Objective: Physical exercise is associated with several benefits in the treatment of cystic fibrosis (CF), associated with a reduction in patient mortality. The aim of this systematic review was to determine the effectiveness of exercise interventions on physical condition and lung function in children and adults with CF to establish the most appropriate type and dose of physical exercise used so far. Methods: The studies included were randomized controlled trials with physical exercise interventions performed with children or adults with CF, analyzing the effects on pulmonary function, cardiorespiratory capacity, and muscle strength. The variables analyzed in at least four studies in the same population (children or adults) with the same measuring test were included in the meta-analysis. Results:Pulmonary function: There were no changes in the forced expiratory volume 1 s, but mouth expiratory/inspiratory pressures were improved in some studies. Physical fitness: In children, the interventions did not manage to improve the VO2peak  but improved muscle strength. In adults, physical exercise interventions based on high-intensity aerobic training showed positive results in the VO2peak, and in some muscle strength outcomes. Conclusions: Exercise interventions in children and adults with CF are effective in improving muscle strength, cardiovascular capacity, and respiratory muscle function. However, they do not achieve improvements in lung function. The most effective programs are those using strength training or cardiovascular high-intensity interval training, although to date there have been few such interventions. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, located on chromosome 7 [Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations of the mosome 7 . The chlmosome 7 . Althougmosome 7 .When CF was described in 1938 by pathologist Dorothy Hansine Andersen, it was a globally fatal disease of early childhood . Thanks 2max and lung function [2max, is a positive prognostic factor for the evolution of the disease, associated with a reduction in the number of annual hospitalizations [Physical exercise is associated with several potential benefits in the treatment of CF, such as positive effects on lung function , mucus cfunction . In thisizations . The dosizations , performizations . It is nizations . AlthougThe current literature contains many studies on exercise interventions in CF children, but few interventions have been carried out in adults. This is possibly because disease progression and pulmonary deterioration do not allow patients to adhere to the exercise programs currently prescribed by hospitals. Also, until very recently, the CF population was not reaching adulthood . For theTherefore, the aim of the present study was to determine the effectiveness of exercise interventions on physical condition and lung function in children and adults with CF, updating the scientific evidence about this topic .This systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement  and was Studies in four databases were reviewed: PubMed, Scopus, SPORTDiscus, and Web of Science, published from 2017 to 19 July 2022. The search terms were: “cystic fibrosis AND  AND ”. Reviews and grey literature were excluded. After removal of the duplicates, two authors (GGPS and ABV) independently screened the titles and abstracts and then evaluated the full text of potentially relevant studies. Disagreements were resolved by consultation with a third reviewer (MPR). Studies were eligible for inclusion if they met the inclusion criteria and did not meet the exclusion criteria. All the excluded studies were recorded, with the reasons for exclusion.The criteria for inclusion were (1) population—children or adults with CF; (2) type of study—randomized controlled trials (RCT) only; (3) type of intervention—physical exercise program with real exercise practice; (4) outcomes—short term or long-term measurement of pulmonary function, cardiorespiratory capacity, or muscle strength.Finally, the exclusion criteria were: (1) abstract not in English; (2) exercise protocol not included in the paper; (3) studies involving CFTR modulator therapies; (4) studies published before 2017.The full text of all the studies matching the inclusion criteria was retrieved, and then stored electronically and systematically reviewed.Pre- and post-exercise mean and standard deviation of descriptive characteristics of the participants and the following outcomes were extracted and recorded, by two authors (GGPS and ABV):1, forced vital capacity, maximal expiratory and inspiratory mouth pressures (MEP and MIP), and respiratory muscle endurance test.FEVCardiorespiratory outcomes: 6-Minute-Walking Test (6MWT) distance, VO2peak, modified shuttle run distance, and endurance exercise capacity.Muscle strength and functionality outcomes: horizontal jump test, medicine ball throw, handgrip strength, bench press strength, pectoral strength, dorsal strength, time up and go test, leg press, sit ups, pushups, biceps curls, and quadriceps strength.The characteristics of the physical exercise programs were also extracted and recorded.Three authors were contacted by e-mail to request missing data. Two of them provided the necessary data.Characteristics of studies, participants, and interventions were summarized in tables. The Revised Cochrane risk-of-bias tool for randomized trials (RoB 2)  was used2peak in children with CF.The meta-analysis of this review has been limited to the outcomes analyzed in at least four studies, in the same population (children or adults), with the same measuring test, which was only the VOMeta-analyses were conducted using the statistical software package Stata 16.1 .The mean of differences and pooled standard deviation (SD) was calculated using pre- and post-intervention data.At first, effect sizes (ESs) and adjusted Hedges’ g ) were calculated for each study by means of t-scores, number of subjects, and standard deviation (SD).2 statistics were calculated to find the proportion of the observed variability due to heterogeneity but not to randomness. I2 values of <25%, 25–50%, and >50% are considered to represent small, medium, and large inconsistency, respectively [Then, the Q and Iectively .In addition, an analysis of heterogeneity was carried out by interpreting the L’Abbé and Galbraith graphs .Finally, publication biases were identified using the funnel plot test and the Egger test, allowing us to detect asymmetries in the funnel graph . SignifiThe search strategy identified 434 articles from the databases. After removal of duplicates, 258 articles were initially screened via title and abstract, and 29 were iden-tified as potentially relevant. Full-text examination further excluded 17 studies, leaving 12 studies for inclusion in this analysis, all RCTs .Participant demographics, intervention characteristics, and outcomes are outlined in Pulmonary, cardiorespiratory, and strength outcomes were analyzed in seven studies ,28,29,30Interventions in children with CF were conducted for 2 to 12 months, and the modes of exercise were resistance training , The participants trained for 30–180 min per week divided into 2 to 3 sessions per week, at a moderate , maximal expiratory and inspiratory mouth pressures (MEP and MIP), forced vital capacity, and respiratory muscle endurance.Forced-expiratory volume 1 s  ,32,34,352O; p < 0.001), while another study [2O; p = 0.003), while another study [p < 0.01)  .1, without observing any improvement. In contrast, another study [In adults with CF, one study  analyzeder study  showed pCardiorespiratory Capacityp > 0.01), while two studies [2peak, and only one study [p = 0.006) , with low heterogeneity   . The resI2 = 8%) .2peak, with two studies [In adults with CF, four studies ,33,34,35Muscle Strength and Functionalityp < 0.05), but no changes in the medicine ball throw. Two studies [p < 0.01)  and two studies [In children with CF, one study  showed s studies ,27 obser studies ,27 obserp = 0.02), bench press , and number of push-ups, but no changes in the handgrip strength, biceps curls, and number of sit-ups. Another study based [In adults with CF, one study based  on resisdy based  on aerobThe aim of this systematic review was to analyze the effectiveness and characteristics of physical exercise interventions on pulmonary function and physical condition (cardiorespiratory function and muscle strength) carried out in children and adults with CF over the last 5 years. All the studies included in this review were RCTs of fair–good methodological quality. They showed that patients enrolled in exercise programs obtained better improvements in physical condition compared to patients undergoing conventional therapy . In addition, we have noted that few studies have analyzed both lung function and physical fitness as target variables. Regarding the characteristics of the exercise interventions proposed to date, they are mixed programs combining cardiorespiratory and strength exercise with a predominance of moderate intensity. The results of this review allow us to be aware of the components of the workload  used to date in children and adults with CF. We believe these results can be of great support to progress in this field and to be able to propose new, and perhaps more effective, approaches.1 [2O) and MEP (+30 cm H2O) using interval training at an intensity of 70% of VO2peak for 12 weeks [2O) after inspiratory muscle training with a Threshold Inspiratory Muscle Trainer at an intensity of 30% of MIP, 15 min, two times a day for eight weeks [2O) after training the expiratory muscles with a Threshold Respiratory Muscle Trainer at an intensity of 30% of MEP, 20 min, five times a week for six weeks [1, forced vital capacity, nor in the other pulmonary function tests. The reason that these studies are successful in improving respiratory muscle function but not lung function per se may be since most of these studies are conducted in patients with mild-to-moderate CF [Both in children and adults with CF, the physical exercise interventions included in this systematic review failed to improve lung function measured by FEV1 ,28,29,351 ,28,29. I12 weeks . In chilix weeks . Finallyix weeks ,28,29, derate CF .2peak in children with CF, of which two studies [2peak (+2.71 mL/kg/min) and was based on strength exercise recommendations performed at home, three days per week for 12 months, without providing data on the duration or intensity of the sessions. Nevertheless, this intervention did not show improvements in lung function.Concerning physical condition and particularly cardiorespiratory function, it is worth noting that physical capacity is one of the main predictors of risk of exacerbation and mortality in CF patients ,14. Thre studies ,27 showe studies  was the p = 0.73).The results of our meta-analysis see  on this 2peak [2peak , as welp > 0.01). Possibly, strength exercise can be well tolerated in patients with CF, and if performed prior to cardiovascular training may be useful to strengthen peripheral muscles and reduce ventilatory demands during exercise, and thereby improve cardiovascular capacity [Another variable of interest is muscle strength. Improved muscle strength in CF patients indicates peripheral physiological adaptations in a tissue markedly affected in CF, for example in its mitochondrial function . In chilcapacity . In the capacity . In adulcapacity  analyzedcapacity .2peak and prolonged recoveries, as is being done in other pulmonary pathologies [This systematic review provides novel findings regarding physical exercise interventions in CF patients. However, it suffers from some limitations. Mainly, we did not find enough RCTs that analyzed the same variables with the same instruments to perform quantitative analysis, in both children and adults. Furthermore, most of the studies had low sample sizes. Similarly, very few studies have analyzed pulmonary, cardiorespiratory, and muscular function at the same time. This would be very useful to observe interactions between these variables, and to determine which adaptations to exercise occur with which types of programs and which do not. Similarly, there was marked heterogeneity in the interventions in terms of type and dose of exercise, as well as in terms of exercise supervision, with unsupervised programs presenting risks of bias. Finally, we believe shorter exercise interventions are needed, with intensities above 70% of VOhologies . Continuhologies . Intervahologies .2peak. On the other hand, it is also important to undertake trials with different types and doses of exercise in adults with CF, since, as we have seen in this review, these studies are still scarce, and less relevant improvements are observed compared to children, due to the deterioration that already exists in the lung.The results of this systematic review indicate that current physical exercise interventions in CF patients improve muscle strength and respiratory muscle function in both children and adults, and cardiorespiratory function in adults, although they do not improve lung function. Therefore, physical exercise achieves positive physiological adaptations at the peripheral level in these patients, possibly involving muscle oxidative enhancement and stimulation of mitochondrial function. Future studies should use interventions that combine strength exercise with HIIT, with the aim of increasing the exercise dose without generating a high pulmonary demand. This may lead to greater improvement in cardiovascular and pulmonary function. Similarly, efforts should be made to improve adherence to exercise to ensure it becomes part of the patient’s lifestyle, since those studies lasting more than 12 months achieve greater changes in important variables such as VOExercise interventions in children and adults with CF are effective in improving muscle strength and respiratory muscle function. In adults with CF, they also improve cardiovascular capacity. However, these interventions do not achieve improvements in lung function. The latter could be since most of the patients had mild-moderate lung involvement and might need very specific exercise doses to achieve significant improvements. The most effective programs are those using strength training or cardiovascular high-intensity interval training, although to date there have been few such interventions.


After a screening period of 7 days, patients were randomized to receive either paste-type ADM or standard wound care. The wound status was evaluated at baseline, 1, 2, 4, 8, and 12 weeks. A total of 86 patients were enrolled in this study. The wounds continuously and constantly reduced in size from week 1, and the reduction rate was significantly greater in the study group from week 2 until the end (week 12). In the study group, wound healing was achieved in 29 of 38 wounds (76.3%). Paste-type ADM might be a useful option for wound healing and can be applied safely and efficiently for advanced wound care.The treatment of chronic wounds remains challenging. Acellular dermal matrix (ADM) has been shown to be effective for various types of wound healing. This study was designed to compare the wound size reduction rate after 12 weeks between patients receiving paste-type ADM and standard wound care. Patients over 19 years old with chronic wounds, deeper than full-thickness skin defects, more than 4 cm Wound healing progresses systematically through inflammation, proliferation, and remodeling phases ,2. InterThe treatment of chronic wounds remains challenging. When these wounds are non-responsive to conventional wound management modalities, advanced wound care materials, including cultured autologous material, allogenic materials, and bioengineered products, are required to accelerate wound healing ,10,11,12Acellular dermal matrix (ADM) is a biomaterial derived from autologous and allogenic tissues that undergoes processing to remove cells, while still retaining the bioactive dermal matrix, consisting of collagen, elastin, and fibronectin ,3,4,7. AAlthough ADM is commonly used in sheet form, paste-type ADM manufactured by crushing and micronizing allograft material derived from donated human skin has recently been introduced. This transformation makes it is easy to handle and paste-type ADM can be applied to various types of wounds, including external, ulcerative and irregularly shaped tunneling wounds ,13,14,15The primary objective of this study was to compare the wound size reduction rate after 12 weeks between patients receiving ADM therapy and standard wound care. The secondary objectives were to compare the complete wound healing rate, the epithelization rate, granulation tissue formation, and safety.This was a 12-week prospective randomized controlled multicenter clinical trial conducted to determine the efficacy and safety of paste-type ADM therapy. This study was approved by the institutional review boards of Seoul National University (1704-063-845), Hanyang University (2017-01-061), and the Catholic University of Korea (VC17DNSI0079). All participants provided written informed consent for the publication of the case details, including images. The study was registered at ClinicalTrials.gov (NCT04019639). All of the data were analyzed anonymously and in accordance with the principles of the 1975 Declaration of Helsinki (revised in 2008).Two products were used in this study: CG-PASTE  and Easyfoam . CG-PASTE is a paste-type micronized acellular dermal matrix that is currently used safely in clinical practice; it has been approved as a medical device applicable to open wounds except for third-degree burns. Easyfoam is a wound dressing applied to wounds with exudates and protects wounds by maintaining a moist environment on the wound.Each patient was screened for eligibility, including a complete medical history, physical examination, and full assessment of the wound, based on the inclusion and exclusion criteria shown in 2 and failing to heal during a minimum of 3 weeks before the study [Patients > 19 years old, with chronic wounds with the wound depth ranging from full-thickness skin to bone exposure measuring more than 4 cmhe study ,15, wereThe exclusion criteria were superficial or partial-thickness skin defects, undermining or tunneling wounds for which it was difficult to measure the wound depth, and uncontrolled infection, including osteomyelitis. Patients with poor metabolic control (HgA1c > 12% within the previous 3 months), a serum creatinine level > 3.0 mg/dL, treatment with other medical devices or topical growth factors that can influence wound healing within the previous 30 days were excluded.Patients were evaluated during a screening period up to 7 days before baseline surgical debridement and treatment. All patients underwent debridement until healthy, viable tissue was visible in the wounds. After the surgical preparation of the wound site, patients were randomized into either the experimental group  or control group  using sequentially numbered, opaque, sealed envelopes to avoid selection bias.Wounds were assessed at 0 , 1, 2, 4, 8, and 12 weeks after randomization, and upon study exit or withdrawal. Photographs of the wounds were taken at a distance of 30 cm. A centimeter scale was placed adjacent to the wound. Wound size, granulation tissue formation, epithelization, complete healing status, and adverse events were recorded at each follow-up visit.For patients assigned to the experimental group, paste-type ADM (CGPaste) was placed on the wound bed to cover the entire wound surface, and then covered with polyurethane foam (EasyFoam). It was applied at 0, 1, 2, and 4 weeks after the initial surgical preparation of the wound. For patients in the control group, wounds were covered with conventional dressing using polyurethane foam only.The main outcome was wound size reduction over the 12-week follow-up period. Secondary outcomes were the achievement of complete healing , time to complete healing, and granulation tissue formation during the follow-up period. Wound granulation and epithelialization were evaluated by using photographs of the wounds taken under similar conditions . The evaluation of photographs was performed by two independent evaluators who are experts in the plastic surgery department. Granulation tissue formation was evaluated as the percentage of the wound surface that was covered with bright-red healthy granulation tissue. The granulation rate was defined as the percentage of patients who achieved over 75% granulation. Epithelialization is defined as the wound covered with an epithelial surface. The epithelialization rate was calculated as the percentage of patients who achieved epithelization. Adverse events, including wound infection or any complications, were also evaluated.t-test or Mann–Whitney test, depending on whether the data met the criteria for parametric analysis. The times to healing and granulation were compared between the two treatment arms using the log-rank test. A statistical analysis was performed using GraphPad Prism for Windows , and a two-sided p < 0.05 was taken to indicate statistical significance.Categorical variables were analyzed using contingency tables (Chi-square) and continuous variables were analyzed using either the independent A flow chart of study enrollment and participation through the clinical trial is shown in According to the literature, the chronic wound area of the control group after 12 weeks was expected to decrease by about 92.3% compared to the baseline , and thaOf the 86 patients enrolled in the study, five were considered screening failures. The remaining 81 patients were randomized into two treatment groups, with 41 patients (42 wounds) receiving paste-type ADM (study group) and 40 (40 wounds) receiving standard care (control group). Eight patients (four in the study group and four in the control group) did not complete the clinical trial.The wound size reductions at the evaluation points in both treatment groups are presented in p = 0.0006 and p = 0.0016, respectively).The percentage of granulation tissue in the wound , as wellp = 0.001).Wound healing was defined as complete epithelization without a raw surface. No adverse events were noted during treatment.A 27-year-old female patient presented with a third-degree contact burn on her lower left leg. After debridement, the wound measured 6.0 × 4 cm . We applAn 81-year-old male patient presented with an open wound on his lower left leg due to trauma. The patient was treated at a local clinic for over 1 month, but the wound did not heal. A 5 × 4 cm skin defect was observed after debridement . We applA 77-year-old male patient presented with a diabetic foot ulcer in the right lateral malleolus region. A rotation flap was applied from the foot dorsum and skin grafting was performed at the donor site. However, the flap was necrotized and the skin graft only partially took. After debridement, an open wound measuring about 5 × 3 cm was observed in the lateral malleolus region and on the foot . After tThe patient was satisfied that the wound had healed completely without surgery, with no discomfort in the foot or ankle and normal function.Wound healing is a well-coordinated process involving interactions of cells with the microenvironment. The extracellular matrix (ECM) is one of the key elements in wound healing, providing structural support as the largest component of the dermal layer ,15 and aThe use of ADM provides several advantages. First, the ADM undergone processing to remove cellular components, which makes it immunologically inert ,4,7,12. This study used paste-type ADM, which is crushed, micronized, and packed in a syringe, and can therefore be applied more easily than sheet-type ADM. Most of the participants in this study were enrolled on an outpatient basis. In addition, it can be applied to complicated wounds, including deep wounds, cavitary wounds, undermining and tunneling wounds, wounds with dead space, etc. ,30,31. TThe clinical efficacy of a paste-type ADM for various wounds has recently been studied in animal experiments and clinical trials. However, there has been little progress in clinical studies and most such reports to date have been case studies. Paste-type ADM has shown comparable effectiveness for wound healing to subcutaneous injection in rat models . SeveralThe results of this prospective randomized multicenter study indicated that chronic wounds treated with ADM have a higher probability of healing compared to those treated with conventional management. This study had two main goals. The first was to compare the wound size reduction rate after 12 weeks between patients receiving paste-type ADM and standard wound care, and the second was to compare the epithelization rate, growth of granulation tissue, complete wound healing rate, and safety between treatment groups. Immediately after surgical preparation and the application of ADM, the wound size continuously and constantly reduced from week 1, and from week 2, the wound size reduction was significantly greater in the study group until the end (week 12). Furthermore, granulation tissue formation was observed in 36 of 38 wounds (94.7%) in the study group compared to 26 of 36 wounds (72.2%) in the control group, while full epithelization was observed in 34 of 38 wounds (89.5%) in the study group and 18 of 36 wounds (50%) in the control group. Consequently, wound healing was achieved in 29 of 38 wounds (76.3%) in the study group compared to 11 of 36 wounds (30.6%) in the control group. In addition, no adverse events were noted during treatment.Although debridement is not the standard of care for wound management, it was performed in this study to ensure that the two treatment groups were treated equally, and to promote wound healing while minimizing differences by wound type. The failure of wound healing is often caused by a prolonged inflammatory phase or poor vascularization. Debridement reduces the bacterial burden, removes biofilms and necrotic tissue, ensures viable cells at the wound edges, and helps prepare the wound bed before wound management. We assumed that the appropriate preparation of the wound bed improved the wound healing process in both treatment groups, resulting in complete wound healing in 40 of 74 wounds. There were no adverse events during treatment, including infection, indicating that the process was performed carefully in a sterile environment, and that the paste-type ADM infection rate is low such that it can be used safely.2 that failed to heal during a minimum of 3 weeks of conservative care before the study. As various factors can lead to chronic wounds, it is difficult to characterize a wound only according to location or type. Therefore, wound depth, size, and duration were considered in this study.The strengths of this study include the prospective randomized controlled design and involvement of multiple centers. Although 12 weeks is a common endpoint in wound studies, a longer follow-up would have been beneficial. In addition, there were no significant differences in demographic characteristics, including initial wound size, between the treatment groups, such that the outcomes reflected only the effects of the different treatments. The inclusion criterion was chronic non-healing wounds, with a depth from full-thickness skin defects to bone exposure, and a size measuring more than 4 cmRegarding study limitations, paste-type ADM application was applied with polyurethane foam dressing in all cases. There may be differences in the effects of ADM according to the dressing material used at the same time. In addition, paste-type ADM was not compared to other types of conventional dressing, such as gauze or NPWT, or to other types of ADM.This prospective randomized multicenter study showed that treatment of chronic wounds with ADM reduced wound size, increased the epithelization rate and granulation tissue formation, and achieved a higher rate of complete wound healing compared to conventional management. Therefore, paste-type ADM might be a useful option for wound healing and can be used safely and efficiently for advanced wound care.


Since the outbreak of the respiratory infectious disease caused by the novel coronavirus in 2019, the COVID-19 epidemic has posed a serious threat to the life and safety of the public, and has also seriously affected the normal study and life of college students in China. Although a series of studies have been conducted on college students’ knowledge, attitudes and practices of COVID-19, the results vary widely. This study aimed to evaluate the pooled estimated level of knowledge, attitudes, and practices (KAP) about COVID-19 among college students in China.We conducted a comprehensive search on Scopus, ProQuest, PubMed, EMbase, Web of Science, the Cochrane Library, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), VIP Database and Wanfang Database up to 13 February 2022. We then assessed the quality of included studies using a checklist developed by the Joanna Briggs Institute (JBI) for cross-sectional studies and analyzed using STATA.15 after two researchers independently extracted relevant data and entered them into Microsoft Excel. Funnel plots and Egger’s regression tests were used to check for publication bias, and sensitivity analysis was performed to assess the robustness of the results. A random-effects model was used for the meta-analysis, on the basis of which subgroup analyses were performed by time of investigation (study period) and by gender and major of the subjects.A total of 42 studies including 174,440 subjects were included in this review, and the quality of the included studies was mainly intermediate and advanced. The findings of the meta-analysis showed that the overall levels of Chinese college students’ knowledge, positive and negative attitudes, and practice of preventive measures towards COVID-19 were 74% (95%CI: 69%-79%), 84% (95%CI: 80%-88%), 31% (95%CI: 23%-38%) and 82% (95%CI: 77%-86%), respectively. The results of subgroup analysis showed that female and medical college students had higher levels of knowledge and practice on COVID-19.The study findings showed that the overall KAP level of college students in China included in the study was relatively optimistic. Influenced by gender, major and time, there were differences in the KAP level of college students. In order to promote the effective prophylaxis and control of pandemic, we recommend implementing targeted measures to improve the awareness rate of COVID-19-related knowledge among this group and the implementation rate of COVID-19 preventive measures among male and non-medical college students. In late December 2019, a cluster of severe pneumonia patients of unknown cause was reported in Wuhan, China. In the testing of lower respiratory tract samples from 4 patients, a novel strain of coronavirus belonging to the same family of viruses that cause Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), as well as the four human coronaviruses related to the common cold, was isolated .According to existing studies, COVID-19 has the characteristics of strong infectivity, easy mutation, and general susceptibility of the population , 5. AlthWhile there were existing studies on the knowledge, attitudes and practices (KAP) towards COVID-19 among college students in China, they were not comprehensive and the results obtained vary. A review article  evaluateThis systematic review and meta-analysis was conducted in accordance with the ‘Preferred Reporting Items for Systematic Reviews and Meta-analyses’ (PRISMA)  S2 FileS2 File. All observational studies on KAP towards COVID-19 among college students in China were considered for this study, with no restrictions on the gender, health status of the subjects, and language, time, quality or geographic location of the study. However, only studies that were available in full text and reported the sample size of the study and data related to any one component of the KAP, or provided data from which required outcomes could be calculated, were included.We excluded certain studies that were conducted only on specific populations, such as medical students. In addition, review articles, studies with confused or potentially erroneous data, studies for which raw data could not be extracted or transformed, and studies reporting perception on coronaviruses other than COVID-19 would also be excluded.http://www.sinomed.ac.cn/index.jsp), China National Knowledge Infrastructure , VIP Database (http://lib.cqvip.com/) and Wanfang Database (https://new.wanfangdata.com.cn/index.html). In addition, other studies including grey literature were searched through Baidu Xueshu and Google Scholar. The main keywords for the search strategy included “Covid-19”, “2019-nCoV”, “SARS-CoV-2”, “Severe Acute Respiratory Syndrome Coronavirus 2”, “knowledge”, “perception”, “awareness”, “consciousness”, “attitude”, “practice”, “action” and “KAP”. Search strategies for PubMed and CNKI databases are provided in The two researchers conducted systematic searches in Scopus, ProQuest, PubMed, EMbase, Web of Science, the Cochrane Library, Chinese Biomedical Literature Database  In addition, the proportion of specific content in each component of KAP was also extracted from the included studies. Any disagreements during extraction were resolved through discussion and negotiation. When necessary, we would contact study authors for missing data.The quality of included studies was independently assessed by two researchers using the JBI Quality Assessment Checklist , which c2 value, where 25%, 50%, and 75% indicated low, moderate, and high heterogeneity, respectively [Descriptive analysis was used in most sections to report relevant content, and the statistical software package STATA.15 was used to analyze quantitative data extracted from each study. Funnel plots and Egger’s regression test were used to check for publication bias, with P <0.05 considered to exist potential publication bias . The Cocectively . As heteA total of 9,688 articles were retrieved from the selected database. After excluding 4,599 duplicate articles, another 5,047 articles were excluded according to the inclusion and exclusion criteria on the basis of reading the title, abstract and full text. Finally, 42 articles were included for qualitative and quantitative analysis, including 174,804 participants –57. The A total of 42 studies encompassing 174,440 participants were included, most of which were conducted in 2020. Except for the 4 studies that did not elucidate the gender characteristics of the participants, in the remaining 38 studies, 60.63% of the participants were female.All studies employed a cross-sectional design, and data were collected primarily through online questionnaires. Nine studies reported all three components of KAP, and the remaining 33 reported only two components or one component of KAP. The sample size of each study varied from 134 to 44446. For more information on included studies and participants characteristics, see The overall average score of the included studies was 4.74 according to the JBI quality assessment checklist. Among them, 16 studies (38.1%) were rated as good quality (score ≥6) and 26 (61.9%) as moderate quality (score 3–5). All studies failed to score on questions 5 and 6, which were related to the failure to identify and deal with confounding factors in the research process. (See 2 = 99.8%), the pooled proportions of positive and negative attitudes towards COVID-19 were 84%  versus 31% , and the pooled proportion for COVID-19 practice level was 82% .The pooled proportion and 95% confidence interval of knowledge, attitudes, and practices towards COVID-19 among college students in China is presented in a forest plot Figs –5. AmongIn addition, further analysis was carried out on the specific content of each component of KAP. The results showed that the pooled awareness proportions of Chinese college students about the main symptoms, routes of transmission, susceptible population, incubation period and preventive measures of COVID-19 were 80%, 73%, 43%, 87%, and 70%, respectively. The pooled proportions of practice for specific precautions against COVID-19  were 90%, 84%, and 87%, respectively.  . In addiThe robustness of the results was assessed using a leave-out-one sensitivity analysis, which showed that stepwise exclusion of each study did not result in any significant changes in the pooled proportion for knowledge, positive and negative attitudes, and level of practice.  and practice  compared with men, with no significant difference in attitude towards COVID-19 . Compared with non-medical college students, medical college students had a higher level of knowledge towards COVID-19 , more positive attitude  and higher level of practice .The results of subgroup analysis based on the study period showed that over time, the pooled proportions of the mastery and practice of COVID-19-related knowledge and preventive measures among college students in China showed an upward and downward trend, respectively. But there was no noticeable change in their attitudes towards COVID-19 . SubgrouAlthough China has long entered the stage of normalizing the prophylaxis and control of the COVID-19 epidemic, clustered epidemic events on campus still occured from time to time. As a global pandemic that the most extensive to afflict humanity in a century , the proThe findings of this meta-analysis showed that the pooled proportion of college students’ knowledge of COVID-19 was 74%, which is similar to the findings reported by Aynalem YA et al. . The resThe pooled proportion of subjects with positive attitudes about COVID-19 in this study was 84%, which was higher than the reported results of two studies conducted in Ethiopia 67.2%)  and Japa.2%  and Furthermore, the pooled proportion for COVID-19 practice level was 82%, which was slightly lower than the findings of Yang K et al.  (84.4%).2>99%) in the pooled proportions of KAP components. To find the sources of heterogeneity, we used subgroup analysis and “a leave-out-one” sensitivity analysis were conducted to further assess relevant studies. The results showed that the pooled results of KAP components were robust and not influenced by a single study. Therefore, we considered that the high heterogeneity might be caused by differences in the original study sample size, questionnaire content, definition of results, and measurement methods.In this study, we observed a significant heterogeneity Click here for additional data file.S1 File(XLSX)Click here for additional data file.S2 File(DOC)Click here for additional data file.


Background: The classic ketogenic diet (cKD) has been used worldwide as an effective therapy for children with drug-resistant epilepsy. However, there have been no studies performed in Middle Eastern countries in order to assess the efficacy, side effects, predictors of cKD response and factors mostly associated with diet adherence. This study aims to assess the efficacy of cKD ratios of 4:1 and 3:1 and their influence on growth and biochemical parameters, particularly lipid profile and liver function tests (LFTs), and the factors most associated with diet adherence in a cohort of children with drug-resistant epilepsy in Bahrain. Methods: Baseline and follow-up data related to patients’ demographic and biochemical variables, epilepsy episodes, diet history and anthropometric measurements were retrieved for a total of 24 children treated with cKD in Bahrain. Results: After 6 months cKD initiation, 58.3% were positive responders with >50% seizure rate reduction, and 33.3% became seizure-free at 12 months. After 6 months of intervention with cKD, the level of triglycerides and albumin had a significant (p < 0.05) average increase over time of +1.47 mmol/L and 4.3 g/L, respectively. Although the median values of total cholesterol and alanine transaminase increased, respectively, following cKD initiation, the difference over time was not statistically significant. The mean z-scores for weight, height, and body mass index (or weight-for-length) did not change significantly at 12 months follow-up. cKD duration was the highest correlated variable with cKD efficacy (r = 0.76), which was followed by age at cKD initiation (r = 0.47). The cKD was discontinued by 14 patients (58.3%) during the first follow-up period (6 months), which was mainly due to inefficacy (n = 8), poor compliance (n = 3), food refusal (n = 1), achieved required efficacy (n = 1) and death (n = 1). Conclusions: cKD is an effective treatment for patients with drug-resistant epilepsy, and positive response to cKD was the main factor that increased adherence to the diet. Although long-term cKD could increase the risk of dyslipidemia and hepatic problems, it appears safe for children. Consequently, close monitoring and emphasis on healthy fats is of high priority. Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria . The WorEpilepsy has significant economic and social impacts, including susceptibility to disability, frequent hospitalization, social isolation and discrimination, and premature death . Most paThe classic ketogenic diet (cKD) has been used since the 1920s as an effective treatment option for many patients with drug-resistant epilepsy . HoweverThe cKD is composed of a 3:1 to 4:1 ketogenic diet ratio of fat to carbohydrate and protein . The MADA large percentage of patients with epilepsy fail to respond to the AEDs. Furthermore, uncontrolled epilepsy leads to frequent hospitalization and negatively impacts patients’ and caregivers’ quality of life. For many, KDTs represent the last hope for a lasting relief of their epilepsy ,15.However, several factors may interfere with the adherence to KDTs including restrictiveness of the diet, adverse side effects and lack of efficacy . The carbohydrate restriction in KDTs is one of the challenges that made the diet adherence more difficult due to the limited food options and decreased palatability—particularly when considering the dietary patterns of the country. For example, in Bahrain, the carbohydrate foods such as rice and bread are considered a staple food and a main component in almost every meal. Furthermore, almost all of the traditional Bahraini foods are carbohydrate-based such as harees, jareesh, balaleet, qaimat, khanfaroosh and machboos.Because of this, the adherence of the cKD is a critical factor to consider in the Middle East. The features of the ketogenic diet in the Middle East are based on a mixing contamination of local and foreign foods. Basically, it is a fusion of several food cultures including Arabic, Turkish, Iranian, Iraqi, Indian, Pakistan, Lebanon and Sub-Saharan Africa.The ketogenic diet in the Middle East includes the use of herbs and spices with high-fat food preferences including heavy cream, cultured cream, butter and safflower oil. Protein-rich food choices include lamb, fish, chicken and beef. Olives (high in fat) are grown in these regions, and children are accustomed to eating them regularly. Very common in this area is the attitude to eat nuts such as pistachios that make great snacking options for anyone following the ketogenic diet. They are excellent sources of both dietary fat and fiber. Very common are the coconut biscuits that could provide an alternative for a fitting breakfast.The Middle Eastern diet is very suitable for adapting itself to a ketogenic diet, since there are a variety of local recipes and foods with more than 70% of fats and less than 10% of sugar. As showed in The most common side effects reported were gastrointestinal disturbance, cardiovascular complaints, and renal and skeletal problems ,13. GrowFrom this literature review, apparently, there is a lack of a study conducted on cKD in children with epilepsy in the Middle East region; consequently, the significance of performing such a study in this region is increasing. In addition, it is important to ensure the safety of cKD in terms of its impact on children’s growth and biochemical markers, especially lipid profile, which continued to be controversial. Furthermore, detecting the variables that are most likely linked with favorable response to cKD will assist in the improvement of cKD therapy protocol in children with epilepsy.It can be hypothesized that cKD might convey risks of increased lipid profile, liver enzyme derangement, and declined growth in children with drug-resistant epilepsy. In addition, the adherence to cKD will increase with increased efficacy and tolerance.This study aims to assess the efficacy of cKD and its influence on growth and biochemical parameters, particularly lipid profile and liver function tests (LFTs) and the factors most associated with diet adherence in a cohort of children with drug-resistant epilepsy in Bahrain. Specifically, this study was performed to identify the factors that can predict the cKD efficacy, to measure the dropout rate, to distinguish the factors that enhance ketogenic diet adherence, to investigate the association between different factors related to patients, seizures, and diet treatment and the response to ketogenic diet and to assess the influence of ketogenic diet on the growth of children with epilepsy.This is a retrospective cohort study conducted at the Salmaniya Medical Complex (SMC) in Bahrain between March 2018 and June 2021. The study protocol was approved by the Secondary Health Care Research Subcommittee (SHCRC) of the Ministry of Health, Bahrain . The study was conducted in full compliance with the Declaration of Helsinki, and written parental consent was obtained. The cKD has been used as a treatment for children with drug-resistant epilepsy at SMC since 2010. Patients are monitored by a multidisciplinary team including pediatricians, neurologists and licensed dietitians. Patients were under treatment with these AEDs drugs: clobazam, oxcabazepine, levetiracetam, topiramate, phenobarbiton, clonazepam, sabril, vigabatrin, rivotrel and clonazepam.Medical records were used retrospectively to identify all infants and children aged 0 to 14 years who were treated with cKD for drug-resistant epilepsy at SMC between 2010 and 2021. Patients’ demographic data were collected at baseline including sex, age at epilepsy onset, age at cKD initiation, epilepsy duration (time between epilepsy onset and cKD initiation), epilepsy diagnosis/etiology, number of AEDs used, and seizure frequency. Furthermore, biochemical  were collected at baseline and at outpatient clinic follow-ups at 6 months, and anthropometric  data were also collected at baseline and at outpatient clinic follow-ups at 12 months. cKD efficacy in patients was categorized into three categories: responders (>50% seizure reduction), non-responders (<50% seizure reduction) and seizure freedom after a follow-up at 3, 6 and 12 months. Diet information of cKD type, route of feeding, cKD duration and reason of cKD discontinuation were recorded as well. The WHO growth reference and Centers for Disease Control and Prevention (CDC) reference chart were used to determine z-scores for weight-for-age, height-for-age, BMI-for-age, and weight-for-length. WHO growth standards were used for children less than 2 years old, while CDC growth charts were used for children aged 2 years and older as recommended by the CDC. Differences in baseline and 12 months follow-up after cKD initiation z-scores were calculated for height (∆ height z-score), weight (∆ weight z-score) and BMI (∆ BMI z-score).® KD formula  was used as the sole source of nutrition for both infants < 6 months old and enterally fed patients. In addition, KetoCal® was used to supplement the intake of other orally fed patients. During admission, patients were closely monitored for ketosis and hypoglycemia. After verification of cKD tolerance and positive urinary or blood ketones was achieved, patients were discharged from the hospital and followed up in the dietetic outpatient clinic every 3 and 6 months to monitor cKD efficacy and tolerability and to assess growth and biochemical status. Following a standardized protocol , patientAfter discharge, caregivers were instructed to monitor urine ketones several times per week to ensure cKD adherence and monitor the ketosis level. If the level of ketosis was low at follow-up (urine ketones less than 80 mg/dL), the ketogenic ratio was increased. After 6 months of cKD, the discontinuation rate was reported. This paper did not include data about the hydroxybutyrate, since the database had incomplete data related to this outcome, since the data collection was provided by the caregivers.n > 12, as previously suggested by Julious [A retrospective open label, experimental pre–post study was designed, and sample size was not determined a priori because the subjects were  Julious . R softw Julious .n = 9) and 3:1 (n = 13), was performed. A GEE model was fitted, where the time reflected a categorical two-level factor, based on the number of time points  as reference and the last measurement (t1)) and the type , and their interaction terms were ‘‘focus’’ predictors. Accounting for these GEE models, ΔT were interpreted as mean differences of the outcome at the time point t1 from baseline in the 3:1 group; the interaction parameters (ΔTxTy) were interpreted as mean differences of the outcome between type at a given time point. Finally, type-associated parameters (ΔTy) were interpreted as baseline mean differences between type. Wald tests were performed, and statistical significance for model variables was assessed by 95% confidence intervals. Two-tailed p-values <0.05 were considered to be statistically significant.Non-normally distributed data were checked by Shapiro–Wilk test. Generalized estimating equation (GEE) models ,21 for rn = 8), structural (n = 2) and infectious (n = 1). The identified epilepsy syndromes were infantile spasm (n = 5), epileptic spasm (n = 5), Ohtahara syndrome (n = 3), myoclonic epilepsy (n = 2) and one case each of Rett syndrome, multifocal seizure syndrome, complex partial seizure, myoclonic encephalopathy, Lennox–Gastaut syndrome and Aicardi syndrome. The mean age at epilepsy onset was 6.25 months (age ranged between 4 months and 11.25 years), whereas at cKD initiation, it was 27.6 months (age ranged between 4 months and 8 years). All patients received cKD, with a 3:1 ratio in 62.5% (n = 15) and 4:1 ratio in 37.5% (n = 9) of the patients, respectively. Oral feeding was the administration route for the majority of the study population , except for five patients (20.83%) who were on enteral feeding. The mean duration of the cKD was 22 months (range between 3 months and 6 years). The mode of AEDs drugs was 2 (IQR: 1–5).Initially, 37 epileptic patients treated with cKD at SMC were identified from medical records. However, 13 patients were excluded due to insufficient information. Therefore, the final study cohort consisted of 24 children  who were treated with cKD for drug-resistant epilepsy. The demographic and clinical characteristics of the study sample are summarized in In total, 14 patients (58.3%) were cKD responders with >50% seizure reduction at 3 months, and one-third (33.3%) achieved seizure freedom at 12 months. However; 10 patients (41.7%) were non-responders (<50% seizure reduction).n = 3), Rett syndrome (n = 1), epileptic spasm (n = 5), multifocal seizure syndrome (n = 1), complex partial seizure (n = 1), myoclonic encephalopathy (n = 1), infantile spasm (n = 5), Lennox–Gastaut Syndrome (n = 1), Aicardi syndrome (n = 1), and myoclonic epilepsy (n = 2). As shown in n = 15) and a 4:1 ratio in 37.5% (n = 9) of the patients. Oral feeding was the administration route for the majority of the study sample , except for five patients (20.83%) who were on enteral feeding. The median duration of cKD was 21 months (IQR 72 months).The mean age at epilepsy onset was 7 months (IRQ: 36 months), whereas at cKD initiation, it was 24 months (IQR 28.5 months). All patients received cKD, with a 3:1 ratio in 62.5% (p = 0.002) and albumin  were detected by pre–post modeling (see p = 0.010). Although the mean value of TC and ALT increased by 0.21 mmol/L and 6.29 U/L, respectively, after cKD initiation, the difference was statistically not significant. Additionally, insignificant reductions of both ALP and GGT mean levels were observed. Notably, no cKD type interactions resulted in significant biochemical outcomes , which was followed by age at xKD initiation (0.47). The number of AEDs drugs was not correlated with the duration of cKD.n = 8), poor compliance (n = 3), food refusal (n = 1), achieved required efficacy (n = 1) and death (n = 1). The death case had lost follow-up, and death happened outside Bahrain. Although no detailed information could be obtained, it was most probably related to the disease complications and not the cKD.The cKD was discontinued by 14 patients (58.3%) at 6 months. The reported reasons of discontinuation were inefficacy  did not change significantly at 12 months follow-up compared to the baseline values. The present finding is comparable to the findings of Tagliabue et al.  and FerrThese results can be explained by the fact that patients of this study had received adequate calories, in addition to the intensive follow-up program provided at SMC, which allowed patients access to dietitians by phone for diet troubleshooting and ensuring compliance with the KD that meets energy requirements. Furthermore, most of the study patients were receiving a specialized ketogenic formula to supplement their food intake, which further improved their calorie intake. In addition, more importantly, this result indicates that calorie needs can be fulfilled by cKD to promote the normal growth of children.The findings of this study found a favorable response to cKD being correlated with the duration of cKD, age at cKD initiation, epilepsy duration, and number of AEDs at baseline. These factors have also been identified in several studies as predictors of cKD efficacy ,32,43. HIn the present study, inefficacy was the most reported reason for discontinuing the cKD by the majority of the study sample followed by poor compliance. These results coincide with previous studies which reported that inefficacy was the factor most associated with cKD withdrawal ,43,44,45Despite the efficacy of cKD in the treatment of drug-resistant epilepsy, it may convey clinical and nutritional risks, including hyperlipidemia and hepatic side effects. In this study, a significant increase in triglycerides was observed after cKD initiation, as well as the increase in levels of the liver enzyme ALT. Consequently, it is highly recommended to closely monitor liver enzymes and lipid profile and to focus on healthy fats such as monounsaturated and polyunsaturated fats instead of unhealthy saturated fats when preparing dietary plans for these patients. However, the cKD had no significant influence on the growth parameters of the studied patients at 12 months follow-up.cKD efficacy was highly correlated with the duration of cKD in this study, which indicates that a positive response increases the adherence to cKD. Furthermore, cKD tolerance in terms of absence of side effects is another factor that affected the adherence in the cohort.Interestingly, this study is the first study conducted in Bahrain to evaluate cKD treatment for childhood drug-resistant epilepsy, which makes it a valuable contribution in the existing literature. However, like other studies, this study has a number of limitations, including its retrospective nature and the small sample size. In addition, it was not possible to exclude the effect of AEDs on liver enzymes. Moreover, the absence of ketonemia levels was another important limit.It is highly recommended that future research includes larger sample sizes and a prospective study design to assess the nutritional and clinical effects of cKD, both in the short and long term. In addition, other benefits of cKD in terms of quality of life can be investigated in patients with epilepsy. Finally, other less restrictive types of cKD including MCTKD, modified Atkins and low-glycemic index diets could be evaluated in future studies.


Uveal melanoma (UM) is the most frequent primary intraocular tumor in adults. This study aims to develop a nomogram and an individualized web-based calculator to predict the overall survival (OS) of elderly patients with UM.https://yuexinupup.shinyapps.io/DynNomapp/).Patients aged more than 60 years and diagnosed with UM were derived from the Surveillance, Epidemiology, and End Results (SEER) database during 2004–2015. The selected patients were randomly divided into training and validation cohorts. In the training cohort, the univariate and multivariate Cox analyses were carried out to determine the independent prognostic factors, and the predictors were integrated to establish a nomogram for predicting the 1-, 2-, and 3-year OS of elderly patients with UM. The discrimination of the nomogram was validated by receiver operating characteristic (ROC) curves and the area under the curve (AUC). The clinical practicability and accuracy of the nomogram were evaluated by the calibration curves and decision curve analysis (DCA). A web-based survival calculator was then constructed using a fitted survival prediction model  were identified as independent prognostic factors. Based on the abovementioned factors, the nomogram was then constructed. The AUC values of the nomogram predicting 1-, 2-, and 3-year OS were 0.841, 0.801, and 0.768 in the training cohort, and 0.745, 0.717, and 0.710 in the validation cohort, respectively. The calibration curves and DCA also indicated the good performance of the predictive model.This study established and validated a novel nomogram risk stratification model and a web-based survival rate calculator that can dynamically predict the long-term OS for elderly patients with UM. Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults, accounting for 5% of all melanoma cases and mainly originating from the choroid (90%), followed by the ciliary body 7%) and the iris 2%) . Approxi% . Appro% and theA number of clinical and histopathological features have been investigated in order to predict the prognosis for patients with UM; age and tumor size have been identified to be prognostic indicators for patients with UM . In addiThe SEER database, supported by the National Cancer Institute, constituted approximately 27.8% of the US population. The research data of patients with UM were downloaded from the SEER database by the SEER*Stat software version 8.3.5 during 2004–2015. We used the International Classification of Disease for Oncology third edition (ICDO-3) to identify UM cases, namely, C69.3 (choroid) and C69.4 (ciliary body and iris). The inclusion criteria of patient selection were as follows: (a) patients were diagnosed with UM during 2004–2015; (b) patients older than 60 years; and (c) patients with complete follow-up. The exclusion criteria of patient selection were as follows: (a) patients whose selected variables were unknown; (b) UM was not the patient’s first primary tumor; and (c) patients were diagnosed with autopsies or death certificates. Selected variables included age, marital status, insurance status, sex, race, primary site, laterality, histologic type, T stage, N stage, M stage, surgery, radiotherapy (RT), chemotherapy, and historic stage. X-tile software provides the best cutoff point and changes continuous variables into categorical variables; therefore, the age of patients is divided into three groups, including <70 years, 70–82 years, and >82 years  curves, and the value of area under the curve (AUC) was used to estimate the performance of the nomogram. The calibration curves and decision curve analysis (DCA) curves were also generated. Besides, we calculated the total point of all patients based on nomogram and divided them into three subgroups at different risks of mortality according to an optimal cutoff value determined by X-tile, including high-, medium-, and low-risk groups. The Kaplan-Meier survival analysis with the log-rank tests was conducted to compare the survival difference among the three subgroups. The value of p < 0.05 was considered statistically significant.In our study, the statistical method was performed using SPSS version 25.0 and R software (version 3.5.1). Differences in baseline characteristics were examined using the chi-square test. Elderly patients with UM were randomized into training and validation cohorts at a ratio of 7:3. The univariate Cox regression analysis was first used to explore OS-related variables. Those variables with n = 1,000) and the validation cohort (n = 427). Patients in the age groups of <70 years (50.3%) and 70–82 years (38.7%) made up the majority of the study sample. The number of married patients  was nearly twice than that of unmarried patients . Almost all patients had insurance coverage . In the distribution of race, most of the patients  were white. Both the male-to-female ratio and the right eye-to-left eye ratio were close to 1:1. The most common primary site of UM was choroid , while another common site was ciliary body . According to the 7th AJCC/TNM staging system, 1,124 cases were staged as T1–T2, while 303 cases were staged as T3–T4. In terms of the N and M stages, 1,398 cases were staged as N0, 29 cases as N1, 1,408 cases as M0, and another 19 cases as M1. In terms of treatment information, only a quarter of patients (25.7%) underwent surgery, while the other cases weren’t. Most of the patients received RT . The detailed demographic and clinicopathological information of the two cohorts are listed in In this study, we finally included 1,427 elderly patients diagnosed with UM. The study population were randomly allocated into two cohorts, namely, the training cohort   . All thes <0.05) .We constructed a nomogram to predict the 1-, 2-, and 3-year OS of elderly patients with UM based on the abovementioned factors . Based op < 0.05) , medium-risk group (score 166–233), or high-risk group (score >233). The Kaplan–Meier survival curves showed that patients who were assigned to the high-risk group had a worst survival outcome in both cohorts ( < 0.05) . Patientviahttps://yuexinupup.shinyapps.io/DynNomapp/ , with choroidal melanoma surrounding the optic nerve, or presenting with severe hemorrhage, retinal detachment, or vitreous hemorrhage . ZimmermThere are still several limitations to this study. First, it is difficult to avoid selection bias because this study was designed in a retrospective way. Second, there is a lack of external data from different regions due to the rarity of UM; therefore, further validation with external data is needed to verify whether these results are generally applicable. Third, we are unable to consider other clinical factors and biomarkers not collected in the database that may have affected the outcomes, such as target therapy, postoperative complications, gene expression, and chromosomal alteration.This study determined that age, sex, marital status, T stage, N stage, M stage, and RT were independent predictors for OS of elderly patients with UM. A nomogram and a web-based survival calculator were developed to distinguish the high-risk elderly patients with UM, which might help ophthalmologist to develop better clinical management and treatment strategies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.ML and YT conceived and designed the study and critically reviewed the manuscript. ML performed the literature search, analyzed the data, and wrote the manuscript. ML and XY generated the figures and tables. YT supervised the research. All authors critically read the manuscript to improve intellectual content and read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Calcium signaling is crucial for many physiological processes and can mobilize intracellular calcium stores in response to environmental sensory stimuli. The endolysosomal two-pore channel (TPC), regulated by the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP), is one of the key components in calcium signaling. However, its role in neuronal physiology remains largely unknown. Here, we investigated to what extent the acoustic thresholds differed between the WT mice and the TPC KO mice. We determined the thresholds based on the auditory brainstem responses (ABRs) at five frequencies (between 4 and 32 kHz) and found no threshold difference between the WT and KO in virgin female mice. Surprisingly, in lactating mothers (at P9–P10), the thresholds were higher from 8 to 32 kHz in the TPC KO mice compared to the WT mice. This result indicates that in the TPC KO mice, physiological events occurring during parturition altered the detection of sounds already at the brainstem level, or even earlier. Hearing loss, the most common sensory impairment in humans, affects a growing proportion of people all over the world. Hearing loss can be congenital or acquired and can be caused by many genetic and/or environmental factors. About half of these disorders have a genetic basis, with hearing loss occurring either as an isolated condition (non-syndromic) or with additional phenotypes (syndromic). Over the last three decades, about 110 genes responsible for non-syndromic deafness and more than 300 genes responsible for syndromic forms of deafness in humans and/or mice have been reported . HoweverOver these last decades, several environmental factors have been found to influence the expression of ARHL. A first obvious factor is noise exposure (acute or chronic), which can exacerbate ARHL. In a set of elegant studies, Kujawa and Liberman ,12 demonThe status of the stria vascularis (SV) and its vasculature has been measured in aged human temporal bones and represents a major pathology of hearing loss ,14. The Another cause of ARHL occurring at the periphery is the sclerosis of the middle ear bones. Otosclerosis is a disease of the otic capsule bone responsible for the abnormal growth of poor-quality new bone in the middle ear. This new bone blocks the stape movements, causing conductive hearing loss. This disease, which affects 0.2 to 1% of the population, mostly occurs between 20 and 40 years old, and is more prevalent in women, suggesting that hormonal factors are involved. Half of the cases of otosclerosis are so-called familial forms, indicating genetic transmission. However, no specific gene has been identified yet, and the mode of hereditary transmission would be autosomal dominant. The other half of the cases constitute sporadic forms. For women, it is not uncommon for otosclerosis to appear, or worsen, during pregnancy, which explains why otosclerosis has been initially associated with pregnancy . This li2+ although they also display H+ and Na+ conductances [Numerous studies have shown that lysosomes and autophagy dysfunction underlying ARHL are often associated with cochlear hair cell degeneration ,25,26. Fuctances ,32. TPCsuctances ,34,35. Iuctances ,36 as weuctances  and by Vuctances .2+ stores and neuronal physiology, a mouse lacking endolysosomal two-pore channels (TPC KO) was created, knowing that the copy number variation of genes encoding TPCNs in chromosomal regions in humans have been associated with autism spectrum disorders (ASD), a disorder often associated with sensory perception impairments. In these TPC KO mice, altered social behaviors have recently been reported .To better understand the link between lysosomal CaBased upon auditory brainstem responses (ABRs), we report here the surprising discovery, that despite similar audiograms in normal physiological conditions (virgin mice), at 9–10 days post-partum, TPC KO lactating mothers displayed higher ABR thresholds compared to the WT mothers. This sudden increase in the ABR threshold observed in our study could potentially be related to the rare disease of sudden sensorineural hearing loss reported in pregnant women.t-test < 1, ns). The TPC KO (TPC1/2−/−) mice were generated by crossing mutants homozygous for the TPC1 isoform (Tpcn1T159) [YHD437) [These experiments were performed under the national license A-91-557 (project 12471) using procedure No. 32-2011 validated by the Ethics Committee No. 59 (CEEA Paris Centre et Sud). All procedures were performed in accordance with the guidelines established by the European Communities Council Directive (2010/63/EU Council Directive Decree). Data were from four groups of animals. First, we used 15 virgin and 15 mother WT mice (9 to 24 weeks old) weighing from 21 to 40 g . Second, we used 14 virgin and 19 mother TPC KO mice (10 to 25 weeks old) weighing from 22 g to 37 g . Globally, there was no age difference between the two genotypes (cn1T159)  obtained[YHD437) . The TPC[YHD437) . On the Pure-tone audiograms were determined by testing the auditory brainstem responses (ABRs) under deep anesthesia . Mice were placed on a heating blanket to avoid hypothermia. Auditory stimuli  were presented monaurally using an insert earphone (Knowles Electronics) placed in the animal right ear. ABRs were recorded using two subcutaneous electrodes  located just above the tympanic bulla and skull dorsal midline, and one ground electrode was placed in the thigh. Insertion of the subcutaneous electrodes was not associated with any sign of discomfort. The signal was digitized  and filtered (150–1500 Hz). The software  allowed for the averaging of 500 responses during the presentation of five pure-tone frequencies (between 4 and 32 kHz). The auditory threshold for each frequency was the lowest intensity at which a detectable ABR wave could still be detected . For each frequency, the threshold was determined by gradually decreasing the sound intensity (from 70 dB down to −10 dB SPL). For the four groups, we excluded partially deaf animals . This was the case for 3/33 WT mice (10%) and for 5/38 KO mice (13%). Aside from these animals, all the animals used in this study had normal pure-tone audiograms for their age (9–25 weeks) and for the C57 BL/6 genetic background ,41,42,43t-tests. To compare the mean amplitude and latency of the five ABR waves at 16 or 8 kHz between groups, a N-way ANOVA was performed. Post-hoc comparisons were performed with Fisher LSD tests, which were corrected for multiple comparisons using Bonferroni corrections and were considered as significant if the p value was below 0.05. In all figures displaying group data, we indicated by * a p value < 0.05.All data are presented as mean values ± standard error (s.e.m.). To assess the significance of between group differences for the ABR thresholds, we used unpaired 3,4 = 30.26, p < 0.001), a significant frequency-effect , and a significant interaction between the groups and frequencies . At all of the tested frequencies, the mean ABR threshold did not differ between the WT virgin and WT mother mice . The mean ABR threshold of the virgin TPC KO mice did not differ from that of the WT (virgin and mother) mice at 4, 8, 24, and 32 kHz . In the virgin TPC KO mice, it was only at 16 kHz that the mean threshold was slightly higher, and only compared to the WT mother mice . In contrast, in the mother TPC KO mice, the mean ABR thresholds was significantly higher at 8, 16, 24, and 32 kHz compared to the three other groups .t-test, p < 0.05). In addition, there was no relationship between the threshold and age in the TPC KO mice at all of the tested frequencies. p = 0.64) and 16 kHz .t-tests p < 0.05). There was a significant group-effect , a wave-effect , and a tendency for interaction between the groups and waves (p = 0.08). For the TPC KO mice, only the latency of wave V was found to be shorter in the mothers compared to virgins (t-tests p <0.05). There was a significant group-effect  and a wave-effect , but there was no interaction between the groups and waves (p = 0.44).To go further, we quantified the latency and the amplitude of the ABR waves in virgins and in mothers at 8 and 16 kHz as this frequency range often shows lower thresholds in many mouse strains . We pres1.14 = 3.15, p = 0.07). The wave-effect was systematically significant  and there was no interaction between the groups and waves . Post-hoc comparisons revealed that the mean amplitude of wave IV was higher in the mothers than in the virgins (unpaired t-tests p <0.05). For the TPC KO mice, there was no group-effect , but there was a significant wave-effect  and there was no interaction between the groups and waves . Post-hoc analysis did not reveal significant differences between the virgin and mother TPC KO mice for each wave.The analysis of the amplitude of the five ABR waves in the WT mice indicated that there was a tendency for a group-effect . In contrast, the mean amplitude of wave II was significantly smaller in the WT than in the TPC KO mice (p < 0.05). Similar effects were also detected at 8 kHz  and theAs found in the CBA mice using clicks as stimuli , we alsoThese results indicate that the absence of TPC channels under normal physiological conditions did not induce a major apparent auditory deficit, even if we observed a response of the auditory nerve on average lower (amplitude of the wave I in ABRs of virgin TPC KO mice), which seems to be compensated for by a larger wave II . Nevertheless, it appears that in motherhood conditions, the absence of the TPC channels would induce, on average, a reduction in the hearing threshold in the KO mice.The TPC channels are ubiquitous and seem to play many roles depending on the cell type studied ,49,50. HHere, we quantified the ABR thresholds of the WT and TPC KO mother mice at 9–10 days postpartum to be sure of the impact of motherhood on possible audiogram alterations in the TPC KO mice. However, it is important to bear in mind that the majority of human studies on ARHL linked to otosclerosis or sudden hearing loss onset have been analyzed in pregnant women ,53,54, aIn addition to autophagy fluxes, human studies on ARHL and sudden hearing loss in pregnancy have proposed the dysfunction of various cellular processes in which TPCs may actually have a role. For instance, an otosclerosis link to cochlear osteoclast dysfunction and otosclerosis  has also


Primary thyroid lymphoma (PTL) is a very rare entity accounting for 5% of all thyroid malignancies and less than 2% of lymphomas. PTLs are classified as non-Hodgkin’s B-cell lymphomas in the majority of cases, although Hodgkin’s lymphoma of the thyroid has also been identified. This study aimed to identify the clinical, biochemical, and pathological features of primary thyroid lymphomas.From January 2008 to December 2020, data from patients diagnosed with PTL treated at the Gangnam Severance Hospital, including clinical, biochemical, and pathological features of thyroid lymphomas, were assessed.Of 10 patients, nine women and one man, with a median age of 62  years were included. Fine needle aspiration biopsy was performed in nine patients and surgical resection was performed in one patient without biopsy. Excisional and surgical biopsies were performed in all patients, including five who underwent excisional biopsy and five who underwent thyroidectomy. Histological analyses revealed that all 10 lymphomas were non-Hodgkin B-cell lymphoma; six patients had diffuse large B-cell lymphoma, three had mucosa-associated lymphoid tissue lymphoma, and one had Burkitt lymphoma. Four patients received chemotherapy, two were treated with chemoradiation therapy, one received radiation therapy only, one did not require more treatment after surgery, one refused treatment, and one was transferred to another hospital.Although PTLs are scarce, clinicians should be aware of this rare entity and evaluate and treat PTLs on an individual basis. Primary thyroid lymphoma (PTL) is an extremely rare malignancy of the thyroid gland, accounting for 5% of thyroid malignancies and 2% of extranodal lymphomas, with an estimated annual incidence of 2 per 1 million , 4. BecaThis study aimed to introduce and identify the clinical, biochemical, and pathological features of PTLs treated at a single institution. This information can aid clinicians to more accurately determine the pretest probability of thyroid lymphoma and select the diagnostic tests with the highest yield for obtaining a final diagnosis.in situ hybridization.Patients who were diagnosed with PTL had a pathological diagnosis and underwent surgical intervention, excisional biopsy, or thyroidectomy for precise diagnosis at Gangnam Severance Hospital, Yonsei University College of Medicine, Korea, between January 2008 and December 2020. Medical information, including demographic, clinical, and laboratory data, were extracted from electronic medical records and reviewed retrospectively. Pathologic data were independently reviewed by an expert pathologist using a specimen slide. The laboratory data collected included sensitive thyrotropin (TSH), free thyroxine, serum thyroid peroxidase (TPO) antibody, and thyroglobulin antibody with reference ranges of 0.8–4.7 mIU/L, 0.8–1.7 ng/dL, 5–13.6 IU/mL, and 10–124 IU/mL, respectively. Preoperative ultrasound was performed on all patients. On reports of ultrasound imaging, hypoechoic was considered as having decreased echogenicity relative to adjacent thyroid tissue, and very hypoechoic as decreased echogenicity relative to adjacent musculature. FNA biopsy was defined as a biopsy performed using a needle gauge of 25G under ultrasound–guided. Local anesthesia was not routinely used to prevent pain during FNA, but might be helpful for multiple needle punctures. FNA was performed with the needle oriented either parallel or perpendicular to the US probe. Tissue samples were collected with 6 to 7 “to-and fro” needle movements over 5–10 seconds, with 2–3 mL suction applied. The number of needle passes ranged from 2 to 3. Core needle biopsy was defined as a biopsy performed with a spring-loaded tru-cut configured biopsy needle with a gauge of 18G. All patients underwent core needle or surgical biopsy for an accurate diagnosis with immunohistochemistry which included CD3, CD20, cyclinD1, BCL2, CD10, BCL6, MUM1, Myc, Ki-67, CD5, and EBV Hypothyroidism was considered as either an elevated TSH value or levothyroxine replacement therapy at the time of diagnosis. Hashimoto’s thyroiditis was defined as a diagnosis in the medical history. PTL was defined as a disease confined to the neck.2, adriamycin 50 mg/m2, vincristine 1.4 mg/m2, and prednisolone 100 mg/day) with rituximab (375 mg/m2). In current study, one patient diagnosed with Burkitt’s lymphoma received R-Hyper CVAD . Radiation therapy encompassed the entire neck and the upper mediastinum.In PTL treatment, the purpose of surgery is mainly for biopsies; excision biopsy and thyroidectomy are typically performed. Chemotherapy usually includes multiple courses of CHOP  of Gangnam Severance Hospital, Yonsei University College of Medicine (IRB protocol: 3-2022-0237). The study protocol was conducted in accordance with the Declaration of Helsinki. Due to the retrospective nature of the study, neither patient approval nor informed consent was required.The 10 patients comprised nine women and one man with a median age of 62 years, and seven patients were over 60  years. All 10 patients performed preoperative ultrasound and seven patients showed solid mass with very hypoechoic texture . Seventeen cases with these inaccurate FNAs were given the reassuring label “benign.” Core needle biopsy has been shown to improve the accuracy of thyroid lymphoma diagnosis to 93% from 82% with FNA alone  have been considered standard treatments for PTL. However, with high relapse and low survival rates, and the realization that thyroid lymphomas are responsive to chemotherapy and radiation, surgery now plays a limited role , 22. AccOne of the limitations of this study is that it was a retrospective review with inherent biases. A small group analysis was performed, and a control group was not included. Therefore, the test characteristics of the various diagnostic techniques could not be calculated.In conclusion, although PTLs are rare, clinicians should consider the importance of this potential diagnosis when encountering patients with an enlarged neck mass in the setting of Hashimoto’s thyroiditis. FNA biopsy should be considered as the first step, and core needle biopsy or surgical biopsy should be considered promptly if FNA biopsy fails to determine a final diagnosis.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Institutional Review Board (IRB) of Gangnam Severance Hospital, Yonsei University College of Medicine (IRB protocol: 3-2022-0237). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.Study concept and design, YL; data acquisition, analysis, and interpretation, JL and S-JS; drafting of the manuscript, JL, HY, YL, and H-SC. All authors contributed to the article and approved the submitted version.


There is controversy over the optimal energy delivery in intensive care units (ICUs). In this study, we aimed to evaluate the association between different caloric adequacy assessed by a weight-based equation and short-term clinical outcomes in a cohort of critically ill patients.N = 2,772). The energy requirement was estimated as 25 kcal/kg of body weight. The study subjects were divided into three groups according to their caloric adequacy as calculated by the mean energy delivered from days 3 to 7 of enrollment divided by the estimated energy requirements: (1) received < 70% of energy requirement , (2) received 70–100% of energy requirement , and (3) received > 100% of energy requirement . Cox proportional hazards models were used to analyze the association between caloric adequacy and 28-day mortality and time to discharge alive from the ICU.This is a secondary analysis of a cluster-randomized controlled trial , while hypercaloric feeding did not. After controlling for potential confounders, the association remained valid . The caloric adequacy was not associated with time to discharge alive from the ICU in the unadjusted and the adjusted models.A total of 1,694 patients were included. Compared with normocaloric feeding, hypocaloric feeding significantly increased the risk of 28-day mortality (hazard ratio [Energy delivery below 70% of the estimated energy requirement during days 3–7 of critical illness is associated with 28-day mortality.https://www.isrctn.com/ISRCTN12233792], identifier [ISRCTN12233792].[ Nutrition therapy is essential in the management of critically ill patients, as they are vulnerable to energy/protein deficits due to severe catabolism and inadequate intake, which may result in increased infectious complications and prolonged intensive care unit (ICU) stay , 2. HoweThe European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines  recommenIn the present study, we classified caloric adequacy using the three-category system  based on a weight-based equation . We aimed to investigate the association between caloric adequacy and short-term clinical outcomes in a cohort of critically ill patients from a large trial.post hoc analysis of a multicenter, cluster-randomized, controlled trial assessing the impact of an evidence-based nutrition guideline in critically ill patients .All eligible patients were divided into three groups according to their caloric adequacy: (1) received < 70% of energy requirement , (2) received 70–100% of energy requirement , and (3) received > 100% of energy requirement .The coprimary outcomes are 28-day mortality and time to discharge alive from the ICU. The secondary outcomes include the length of ICU stay and new receipt of organ support therapy within the first 7 days after enrollment. Time to discharge alive from the ICU was only considered in survivors and censored at 28 days after enrollment. New receipt of organ support therapy was defined as a requirement of organ support therapy  not applied at enrollment.All data were extracted from the electronic database, such as de-identified data on patient characteristics, daily nutritional therapy, and utilization of organ support. The baseline characteristics included age, gender, weight, body mass index (BMI), modified Nutrition Risk in the Critically Ill (mNUTRIC) score , site bepost hoc pairwise comparisons. The Kaplan–Meier methods were used to display survival curves for time to discharge alive from the ICU within 28 days after enrollment and 28-day mortality. Noncross- and cross-survival curves were compared by the log-rank test and two-stage test  and R software version 4.1.0. The normality of continuous variables was examined by the Kolmogorov–Smirnov test. Continuous data were presented as mean ± standard deviation (SD) or median . Categorical data were presented as numbers and percentages. Differences in baseline and nutritional characteristics among the three energy delivery categories were compared using the one-way analysis of variance (ANOVA) or the Kruskal–Wallis tests for continuous data and the chi-square test for categorical data. A Bonferroni correction was applied for the age test , respectp < 0.1 were considered covariates and included in the adjusted model 1.Cox proportional hazards models were used to analyze the effect of caloric adequacy on 28-day mortality and time to discharge alive from the ICU. The covariates, such as age, gender, BMI, APACHE II score, SOFA score, number of comorbidities, mNUTIRC score, the number of evaluable nutrition days, initiation of enteral nutrition within 48 h, mean parental nutrition intake from days 3 to 7, and AGI score were entered separately in the multivariable model. The relationships between caloric adequacy and the two coprimary outcomes were tested in the unadjusted and the adjusted models. Based on unadjusted analyses, variables of clinical significance or with p-value of <0.05 was considered significant.The multicollinearity between potential confounding factors was evaluated in the multivariable model by assessing the variance inflation factor (VIF) , 23. Then = 1,251, 73.8%) and were admitted to the emergency department . The overall 28-day mortality was 13.1% (222/1694), and the median length of ICU stay was 16 days (interquartile range: 9–28 days). The variables of age, gender, BMI, and SOFA score were different among the three groups, whereas others were similar among the groups.All the 2,772 trial participants were screened for potential inclusion, and 1,694 patients were included in the current analysis . A totalData regarding nutrition therapy are shown in p-value of < 0.1 were then taken into the multivariate model as potential confounders. In terms of the 28-day mortality, the variables, such as age, gender, BMI, initiation of enteral nutrition within 48 h, mean parental nutrition intake from days 3 to 7, the number of evaluable nutrition days, SOFA score, and the number of comorbidities were entered into a multivariable model. For the outcome of time to discharge alive from the ICU, the covariates include age, gender, BMI, initiation of enteral nutrition within 48 h, the mean parental nutrition intake from days 3 to 7, and SOFA score. The relationships of caloric adequacy with 28-day mortality and time to discharge alive from the ICU are presented in HR] = 1.590, 95% CI: 1.162–2.176, p = 0.004), while hypercaloric feeding did not . The association remains valid after controlling for potential confounders , with an adjusted HR of 1.596 . The caloric adequacy was not associated with time to discharge alive from the ICU in the unadjusted and the adjusted models.After the multicollinearity analysis for coprimary outcomes, the mNUTRIC score and protein intake were removed from the adjusted models given to its collinearity with SOFA score and calorie intake, respectively. After performing a univariate Cox analysis for coprimary outcomes, factors of clinical importance or those with a ptwo–stage = 0.01), while other comparisons did not differ. Meanwhile, there was no significant difference in the time to discharge alive from the ICU among the three groups (plog–rank = 0.0633).The Kaplan–Meier survival curves for the association of caloric adequacy with coprimary outcomes are shown in Our study found that hypocaloric feeding (below 70% of energy requirement estimated by a weight-based equation) was associated with increased 28-day mortality, but caloric adequacy was not associated with time to discharge alive from the ICU in the unadjusted and adjusted models.The optimal calorie intake remains controversial since many studies have shown conflicting results regarding the impact of different caloric adequacy on outcomes in critically ill patients. Several observational studies demonstrated that early target reaching is beneficial –26, wherThe time range we selected in this study is based on the 2019 ESPEN guidelines . This deFor nutrition therapy in critically ill patients, several observational studies have shown that adequate protein intake might outweigh calorie intake , 40. Twopost hoc analysis), a causal relationship cannot be inferred. Third, since most of the study subjects did not undergo indirect calorimetry (IC) to evaluate energy expenditure, the generalizability of our findings was unknown in patients using IC to determine their energy requirements.This study has several strengths and limitations. First, the nutritional data in the analysis were prospectively collected during a large-scale RCT conducted in 90 ICUs, implicating good generalizability of the findings. Second, to minimize the bias, we did not calculate the energy and protein delivery when patients received oral intake. However, due to the nature of this study (a This study showed that energy delivery below 70% of energy requirement during days 3–7 of critical illness is associated with increased 28-day mortality when using the weight-based equation to estimate the energy requirement.The datasets used and analyzed during the current study are available from the corresponding authors on reasonable request.The studies involving human participants were reviewed and approved by the Ethics Committee of Jinling Hospital. The patients/participants provided their written informed consent to participate in this study.LK, ZT, ZJ, and WL: conceptualization. XJ, ZL, and YiL: data curation. CL: formal analysis. RY, YXL, ML, YaL, and WC: methodology. CW, XY, and LG: resources. WL: supervision. JL and LK: writing – original draft. CL, XJ, and YXL: writing – review, and editing. All authors contributed to the article and approved the submitted version.