. HowevRecent reports have shown that physical function improvement can be expected in some patients when rehabilitation is started within 72 h of ICU admission . NeverthTherefore, in this SRMA, we aimed to review randomized controlled trials (RCTs) to examine the effects of rehabilitation initiated within 72 h of ICU admission on the long-term physical, cognitive, and mental functioning of critically ill patients and on the safety of rehabilitation.The patient population under study comprised critically ill patients within the ICU. The intervention being investigated was early rehabilitation, defined as commencing within 72 h of ICU admission. The intervention involved initiating rehabilitation earlier than in the control group. The control group received usual care. The primary outcomes assessed were muscle strength, cognitive function, and adverse events associated with rehabilitation, serving as indicators of physical function in the context of PICS. Secondary outcomes included activities of daily living (ADL), QOL, mental function, and mortality. The study’s settings encompassed both the ICU and the post-discharge period. As a general guideline, parameters concerning muscle strength, cognitive function, mental function, ADL, and QOL were measured approximately 6 months after discharge. However, in cases where values at the 6-month mark were unavailable, measurements taken closest to the 6-month point post-discharge were used.This study is an updated SRMA of the Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock 2020 and a previous systematic review ,10. The We searched the following databases for eligible trials: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE via PubMed, and Igaku Chuo Zasshi. The studies were limited to those published in English or Japanese. We searched for studies conducted between April 2019 and November 2022 because the previous systematic review search was conducted in April 2019  Table S. We alsoTwo independent researchers (AM and HS) performed study selection and exclusion and extracted data using the titles and abstracts. The full text of all selected articles was independently reviewed by the two researchers to determine whether the articles were eligible for final inclusion in the review. Any disagreements between the two reviewers were discussed and resolved; if this failed, a third reviewer (SY) acted as an arbiter.Only RCTs involving critically ill adult (≥18 years) patients admitted to the ICU were included in the study. Interventions were defined as early mobilization initiated within 72 h of ICU admission or earlier than that conducted in the control group . StudiesMuscle strength, cognitive function, and adverse events were assessed as primary outcomes. We used the MRC scores and grip strength as measures of muscle strength, prioritizing the MRC during data extraction if both were measured. We evaluated muscle strength and cognitive function measured 6 months after hospital discharge, or sooner if these factors were not assessed at 6 months. Adverse events included all adverse events identified during each study period. ADL, QOL, mental health, and mortality were secondary outcomes in our study. The Barthel index, a functional independence metric, was used to measure ADL, and the Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36) and EuroQol five-dimension questionnaire (EQ-5D) were used to assess QOL. ADL, QOL, and mental health were measured approximately 6 months after hospital discharge. Finally, mortality was measured 28–30 days after discharge, and hospital mortality was determined if it was not evaluated in the original study.When evaluating the risk of bias, each study was individually assessed for specific outcomes, focusing on aspects such as the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results. An overarching assessment was subsequently derived from these various domains. The Cochrane Risk of Bias 2 (RoB 2) tool  is used A meta-analysis was conducted using Review Manager software version 5.4  in accordance with the “Cochrane Handbook for Systematic Reviews of Interventions”  and the The CoE was established through an evaluation of five domains: risk of bias, non-consistency, non-directness, imprecision, and other considerations. A “high” CoE was assigned when no downgrading or one-step downgrading was applied within each domain, with no points being deducted. A CoE of “moderate” was attributed if there was a one-level downgrade, while a “low“ CoE was given if a two-level downgrade was applicable. Furthermore, a CoE of “very low” was designated if the evidence was downgraded by three levels or more. The two reviewers (AM and HS) evaluated the CoE based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach . Disagre2 statistic to quantify the magnitude of statistical heterogeneity among the included studies. Heterogeneity was defined as follows: I2 = 0–40%, possibly not important; 30–60%, possible moderate heterogeneity; 50–90%, possible substantial heterogeneity; 75–100%, considerable heterogeneity. If heterogeneity was detected (I2 > 50%), we examined its causes using a Cochrane chi-square test (Q-test) performed for the I2 value, with p < 0.10 considered statistically significant. If significant heterogeneity was identified, the median of the estimates was reported instead of the weighted estimates.Heterogeneity was evaluated by visual inspection of forest plots and calculation of the IThe original authors were contacted in cases of missing data. If the missing value remained unknown, we performed an intention-to-treat analysis for all dichotomous data, if possible. For continuous data, we imputed missing data based on the recommendations of the Cochrane handbook. We performed a meta-analysis of the data available in the original studies.The PROSPERO-registered protocol included subgroup analyses for studies involving patients with sepsis or those in which rehabilitation was performed at least five times per week. However, only one study was conducted in patients with sepsis, and the outcomes required for analysis were not measured. Furthermore, subgroup analyses were not conducted because the interventions were performed at least five times per week in all the included studies.The PRISMA flow diagram of the study selection process is shown in Muscle strength. Three RCTs ,22,24 evCognitive function. Two RCTs ,24 invesAdverse events. Five RCTs ,21,23,24Activities of Daily Living. Three RCTs ,22,23 asQuality of Life. Six RCTs ,20,23,24Mental health. One RCT  evaluateMortality. Seven RCTs ,21,23,24We conducted an updated SRMA of 1301 patients in 11 RCTs to investigate the prognostic impact of early rehabilitation in critically ill patients in the ICU. According to the GRADE framework, which is based on point estimates and CoE evaluation, we determined that early rehabilitation of critically ill patients may improve cognitive function. In addition, early mobilization may have ameliorated muscle strength, ADL, and QOL without increasing mortality or adverse events.Early rehabilitation starting less than 72 h after admission may improve physical and cognitive function and prevent PICS. Fuke et al. performed a systematic review on the impact of early rehabilitation, defined as rehabilitation initiated within 1 week of ICU admission, on PICS in critically ill patients . RecentlThe SRMA showed that early rehabilitation can be performed safely without increasing the incidence of adverse events or death. In a previous systematic review, Nydahl et al. reported that early rehabilitation in critically ill patients was not associated with more adverse events . AnotherThe RCT conducted by Hodgson et al. in 2022  was not This review suggests that starting rehabilitation within 72 h prevents PICS and improves ADL and QOL. Previous reports state that early rehabilitation improves mobility and ADL ,30,31, aIn this study, the effect of early rehabilitation on mental functioning remained uncertain. Observational studies investigating the long-term physical and mental functional outcomes of COVID-19 critically ill patients one year post-ICU discharge have indicated an association between PTSD and a reduced QOL . Within This study has several limitations. First, the number of studies included in the SRMA was small, and subgroup analyses could not be performed. Second, the timing of outcome measurements differed among the included studies, ranging from 3–12 months after hospital discharge. Third, rehabilitation in the control group was described as “usual care” or “hospital standard treatment” in each article, with no detailed description of what these treatments entailed. In a previous systematic review, early rehabilitation reportedly did not improve physical function when the control group received high-dose as opposed to low-dose rehabilitation . The intInitiating rehabilitation within 72 h of ICU admission in critically ill patients may improve physical and cognitive function, preventing PICS without increasing the rate of adverse events. The effect of early rehabilitation on mental functioning remains unknown based on the findings of the present study. Further large-scale studies with a low risk of bias are needed to clarify the impact of early rehabilitation on mental health.


Dear Editor,Ideal Plant Architecture 1 (IPA1), an miR156 target gene, encodes SPL14 and it is able to bind directly to the promoters of multiple GA biosynthetic, signal, and deactivating genes in rice [IPA1 loss-of-function mutants exhibit dwarf phenotypes [Reduction in plant height has been associated with yield increases and yield stability in a number of important crop species, such as wheat and rice . In thes in rice . MoreoveAsparagus officinalis L.), known as the ‘king of vegetables’, is one of the top 10 most popular vegetables owing to its unique texture, taste, and high nutritional value. This species is a diecious and perennial plant with a 1C genome size of 1.3 Gb and 2n = 2x = 20 chromosomes [Garden asparagus -associated protein 9 (Cas9) has been successfully applied to induce site-specific double-strand DNA breaks (DSBs) for genome editing in numerous plant species , but it IPA1 from garden asparagus, a maximum likelihood tree was constructed using 17 SPL asparagus proteins and the rice IPA1 protein with MEGA5 software. The phylogenetic tree showed that AsparagusV1 05.1067 was more closely related the rice IPA1 protein than other SPL asparagus proteins, indicating that AsparagusV1 05.1067 is an IPA1 homolog from garden asparagus , and then an A. officinalis promoter was cloned and applied to express sgRNA, leading to the vector pAspU6-SpCas9  and biallelic (11.1%) mutations at the sgRNA3 target site, while seven of the T0 lines showed heterozygous (one out of nine) or chimeric (six out of nine) mutations  or chimeric (seven out of nine) mutations (AspSPL1), was chosen for further experiments and sequencing, which did not reveal any editing events  and Natural Science Foundation of Jiangxi Province (grant 20171ACB20001).Y.Z. and D.W. conceived the project. D.W. and R.H. designed the experiments and wrote the manuscript. J.Z., X.L., and B.Z. performed the experiments. J.Z., R.H., D.W., Y.Z., and G.C. analyzed the results. All authors read and approved the final manuscript.Data generated or analyzed during this study are included in this article and its supplementary information files.The authors declare no conflict of interest.Horticulture Research online.Web_Material_uhad093Click here for additional data file.