During the last decade, leadless pacemakers (LPMs) have turned into a prevalent alternative to traditional transvenous (TV) pacemakers; however, there is no consolidated data on LPM implantation in emergencies.Digital databases were searched for this review and four relevant studies, including 1276 patients were included in this review with procedure duration, fluoroscopic time, major complications, and mortality as primary outcomes and pacing threshold, impedance, sensing of LPM, and hospital stay as secondary outcomes.Gonzales et al. and Marschall et al. showed the duration of the procedure to be 180 ± 45 versus 324.6 ± 92 and 39.9 ± 8.7 versus 54.9 ± 9.8, respectively. Zhang et al. demonstrated the duration of the procedure and fluoroscopy time to be 36 ± 13.4 and 11.1 ± 3.1, respectively. Similarly, Schiavone et al. exhibited intermediate times of implantation at 60 (45–80) versus 50 (40–65) and fluoroscopic times at 6.5 (5–9.7) versus 5.1 (3.1–9). Hospital stay was more with a temp‐perm pacemaker as compared to LPM and pacing parameters were not significantly different in all the studies.For underlying arrhythmias, whenever appropriate, our review shows that LPMs may be a better option than temporary pacemakers, even as an urgent treatment. During the last decade, leadless pacemakers (LPMs) have turned into a prevalent alternative to traditional transvenous pacemakers; however, there are no consolidated data on LPM implantation in emergencies. LPMs are a significant contemporary breakthrough in technology in the field of cardiac pacing, and they are feasible in patients requiring emergency implantation of permanent pacing devices. For underlying arrhythmias, whenever appropriate, our review shows that LPMs may be a better option than temporary pacemakers, even as an urgent treatment. No language restrictions or time filters were placed; the search strategy and extraction of unidentified articles were performed via backward snowballing (references screening of the relevant articles). The following MeSH terms were used: “Leadless pacemaker” OR “Micra pacemaker” AND “Emergency implantation” OR “Urgent implantation”. The two subsets were combined with Boolean operators. The results from all the combinations were downloaded into the Covidence library for qualitative review.All titles and abstracts were reviewed independently by two investigators (M.F. and J.M.) who then extracted the articles that reported outcomes of emergency implantation of LPMs, including randomized registries, controlled trials, observational studies, case reports, and research letters. Finally, the analysis did not consider preprints, abstracts, and unpublished data presented at conferences. All data were validated by the senior author (A.H.); in case of missing data, authors of the original article were contacted. The last search ended on January 25, 2023.2.2The two authors (M.F. and J.M.) extracted the data about LPM implantation in emergencies and its outcomes on patient safety and mortality. Detailed study and patient‐level baseline characteristics, including the type of study, sample size, type of LPM, and patient outcomes were abstracted. Finally, predictors of major adverse events were extracted from each article.The overall quality was not in the exclusion criteria and the methodological quality of the available studies was performed using the Newcastle‐Ottawa Scale for nonrandomized studies. The quality of the studies is presented in Figure 2.3Statistical Package for Social Sciences version 26 (IBM Corp.) was used for statistical analysis. The continuous data were presented as mean and standard deviation while categorical data were expressed with frequency and percentage.33.1The initial search revealed 89 articles. After the removal of duplicates (75) and irrelevant items (7), seven studies were sought for full‐text screens. Of these, three articles were excluded based on different reasons. A total of four studies qualified for qualitative analysis. The PRISMA flow diagram is shown in Figure 3.2In a total of four studies, 1276 patients were included, of which 114 (8.9%) were implanted with LPM and the rest were implanted with either conventional PMs or some other alternatives. In the included studies, 468 (36.6%) patients were males. All four investigations were prospective cohort studies and the included studies were published between 2019 and 2023.The primary outcomes of our review were procedure duration, fluoroscopic time, major complications, and mortality. The secondary outcomes were pacing threshold, impedance, sensing of LPM, and hospital stay.3.3Of the four studies, one did not compare with any other device, while two studies compared with temporary‐permanent PMs and single chamber PMs. The fourth study compared LPM implantation between emergency and elective cases. Gonzales et al. and Marschall et al. showed the duration of the procedure to be 180 ± 45 versus 324.6 ± 92 and 39.9 ± 8.7 versus 54.9 ± 9.8, respectively, when compared with temporary‐permanent pacemaker implantation. Zhang et al. demonstrated the duration of the procedure and fluoroscopy time to be 36 ± 13.4 and 11.1 ± 3.1, respectively. Similarly, Schiavone et al. exhibited intermediate times of implantation at 60 (45–80) versus 50 (40–65) and fluoroscopic times at 6.5 (5–9.7) versus 5.1 (3.1–9).Two studies did not report mortality data while Gonzales et al. demonstrated equal mortality among the LPM and temp‐perm group (11% vs. 11%). Marschall et al. showed increased mortality in a very elderly group with implantation of a single chamber pacemaker .No complications were reported by Zhang et al. In Gonzales et al., no significant complications were reported in the two groups (11% vs. 15%). In Marschall et al., there were no complications in the LPM group in the elderly and very elderly while the single chamber pacemaker group showed 5.7% in the elderly and 4.2% in the very elderly population. Similarly, in Schiavone et al., the overall complication rate was more in emergency LPM implantation when compared with elective implantation (6.9% vs. 4.2%). Other specific complications are shown in Table 3.4The secondary outcomes for our review, that is, hospital stay were reported in two studies, and pacing parameters were shown in three studies. Hospital stay was more with a temp‐perm pacemaker than LPM (8.5 ± 5.2 vs. 2.3 ± 2.1) in Gonzales et al. In Schiavone et al., the emergency LPM implantation had higher days of hospital stay when compared with elective procedures (7 (3–16) vs. 3 (2–5)). Pacing parameters were not significantly different in all the studies  LPM implantation is a feasible option for urgent implantation for the treatment of severe bradyarrhythmias as an urgent treatment strategy, (ii) LPM implantation was correlated with decreased mortality and a decreased rate of major complications, (iii) LPM implantation demonstrated low procedural times, hospital stay, and fluoroscopy time but one study demonstrated more procedure time in an urgent setting, and (iv) pacing parameters were comparable in both comparison with other cardiac implantable electronic devices and elective LPM implantation.TV‐PMs are an established treatment option for the treatment of bradycardia, even in emergency implantations. In previous years, LPMs have evolved into the contemporary form of permanent pacing therapy, particularly in patients requiring single‐chamber PMs. Observation of device‐related complications, including lead fractures, pocket and lead infections, and venous complications has led to the advent of LPMs and defibrillator systems. The LPM has numerous advantages over TV‐PMs, especially in patients undergoing lead extractions. It confers a lower risk of device infection, it can avoid the pocket formation and venous access. In selected patients, an LPM can be considered an alternative to a TV‐PM when continuous pacing support is necessary for the patient.Studies included in this review suggest that LPMs are tolerated well in all age groups, including the elderly and the very elderly. Previous studies have shown concerns about lead perforation in elderly patients with LPM implantation. Therefore, LPMs have been generally restricted to a highly selected group of patients, even in elective settings. However, given the cumulative results of this review, we believe that all patients with urgent indications for pacemaker implantation might benefit from LPMs rather than other devices or temporary PMs. The overall complication rate is less when compared with other devices, despite the effect of the learning curve of the operators involved.At present, no randomized trials have directly evaluated the performance and safety of LPM with conventional devices and all data were derived from observational studies using historical cohorts of conventional devices. In a recent study, the results of the longitudinal coverage with evidence development study on the micra leadless pacemaker (Micra CED) demonstrated the safety profile of LPM, compared with traditional devices  showed the feasibility of atrial mechanical activity tracking and confirmed the efficacy and safety of this algorithm  there was a paucity of literature on our review question and the only available studies were observational cohort studies, limiting the cause‐and‐effect relationship of LPM and complications, (ii) the experience of different operators in all included investigations cannot be assessed and this may have introduced a selection bias in patient groups, and (iii) the sample size was too small for a quantitative review and larger observational studies and randomized controlled trials are needed to evaluate safety and efficacy of LPMs in emergency settings.5LPMs are a significant contemporary breakthrough in technology in the field of cardiac pacing, and they are feasible in patients requiring emergency implantation of permanent pacing devices. For underlying arrhythmias, whenever appropriate, our review shows that LPMs may be a better option than temporary PMs, even as an urgent treatment.Concept: MF, JM, AM. Methodology: MORR, TAN, SK, BU. Lit search: AA, MF, TH, MA. Writing: JM, MF, MA, AH, AM, BU. Supervision: AM, AZ.The authors have no competing interests to declare.No ethical review was necessary for this review as no human participants were analysed.Figure S1Click here for additional data file.


Describe features unique to head and neck (H&N) necrotizing fasciitis (NF) compared to other anatomic regions and specify a prognostic score associated with death and descending necrotizing mediastinitis (DNM).Retrospective cohort.Tertiary care, level 1 trauma center.A single‐institution database identified 399 confirmed cases of NF between 2006 and 2021, 33 of which involved the H&N. Patients with confirmed H&N NF were sorted into cohorts based on clinical outcomes, with the “poor” outcomes group defined by death and/or DNM.p = .041) and significantly lower rates of obesity  and hypertension . Within the H&N group, there were 2 deaths (6.06%) and 8 cases of DNM (24.2%). Diabetes was associated with poor outcomes (p = .047), as was an abbreviated sequential organ failure assessment score for necrotizing fasciitis (nfSOFA) of 2 or greater (p = .015).Thirty‐three patients with H&N NF were included. Compared to NF of other regions, patients with H&N NF had a significantly lower mortality rate (6.06% vs 20.8%, H&N NF is unique among other forms of NF, with a lower mortality rate and lower rates of obesity and hypertension in affected patients. Within the H&N cohort, worse outcomes were associated with diabetes as well as a nfSOFA score of 2 or greater. Timely surgical debridement alongside broad‐spectrum antibiotics remains the mainstay of treatment for NF; however, this simple prognostic score may play a role during the early stages of care for patients with H&N NF. Necrotizing fasciitis (NF) of the head and neck (H&N) is a rare, rapidly progressive infection that requires timely surgical debridement for effective management.Numerous acute phase reactantsThis case series of 33 patients with H&N necrotizing fasciitis analyzes clinical data to establish patient characteristics associated with poor outcomes, specifically death and DNM, in H&N necrotizing fasciitis. Furthermore, the present study proposes an abbreviated SOFA score for necrotizing fasciitis (nfSOFA) associated with poor outcomes.Following approval from the Vanderbilt University Institutional Review Board (IRB #181591), a single‐institution database was queried using International Classification of Diseases (ICD)‐9 (728.86) and ICD‐10 (M72.6) codes to identify cases of necrotizing fasciitis (N = 1213). A focused chart review resulted in 399 confirmed cases of necrotizing fasciitis between 2006 and 2021; of these, 33 involved the H&N. To be included in the study, patients had to be at least 18 years of age and have both a pathology report and operative findings consistent with necrotizing fasciitis.A retrospective chart review was then used to collect patient demographics, comorbidities, laboratory data, surgical interventions, and outcomes. Using admission labs, respiratory status, and past medical history, an abbreviated nfSOFA was calculated for each patient, incorporating platelets and creatinine as well as the need for mechanical ventilation and the presence of diabetes . Patients who survived their infections without spreading to the thorax comprised the “good” outcomes group . CompariFrom the total study cohort of 399 patients with confirmed necrotizing fasciitis, 33 patients had necrotizing fasciitis involving the H&N. The H&N cohort included 18 men (54.5%) and 15 women (45.5%) with a median age of 52 years (range 19‐75 years). Twenty‐five patients (75.8%) presented as transfers from outside hospitals. The most common known mechanism of infection was odontogenic , followed by infection from a traumatic injury . Twelve patients (36.4%) had H&N necrotizing fasciitis infections of unknown cause. At the time of presentation, 42.4% of patients had at least 2 medical comorbidities, the most common of which was obesity . There were also lower rates of both obesity and hypertension in the H&N group compared to the non‐H&N group. In the H&N group, 27.3% of patients had a BMI that qualified them as obese, compared to 63.7% in the non‐H&N group (p < .001). Additionally, 42.4% of patients in the H&N group had a known diagnosis of hypertension, compared to 60.9% in the non‐H&N group (p = .038). There was no difference in the prevalence of diabetes, cancer, heart disease, liver disease, kidney disease, or peripheral vascular disease between groups (p > .05).Comparing the H&N cohort to necrotizing fasciitis of all other anatomic regions, there was no difference in biological sex, age, or length of stay between groups. There were, however, significant differences in overall mortality as well as the prevalence of obesity and hypertension between groups. In the H&N group, 2 patients (6.08%) died as a result of their infections, compared to a 20.8% mortality rate in the non‐H&N group  was due to methicillin‐resistant Staphylococcus aureus . One patient died prior to the finalization of their tissue culture results, and another patient's results were unavailable due to a transfer from an outside institution. Of all available tissue cultures, 48% were polymicrobial, 40% were monomicrobial, and 1 showed no growth on tissue culture . Tissue  A strep . Of the s aureus . Blood cEight patients (24.2%) with confirmed H&N necrotizing fasciitis required tracheostomy, and 9 additional patients (27.3%) required intubation, for a total of 17 patients (51.5%) who required respiratory intervention and mechanical ventilation. The median number of total debridements per patient was 4 (range 1‐12). Eight patients (24.2%) experienced a spread of infection to the mediastinum, and 2 patients (6.1%) did not survive their infections. Details regarding surgical management for each patient can be found in Supplemental Table p = .179). In the “poor” outcomes group, 7 patients (77.8%) had a diagnosis of type 2 diabetes mellitus, compared to 8 of 24 (33.3%) patients in the “good” outcomes group (p = .047). Median A1C in the “poor” outcomes group was 9.2 (range 5.3‐13.8) compared to the median A1C of 5.7 (range 4.4‐14.1) in the “good” outcomes group (p = .058). When only those patients with a clinical diagnosis of diabetes were compared between groups, the median A1C in the “good” outcomes group was 6  (p = .187).Patients whose infections resulted in either DNM or death comprised the “poor” outcomes group, and patients who survived their infections without spreading to the thorax comprised the “good” outcomes group. There was no significant difference in the number of medical comorbidities in the “poor” outcomes group  compared to the “good” outcomes group  (p = .017). The difference in total debridements performed between groups did not reach our predetermined cutoff for statistical significance. The was a median of 5 debridements in the “poor” outcomes group (range 1‐12) and a median of 3 debridements in the “good” outcomes group (range 1‐7) (p = .067)  in the “poor” outcomes group required intubation or tracheostomy, compared to 9 of 24 patients (37.5%) in the “good” outcomes group (p = .418).The LRINEC score, designed to distinguish necrotizing fasciitis from other soft tissue cellulitis, requires C‐reactive protein(CRP), white blood cells, hemoglobin, sodium, glucose, and creatinine for calculation.p = .017). In other words, in our cohort, patients with a nfSOFA score of 2 or greater were significantly more likely to be in the “poor” outcomes group.Using admission labs, respiratory status, and diabetes history, an abbreviated nfSOFA was calculated for each patient  in the H&N cohort presented as transfers from outside hospitals without definitive data on time to presentation available in retrospective chart review. A future prospective study and focused data collection on time to presentation would be needed to address this hypothesis.Prior studies investigating prognostic markers for necrotizing fasciitis of the H&N have focused on distinguishing necrotizing fasciitis from other soft tissue infections using scores such as the LRINEC score.The abbreviated nfSOFA presented in this study tailors the SOFA score to include specific but readily available data relevant to necrotizing fasciitis outcomes (Supplemental Table Further adjustment of the nfSOFA score utilizing a larger, multi‐institutional cohort will be necessary. In the current model, the presence of diabetes and the need for mechanical ventilation are scored as binary variables, with 1 point each assigned for these factors. This system likely undervalues the clinical impact of diabetes and intubation and/or tracheostomy requirement on H&N necrotizing fasciitis, as the need for intubation alone has been shown to correlate with mortality in sepsis of all causes.Regarding limitations, this study is limited foremost by its retrospective nature and therefore its reliance on ICD‐9 and ICD‐10 codes for identification of cases. For this reason, only cases identified as necrotizing fasciitis via electronic coding were identified, and only those cases with operative and pathology reports consistent with necrotizing fasciitis were included. This methodology makes it likely that many cases of H&N necrotizing fasciitis were missed in our search strategy due to imprecise or incomplete coding. Additionally, this study included patients who received care over a 15‐year period between 2006 and 2021. Trends in diagnosis and treatment for necrotizing fasciitis have evolved over time, and these changes in practice patterns were unable to be controlled given the small sample size. Further, because this study of a rare disease process was conducted at a single institution, the sample size was also insufficient to conduct multivariate analyses. Future studies may consider analyzing across institutions to obtain a larger sample size of patients to better address confounding variables via multivariate analyses. Finally, due to the limited availability of data to calculate complete SOFA and LRINEC scores for each patient, comparative analytics between these metrics and the nfSOFA score is not possible in the present study. This may be an area for future investigation, especially in a prospective setting in which all necessary clinical data can be obtained to calculate each score for a sufficient number of patients. Future prospective studies will also be required for formal validation of the nfSOFA score proposed herein.Ultimately, necrotizing fasciitis remains an emergent condition that relies upon experienced clinical acumen for diagnosis and urgent surgical debridement for management. A prognostic score such as the nfSOFA may be helpful for communication—both between providers as well as between providers and patient families—during the early stages of care for patients with H&N necrotizing fasciitis.Necrotizing fasciitis of the H&N is clinically distinct from necrotizing fasciitis of other anatomic regions, with a lower mortality rate and lower prevalence of obesity and hypertension. Patients with H&N necrotizing fasciitis whose infections led to DNM or death were more likely to have diabetes compared to patients who survived without infection spread. An abbreviated nfSOFA—which includes platelet count, creatinine, diabetes, and respiratory status—of 2 or greater was associated with poor outcomes, specifically death and DNM.Kelly L. Vittetoe, study design, data collection, data analysis, manuscript composition; Samuel R. Johnson, data collection, data analysis, manuscript review; Teresa A. Benvenuti, data collection, manuscript review; Jonathan G. Schoenecker, study design/oversight, manuscript review; Stephanie N. Moore‐Lotridge, study design/oversight, data analysis, manuscript review; Sarah L. Rohde, study design/oversight, manuscript review.None.None.Supplemental Material.Click here for additional data file.


To investigate the possible correlation between the development of adverse events (AEs) and prognosis in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev).A total of 286 patients with unresectable HCC treated with Atez/Bev as first‐line systematic therapy were included.p = 0.009) and α‐fetoprotein ≥100 ng/ml  were independently associated with progression‐free survival. Multivariate analysis adjusted for the same AEs showed that fatigue  was independently associated with overall survival. Median progression‐free survival was 6.5 months  in patients without hypertension of any grade and 12.6 months  in patients with hypertension of any grade (p = 0.035). The overall survival was significantly shorter in patients in whom treatment‐related fatigue of any grade was observed (p < 0.001). Regarding response rates, the disease control rate of patients who developed treatment‐related hypertension (94.2%) was significantly higher than those who did not (79.1%) (p = 0.009).Regarding treatment‐related AEs, decreased appetite of any grade, proteinuria of any grade, and fatigue of any grade were found with a frequency of ≥20%. Multivariate analysis adjusted for immune‐related liver injury, immune‐related endocrine dysfunction, proteinuria, fatigue, decreased appetite, hypertension, sex, age, Eastern Cooperative Oncology Group performance status, HCC etiology, HCC stage, Child–Pugh score, and α‐fetoprotein showed that hypertension of any grade (hazard ratio [HR], 0.527; 95% confidence interval [CI], 0.326–0.854; Treatment‐related hypertension is associated with good outcomes in patients with HCC treated with Atez/Bev. Treatment‐related decreased appetite, proteinuria, and fatigue were found with a frequency of =20% during atezolizumab plus bevacizumab therapy for hepatocellular carcinoma. Treatment‐related hypertension was associated with good outcomes in patients treated with atezolizumab plus bevacizumab. Treatment‐related fatigue was associated with poor outcome in patients treated with atezolizumab plus bevacizumab. This 1st‐line systemic therapy is comprised of the combination of an immune checkpoint inhibitor (Atez) and a molecular targeted agent (Bev).Management of adverse events (AEs) is important to prolong survival of patients with malignant disease receiving systemic therapy. Several studies have investigated the relationship between the AEs development in patients who were treated with immune checkpoint inhibitors or molecular targeted agents and their outcomes in various malignancies.With this aim, we performed a large‐scale retrospective investigation in patients with HCC who were treated with Atez/Bev in a 1st‐line systemic therapy setting at multicenter of liver disease in Japan, and researched the possible relationship between the development of AEs and three different outcome assessment: overall survival, progression‐free survival, and therapeutic response.22.1This multicenter study was implemented as a retrospective database research according to the Guidelines for Clinical Research created by the Ministry of Health and Welfare of Japan after receiving the Ministry's official approval. This retrospective research protocol was approved by the Institutional Ethics Committee of Ehime Prefectural Central Hospital (IRB no. 30–66) (UMIN000043219). All process of this study were performed based on the Declaration of Helsinki. In this study, written informed consent was obtained from all patients who participated in this study.Between September 2020 and March 2022, a total of 467 patients with unresectable HCC were treated with Atez/Bev at 22 institutions in Japan. Of these, 263 patients who met the following eligibility criteria were enrolled: (1) Atez/Bev was used for HCC as the 1st‐line systemic therapy, and (2) clinical data including therapeutic response were available.The HCC etiology was defined to be hepatitis C virus in patients with positive for hepatitis C virus antibodies, and hepatitis B virus in patients with positive for hepatitis B virus surface antigen.The date of initiation of Atez/Bev therapy was determined as the start of follow‐up. The end of follow‐up was determined as the date of the last visit for patients who survived and the date of death for patients who died during the observation period.2.2In this study, HCC was confirmed based on one or more of the following: increased α‐fetoprotein levels, typical imaging findings on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid–enhanced magnetic resonance imaging, dynamic‐computed tomography (CT), or contrast‐enhanced ultrasonography, and pathological findings.The optimal treatment for HCC for each patient was determined by discussions among hepatologists, surgeons, oncologists, and radiologists at each hospital in accordance with Japanese practice guidelines for HCC.2.3After affirmation written informed consent from each patient, intravenous Atez/Bev therapy comprising of 1200 mg of Atez plus 15 mg/kg of body weight of Bev was given every 3 weeks.AEs were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.2.4The Response Evaluation Criteria in Solid Tumors, ver. 1.1,The best responses were defined after excluding patients who did not undergo imaging assessment due to a short follow‐up period .2.5n = 131) and overall  survival and their hazard ratios (HRs) were determined by multivariate Cox proportional hazards modeling that adjusted for AEs of any grade that occurred with a frequency of ≥10% in the study population. In the multivariate Cox proportional hazards modeling for progression‐free survival, we additionally adjusted the following factors that were previously reported to be predictors of liver disease prognosis or risk factors for HCC: sex, age, HCC etiology, Eastern Cooperative Oncology Group performance status (ECOG‐PS), HCC stage, α‐fetoprotein, and Child–Pugh score.Continuous variables are described as medians (interquartile range). The progression‐free survival was determined as the duration between the date of Atez/Bev started and the date of PD or death, and the overall survival was determined as the duration between the date of Atez/Bev started and the end of follow‐up. Evaluation of cumulative progression‐free survival and overall survival was carried out using the Kaplan–Meier method, and statistical differences were evaluated with the log‐rank test. Progression‐free , which is a graphical user interface for R .Statistical difference was defined as 33.1The characteristics of the 263 patients are listed in Table 3.2Figure Figure 3.3The radiological best response rates for CR, PR, SD, and PD were 4.9%, 27.0%, 50.2%, and 17.9%, respectively (Table 3.4Table 3.5p = 0.009) and α‐fetoprotein ≥100 ng/ml  were independently related to progression‐free survival (Table p = 0.010) was independently related to overall survival .Figure p < 0.001). The baseline characteristics of the study patients stratified by the presence or absence of treatment‐related fatigue of any grade are summarized in Table Figure 3.7p = 0.042) (Table p = 0.009)  Table . The DCR9) Table .p = 0.042 and 0.001) (Table p = 0.042)  Table . The rad2) Table .4In this multicenter investigation, multivariate analysis for survival showed correlations between AEs and outcomes. Specifically, treatment‐related hypertension of any grade was independently related to good progression‐free survival in patients with HCC who were treated with Atez/Bev, the combination of an immune checkpoint inhibitor (Atez) and a molecular targeted agent (Bev) that was developed as 1st‐line systemic therapy for patients with advanced unresectable HCC. In addition, treatment‐related fatigue of any grade was independently related to poor overall survival. Furthermore, in the evaluation of therapeutic response, the DCR was significantly higher in patients who developed treatment‐related hypertension of any grade than in those who did not. These results of this study suggest that treatment‐related hypertension is related to good therapeutic response and progression‐free survival, whereas fatigue is related to poor outcomes in patients with advanced unresectable HCC who were treated with Atez/Bev.Regarding safety in the phase 3 IMbrave150 study,Studies of several malignancies, such as lung cancer and malignant melanoma, reported that patients treated with immune checkpoint inhibitors who developed immune‐related AEs showed significantly better prognosis than those who did not develop these AEs.p = 0.019) in multivariate analysis. The development of hand–foot skin reaction, hypertension, and diarrhea are all likely to be associated with the mechanism of action of tyrosine kinase inhibitors. These drugs may cause hypertension by suppressing vascular endothelial growth factor (VEGF)‐mediated upregulation of nitric oxide synthase, thereby inhibiting vasomotor function and promoting degeneration of small blood vessels.Some tyrosine kinase inhibitor–related AEs have been shown to correlate with good HCC patient outcomes; for instance, sorafenib‐, regorafenib‐, and lenvatinib‐related dermatological AEs were associated with improved survival.Bev is a humanized monoclonal antibody that connects to all isoforms of VEGF.p = 0.021) and overall survival . In addition, we showed that AEs such as liver injury (including immune related), decreased appetite, and proteinuria occurred more frequently in patients with Bev interruption than in those without it. In this study, decreased appetite and proteinuria were not related to progression‐free or overall survival. They are probably due to the fact that our previous studyOur finding that treatment‐related fatigue was associated with worse outcomes is consistent with another report showing that this AE was negative prognostic factor in patients with HCC treated with systematic therapy.The strength of this study was that it determined the relationship between treatment‐related AEs and outcomes in patients treated with Atez/Bev, the current first‐line systematic therapy for unresectable HCC, in a first‐line setting.This study is not without limitations, such as the hospital‐based population and retrospective design. Although the study included patients who were treated with Atez/Bev in a 1st‐line setting at multiple centers in Japan, future prospective studies should include a larger number of patients and those recruited on a nationwide basis, and should also use a longer‐term follow‐up period. This study did not analyze the treatment of HCC after Atez/Bev therapy. As sequential systemic treatment may influence prognosis, especially overall survival, further studies that include an assessment of HCC treatment after Atez/Bev therapy are also warranted. There was concern that grouping patients after the start of observation may introduce immortality time bias. Specific statistical methods, such as the landmark method of grouping by the onset of each AE, should be considered in the future. The current study did not sufficiently investigate the timing of the onset of each AE, and detailed studies of the relationship between the onset of each AE and its grade are needed in the future.In conclusion, treatment‐related hypertension was related to good outcomes in HCC patients treated with Atez/Bev. Conversely, treatment‐related fatigue was related to poor outcome in these patients. Therefore, careful management of AEs is necessary to maintain patients' quality of life, minimize the need for treatment discontinuation, and achieve desirable outcomes such as prolonged survival. More studies are needed to confirm these findings in other patient populations.Toshifumi Tada: Conceptualization (lead); data curation ; formal analysis (lead); methodology (lead); writing – original draft (lead); writing – review and editing (lead). Takashi Kumada: Conceptualization ; formal analysis (supporting); investigation (supporting); methodology (supporting); project administration (lead); supervision (lead); writing – original draft (supporting); writing – review and editing (supporting). Atsushi Hiraoka: Conceptualization ; data curation (lead); methodology ; project administration (lead); supervision (supporting); writing – original draft (supporting); writing – review and editing (supporting). Masashi Hirooka: Data curation . Kazuya Kariyama: Data curation ; writing – original draft (supporting); writing – review and editing (supporting). Joji Tani: Data curation . Masanori Atsukawa: Data curation . Koichi Takaguchi: Data curation . Ei Itobayashi: Data curation . Shinya Fukunishi: Data curation . Kunihiko Tsuji: Data curation . Toru Ishikawa: Data curation . Kazuto Tajiri: Data curation . Hironori Ochi: Data curation . Satoshi Yasuda: Data curation . Hidenori Toyoda: Data curation . Chikara Ogawa: Data curation . Takashi Nishimura: Data curation . Takeshi Hatanaka: Conceptualization ; data curation ; formal analysis (supporting); methodology ; project administration ; writing – original draft (supporting); writing – review and editing (supporting). Kakizaki Satoru: Data curation . Noritomo Shimada: Data curation . Kazuhito Kawata: Data curation . Fujimasa Tada: Data curation . Hideko Ohama: Data curation . Kazuhiro Nouso: Data curation . Asahiro Morishita: Data curation . Akemi Tsutsui: Data curation . Takuya Nagano: Data curation . Norio Itokawa: Data curation . Tomomi Okubo: Data curation . Taeang Arai: Data curation . Michitaka Imai: Data curation . Hisashi Kosaka: Data curation . Atsushi Naganuma: Data curation . Yohei Koizumi: Data curation . Shinichiro Nakamura: Data curation . Masaki Kaibori: Data curation . Hiroko Iijima: Data curation ; funding acquisition (lead); supervision (supporting). Yoichi Hiasa: Data curation ; supervision (supporting).This work was supported by JSPS KAKENHI 21 K07902.tadat0627@gmail.com): lecture fees from AbbVie and Eisai. Atsushi Hiraoka (hirage@m.ehime-u.ac.jp): lecture fees from Bayer, Eisai, Eli Lilly, and Otsuka. Takashi Kumada (takashi.kumada@gmail.com): lecture fees from Eisai. Hidenori Toyoda (hmtoyoda@spice.ocn.ne.jp): lecture fees from AbbVie, Bayer, Eisai, Gilead, and Terumo. Takeshi Hatanaka (hatanaka@qk9.so-net.ne.jp): lecture fees from Eisai. None of the other authors have potential conflicts of interest to declare.Toshifumi Tada  (UMIN000043219).Table S1.Click here for additional data file.


Hydrilla verticillata to extremely and mildly low light , that is, EL and ML, with the radiation intensity of 180 μmol photons m−2 s−1 as the control. Low‐light exposure continued for 9 days, followed by a 7‐day recovery phase (180 μmol photons m−2 s−1). At the exposure phase, the low‐light treatments, in particular the EL, decreased the relative growth ratio, but induced greater height and longer stem internode distance and epidermal cell. Such responses/acclimations continued into the recovery phase, despite more or less changes in the magnitude. Transcriptome showed that the photosynthetic system was inhibited at the exposure phase, but the macrophyte adjusted hormone synthesis relating to cell division and elongation. Moreover, the EL activated cell stress responses such as DNA repair. Following light recovery, the macrophyte exhibited a strong‐light response, although energy metabolism enhanced. Especially, the EL enriched the pathways relating to anthocyanin synthesis at such phase, indicating an activation of photoprotective mechanism. Our findings suggest that negative influences of low light occur at both low‐light exposure and recovery phases, but submerged macrophytes would acclimate to light environments. Transcriptome can show molecular basis of plant responses/acclimations, including but not limited to morphology. This study establishes a bridge connecting morphological and molecular responses/acclimations.Light intensity is a determinant for submerged macrophytes. Little is known about their molecular responses to low‐light exposure, despite more informative and responsive than morphological traits. For erect‐type submerged macrophytes, the stem is more crucial relative to the leaf in acclimation to low‐light stress, but receives less attention. We determined morphological and stem transcriptomic responses/acclimations of  Negative influences of low light occur both at the low‐light exposure and recovery phases, but submerged macrophytes would acclimate to light environments. The transcriptome can show molecular basis of plant responses/acclimations, including but not limited to the morphology. The truth is, though, the stem also plays a pivotal role in plant acclimation to low‐light environments , a shallow lake with a water area of 2338 km2 and an average water depth of 1.9 m. The top 8‐cm segments were cut from healthy individuals, weighed, and used as the asexual propagules in this experiment. After rinsed with distilled water, the propagules were planted in plastic bottles  containing 2 L distilled water and 200 g sediment, with total organic carbon 12.8 mg g−1, total nitrogen 2.73 mg g−1, and total phosphorus 0.730 mg g−1. These propagules in bottles were pre‐incubated at 27°C for 15 days in three growth chambers, with the light–dark regime of 12 h:12 h and the radiation intensity of 180 μmol photons m−2 s−1. Following the pre‐incubation, based on the light compensation point of H. verticillata  and a mildly low‐light environment (ML), respectively, with another chamber still maintained the light intensity at 180 μmol photons m−2 s−1 (CK). According to the mean duration of flood in Lake Taihu in the past 30 years, the low‐light exposure continued for 9 days in this study. Subsequently, the light intensity of both EL and ML treatments returned to 180 μmol photons m−2 s−1, and the recovery phase continued for 7 days. For this experiment, there were six bottles evenly placed in each growth chamber, and transposition was carried out every day to avoid unequal light radiation. Moreover, distilled water was supplemented as needed to maintain a constant water level throughout the experiment.2.2H. verticillata. Two healthy individuals from each plastic bottle were harvested, washed, and dried with filter paper to determine the total biomass, the number of stem internode, and the average distance of stem internode. In addition, plant height and stem diameter (at 5 cm down the tip) were measured with a ruler (0.1 cm precision) and a micrometer (0.02 mm precision), respectively. After the measurement, the H. verticillata individuals in each plastic bottle were separated into leaves, stems, and roots, oven‐dried at 80°C to a constant weight, and then weighed to obtain the dry weight. The stem mass ratio was defined as the ratio of stem dry weight to total dry weight. Relative growth rate (RGR) was calculated asW1 is the initial fresh weight (mg), W2 is the final fresh weight (mg), and ∆T is the time (day). In addition, a scan with the electron microscope  was used to determine stem epidermal cell length (at least 15 cells per sample) at 5 cm down the tip.At the end of both low‐light exposure and light recovery phases, we chose three replicated plastic bottles from each growth chamber and determined morphological parameters of 2.3H. verticillata was clipped, shock‐frozen in liquid nitrogen, stored at −80°C, and used for transcriptome analysis. Total RNA was extracted from the stem samples with RNA 6000 Nano kit (Agilent). RNA concentration and purity were determined by UV spectrophotometry, and the integrity was assessed by an Agilent 2100 Bioanalyzer (Agilent). The total amount of RNA required for a single library construction is ≥1 μg, the concentration is ≥35 ng/μL, OD260/280 is ≥1.8, and OD260/230 is ≥1.0. In this experiment, all RIN (RNA Integrity) numbers were above eight, indicating that high‐quality material was used for sequencing. Fifteen indexed cDNA libraries, that is, (three light treatments at the end of the low‐light exposure phase + two low‐light treatments at the end of light recovery phase) × three replicates, were constructed and sequenced with an Illumina Novaseq 6000 platform (Paired‐ends 2 × 150 cycles).In addition to the morphological parameters, the apical 5‐cm stem of 2.4H. verticillata. The longest transcript was selected and used for subsequent analysis. Benchmarking Universal Single‐copy Orthologs (BUSCOs) was used to complete the integrity of the assembled transcriptome.Samples were collected at the end of both low‐light exposure and light recovery phases, and transcripts were spliced after each sampling. For this study, the cDNA libraries of CK treatment constructed at the end of the low‐light exposure phase were as the control both at the low‐light exposure and recovery phases. Sequence raw reads were checked for data quality using FastQC. Cutadapt was used to remove sequences with adapters at the 3′ end and reads with an average quality score below Q20. We used Trinity with default parameters to assemble clean reads into a transcriptome, as there is no available reference genome for https://www.genome.jp/tools/kaas/).Assembled transcripts were annotated through sequence similarity search against UniProt databases with Blast+ software . Subsequently, results were loaded on Blast2GO v.6 to retrieve Gene Ontology terms . KO assignment and Pathway mapping were performed with KAAS . Transcripts were considered differentially expressed when FDR < 0.05 and logFC > ±1.https://www.omicshare.com/tools). The ggord package based on R was used for Principal Co‐ordinates Aanalysis (PCoA) to reflect the similarity between samples. Venn diagram (http://www.ehbio.com/test/venn/#/) was used to show the distribution of the number of DEGs that were unique and shared by ML versus CK and EL versus CK at the low‐light exposure and light recovery phases. The heatmap showed the expression levels of genes in KEGG pathways at the low‐light exposure and light recovery phases. Transcriptomics data used in this study are publicly available from NCBI (BioProject ID PRJNA977960).The differentially expressed genes (DEGs) were further analyzed by KEGG enrichment analysis with the online platform  was used to assess the effects of light treatment, incubation phase, and their interactions on morphological traits. Following one‐way ANOVA, Tukey's multiple comparison test was used to detect the differences in plant height, the number of stem internode, the average distance of stem internode, stem diameter, stem mass ratio, fresh weight, and RGR among light treatments at the same phase, that is, the low‐light exposure phase or the light recovery phase.All statistical analyses were performed with R  and 338 (44.0%) down‐ and up‐regulated genes, respectively, were detected in ML versus CK Figure . For EL Seven days into the light recovery phase, there were 164 (50.0%) and 310 (57.0%) up‐regulated genes in ML and EL treatments, respectively, while the number of down‐regulated genes were, respectively, 164 (50.0%) and 244 (43.0%) Figure . In the 3.4At the end of low‐light exposure phase, 814 DEGs were significantly enriched (FDR < 0.05) into eight pathways in the ML treatment, most of which relate to metabolism, such as photosynthesis, photosynthesis‐antenna proteins, and carbon fixation in photosynthetic organisms. In addition, plant hormone signaling transduction (FDR = 0.094) and flavonoid biosynthesis (FDR = 0.18) were also enriched Figure . A similpsbW and psbS. In photosynthetic‐antenna proteins, most of the differential genes encoding LHCII were down‐regulated in two low‐light treatments, including Lhcb1, Lhcb2, Lhcb3, Lhcb4, Lhcb5, and Lhcb6  were overexpressed in the EL treatment, which implies oversynthesis of auxin. The auxin is considered to promote the elongation of plant cells, but also plays a regulatory role in the distribution of carbohydrates and energy  were significantly up‐regulated in the EL treatment. Considering that MCM takes part in DNA replication by controlling cell mitosis at the S‐phase ; investigation (lead); visualization (lead); writing – original draft ; writing – review and editing . Yuxuan Gao: Formal analysis (supporting); writing – review and editing (supporting). Chao Song: Investigation (supporting). Xinhou Zhang: Conceptualization ; supervision ; writing – original draft ; writing – review and editing (lead). Guoxiang Wang: Conceptualization ; funding acquisition (lead); supervision .The authors declare that there are no conflicts of interest.


To investigate the post‐COVID‐19 long‐term complications or long COVID of various organ systems in patients after 3 months of the infection, specifically before the Omicron variant, with comparative literature analysis.A systemic literature search and meta‐analysis were conducted using multiple electronic databases  with predefined search terms to identify eligible articles. Eligible studies reported long‐term complications of COVID‐19 infection before the Omicron variant infection. Case reports, case series, observational studies with cross‐sectional or prospective research design, case–control studies, and experimental studies that reported post‐COVID‐19 complications were included. The complications reported after 3 months after the recovery from COVID‐19 infection were included in the study.The total number of studies available for analysis was 34. The effect size (ES) for neurological complications was 29% with 95% confidence interval (CI): 19%–39%. ES for psychiatric complications was 24% with 95% CI: 7%–41%. ES was 9% for cardiac outcomes, with a 95% CI of 1%–18%. ES was 22%, 95% CI: 5%–39% for the gastrointestinal outcome. ES for musculoskeletal symptoms was 18% with 95% CI: 9%–28%. ES for pulmonary complications was 28% with 95% CI: 18%–37%. ES for dermatological complications was 25%, with a 95% CI of 23%–26%. ES for endocrine outcomes was 8%, with a 95% CI of 8%–9%. ES size for renal outcomes was 3% with a 95% CI of 1%–7%. At the same time, other miscellaneous uncategorized outcomes had ES of 39% with 95% CI of 21%–57%. Apart from analyzing COVID‐19 systemic complications outcomes, the ES for hospitalization and intensive care unit admissions were found to be 4%, 95% CI: 0%–7%, and 11% with 95% CI: 8%–14%.By acquiring the data and statistically analyzing the post‐COVID‐19 complications during the prevalence of most virulent strains, this study has generated a different way of understanding COVID‐19 and its complications for better community health. Moreover, till now, the world has been struggling to overcome the disease and its aftermath. Initially, many acute cases of COVID‐19 have overwhelmed healthcare resources worldwide, especially the intensive care unit (ICU) departments, and the recovered cases with post‐COVID‐19 complications have created a challenge for healthcare workers.Highly infectious and virulent variants of COVID‐19, that is, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) and later its variant AY.4.2, sometimes known as delta plus were seen earlier in the course of the pandemic. COVID‐19 alpha variant was first reported in Great Britain, a Beta variant in South Africa, and a delta in India in the late 2020s.On the contrary, the COVID‐19 Omicron variant is considered relatively less virulent owing to its genetic makeup, mutation, and the increased number of vaccinations across the globe.22.1A systemic literature search and meta‐analysis were conducted using multiple electronic databases  with predefined search terms to identify eligible articles. Eligible studies reporting long‐term complications of COVID‐19 infection before the Omicron variant infection worldwide, including case reports, case series, observational studies with cross‐sectional or prospective research design, case–control studies, and experimental studies that reported post‐COVID‐19 complications, were included. The complications reported after 3 months after the recovery from COVID‐19 infection were included in the study. The following search term will be used: (“Post COVID”) OR (“Post Covid‐19”) OR (“Post coronavirus”) OR (“After COVID”) OR (“Post Severe acute respiratory syndrome coronavirus [SARS‐CoV‐2]”) OR (“After SARS‐CoV‐2”) AND (“Complications”) AND (“sequelae”). This protocol follows MOOSE Guidelines for Meta‐Analyses and Systematic Reviews of Observational Studies and the PRISMA‐P  guidelines.2.2Eligible studies should report the complications of COVID‐19 infection in patients who recovered from the infection. All literature, including clinical trials, case reports, case series, and observational studies (retrospective and prospective) from any date till March 2021 in the English language, will be included. Studies in languages other than English will not be included. The study population will include pediatric (≤18 years) as well as adult (>18 years) patients who developed long‐term complications of COVID‐19 infection. The included patients should have a confirmed diagnosis of SARS‐CoV‐2 infection and should have a documented recovery confirmed with a negative reverse transcription polymerase chain reaction (RT‐PCR). Patients should have a complication in any system at least 3 months after the first positive RT‐PCR. Exclusion criteria include patients with COVID‐19 who did not have a positive RT‐PCR upon diagnosis, those who had complications during the infection (defined by a positive RT‐PCR), and those who had the onset of complications in less than 3 months of the positive RT‐PCR.2.3Two reviewers independently evaluated study quality using the statistical methodology and categories guided by the Cochrane Collaboration Handbook and PRISMA guidelines Figure . The pro2.4I2 statistic assessed the heterogeneity of study estimates.Results were analyzed descriptively, and meta‐analysis was conducted to derive the pooled proportions and effect estimates. We used pooled proportional analysis using STATA software with the command “Metaprop.” The total number of studies was 34, with a total cohort of 247,209 patients. We excluded case reports and case series during the analysis because of concerns regarding the precision and potential bias of prevalence estimates. We compared studies with the number of patients having each outcome available. Random effects single‐arm meta‐analysis of proportions were performed. The pooled effect sizes (ESs) for post‐COVID‐19 systemic complications were represented as forest plots and included neurological, psychiatric, cardiac, gastrointestinal, musculoskeletal, pulmonary, dermatological, endocrine, renal, and other systemic complications, respectively. Furthermore, hospitalizations and ICU admission were also analyzed and interpreted using Forest Plot. Hedge's 3The total number of studies available for analysis was 34, and the studies that reported patient outcomes have been included for pooled proportion from a single‐arm meta‐analysis of proportions of various long‐term COVID outcomes. Most studies were conducted in China, the United States, and France, while other countries like the United Kingdom, India, Germany, Singapore, Sweden, Norwegian, Denmark, and Italy were also included. The mean age of the population ranged from 18 to 55 ± 10 years. Heterogeneity among the studies was found to be above 90%. The ES for neurological complications was 29%, with a confidence interval (CI): of 19%–39%. ES for psychiatric complications was 24% with CI: 7%–41%. ES was 9% for cardiac outcomes, with a CI of 1%–18%. For gastrointestinal outcome, ES was 22%, CI: 5%–39%. ES for musculoskeletal symptoms was 18% with CI: 9%–28%. ES for pulmonary complications was 28% with CI: 18%–37%. ES for dermatological complications was 25% with CI: of 23%–26%. ES for endocrine outcomes was 8% with CI: 8%–9%. ES size for renal outcomes was 3% with CI: 1%–7%. At the same time, other miscellaneous uncategorized outcomes had ES of 39% with CI: 21%–57%. Apart from analyzing COVID‐19 systemic complications outcomes, the ES for hospitalization and ICU admissions was found to be 4%, CI: 0%–7%, and 11% with CI: 8%–14%. The pooled proportional analysis is mentioned in the forest plot  receptor on the host cell leading to endocytosis, releasing of the viral genome into the host cell thus incorporating virus into the host cellular machinery to replicate/release viral particles extracellularly, thus infecting neighboring cells.Furthermore, this inflammatory response creates an imbalance in the coagulation cascade and creates a life‐threatening risk of thrombosis that can ensue in the form of stroke, myocardial infarction, pulmonary embolism, deep venous thromboembolism, and even sudden cardiac arrest and death.4.2Upon literature review of systematic reviews and meta‐analysis of post‐COVID‐19 complications for comparative analysis with our study, it was acknowledged that few of them had mentioned post‐COVID‐19 general systemic complications and with a specific timeframe of postrecovery. Lopez‐Leon et al. have reported more than 50 long COVID symptoms, being fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%) as the most common ones while others also include cough, chest discomfort, sleep apnea, reduced pulmonary diffusing capacity, anxiety, depression, attention deficit, arrhythmias, myocarditis, loss of taste and smell, tinnitus, and so on.Our study has consolidated the symptoms according to the specific organ/system involved, as mentioned in Table In comparison, psychiatric complications include anxiety, depression, sleep disturbances, cognitive impairment, angry mood, and posttraumatic stress disorder. Cardiac complications included chest pain, palpitations, perimyocarditis, and myocarditis. Gastrointestinal complications included diarrhea/vomiting, sore throat, dysphagia, abdominal pain, gastroparesis, anorexia, and constipation. Renal complications were acute renal failure with or without dialysis dependency and acute kidney injury. Endocrine complications included new‐onset diabetes mellitus, increasing morbidity and mortality risk. Musculoskeletal complications included mainly muscle weakness, fatigue, joint pains, a decline in mobility, and persistent generalized fatigue/weakness.4.3There is limited data regarding the management of post‐COVID symptoms as there is no diagnostic tool or criteria for it, and patients come with various symptoms that may also be related to other diseases.4.4Our study has managed to integrate the organ‐specific system‐wise post‐COVID‐19 complications. We addressed mainly the timeline of COVID‐19 when the virulent strains were prevalent, that is, until mid‐late 2021 before the emergence of the Omicron variant, which was declared by WHO in November 2021.I2 < 25%, 25%–50%, 50%–75%, and >75%, which indicates no, low, moderate, and high between‐study heterogeneity.Several limitations of the studies are noted. First, our study has a heterogeneous population due to the different quality of articles, types of studies, and methodology. Heterogeneity was above 90% in significant studies, which is considered high. It was interpreted as 5Long COVID concerns the scientific community due to insufficient data and evidence. Due to the vague presentation of post‐COVID‐19 symptoms, it is likely to be underreported and documented, leading to underestimation. Through our study, we aim to report the systemic complications of post‐COVID‐19 and highlight the prevalence of virulent strains, that is, delta, alpha, and beta variants as the possible contribution of such outcomes, which will further add to the current literature for better understanding. Such studies can be considered a milestone in providing insight for developing future management strategies for long COVID. Further, similar studies regarding long COVID and categorizing COVID‐19 strains and the effect of mass vaccinations can guide the community to provide better health.Phool Iqbal: Data curation; formal analysis; methodology; project administration; supervision; validation; writing—original draft; writing—review and editing. Fateen Ata: Conceptualization; data curation; investigation; methodology; project administration; supervision; writing—original draft; writing—review and editing. Hassan Chaudhry: Data curation; formal analysis; investigation; methodology; visualization; writing—review and editing. Bassam Muthanna: Data curation; methodology; writing—review and editing. Hafiz Waqas Younas: Data curation; writing—original draft; writing—review and editing. Syed Ata ul Munamm: Data curation; formal analysis; methodology; software. Rohit Sharma: Formal analysis; writing—original draft. Kahtan Fadah: Writing—review and editing. Shereen Elazzazy: Data curation. Anas Hamad: Data curation. Osama Said Abu Tabar: Data curation. Nabil E. Omar: Conceptualization.The authors declare no conflict of interest.Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval was not required. It is a meta‐analysis with literature review therefore consent is not required for the article.The lead author Fateen Ata affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.


Further improvement in clinical outcomes is needed for patients with head and neck squamous cell carcinoma (HNSCC), as there is typically a poor prognosis at diagnosis. This study aimed to report the preliminary therapeutic outcomes and side effects in patients with HNSCC receiving particle beam radiotherapy (PBRT), owing to the physical and biological advantages of this approach.We retrospectively analyzed 68 patients with newly diagnosed HNSCC who received PBRT at the Shanghai Proton and Heavy Ion Center (SPHIC) between August 2015 and December 2020. The Kaplan–Meier approach was used to determine overall survival (OS), disease‐specific survival (DSS), progression‐free survival (PFS), local recurrence‐free survival (LRFS), regional recurrence‐free survival (RRFS), and distant metastasis‐free survival (DMFS). Common Terminology Criteria for Adverse Events (CTCAE) 4.03 was also used to grade acute and late toxicities.With a median follow‐up time of 24.5 months , the 3‐year OS, DSS, PFS, LRFS, RRFS, and DMFS rates for the entire cohort were 79.0%, 84.7%, 67.9%, 83.5%, 83.3%, and 96.1%, respectively. Univariate and multivariate analyses showed that N category was a significant predictor of OS, PFS, and RRFS. In terms of acute toxicities, two patients demonstrated severe mucositis or dysphagia, and two patients also displayed a late toxicity of significant mucosal necrosis.These findings suggest that PBRT can provide patients with HNSCC with a promising therapeutic benefit and manageable toxicity. Prospective evaluation of clinical outcomes with PBRT for HNSCC is warranted, with an emphasis on clinical effectiveness as well as adverse effects and patient quality of life. Intensity‐modulated proton and/or carbon‐ion radiation therapy provided satisfactory therapeutic effectiveness in our head and neck squamous cell carcinoma patients with tolerable acute and late toxicities. HNSCC is a diverse group of neoplasms derived from the mucosal epithelium in the oral cavity, oropharynx, hypopharynx, or larynx.Particle beam RT (PBRT) is one of the most advanced RT techniques and exhibits significant physical and biological advantages. Previous studies have demonstrated the potential benefit of PBRT in the treatment of head and neck malignancy.We recently published preliminary findings regarding the benefit of PBRT in major salivary gland carcinomas, showing a 2‐year local‐regional recurrence‐free survival rate of 94.2% and mild toxicities.22.1This retrospective research covered 68 consecutive patients treated at the SPHIC between August 2015 and December 2020 who had HNSCC  that had been newly diagnosed and histologically verified. Patients with distant metastases and prior head and neck radiotherapy for any malignancy were ineligible. As part of the pretreatment evaluation, all patients should have a history‐taking and physical assessment, as well as an enhanced magnetic resonance imaging (MRI) or computed tomography (CT) of the head and neck region. To rule out distant metastases, either positron emission tomography (PET)/CT was used, or a combination of chest CT, abdominal ultrasonography, and bone scanning. The American Joint Committee on Cancer (AJCC) staging system for this disease was used to stage all patients.2.2All patients had simulation CT scanning from the vertex to the inferior margin of the clavicular head after being positioned in supine position and fitted with thermoplastic masks to immobilize their heads, necks, and shoulders. Then, to identify targets and organs at risks (OARs), simulated CT was combined with the MRI used in the treatment position. The primary lesion and metastatic lymph nodes identified on clinical examination or radiographic evidence were contoured in the gross tumor volume (GTV). The GTV with a 1–3 mm margin to achieve the prescribed dose was designated as the clinical target volume (CTV) for boost (CTV‐boost). The high‐risk clinical target volume (CTV1) includes the CTV‐boost (or tumor bed) and subclinical extension according to clinical high‐risk area. In the case of individuals with ipsilateral upper neck lymphadenopathy, nodal levels IV and Vb were contained in CTV2. Based on the CTV, the planning target volume was formed by adding 3 mm for setup variability and 3–5 mm for range uncertainty.The total dose coverage of the targets and the OAR limitations were integrated and analyzed as a sum plan after the physical planning of a mixed photon or proton and carbon ion boost was evaluated individually. Except for the temporal lobes, brain stem, spinal cord, and optic nerve, which were based on previous experience from the National Institute of Quantum and Radiation Science (NIQRS) of Japan, the dosage limitations of the OARs are based on TD5/5 as stated by Emami et al.2.3Patients were advised to receive concurrent chemotherapy, which consisted of weekly or tri‐weekly doses of either cisplatin or nedaplatin, if their disease was locally advanced , node positive, and/or had high‐risk pathological factors after surgery, such as positive margin and extracapsular extension of lymph node metastasis. In general, adjuvant chemotherapy was not offered.2.4After the termination of radiotherapy, all patients followed the same routine for follow‐up appointments. Four to 6 weeks after the end of RT, the first follow‐up visit was planned. Thereafter, visits were set for every 3 months for the first 2 years, every 6 months for the following 3 years, and then once a year thereafter. The Radiation Therapy Oncology Group (RTOG) was used to grade late adverse events (occurring >3 months after initiation of RT), and the toxicity criteria of the Common Terminology Criteria for Adverse Events (CTCAE 4.0) was used to grade acute toxicities (occurring within 3 months after initiation of RT).2.5From the date of the pathology diagnosis to the date of death or the last follow‐up, the time of survival was determined. The interval between the date of diagnosis and documented failure date was used to calculate the time to local, regional, or distant failure. The Kaplan–Meier method was used to calculate survival rates, and the Cox proportional hazard analysis approach was used to identify independent prognostic factors. The statistical program SPSS (version 23.0) was used for all analyses.33.1n = 29), oropharynx (n = 22), hypopharynx (n = 10), and larynx (n = 7) were the primary tumor locations. The T category/N category (T3‐T4/N2‐3) or a positive surgical margin were indicators of adjuvant radiation in 27 patients who underwent prior surgery with R0 or R1 resection. Proton alone (n = 21), carbon ion alone (n = 10), proton combined with carbon ion boost (n = 24), and photon combined with carbon ion boost (n = 13) were administered to all patients. Twenty‐seven patients who underwent R0/R1 resection received adjuvant proton RT  or adjuvant carbon ion RT . Thirty‐seven patients with R2 resection or unresectable disease received proton (56 GyE/28 fractions) combined with carbon ion boost (12–18 Gy/4–6 fractions) in 24 cases and photon (56 Gy/28 fractions) combined with carbon ion boost (15–18 Gy/5–6 fractions) in 13 cases (n = 13), all with curative intent. The remaining four patients with unresectable disease received radical proton RT . Table Sixty‐eight consecutive newly diagnosed HNSCC patients who underwent proton, carbon ion, mixed photon, or proton and carbon ion boost at the SPHIC between August 2015 and December 2020 were examined. For the entire group, the median follow‐up was 24.5 months . The oral cavity , seven patients died from local and/or regional recurrence, one patient died from incision infection after mucosal necrotic excision, and another two patients died from other diseases (such as diabetes). Sixteen patients experienced recurrence events: six with local recurrence only, six with regional failure only, and four with both local and regional recurrences. In addition, three patients developed distant metastases (lung or bone metastases). The 3‐year OS, disease‐specific survival (DSS), progression‐free survival (PFS), local recurrence‐free survival (LRFS), regional recurrence‐free survival (RRFS), and distant metastasis‐free survival (DMFS) rates were 79.0%, 84.7%, 67.9%, 83.5%, 83.3%, and 96.1%, respectively, for the entire cohort Figure .3.3p = 0.004), and the 3‐year OS rates for patients with N0–1 and N2–3 disease were 96.6% and 61.5%, respectively , primary site (p = 0.029), T category (p = 0.022), and N category (p = 0.019) were significantly correlated with PFS. For T1–2 versus T3/4 disease, the 3‐year PFS rates were 77.4% and 56.0%, respectively, and for N0–1 versus N2–3, they were 87.8% and 46.5%, respectively , comprising 68.4% of LRFS cases , RT parameter (p = 0.025), and sex (p = 0.039) for RRFS. The 3‐year RRFS rates were 100% in patients treated with adjuvant RT, 74.8% in cases treated with definitive RT, 95.5% in cases of N0–1, and 68.9% in cases of N2–3, respectively , PFS (p = 0.04), and RRFS (p = 0.01), that sex was a significant predictor of PFS (p = 0.02), and that age was a prognostic factor for RRFS (p = 0.03) , sex , primary site, RT parameter , stage (I–II vs. III–IV), induction chemotherapy, and concurrent chemotherapy status Table . OS was y Figure . Additioy Figure . The out3.4The most frequently reported acute adverse effects were mucositis, dermatitis, xerostomia, and dysphagia. Two patients presented with Grade 3 mucositis and dysphagia. Thirty‐six (53%), 14 (21%), 14 (21%), and 6 (9%) patients developed Grade 2 mucositis, dermatitis, xerostomia, and dysphagia, respectively. The incidence of weight loss during RT was 35% (25% Grade 1 and 10% Grade 2). Gastrostomy was performed in 18 patients (26.5%) before RT, which may affect the grade of mucositis based on CTCAE criteria, while acute mucositis was graded using the RTOG criteria, with 31 cases (45.6%) of Grade 3 and 28 (41.2%) of Grade 2.Additionally, the treatment exacerbated long‐term side effects, such as dysphagia, xerostomia, and mucosal necrosis. Two patients (2%) each experienced Grade 4 and Grade 3 mucosal necrosis. Thirteen (19%) and 8 (12%) patients had Grade 2 xerostomia and dysphagia, respectively. RT‐related acute and late toxicities are shown in Table 4The results of 68 consecutive, non‐selected patients with HNSCC who received adjuvant or definitive RT at the SPHIC are presented in this study. The 3‐year OS, DSS, PFS, LRFS, RRFS, and DMFS rates were 79.0%, 84.7%, 67.9%, 83.5%, 83.3%, and 96.1%, respectively, with a median follow‐up length of 24.5 months . Local, regional, and distant failure (lung or bone metastases) occurred in six, six, and three patients, respectively. Both local and regional recurrences occurred in the other four cases. In terms of acute toxicities, two patients demonstrated severe mucositis or dysphagia, and two patients also displayed late toxicities with significant mucosal necrosis.In a study on the clinical outcomes of patients with locally advanced HNSCC treated with photon‐based chemoradiotherapy, Leeman et al. found that the 5‐year OS rates for herpes virus (HPV)‐associated oropharyngeal carcinoma (OPC), HPV‐negative OPC, oral cavity carcinoma, laryngeal carcinoma, and hypopharyngeal carcinoma were 85.2%, 66.9%, 53.2%, 56.3%, and 48.9%, respectively.A preclinical investigation discovered that carbon‐ion beam treatment was more beneficial to HPV‐negative cell lines and might be an effective HNSCC treatment option.p = 0.05) and 8% versus 24.7% (p = 0.01), respectively. Manzar et al. also explored whether this physical superiority of protons for OPC could translate into clinical benefits compared to photons and the decrease in the incidence of Grade 3 mucositis (14.7% vs. 35.9%) and Grade 2 pain (3.2% vs. 24.3%) in the proton group.In term of toxicities, patients with HNSCC treated with proton therapy have been reported to present with a lower incidence of toxicities, including mucositis, xerostomia, dysgeusia, tube feeding, and weight loss.Results regarding toxicities induced by mixed treatment based on carbon ions for HNSCC are limited. Hu et al. found that mixed photons with carbon ion boost were well tolerated in nasopharyngeal cancer patients, with only two patients experiencing significant acute toxicities (Grade 3 dermatitis).The current study has a few limitations that need to be addressed. First, the median follow‐up period (24.5 months) was quite brief; a longer follow‐up is required for tumors with specific subsites or varied HPV status to assess long‐term outcomes and toxicities. Second, the effectiveness and adverse effects of treatment may be affected by patient‐specific variations in RT techniques. Further stratified analysis based on various RT modalities needs to be performed. Third, there were relatively few patients included in our investigation, which was a retrospective analysis. The majority of earlier research on this topic have also been constrained by their retrospective nature and sample sizes due to the heterogeneity among subsites and the rarity of HNSCC. However, the design and execution of a prospective clinical study is challenging.5In conclusion, our findings highlight that PBRT generates moderate acute and late toxicities and demonstrates promising treatment efficacy in patients with HNSCC. The relative 3‐year OS, DSS, PFS, LRFS, RRFS, and DMFS rates were 79.0%, 84.7%, 67.9%, 83.5%, 83.3%, and 96.1%, respectively. Long‐term follow‐up is required to confirm the benefits and safety of PBRT in HNSCC management. Prospective evaluation of clinical outcomes with PBRT for HNSCC is further warranted, with an emphasis on clinical effectiveness as well as side effects.Qingting Huang: Data curation ; funding acquisition ; investigation ; software ; validation ; writing – original draft (lead). Jiyi Hu: Conceptualization ; data curation ; software ; validation ; writing – review and editing . Weixu Hu: Data curation ; formal analysis ; methodology ; software . Jing Gao: Methodology ; project administration ; resources ; supervision ; visualization . Jing Yang: Data curation ; formal analysis ; resources . Xianxin Qiu: Data curation ; investigation ; resources ; software . Haojiong Zhang: Formal analysis ; investigation ; methodology ; software . Jiade Jay Lu: Conceptualization ; supervision ; validation ; visualization ; writing – review and editing . Lin Kong: Conceptualization (lead); funding acquisition ; methodology ; resources ; validation (lead); writing – review and editing (lead).This work was mainly supported by the Key Research and Development Program of the Ministry of Science and Technology (project no. 2022YFC2401505), the Shanghai Sailing Program (project no. 22YF1444800), the Science and Technology Development Fund of Shanghai Pudong New Area (project no. PKJ2020‐Y53), and the Health Industry Clinical Research Project of Shanghai Municipal Health Commission (project no. 20224Y0062).The authors declare no conflicts of interest related to this study.The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the institutional review board (IRB) of the Shanghai Proton and Heavy Ion Center, Shanghai, China (No. 230208EXP‐01).Not applicable.


Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children. We aimed to analyze the factors affecting the estimation of RSV‐related disease burden, and to provide evidence to help establish a surveillance system.We searched the English‐ and Chinese‐language databases for articles published between January 1, 2010 and June 2, 2022. The quality of the included articles was assessed using the Agency for Healthcare Research and Quality scale. Random‐effects models were used for data synthesis and subgroup analyses. This review was registered in the Prospective Register of Systematic Reviews (PROSPERO: CRD42022372972).We included 44 studies , all of which were of medium or high quality. The pooled RSV‐related disease incidence, hospitalization rate, in‐hospital mortality, and overall mortality rates in children aged 5 years and younger were 9.0 per 100 children per year , 1.7 per 100 children per year (95% CI: 1.3–2.1), 0.5 per 100 children per year (95% CI: 0.4–0.5), and 0.05 per 100 children per year (95% CI: 0.04–0.06), respectively. Age, economics, surveillance types, case definition, and data source were all recognized as influencing factors.A standardized and unified RSV surveillance system is required. Case definition and surveillance types should be fully considered for surveillance of different age groups. We excluded studies without data on children aged under 5 years or that only reported data on children with comorbidities or underlying conditions, such as Down syndrome, congenital heart disease, and immunodeficiency. Further, we excluded studies that reported proportions, comparison of RSV diagnostic tests, animal research, repeated publications, letters, comments, case reports, case series, editorials, reviews, pure modeling studies or modeling studies for trend estimation, and studies with unavailable full text or those that were published in languages other than Chinese or English. The full texts of included studies were reviewed by two independent reviewers to assess their eligibility based on the inclusion and exclusion criteria. A third reviewer was consulted to reach consensus if the two reviewers' assessments did not concur.2.2Data on the eligible studies were extracted by two researchers independently and simultaneously, and then exchanged for checking to prevent data errors. When data were inconsistent among reviewers, they discussed and reassessed the article until they reached agreement. The data extraction checklist included the name of the first author, survey period, region or country where the study was conducted, race, study design (active or passive surveillance), data source , case definition  All statistical analyses were performed using Stata 17.0 .Pooled estimates of one‐group meta‐analyses were used to estimate the synthesis effect size and 95% CIs for RSV‐related disease incidence, hospitalization rate, in‐hospital mortality rate, and overall mortality in children aged 0–5 years. Subgroup analyses were performed to explore potential determinants affecting the RSV‐related disease burden, such as age, income level (according to the 2021 World Bank classification), surveillance type (active or passive surveillance), case definition (extended ARI or ILI), and data source. Table 33.1A total of 12,101 records were retrieved, and 2426 duplicates were excluded. Subsequently, an additional 9675 records were excluded after reviewing the title and abstract. A total of 44 studies were included in the final meta‐analysis, of which 34 were classified as high quality, and 10 were classified as moderate quality Table . The det3.2A total of 149,321,171 participants took part in the 44 included studies, with study sample sizes ranging from 1153 to 30,417,106. The first study was conducted in 1997 and published in 2015, whereas the most recent study was conducted in 2020 and published in 2022. Fifteen of the included studies reported RSV‐related disease incidence in 107,527 participants, 25 reported RSV‐related hospitalization rates in 62,691,095 participants, nine reported RSV‐related in‐hospital mortality rates in 55,149,680 participants, and five reported RSV‐related overall mortality in 31,317,106 participants. Eleven surveys (25.0%) employed active surveillance, 31 (70.5%) employed passive surveillance, and two studies (4.5%) did not mention the surveillance type. Twenty‐seven studies (61.4%) were based on national databases, 13 (29.5%) were based on sentinel hospital databases, and four (9.1%) were birth‐cohort studies. Two studies (4.5%) used the ILI definition for patient inclusion, and the remaining (95.5%) used the extended ARI definition. Eighteen studies (40.9%) were conducted in high‐income countries, 23 (52.3%) in middle‐income countries, and three (6.8%) in low‐income countries. Overall, participants were aged 0–5 years. A summary of the characteristics of the included studies is shown in Tables 3.3Based on the random‐effects model, pooled incidence, hospitalization rate, in‐hospital mortality rate, and overall mortality rate among children aged 5 years and younger were 9.0 (95% CI: 7.0–11.0), 1.7 (95% CI: 1.3–2.1), 0.5 (95% CI: 0.4–0.5), and 0.05 per 100 children per year (95% CI: 0.04–0.06), respectively  was significantly lower than that in 0–1‐year‐olds  and 0–2‐year‐old children , and the same trend was observed in RSV‐related hospitalization rate , in‐hospital mortality rate , and overall mortality rate .According to the World Bank classification, the RSV‐related disease incidence in high‐income countries was higher than that in low‐ and middle‐income countries combined . The same trend was found in RSV‐related hospitalization rate . However, the opposite trend was observed in the RSV‐related in‐hospital mortality rate and overall mortality rate. The RSV‐related in‐hospital mortality rate in high‐income countries was lower than that in low‐ and middle‐income countries combined . The RSV‐related overall mortality in high‐income countries was lower than that in low‐ and middle‐income countries combined  Table .The pooled estimated RSV‐related disease incidence in active surveillance studies was significantly higher than that in passive surveillance studies . Moreover, the RSV‐related in‐hospital mortality rate was lower in studies that used nationwide databases  and higher in studies conducted in single hospitals . The estimated RSV‐related disease incidence was higher using the extended ARI‐based case definition than that estimated using the ILI‐based case definition .3.5p = 0.5; hospitalization rate: t = 1.6, p = 0.1, in‐hospital mortality rate: t = 4.3, p = 0.4; overall mortality rate: t = 2.6, p = 0.1). Details are shown in Figure The results of the Egger's test did not show any significant publication bias .The pooled RSV‐related hospitalization rate was 1.7 per 100 children per year in our study, which was considerably higher than that in the model study conducted by Li et al. in 2019 (0.5 per 100 children per year),To fully understand current studies on RSV‐related disease burden among young children, we included studies focused on the whole population and reported corresponding results of 0–5 years old children. Thus, we studied on children ≤5 years rather than <5 years as normally used. Meanwhile, the incidence of RSV‐related disease was likely low among 5 years old children, which was also confirmed in our subgroup analysis. Among children ≤5 years, RSV‐related disease incidence decreased with increasing age, and the incidence in the 0–1‐year‐old group was three times higher than that in the 2–5‐year‐old group (9.0 per 100 children per year vs. 3.0 per 100 children per year), which was consistent with the findings of Nair et al.The RSV‐related disease incidence in children aged 5 years and younger was significantly higher in high‐income countries (15.0 per 100 children per year) than that in low‐ and middle‐income countries combined (7.0 per 100 children per year). Nair and Li et al. estimated that over 95% of the global RSV‐related ALRI cases occurred in developing countries, whereas the positivity rate was higher in high‐income countries,Methods of surveillance and case definitions were crucial points for a feasible surveillance system. In our study, the RSV‐related disease incidence was higher in active surveillance studies than that in passive surveillance studies (12.0 per 100 children per year vs. 3.0 per 100 children per year), consistent with the findings reported by Nair et al.This systematic review and meta‐analysis included many high‐quality original studies, among which 75% were ranked as high quality, and none were ranked as low quality. Additionally, we performed a specific and comprehensive subgroup analysis, which provides detailed information about the target high‐risk population and areas for RSV surveillance. The evaluation of various surveillance methods can provide scientific suggestions for constructing a standard and feasible surveillance system.p > 0.05).Our study also has some limitations. First, studies published in languages other than English and Chinese were excluded, which may lead to language bias. Second, the included studies had some obvious outliers and considerable heterogeneity owing to the differences in income level, age groups, surveillance types, case ascertainment standards, the diagnostic assays used to identify RSV, and the disparity in access to hospital care across studies. However, we did not exclude those studies considering that they met the inclusion criteria. We calculated the pooled rate and used a random‐effects model to synthesize the disease burden, which allows for some outliers and heterogeneity. The sensitivity analyses also confirmed the stability of the result. In addition, the aim of our study was to explore the influencing factors of heterogeneity and to eliminate the lack of comparability between studies in the future. We conducted a supplementary analysis of the studies that constituted the outliers in this section. Third, we only included studies relating to outpatients and community‐based surveillance to analyze RSV‐related incidence, which may have contributed to a higher incidence rate than that in other studies. However, this could provide a supplementary result for RSV‐related incidence in specific primary care settings. Finally, for the publication bias, studies did not conform well to the expected funnel shape, which may be due to the large heterogeneity and small number of the included studies. We further conducted a quantified Egger's test, and the results showed that there was no publication bias (all 5Our research provides an overall estimate of the RSV‐related disease burden in children aged 5 years and younger. More attention should be paid to RSV infection in children aged 2 years and younger, who are the target population of the surveillance project. Early detection and treatment can reduce disease severity and RSV‐related mortality. Awareness of RSV case ascertainment should be promoted among healthcare providers in low‐ and middle‐income countries. It is necessary to establish a feasible and standardized RSV surveillance system based on various considerations. Using the definition of extended ARI to determine patient inclusion will increase the sensitivity of case ascertainment. Active community surveillance is the top recommendation, whereas implementing a standard ICD code will be useful in retrospective passive surveillance and hospital‐based surveillance.Concept and design: Luzhao Feng and Weizhong Yang. Acquisition of data: Yuping Duan and Mingyue Jiang. Analysis and interpretation of data: Yuping Duan, Qiangru Huang, Mingyue Jiang, Mengmeng Jia, Luzhao Feng, and Weizhong Yang. Drafting of the manuscript: Yuping Duan and Mingyue Jiang. Critical revision of the paper for important intellectual content: Luzhao Feng and Weizhong Yang. Statistical analysis: Yuping Duan, Qiangru Huang, Mingyue Jiang, and Mengmeng Jia. Obtaining funding: Luzhao Feng and Weizhong Yang. Administrative, technical, or logistic support: Mingyue Jiang and Luzhao Feng. Supervision: Luzhao Feng and Weizhong Yang. All authors have read and agreed to the published version of the manuscript.The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/irv.13145.The peer review history for this article is available at Table S1. Search strategy.Table S2. Related definitions.Table S3. Summary of studies that contributed to RSV‐related incidence rate.Table S4. Summary of studies that contributed to RSV‐related hospitalization rate.Table S5. Summary of studies that contributed to RSV‐related in‐hospital mortality rate.Table S6. Summary of studies that contributed to RSV‐related overall mortality.Figure S1. Subgroup analysis of RSV‐related incidence among children ≤5 years old.Figure S2. Subgroup analysis of RSV‐related hospitalization rate among children ≤5 years old.Figure S3. Subgroup analysis of RSV‐related in‐hospital mortality rate among children ≤5 years old.Figure S4. Subgroup analysis of RSV‐related overall mortality rate among children ≤5 years old.Figure S5. Publication bias analyzed by funnel plot.Figure S6. Sensitivity analysis.Table S7. Quality scoring criteria for observational study studies.Table S8. Comparation of RSV‐related disease burden in different studies.Outliers' analysis.Click here for additional data file.