Background: Discontinuing chemotherapy worsens cancer prognosis. This study aimed to investigate the relationship between nutritional status at the start of chemotherapy and chemotherapy discontinuation in patients with ovarian, fallopian tube, and primary peritoneal cancer. Methods: This was a retrospective cohort study. One hundred and forty-six patients to whom weekly paclitaxel and carboplatin were administered as postoperative chemotherapy were included. Six courses in 21-day cycles were defined as complete treatment. As nutritional indicators, body mass index, weight change rate, serum albumin, total lymphocyte count, prognostic nutritional index, and C-reactive protein-to-albumin ratio (CAR) were compared between complete and incomplete treatment groups. Patients were divided into two groups according to CAR. The number of chemotherapy cycles was compared between these two groups. A Cox proportional hazard model was used for covariate adjustment. Results: Several indicators differed between complete and incomplete treatment groups, and among the indicators, CAR had the highest discriminatory ability. The number of chemotherapy cycles was shorter in the high CAR group than in the low CAR group. A high CAR was associated with chemotherapy interruption even after adjusting for covariates. Conclusion: Based on CAR, nutritional status before chemotherapy is suggested to be associated with the risk of chemotherapy discontinuation. Cancer is one of the leading causes of morbidity and mortality worldwide . The incChemotherapy is classified into four categories, first-line chemotherapy, neoadjuvant chemotherapy (NAC), maintenance chemotherapy, and secondary chemotherapy. First-line chemotherapy is the first chemotherapy aimed at improving treatment outcomes and is performed postoperatively. NAC is preoperative chemotherapy performed to improve the completion rate of radical surgery. Maintenance chemotherapy is a treatment performed for long-term survival after remission. Secondary chemotherapy is chemotherapy in the event of a relapse or resistance to initial chemotherapy. The prognosis of several cancers has been reported to improve in cases where chemotherapy is fully completed . HoweverOvarian cancer is the second most common gynecological cancer worldwide among women . The ageNutritional status plays an important role in treating various diseases, and cancer is no exception. Nutritional interventions are known to improve the results of cancer treatment as an adjunctive therapy . The preAlthough nutritional status influences the course of chemotherapy, little data are available on the association between nutritional status and chemotherapy discontinuation . In addiWe extracted patients from the clinical database of Chiba University Hospital. The inclusion criteria were being diagnosed with ovarian, fallopian tube, or peritoneal cancer; and receiving weekly paclitaxel and carboplatin (WTC) therapy as postoperative chemotherapy after staging laparotomy, primary debulking surgery, or exploratory laparotomy. Staging was performed according to the International Federation of Gynecology and Obstetrics (FIGO) 2014 classification [The exclusion criteria were receiving preoperative chemotherapy, recurrent cancer, having surgery at another hospital, history of chemotherapy, and coexistence of unknown cancers. This study was performed in accordance with the Declaration of Helsinki and other national regulations. The study protocol was approved by the ethics committee of the Graduate School of Medicine, Chiba University. Informed consent was obtained in the form of opt-out, in line with information posted on the bulletin boards in the hospital. We analyzed the records of all patients who received postoperative WTC for ovarian, fallopian tube, or peritoneal cancer between April 2016 and March 2021.2 weekly. The scheduled regimen for the systemic WTC was 1, 8, and 15 over a 21-day cycle for six cycles. The total number of administrations was eighteen; accordingly, this was used to define the completion of chemotherapy. The group that received chemotherapy 18 times was defined as the complete treatment group and the group that did not complete treatment was defined as the incomplete treatment group. All the patients received WTC therapy; carboplatin was administered at an area under the curve (AUC) of 2 from Calvert’s formula and paclitaxel at 80 mg/mHeights and weights were measured by nurses. Blood and biochemical tests were performed at the Division of Laboratory Medicine, Chiba University Hospital. White blood cell count (WBC), hemoglobin level (HGB), and lymphocyte ratio were assessed by XN2000  and biochemical analysis was performed by JCA-BM8040 . As indicators of nutritional assessment, we assessed Onodera’s PNI, ALB, HGB, TLC, and CAR before chemotherapy. The TLC was calculated using the following formula: TLC = WBC × lymphocyte (%). The PNI was calculated using the following formula: PNI = 10 × ALB + 0.005 × TLC. Weight change rate was calculated as (weight before the first course of chemotherapy − weight before surgery)/(weight before surgery) × 100%. As appropriate, clinicopathological parameters were compared using the Mann–Whitney U test, chi-square test, or Fisher’s exact test. Using receiver operating characteristic curve analysis, we compared the discriminatory ability of BMI, weight change rate, TLC, ALB, PNI, and CAR to detect patients who did not complete WTC. The AUC of each indicator was compared, and the indicator with the maximum values was used for survival analysis. The cut-off value was determined using the maximum Youden index, calculated as sensitivity + specificity − 1.We divided the patients into two groups using these cut-off values and compared their treatment times using Kaplan–Meier analysis and the log-rank test. A Cox proportional hazards model was used for the univariate and multivariate analyses of chemotherapy interruption. We used a multivariate Cox proportional hazards model to control for the potential covariant roles of age, body mass index (BMI), weight change rate, TLC, CRE, and alanine aminotransferase as continuous variables, and tumor stage (I–II/III–IV) as a binary variable. CAR was included as a binary variable with a cut-off value. Additionally, stratified analyses by tumor stages were performed.A power analysis was conducted to determine the sample size and power of at least 0.8 at a significance level of α = 0.05. Statistical analyses were performed using the JMP Pro statistical discovery software version 15.0 . Statistical significance was set at 0.05.In total, 204 patients were included in the database. Among them, we excluded 41 patients who had received preoperative chemotherapy, seven with recurrent cancer, eight who underwent surgery at another hospital, and one with previous chemotherapy. Furthermore, one patient with an unknown cancer was excluded. Accordingly, 146 patients were included in this study . We used our pilot study data for the power analysis, with a mean difference of ALB of 2.3 (standard deviation of 4.0) between the complete and incomplete treatment groups. Based on the results of the pilot data, the estimated sample size was 49 in each group and we achieved a sufficient number.Patient characteristics are shown in We compared nutritional indicators between the complete and incomplete treatment groups . The incThe ROC curve of each nutritional index for chemotherapy interruption is shown in p < 0.01)  .p < 0.01) for stages III–IV (n = 125) and 23.8  for stages I–II (n = 18). In stages I–II, the result was not significant due to the small sample size. Furthermore, stratified analysis by tumor stages (I–II/III–IV) showed a similar tendency for the CAR group; the HR of the high CAR group was 1.73 , Mini Nutrition Assessment-Short Form (MNA-SF), Malnutrition Universal Screening Tool (MUST), and Subjective Global Assessment (SGA). In the second step, three are phenotypic criteria , and two are etiologic criteria . Diagnosing malnutrition requires at least one phenotypic criterion and one etiological criterion. At the next step, the severity of malnutrition is assessed based on a phenotypic criterion. The advantage of using the GLIM criteria is that the global consensus standard allows us to compare the prevalence, intervention, and outcomes of malnutrition worldwide. In this study, the GLIM criteria could not be applied for the following reasons: This study is a retrospective study, and the first step, nutritional screening, was not performed at the start of chemotherapy. There was no data on weight loss because the patients’ body weight before the cancer diagnosis was not measured. Their muscle mass was not assessed routinely in our hospital. Food intake before the first chemotherapy could not be assessed. GLIM criteria have been proposed as the global standard. Thus, it is necessary to plan our future study using GLIM criteria  for nutrUsually, low BMI represents a deterioration of the nutritional status . In thisIn the present study, CAR was suggested as a predictor of chemotherapy interruption, indicating that nutrition and inflammation play an important role. Nutritional interventions have been reported to improve nutritional status and inflammation . Fish oiThe strength of our research is that we were able to achieve the required sample size for sufficient statistical power. Secondly, all cases were postoperative and could withstand the surgery. Therefore, the physical conditions were optimal to some extent. Thirdly, the number of doses was fixed. Therefore, the use of a predetermined chemotherapy regimen made it possible to identify a more accurate association between chemotherapy and nutritional status. Despite these strengths, this study also had several limitations. This study reported the result of only one chemotherapy regimen for these tumors. Therefore, the results cannot be generalized to other cancers or chemotherapy regimens. We also included a limited number of nutritional indicators owing to the retrospective study design. We were not able to examine nutritional indicators that were not measured in this study. Especially, information of food intake was not obtained in this study, which is an important indicator for nutritional assessment. There may have also been potential effects of unmeasured confounding. In addition, we included patients from one hospital, which may have caused selection bias. A multicenter study is required to confirm these results. In conclusion, nutritional status before chemotherapy is associated with the risk of chemotherapy discontinuation. CAR is a useful nutritional indicator for predicting the discontinuation of chemotherapy.


The median OS was significantly higher in patients with locally advanced tumors in the with-RFA group , but did not differ significantly in patients with metastasis . Similarly, the median PFS was significantly higher in the with-RFA group in patients with locally advanced disease , while there was no significant difference in patients with metastasis . The rates of various toxicities did not differ significantly between the groups. Conclusions: Endobiliary RFA prolonged the patency period of uncovered SEMS combined with GC therapy in patients with eCCA. Although RFA also yielded survival benefits, its effect was restricted to locally advanced tumors.Background: Endobiliary radiofrequency ablation (RFA) is a promising treatment modality for patients with extrahepatic cholangiocarcinoma (eCCA). However, no study has investigated the combined use of endobiliary RFA and gemcitabine plus cisplatin (GC) chemotherapy. This study aimed to examine the feasibility and efficacy of endobiliary RFA with GC therapy for patients with unresectable eCCA. Methods: The study outcomes included overall survival (OS), progression-free survival (PFS), time to recurrent biliary obstruction (RBO), and adverse events associated with the treatment. These parameters were retrospectively compared between 25 patients who underwent RFA with self-expandable metal stent (SEMS) placement followed by GC therapy (with-RFA group) and a control cohort of 25 patients who underwent SEMS placement alone and GC therapy (without-RFA group). Results: The median time to RBO was significantly longer in the with-RFA group (10.7 versus 5.2 months,  The prognosis of cholangiocarcinoma (CCA), which can be classified into intrahepatic CCA and extrahepatic CCA (eCCA) based on its location, is far poorer compared to that of most other malignancies ,2,3,4,5.Most patients with eCCA develop biliary strictures, which give rise to obstructive jaundice and/or cholangitis. Treating the stricture is an essential step toward the introduction and maintenance of systemic chemotherapy. Endoscopic biliary stent placement is recommended as the first-line approach since it is efficacious and less invasive, and the self-expandable metal stent (SEMS) is recommended because it possesses longer stent patency than that of plastic stents (PS) ,8 HoweveEndobiliary radiofrequency ablation (RFA) is a promising modality that can prolong stent patency and survival in patients with eCCA ,12 and wThis retrospective, comparative, multi-center study enrolled 25 consecutive patients, aged 20 years or above, with unresectable eCCA and biliary obstruction, who underwent endobiliary RFA and GC therapy as first-line chemotherapy between 2016 and 2021. The exclusion criteria were as follows: malignancies that were not proven pathologically, short strictures that were unsuitable for the RFA catheter used in the study , technicThe institutional review board of Aichi Medical University Hospital approved this study, which was conducted in accordance with the principles of the Declaration of Helsinki . All patients were offered the option to opt out of the study if they did not want to have their data published.A standard side-viewing duodenoscope  was inserted into the duodenum, and biliary cannulation was performed using a standard catheter and guidewire. The guidewire was advanced thorough the stricture, followed by the insertion of an RFA catheter  over the guidewire, and subsequently, the stricture was ablated for 90 s with a power of 7–10 W, which was delivered by a VIO300D generator  . If the 2) and cisplatin (25 mg/m2), which was administered on days 1 and 8, followed by 1 week of rest. The dose was modified based on the incidence of adverse events associated with the treatments and/or the physician/patient discretion. GC therapy was continued until disease progression, occurrence of unacceptable toxic effects, or if the patient refused to continue with treatment. RBO was not considered to constitute disease progression. Second-line chemotherapy or best supportive care was initiated in the event of disease progression.Each chemotherapy cycle comprised gemcitabine , best response, adverse events associated with treatment, and the clinical success and incidence of RBO associated with SEMS placement with and without RFA. The outcomes were compared between the treatment cohort that underwent SEMS placement and RFA with GC therapy (with-RFA group) and the control cohort that underwent SEMS placement alone with GC therapy (without-RFA group).The OS was measured from the date of initiation of GC therapy to the date of the patient’s death, and PFS was measured from the date of initiation of GC therapy until either disease progression or the patient’s death. The best response was judged according to the Response Evaluation Criteria in Solid Tumors version 1.1 . Among tp values < 0.05 were considered to indicate statistical significance.Fisher’s exact test was used to evaluate the differences between the categorical variables, and the Mann–Whitney U test was used to compare the continuous variables. The Kaplan–Meier method was used to estimate the OS, PFS, and time to RBO, and the curves were compared using the log-rank test. The data of patients in whom RBO did not occur until the time of death were considered to be censored. All statistical analyses were conducted using EZR version 1.54  . p valuep = 0.571), while the median time to RBO was significantly longer in the with-RFA group  (= 0.048) .p = 0.408). The relative dose intensity was 83% and 81% for gemcitabine and cisplatin in the with-RFA group, and 87% and 80% in the without-RFA group, respectively, without significant differences (p = 0.533 and p = 0.439). Second-line chemotherapy was performed in 40% (10/25) of patients in the with-RFA group and 40% (10/25) of patients in the without-RFA group (p = 1.000). The mean frequency of RFA sessions was 1.84 times (range: 1–4 times) in the with-RFA group.The mean frequency of GC therapy was 8.2 cycles (range: 1–22 cycles) and 7.1 cycles (range: 1–20) in the with-RFA and without-RFA groups, respectively, which lacked a statistically significant difference     , 64% (14/22), and 18% (4/22) in the with-RFA group, and 17% (4/23), 57% (13/23), and 26% (6/23) in the without-RFA group, respectively; thus, significant differences were not observed between the two groups (= 0.722) . The med= 0.014) . The med= 0.015) , while t= 0.529) .The details of grade 3 or higher adverse events are presented in The present study demonstrated that endobiliary RFA prolonged the time to RBO when used concomitantly with uncovered SEMS, followed by GC therapy. Moreover, RFA showed an additive survival prolonging effect on GC therapy for eCCA but was limited to patients with locally advanced tumors.The treatment and management of biliary strictures is a critical aspect of the treatment of eCCA, especially in patients who have undergone chemotherapy. RBO is often accompanied by sequelar cholangitis, which can be serious in patients who are in a state of myelosuppression following chemotherapy. Moreover, reintervention and hospitalization are required in the event of RBO, which can cause deterioration in the patient’s quality of life, while chemotherapy, which is directly related to survival, also needs to be stopped due to RBO. The SEMS possesses longer stent patency compared to PS, and recent guidelines recommend its deployment for unresectable cases . MoreoveEndobiliary RFA was first developed with the goal of extending the duration of stent patency . Howeverp < 0.001), and the other study by Gao et al. [p < 0.001). However, patients who underwent chemotherapy were excluded from the Yang et al. study population, while their number was considerably lower in the Gao et al. study population. Yang et al. [p < 0.001). Therefore, the results of these studies showed that RFA is expected to exert a considerable effect on the survival in patients with eCCA, and chemotherapy is also anticipated to confer an additional survival benefit on RFA. However, to date, no study has verified the additive effect of RFA on chemotherapy for eCCA or investigated the combination of RFA with GC therapy, which is the standard first-line regimen for eCCA. The present study ascertained that the combination of RFA with GC therapy yielded longer survival compared to those of GC therapy alone.Studies have also suggested that endobiliary RFA may prolong survival in patients with eCCA via tumor volume reduction associated with coagulative necrosis, superior stent patency, and antitumor immunity ,21,22,23o et al.  also repg et al.  later coHowever, the present study demonstrated that the significantly longer OS associated with RFA was only observed in the patient cohort with locally advanced tumors. This observation may indicate the survival benefit conferred by endobiliary RFA, whose influence is limited to eCCA without metastasis. Future studies are required to evaluate the systemic effect of endobiliary RFA in greater detail. Moreover, the appropriate number of RFA sessions required to achieve an adequate effect is unclear. Although several studies conducted multiple sessions of RFA, the additional effects of multiple RFA sessions, criteria determining the indications for the need of additional ablation, and the requisite frequency for ablation remain uncertain. The present study performed RFA at the time of initial SEMS placement and RBO occurrence, and the mean frequency of the RFA sessions was 1.84, but the appropriateness of this regimen is also unclear. These aspects unveil important issues and considerations for future studies.Patient selection is another important consideration for RFA. The RFA catheter used in the present study was a bipolar device with two 8 mm ring electrodes placed 8 mm apart at the tip of the catheter. A sufficient ablative effect could not be obtained in some cases, such as those with short-length strictures, because the two electrodes had to be maintained in proper contact with the stricture tissue ,27. AlthThe present study had several limitations. First, the study was retrospective and nonrandomized in design, and thus, the possibility of the resulting selection bias cannot be excluded. The results might have overestimated the utility of RFA because it may have been avoided in difficult cases, such as complicated hilar strictures. Second, the sample size was small. Although there were no significant differences in the several values and outcomes, it is possible that the study was statistically underpowered. Third, all endobiliary RFA procedures were conducted by endoscopists with experience in performing endoscopic biliary stenting and endobiliary RFA. Since RFA is only visible under the fluoroscopy during the procedure, some of the evidence on the ablative effect achieved and safety associated with RFA may be empirical in nature. It was not possible to ascertain whether all the lesions were well ablated or not because not all patients underwent cholangioscopy after ablation in the present study.Despite these limitations, this was the first study that focused on the combination of RFA and SEMS placement with GC therapy for patients with unresectable eCCA, which yielded promising results, especially in cases with locally advanced tumors. This study provided important evidence for the role of endobiliary RFA in treating eCCA and further enhancing the outcomes. Further clinical trials should be performed on the basis of these results.


Dyspnea is a highly alarming sign both for dog owners and veterinarians. Although its recognition is usually easy due to prominent suffering of an animal, finding its cause is challenging because many diseases of the heart, lungs, and airways may manifest themselves this way. Echocardiography and lung ultrasound allow for relatively quick and accurate identification of heart diseases. Dyspneic dogs without a heart and upper airway disease are usually suspected of either bacterial pneumonia or lung neoplasm. Although prognosis in these two conditions is diametrically different, differentiation between them is challenging. Chest radiography is performed in a lateral position, which is barely tolerated by a dyspneic dog, and intensive chest movements often make X-ray scans inconclusive. Computed tomography, although much more accurate, requires general anesthesia, which is difficult and potentially life-threating in a dyspneic dog. Therefore, lung ultrasound, which can be performed quickly in a conscious dog, standing or in sternal position, seems to be the method of choice. We develop and evaluate a diagnostic algorithm based on detection of three well-defined abnormalities in the lung ultrasound. The algorithm allows one to distinguish between bacterial pneumonia and lung neoplasm in a dyspneic dog with high probability of a conclusive result (91%) and high accuracy (>95%).The diagnostics of two of the most prevalent lung diseases in dogs, bacterial pneumonia (BP) and lung neoplasm (LN), are challenging as their clinical signs are identical and may also occur in extrapulmonary diseases. This study aims to identify ultrasonographic criteria and develop a lung ultrasound (LUS)-based diagnostic algorithm which could help distinguish between these two conditions. The study is carried out in 66 dyspneic dogs in which a heart disease was excluded using echocardiography. Based on imaging and laboratory diagnostic tests, as well as follow-up, the dogs are classified into LN (35 dogs) and BP (31 dogs) groups. LUS is performed at admission and the presence of seven lung abnormalities  and classification and regression trees are used to develop an LUS-based diagnostic algorithm. Distribution of all LUS abnormalities except for aerations differs significantly between groups; however, their individual differentiating potential is rather low. Therefore, we combine them in an algorithm which allows for definitive classification of 60 dogs (91%) (32 with LN and 28 with BP) with correct diagnosis of LN and BP in 31 dogs and 27 dogs, respectively. The diagnostics of lung diseases are challenging as their main clinical signs, such as coughing or dyspnea, are not specific for any particular disease of the lungs and may also occur in various extrapulmonary diseases such as congestive heart disease and diseases of the upper airways . The intAccording to this knowledge, the question is: why is TXR still widely and easily accepted in pulmonology whereas LUS is not? One possible answer could be that a more accurate diagnostic algorithm for different lung diseases in human medicine and small animal practice is needed. In contrast to abdominal ultrasound (AUS), the presence of air in the respiratory system precludes ultrasonographic visualization of the lungs. However, in pathological processes such as inflammation, edema, neoplasm, embolism, or contusion, the lung tissue is losing air which is replaced by fluid and so-called consolidations become apparent in the ultrasound image. The vast majority of pneumonia lesions in adults have pleural contact ,13. AlthLUS is based on the visualization of artifacts such as the pleural line, sliding sign, and A-lines ,16. Thesscore has been developed as a sum of points describing the occurrence of B-lines for each of eight standardized thoracic locations. It may help to distinguish between lung neoplasms  and cardiogenic PE or pneumonia  in dogs; however, its accuracy is only fair to moderate ) and child nodes (weighted sum of Gini impurity of child nodes [IGini(Dk)]) and was given by the equation: p was a data set in the parent node, Dk with k = {L,R} was a data set in the left (L) or right (R) child node, n was the number of observations in the parent node, nk with k = {L,R} was the number of observations in the left (L) or right (R) child node, and pLN(k) and pBP(k) with k = {L,R} were the proportion of observations from class LN or BP, respectively, in the left (L) and right (R) child node. IGini(D) was the impurity function (function describing distribution of the same elements to 2 classes) based on the Gini index (GI) and given by the formula:i was a fraction of data of class i with i = {LN,BP} in a subset D. IGini(D) could take values from 0  to 0.50 .Subsequent analysis was carried out using the Classification and Regression Trees (CART), a non-parametric supervised learning technique, built according to the trimming algorithm in the Data Mining module of TIBCO Statistica 13.3 . The classification was done by maximizing the information gain (IG), which showed the difference in impurity between the parent (decision) node (Gini impurity of the parent node [ILN) and BP (pre-PBP) was set as equal . The CART was built assuming an equal cost of misclassification and splitting was stopped when the count at decision  node was ≤10. Positive (LR+) and negative (LR-) likelihood ratios, with CI 95% calculated using the log method [LN) and BP (post-PBP) were calculated by converting probabilities into odds and multiplying by LR+ in terms of LN or LR- in term of BP, analogically to calculating positive and negative predictive value using the Bayesian approach [The pre-test (prior) probability of LN . The study population comprised 66 adult dogs , aged from 1 to 17 years with a median (IQR) of 11 (9–13) years. Thirty-five dogs (53.0%) had lung neoplasm (LN group) and 31 (47.0%) had bacterial pneumonia (BP group). Neither age nor sex distribution differed significantly between groups . Most doOf the 35 dogs from the LN group, 20 (57.1%) had metastatic LN from testis, liver, spleen (three dogs each), mammary gland (two dogs), thyroid gland, prostate, stomach, unknown glandular organ, skin, kidney, mediastinum, and bone—scapula (one dog each); one dog had pulmonary leukemic infiltrates. Nine dogs (25.7%) had primary LN—bronchoalveolar carcinoma (five dogs), adenocarcinoma (three dogs), and histiocytosis (one dog). In six dogs (17.2%), the origin of LN was unknown. p = 0.027), subpleural consolidations (p = 0.012), and pleural thickening (p = 0.012) were significantly more common in the BP group, whereas tumor (p < 0.001), hepatization (p = 0.001), and free pleural fluid (p = 0.004) were more common in the LN group.B-lines, subpleural consolidations, and pleural thickening were the most prevalent LUS abnormalities found in 78.8% , 72.7% , and 65.2%  of dogs, respectively. Tumor and hepatization were observed in roughly one third of dogs—37.9%  and 31.8% , respectively, whereas free pleural fluid and aerations in roughly one fourth of dogs—25.8%  and 22.7% , respectively. Distribution of all abnormalities except for aerations differed significantly between groups , Table 2p = 0.026), subpleural consolidations , and pleural thickening  (p < 0.001), hepatization , and free pleural fluid  were observed in the significantly higher number of quadrants of dogs in the LN group  . The opt= 0.003) . TherefoLN group . The optLN group , and thep = 0.491), so the pre-test probability of LN (pre-PLN) was assumed to be 50%. The CART flowchart is shown in The distribution of LN and BP in the study population was not significantly different from 1:1 (LN) was >99%. The observed post-PLN was 100% . Therefore, detection of a tumor was considered as a leaf node  of CART corresponding to a positive result of LUS for LN. A LUS negative for a tumor was associated with LR- = 0.29, so the estimated post-PLN was 22.5%. The observed post-PLN was 24.4% . Therefore, no tumor in the LUS was considered as an inconclusive result and the diagnostic procedure carried on.A tumor was the first decision  node in CART —I. DetecLN was only 3.4% and the observed post-PLN was 3.6% . As post-PBP was 96.4% (CI 95%: 82.3–99.4%), the parallel combination of negative results for tumor and hepatization was considered as the second leaf node of CART corresponding to a positive result of LUS for BP. A LUS positive result for hepatization in a dog negative for a tumor was associated with LR+ = 7.0, so the estimated post-PLN was 67.0% and the observed post-PLN was 69.2% . The result was considered inconclusive, and the diagnostic procedure carried on.The second decision  node in CART was hepatization —II. LUS LN was 84.6% and the observed post-PLN was 85.7% . Therefore, the detection of subpleural consolidations in <3 quadrants in a dog negative for tumor but positive for hepatization in LUS was considered as a leaf node of CART, corresponding to a positive result of LUS of LN.The third decision  node in CART was subpleural consolidation —III. DetLN was 47.2% (post-PBP = 52.8%) and the observed post-PLN was 50.0% . Therefore, the result was considered inconclusive. The diagnostic procedure was discontinued at this step as no further refinement of the classification could be obtained using LUS abnormalities.Detection of subpleural consolidations in ≥3 quadrants was associated with LR- = 0.44, so the estimated post-PThe procedure led to a conclusive result in 60 of 66 dogs —32 positive for LN and 28 positive for BP. Six dogs (9.1%—three with LN and three with BP) were classified as inconclusive. LN diagnosis was correct in 31 of 32 LN dogs with a conclusive result  and BP diagnosis was correct in 27 of 28 dogs with a conclusive result . Our study evaluated the capability of a set of LUS abnormalities in distinguishing between two very common causes of lung-associated dyspnea—(BP) and (LN). Even though the prevalence of six of seven LUS abnormalities differed significantly between the two groups of dyspneic dogs, the magnitude of individual differences was small . Only the presence of a tumor in LUS was associated with individual diagnostic accuracy that was sufficient from the clinical standpoint  ,31. TherDyspnea is a life-threatening clinical sign associated with high mortality unless properly treated. An appropriate and timely treatment can only be applied if an accurate diagnosis has been made as soon as possible. Many scientific publications have shown that LUS is now an important and accurate diagnostic test for respiratory diseases ,17,34. TIn this study, we focused on pneumonia which can be classified as of bacterial etiology, because definitive diagnosis was based on clinical criteria, mainly recovery on a broad-spectrum antibiotic treatment. There is, however, one important pitfall of such an approach. Pneumonia does not have to be of bacterial etiology. Although it appears to be most prevalent in the canine population , viral, We decided to express LUS abnormalities as dichotomous (binary) variables for two reasons. First, to make the classification of patients with respect to these abnormalities as intuitive and simple as possible. In clinical conditions, including the exact number of lung quadrants affected by a given abnormality in the model would consume time, bring about mistakes, and eventually discourage clinicians from using the diagnostic algorithm. Secondly, dichotomous categorization of a numerical variable made the algorithm more robust because a small change in the number of quadrants affected by the abnormality, which is likely to result from imperfect repeatability and reproducibility of LUS, is unlikely to influence the final patient classification.However, the number of quadrants in which LUS abnormalities could be detected may be considered as a proxy of severity and dissemination of a given pathological process in the lungs. As binary categorization of a numerical variable leads to loss of some amount of information, the method that retains maximum information should be chosen. We used methods commonly used in epidemiology  to search for a better classification than the method based on simple “present vs. absent” categorization. They allowed for the dichotomization of three of the LUS abnormalities  in a manner that separated dogs with LN from dogs with BP more accurately than when a “present vs. absent” method was used. Therefore, we decided to enter them in the CART model in this form.The CART model was finally based on three of six initially included LUS abnormalities—the presence of tumor, hepatization, and less than three vs. at least three quadrants with subpleural consolidations. The first decision node, i.e., the moment for classification of patients in our CART model, was the detection of at least one tumor in LUS. According to our results, such a patient was very likely to have LN as all patients with a tumor in LUS had LN. However, given the limited number of dogs enrolled in our study, it is much safer to claim that the probability of LN in such a patient is at least 85% (lower confidence limit of the observed post-test probability). Anyway, detection of a tumor in LUS is the first conclusive result of our diagnostic algorithm. Subpleurally localized tumors appear as hypoechoic masses, usually with a more clearly marked border from the normal lung, compared to inflammatory consolidations. Most often the masses are round, polypoid, or triangular and less often they irregularly penetrate the normal lung tissue. Contrary to inflammatory condensations, the shape and size of neoplastic lesions do not change over a short period of time. The echogenicity of lung tumors is variable, depending on the type of tumor and its size. It is not possible to diagnose the type of tumor on the basis of the LUS image. Aeration may be also present in the tumor tissue, resulting from air entrapment in the alveoli or bronchi . However, the lack of a tumor in LUS does not exclude LN—roughly one fourth (10/41) of dogs without the tumor in LUS in fact had LN. Therefore, the next decision node was the detection of hepatization, i.e., altered lung tissue that resembled liver tissue on the image. In this situation, the conclusive result was the lack of hepatization in any of eight quadrants of the lungs. If a dyspneic dog did not have either a tumor (as stated in the previous paragraph) or hepatization, it was very likely (96%) to have BP. Again, having taken into account a relatively small number of dogs in our study, it is safe to claim that the probability of BP in such a patient is at least 82% (lower confidence limit of the observed post-test probability). A dyspneic dog without a tumor but with hepatization in LUS still remained a puzzle. In our study, such a patient was more likely to have LN, but the probability was not significantly different from the probability of BP (ratio of roughly 2:1). Therefore, we searched for the next decision node. It turned out to be the presence of subpleural consolidations in less than three quadrants. Such a result in a dog negative for tumor but positive for hepatization was conclusive and indicated LN. It must be stressed that at this level of the analysis the number of dogs was already very low—only seven—out of which one dog had BP and six dogs had LN. Although the expected and observed post-test probabilities of LN were roughly 85%, the precision of this estimation was very low (CI 95% was very wide), so this result should be treated with very high caution. Especially when the diagnosis of LN is going to constitute a basis for euthanasia, another diagnostic method should be used to attain higher confidence of the diagnosis. The weakness of this last decision node is emphasized by the CI 95% for LR+ covering 1, which in fact indicates that such a result may also be obtained in a dog with BP. Regardless, given the fact that the diagnostics of intrathoracic pathological processes are very challenging in veterinary medicine, we think that even such a weak conclusion deserves some attention, at least as a starting point for further studies. A dyspneic dog without a tumor in LUS, with hepatization in LUS, and with subpleural consolidations in ≥3 quadrants was equally likely to have LN and BP, so it had to be considered as an inconclusive result of the CART model. The overall discriminative potential of the diagnostic algorithm was high. Based on the lower limit of the CI 95%, it was very likely to yield conclusive results in over 80% of dyspneic dogs and the classification made with its use was more than 80% likely to be true. Given that an alternative in a dyspneic patient is TXR or CT with their multiple limitations, these figures appear to be sufficient to recommend the use of the diagnostic algorithm based on the LUS-CART model in daily veterinary practice. Obviously, it must be stressed once more that this diagnostic algorithm applies to the patient whose dyspnea does not result from a disease of the heart or upper airways or from lung contusion. Due to the relatively small study population, we could estimate diagnostic accuracy measures of our algorithm with only moderate or sometimes even low precision (wide CI 95%). Therefore, our results warrant verification on a larger study population.In summary, a diagnostic algorithm based on LUS can serve as an accurate and easily available method of differentiation between bacterial pneumonia and lung neoplasia in a dyspneic dog without pulmonary edema (based on TUS examination), upper airway disease, and lung contusion.


In the past two decades, the surge of research on bacterial persisters has been inspired as increasingly concerning about the frequent failure of antibiotics treatment. This study was aimed at presenting a bibliometric and visualized analysis of relative publications on bacterial persisters, which offered insights into the development and research trends of this field.  The Web of Science Core Collection and Ovid MEDLINE databases were utilized to retrieve relevant publications on bacterial persisters from 2001 to 2021. After manual selection, data including titles, authors, journals, author keywords, addresses, the number of citations, and publication years were subsequently extracted. The data analysis and visual mapping were conducted with Excel, SPSS, R studio, and VOSviewer. Antimicrobial Agents and Chemotherapy was the most influential journal with 113 relevant publications. The cooccurrence analysis revealed that studies on bacterial persisters focused on four aspects: “the role of persisters in biofilms,” “clinical persistent infection,” “anti-persister treatment,” and “mechanism of persister formation.”  In this study, 1,903 relevant publications on bacterial persisters were included. During 2001-2021, there was an exponential growth in the quantity of publications. It was found that these studies were conducted by 7,182 authors from 74 different countries. The USA led the scientific production with the highest total number of publications (859) and citation frequency . The  In the past two decades, the global field of bacterial persisters has significantly increased. The USA was the leading country in this field. Mechanistic studies continued to be the future hotspots, which may be helpful to adopt new strategies against persisters and solve the problem of chronic infection in the clinic. The frequent failure of conventional antibiotic treatment has become a serious medical crisis worldwide, which increased mortality, time of hospitalization, and healthcare costs . SeveralBibliometric analysis is a powerful tool, which utilizes mathematical and statistical methods to assess the change in the number of publications, countries, authors, keywords, etc. over time . It can As the field of bacterial persisters has drawn more attention, it is vital to characterize the evolution of this field in detail. Therefore, this study was aimed at tracking the global development status and analyzing the research trends of bacterial persisters through a bibliometric analysis of related publications within the past 20 years. According to the data from the Web of Science Core Collection (WoSCC) and Ovid MEDLINE databases, the contributions of individual countries, institutions, authors, and journals were analyzed to give insights into the field of interests, academic impacts, and collaboration patterns. Besides, the visualized map helped to obtain the research trends and hotspots in the field of bacterial persisters. The results of this study might provide a theoretical basis and new ideas for further in-depth research on bacterial persisters.The MeSH terms from PubMed and Emtree terms from Embase were used. The truncated search terms were used to increase the scope of the search for words that have singular and plural forms or variant endings. In addition, the Boolean operators “AND,” “OR,” and “NEAR” were utilized to construct the search strategy. The WoSCC and Ovid MEDLINE databases were utilized to retrieve all relevant literature in this bibliometric analysis. The literature retrieval was performed on September 6, 2022 to identify studies published between January 1, 2001 and December 30, 2021. The search strategies in WoSCC and Ovid MEDLINE are listed in Table h-index was analyzed by the intrinsic functions of the WoS database, and the 2021 impact factors (IFs) of the journals were supplemented from the Journal Citation Reports .Consequently, a total of 9,317 studies were retrieved. Endnote X9 was utilized to remove the duplicated references. Then, three authors independently assessed the titles or abstracts and excluded irrelevant studies to ensure that the studies focused on bacterial persister. Studies that only mentioned persister in passing were excluded. Any discrepancies were resolved by consensus-based discussion of full texts or corroborated by another author. As a result, 1,903 valid publications were included, and the following information was extracted from each article: title, authors, journal, publication year, document type, keywords, addresses, subject category, and the number of citations in the WoS database. The https://www.vosviewer.com/) [Microsoft Excel and IBM SPSS Statistics were utilized to count the frequency of descriptive characteristics, like countries, authors, and the number of citations. The annual growth rate (AGR) was calculated using the equation suggested by Gracio et al. . The comer.com/) , 28 was In this research, there were 1,903 records related to bacterial persisters from 2001 to 2021. The quantitative characteristics of the publications on bacterial persisters could be divided into three stages. In the first stage (2001-2007), the study on bacterial persisters was at an initial stage. At this stage, a total of 71 papers were published accounting for only 3.73% of the total publications . Moreover = 0.991, P < 0.001), as well as between the annual publications and annual citations . Furthermore, the most cited article  was published in 2004 by Professor Nathalie Q. Balaban, describing the persistence switch between normally growing cells and persister cells having reduced growth rates [In terms of citations, th rates .h-index of 111, followed by England , Belgium , Germany , China , and Canada . In addition, Gambia showed the highest average frequency of citations with 259 citation counts for only one publication, describing nonreplicating persisters in tuberculous sputum [The papers related to bacterial persisters originated from 74 countries. The geographical distribution by the number of publications is shown in s sputum . Israel L) = 35 and total link strength (TLS) = 302. The thickest line is connected to China, and this represented that the USA had the strongest cooperation with China in the field of bacterial persisters. This is followed by England which had L = 30 and TLS = 106; Germany, L = 26 and TLS = 61; and Belgium, L = 23 and TLS = 40. Furthermore, Australia, Canada, Iran, Pakistan, and Saudi Arabia were related to the same cluster in this network. Israel and Mexico were in a separate cluster, respectively.International cooperation was found between 68 countries. h-index are listed in h-index (41) and number of citations ; meanwhile, it ranked third in the list of top 20 productive institutions with 55 publications. Johns Hopkins University was the institution with the most number of publications (69), but the citation count of Johns Hopkins University was much less with a total of 2,409 citations and h-index of 28. It was worth noting that Rockefeller University published only 9 papers but ranked fifth in the list of top 20 cited institutions with 3,041 citations. This indicated that Rockefeller University caused a considerable impact. In terms of the top 20 influential institutions, there were 12 institutions from the USA with an h-index ranging from 41 to 16. Moreover, there were 2 institutions in China with an h-index of 14. In terms of the top 20 prolific institutions, there were 11 institutions from the USA with a total of 404 publications. Similarly, 2 productive institutions were from China and had 51 publications. In addition, the distribution of the top 20 influential institutions demonstrated that studies on bacterial persisters were mainly concentrated on universities (17) and research institutions (2). The number of publications for institutions showed a not very strong correlation with citations .Through analyzing the distributions and cooperation of research institutions, key institutions with large publications and high impact on bacterial persisters could be identified. A total of 1,512 institutions have participated in the research of bacterial persisters. The top 20 influential institutions according to The cooperation network of institutions with a minimum of 10 publications was constructed. Syracuse University, University of Calgary, Indian Institute of Science, Ilam University of Medilam Sciences, and Sungkyunkwan University were excepted as they were “remote” institutions without connecting to other institutions. The size of the node represented the number of links for each institution. 77 connected institutions were presented in 11 clusters with 436 links. As shown in Through analyzing the characterization of the authors' cooperation network, it identified the core group of authors and social connection among researchers on bacterial persisters. 7,182 authors were involved in the publications in the field of bacterial persisters. A total of 19 authors published at least 15 papers on bacterial persisters . Ying ZhAuthors in the field of bacterial persisters presented a high trend for collaborations with DC ranging from 0.76 to 1.00 . From 20The network of authors with 5 or more papers was considered, and 205 authors are shown in Southeast Asian Journal of Tropical Medicine and Public Health) to 112.288 (Nature Reviews Drug Discovery). Moreover, there were 41 journals publishing at least 10 papers concerning bacterial persisters. The top 10 popular journals with the largest number of publications or highest number of citations were listed in Frontiers in Microbiology ranked first with 115 publications, followed by Antimicrobial Agents and Chemotherapy (113), and Journal of Bacteriology (67). The 2021 IFs of these journals are 6.064, 5.938, and 3.476, respectively. In addition, Antimicrobial Agents and Chemotherapy and Journal of Bacteriology obtained a significant frequency of citations . Moreover, Science and International Journal of Antimicrobial Agents published less than or equal to 10 papers but possessed a large frequency of citations . For journals, the Spearman rank test indicated that there was a low correlation  between the number of publications and citation counts. Within journals that had 2021 IFs, the number of publications  and citation counts  both showed weak relationships with 2021 IFs.There were 451 journals that participated in the research on bacterial persisters, and the 2021 impact facts (IFs) of these journals ranged from 0.209  and citations  was closely related to the h-indexes of journals. However, the 2021 IFs were not correlated to the h-indexes of journals .The The keywords were identified as words that have been used in author keywords. After cleaning, screening, and inference, the network offered 439 keywords that appeared more than 2 times . The keyThese keywords were then divided by specific colors based on the average time they appeared in all publications . As the h-index (105). In terms of citations, “Science Technology Other Topics” ranked second with total citations of 17,307 and h-index of 63, followed by “Pharmacology Pharmacy” with 14,241 citations and h-index of 57, “Biochemistry Molecular Biology” with 13,854 citations and h-index of 60, and “Infectious Diseases” with 7,498 citations and h-index of 41. This indicated that there were more citations of multidisciplinary research areas.The publications on bacterial persisters could be concentrated on 67 areas according to the research areas in the WoS database. The areas with more than 10 publications are shown in In this study, we explored the bibliometric characteristics and visualized analyses of the field of bacterial persister research using VOSviewer. The results might provide references and suggestions for further research on bacterial persisters.During 2001-2021, 1,903 relevant publications were produced in the field of bacterial persisters. In 2001, the field of bacterial persisters has not attracted much attention with only 4 publications. At this time, Spoering and Lewis proposed that the presence of persisters in biofilm played an important role in antibiotic tolerance of biofilm [h-index (111). The USA stood at the center of the cooperation networks countries and had more link strength with other countries  and the highest total citation frequency  and ountries . More thountries . These th-index and the sixth place in the total citation frequency. There were several reasons that led to this distance between the quantity and the academic impact of publications. Firstly, publications on bacterial persisters from China were mainly published after 2015. Simultaneously, citations usually have a delay of at least 2 years, and publications by Asian countries are more difficult to receive prompt citations than by western countries [Over the past two decades, the number of publications on bacterial persisters arising from China and India has increased rapidly, as the total number of publications in China has ranked second among countries worldwide. However, China stood at the fifth place in ountries . Secondlountries . This inh-index or the number of publications, 60% or 55% institutions of the top 20 influential institutions or productive institutions originated from the USA, respectively (h-index of 41). Moreover, authors from the USA and Europe demonstrated a domain position, and most of the productive corresponding authors continuously published between 2011 and 2021  and achieved the highest citation/publication (984) with only 1 paper. This paper reviewed strategies to establish platforms for identifying drugs against persisters [The number of publications and citation frequency of journals indirectly reflected the journal ranking in the field of bacterial persisters. The majority of papers were published in microbiology journals, such as sistance , and antaumannii . This suns Table , which mrsisters . In addirsisters , 48.M. tuberculosis that stimulate the growth of persisters [in vitro or in vivo models to detect the presence of Mtb persisters and shorten the treatment duration [The cooccurrence network of keywords severed as an important indicator to reflect the research hotspots and directions. Broadly speaking, the research directions in the field of bacterial persisters could be included into four aspects: the role of persisters in biofilm, clinically persistent infection, anti-persister treatment, and mechanism of persister formation. Several keywords lacked strong cooccurrence links with other keywords, like “ribosome hibernation,” “resuscitation promoting factors,” and “protein acetylation.” Ribosome hibernation was a process that bacteria polymerized 70S ribosomes into inactive 100S ribosomes . In 2015rsisters . They haduration , 52. Resduration . After tduration –56. AlthE. coli, P. aeruginosa, S. aureus, and M. tuberculosis (Mtb). According to our bibliometric study, the appearances of “TA system,” “Agr quorum sensing (QS) system,” “(p)ppGpp stringent response,” “antipersister molecules,” “virulence factors,” and “oxidative stress” were more frequent. The activation of TA systems by (p)ppGpp has become a widely accepted model of persister formation [In this study, the clusters of keywords revealed that the research on bacterial persisters was mainly based on studies of ormation . The hipormation . Afterwaormation . Other Tormation –62. Furtormation , 64. Sevormation –67. Hencormation –70. Moreormation , 71–73. ormation . Under aormation , 76. Subormation . Under tormation , 79. Morormation , 81.The organization of keywords by average publication year provided insights into future trends in the field of bacterial persisters . The keyThe global field of bacterial persisters has rapidly expanded over the past two decades. To our knowledge, this study was the first bibliometric study reflecting the general trends of bacterial persisters. Compared to traditional reviews, this visualized study provided a large volume of information about the global distribution and trends of research on bacterial persisters. Moreover, like other bibliometric analyses, there were nonetheless several limitations of our study , 84. FirAntimicrobial Agents and Chemotherapy was the most influential journal with the great number of relevant publications, citations, and h-index. Kim Lewis achieved academic influence in the field of bacterial persisters with high publication volume and citation frequency. According to the bibliometric and visualized analyses, collaborations between researchers from different institutions should be strengthened to look deeper into bacterial persisters. In this study, we predicted that the publication outputs on bacterial persisters will continue with an upward trend in the coming decade. In-depth studies on the mechanism of persister formation will be the future research trend, and it will hopefully develop novel anti-persister methods to bring benefits to patients with persistent infections.In summary, this study presented the global trends in bacterial persisters based on bibliometric analysis. A series of studies were retrieved from the WoSCC and Ovid MEDLINE database, and 1,903 pieces of data were collected from 2001 to 2021. In total, there were 7,182 authors from 1,512 institutions in 74 countries who participated in the study of bacterial persisters. The USA was globally found as the leading country in this field, as it made the highest contribution to both the total number of publications and citation frequency.


During the COVID-19 pandemic, quality of life (QoL) was reduced among many groups, including Israeli older adults. This study investigated perceived QoL, perceived accessibility of the living environment, and participation in activities among nondisabled older adults and those with disabilities in the community. It also examined whether the perceived accessibility’s effect on QoL occurs directly and/or indirectly via mediators of participation in community activities. A voluntary and anonymous survey was administered from February to May 2021 to 495 participants aged 60 and older. Respondents completed three questionnaires: WHOQOL-BREF, Community Integration Questionnaire-Revised (CIQ-R), and Perceived Accessibility of Living Environment (PALE). The main finding was that participation in activities in the community had a direct positive impact on QoL. Perceived accessibility of the living environment also had indirect positive effects on QoL through participation in activities in the community, for those without disabilities but, interestingly, not for those with disabilities. Hierarchal linear regressions revealed that participation in activities explained 53.3% of the variance for both groups while perceived accessibility added 1.1% for the nondisabled. We conclude that accessibility of living environment is a good indicator of positively perceived QoL through participation in various activities in the community for nondisabled older adults. This may be especially important during a pandemic. The number and proportion of people aged 60 years and older in the world’s population has been increasing at an unprecedented rate, one that is expected to accelerate in coming decades . As of 2Quality of life (QoL) reflects a subjective evaluation which is embedded in a cultural, social, and environmental context in relation to people’s goals, expectations, standards and concerns. In addition, QoL is affected by disease and health interventions [ventions . Enhanceventions . Moreoveventions . Howeverventions ,13,14, iventions ,16, bothventions ,18 and pventions . Workingventions . Howeverventions ,21. Reduventions .social space, represented by the rate of use of shopping facilities, amenities, and social resources outside the household [Perceived accessibility can be defined as the person–environment fit or the level of compatibility between one’s personal abilities  and needs and the environment, which results in psychological well-being and better physical activity according to the ecological theory of aging [Environment is another element found to influence QoL during COVID-19. For example, proximity to large parks and numerous local facilities as well as lower neighborhood density, living further from the city center, and living in a larger dwelling were associated with better health and well-being outcomes for all ages in one study . With inousehold . Perceivof aging . During of aging . Anotherof aging .perceived accessibility of the living environment and participation in activities in the community during COVID-19 in Israel and none have examined older adults with disabilities compared to a nondisabled group. Understanding the interplay between individual participation in activities and environmental factors that influence older adult QoL will inform strategies to target the needs and preferences of community dwelling older adults and thereby improve their QoL. Therefore, the objectives of this study were: 1. to investigate the differences and correlations in perceived QoL, perceived accessibility of the living environment, and participation in activities in the community among nondisabled older adults and those with a disability; 2. to examine whether the effect of perceived accessibility on QoL occurs directly and/or indirectly via mediators of participation in activities in the community.To the best of our knowledge, no other studies have examined the direct and indirect effect on the QoL of This research was a voluntary and anonymous cross-sectional survey. This survey was undertaken during COVID-19 in Israel from February to May of 2021, a period that included social distancing measures such as avoidance of gatherings, wearing facemasks in indoor environments, and the closing of senior clubs . The surA convenience sample of 495 participants responded to the survey. The inclusion criteria were individuals aged 60 and older, Hebrew, or Arabic speakers, and agreement to participate. For the statistical analysis, the sample was divided according to participants who self-reported that they had a functional disability and participants who did not suffer disability referred to as “nondisabled older adults”. The study underwent an institutional review and was approved by the ethics committee of Ariel University (AU-HEA-OSY-20201217).The WHOQOL-BREF  ; the gen; (2) social integration: participation in a variety of activities outside the home and interpersonal relations; (3) productivity: involvement in employment, education, and volunteer activities; (4) electronic social networking: participation in electronic social networking. Most CIQ-R items were scored from 0 to 2: a score of 2 indicated that the individual performs the activity alone, score 1—someone else is also doing or might be doing the activity as interpreted in Hebrew , score 0—someone else does it for them. The total score (0–35) was calculated as well as subtotal scores: home integration (0–12), social integration (0–10), productivity (0–7), and electronic social networking (0–6). A higher score indicates a higher level of community integration [The Community Integration Questionnaire-Revised (CIQ-R) , is an 1egration . Cronbacegration . The CIQPerceived accessibility of living environment and services (PALE): this self-reported questionnaire was developed by the authors for the current research, see A sociodemographic questionnaire was used to elicit participant background characteristics: gender, age, years of education, marital status, person(s) with whom the respondent lived, nation/ethnic sector, and religion. Respondents were also asked to self-identify in one of four religious categories: secular, traditional, religious and very religious/Haredi , commonly understood categories in Israel, each distinguished by variant sets of beliefs and practices, and which have been associated with different types of health and well-being .p < 0.05. Pearson correlation coefficients were used to test the correlations between measures, and linear regression assumptions were tested; Kolmogorov–Smirnov was not significant, meaning the dependent variable of QOL had normal distribution and, no multicollinearity was found between the explanatory variables. Two hierarchal linear regressions were conducted to explain QoL: one for participants who reported that they had a disability and the other for participants without disabilities, referred to as “nondisabled older adults”. The variables were entered into the regressions in the following order: at step 1: age and gender; at step 2: education, religion, and nation; at step 3: three subscales of community integration which were correlated with QoL. Perceived accessibility of living environment was not entered into the regression since it was not correlated with QoL. A mediation analysis [Descriptive, bivariate, and multivariant statistical analyses were performed using Statistical Packages for the Social Sciences (SPSS) version 21 for Windows . Significance level was set at analysis  was thenThe study sample consisted of 495 participants with a mean age of 69.66 (SD 7.02), ranging from 60 to 100. The male to female ratio was 36.8%:62.4%. Significant differences were found in QoL, community integration and participation, and perceived accessibility of the neighborhood environment between participants with disabilities compared to nondisabled older adults. Participants with disabilities reported lower QoL, participation in activities in the community, and perceived accessibility of the neighborhood environment compared to nondisabled older adults, as presented in p < 0.001), social integration , and productivity , and a weak correlation was found for electronic social networking , but not with perceived accessibility. For nondisabled older adults, significant moderate positive correlations were found between QoL and total participation in the community  and electronic social networking , and weak correlations were found with social integration  and productivity . In addition, a significant weak positive correlation was found between QoL and perceived accessibility . The correlations are presented in Among older adults with disabilities, significant moderate positive correlations were found between QoL and total participation in the community  = 3.901, p < 0.01). The third step was significant, but only the effect of social activities and productivity in the community was significant, accounting for 51.5% of the variance  = 22.388, p < 0.001), indicating that social activities in the community enhanced better QoL. The second regression explained QoL for nondisabled older adults and showed that age and gender accounted for 2.8% of the variance  = 6.551, p < 0.01), with younger age and being female increasing QoL at the first step. The second step was significant, accounting for 12.3% of the variance  = 14.678, p < 0.001). In addition, higher education and religiosity were significant, accounting for 12.9% of the variance  = 3.901, p < 0.01). At the third step, participation in the community, social integration, productivity, and electronic social networking activities were significant, with education and Jewish nationality accounting for 53.4% of the variance  = 94.480, p < 0.001). At the fourth step, perceived accessibility of the neighborhood was significant, adding 1.1% of the variance above and beyond participation in the community and personal factors  = 89.201, p < 0.001).Two hierarchal linear regressions are presented in p < 0.000). Higher participation in activities in the community was positively associated with QoL (direct effect of mediator on DV-path b) . Higher perceived accessibility was associated with greater QoL (direct effect of IV to DV-path c’) . The indirect effect of perceived accessibility on QoL through participation in activities in the community was significant (path ab) . Differences between the two last b-values (0.43) were significant according to Sobel’s formula , although the mediation was partial.The mediation model was examined for nondisabled older adults alone since correlation between QoL and perceived accessibility was not significant among older adults with disabilities. The mediation model was analyzed by testing the significance of the indirect effect of the independent variable (perceived accessibility) on the dependent variable (QoL) through participation in activities in the community as presented in QoL is an important concept for older adults, one influenced by a variety of factors . The curWe hypothesize that the possibly surprising differences between the disabled and nondisabled segments of the sample regarding their environments may stem from differential impacts of the COVID-19 period. Due to prior experiences, those with disabilities may have already adjusted to limitations in their physical environment and/or developed a support system. Participants with functional disabilities likely enjoyed the support and alternatives to external adaptation for inaccessibility familiar to them before COVID-19, such as overcoming inaccessibility of the living environment by transportation directly from their home to activities in the community. Previous research found that community-dwelling older adults with disabilities achieved successful aging by using adaptation and coping strategies, such as accepting help, and therefore relied on others to align their perception of successful aging with their experiences . MoreoveThe findings from the current research support the claim that successful aging is a psychological adaptation process, which includes participation in activities in the community, encompassing social, physical, psychological, and productive dimensions ,35. In pConsistent with the current results, previous literature has shown that people with disabilities have less diverse participation, stay home more, have fewer social relationships, and have less active recreation . The parIn the current research, perceived accessibility of the living environment had an indirect impact through participation in activities in the community and some direct impact on QoL among nondisabled older adults. Environments are highly influential on our behavior and our exposure to health risks , access to services , and opportunities that aging brings . AccessiIn the current research, the impact of perceived accessibility of the living environment on QoL among nondisabled older adults was mediated through participation in activities in the community. This is consistent with previous studies showing higher level of participation in a variety of activities in an accessible environment. For example, within-neighborhood recreational walking was found to be positively related with proximity of recreational facilities, infrastructure for walking, indoor places for walking, and presence of bridge/overpasses connecting to services . MoreoveQoL for older adults and participation in community activities.Our results confirm the ecology theory of aging which claims that adaptation of a person to their environment and their alteration of the environment are a part of the process of human adaptation. High person–environment fit is important for good physical and mental health, well-being, and QoL among older adults . The impEnhancing older adult QoL is a challenging goal of our society. The significance of this study is by informing ecological strategies to modify participation in activities and the environment to specifically target the needs and preferences of community-dwelling older adults. The findings from the current study indicate that accessibility of the living environment seems to be a good indicator of positively perceived QoL, through participation in various activities in the community for nondisabled older adults. However, for older adults with disability, participation in productivity and social activities in the community seems to be a good indicator of positively perceived QoL. Therefore, we recommend that policy makers and professionals working with older adults should seek methods for enhancing both accessibility of the living environment and integrated participation in the community. Specifically, for older adults with disability, we recommend providing opportunities for social gatherings and activities in the community, encouraging engagement in activities tailored to their personal needs and abilities in order to improve their perceived QoL.


This study evaluated the knowledge of diabetes mellitus and predictors of the level of diabetes knowledge among the general public of Singapore. Confirmatory factor analysis and exploratory factor analysis were used to evaluate the fit of different factor models for the diabetes knowledge questionnaire. Multiple linear regressions were performed to determine the sociodemographic characteristics associated with diabetes knowledge. The final factor model identified three domains for diabetes knowledge: general knowledge, diabetes specific knowledge and causes of diabetes, and complications of untreated diabetes. Overall knowledge scores were 23.8 ± 2.4 for general diabetes knowledge, 2.3 ± 0.8 for diabetes specific knowledge, 2.3 ± 1.2 for causes, and 5.2 ± 1.2 for complications of untreated diabetes. Patients with diabetes were more knowledgeable than adults without diabetes in the population. While the general public in Singapore has adequate knowledge of diabetes, misconceptions were identified in both groups which underscores the need to tailor specific educational initiatives to reduce these diabetes knowledge gaps. Diabetes mellitus is a complex and chronic disease associated with a state of chronic high blood glucose level, or hyperglycaemia. Diabetes comprises mainly two types, Type 1(insulin dependent) and Type 2 (non-insulin dependent) . To dateThe development of Type 2 diabetes involves multiple factors and mechanistic pathways, notably epigenetics, defective insulin activity, glucotoxicity, lipotoxicity, inflammation, oxidative stress, and pancreatic β-cell dysfunction –11. EnviKnowledge, attitude and practice (KAP) studies on diabetes worldwide have increasingly demonstrated the importance for greater awareness of diabetes symptoms, risk factors, suitable lifestyle practices and regular monitoring of blood glucose levels –25. TherThe present cross-sectional study is part of a larger, national population-based KAP study of diabetes among Singapore residents . The samThe randomly selected residents were sent notification letters followed by home visits by a trained interviewer from a survey research company to obtain their informed consent to participate in the study. For residents who agreed to participate, face-to-face interviews were conducted in their preferred language . Responses were captured using computer-assisted personal interviewing. Individuals who could not be contacted due to incomplete or incorrect addresses, living outside of the country, institutionalization, or hospitalization at the time of the survey, as well as, individuals who were incapable of participating due to language barriers or severe physical or mental conditions were excluded from the study. The study commenced in February 2019 but was temporarily suspended from March 2020 –July 2020 due to the lockdown phase in response to the Coronavirus pandemic in Singapore. The study resumed in August 2020 and was completed in September 2020, achieving a sample size of 2895 and a study response rate of 66.2%. Written informed consent was obtained from all participants prior to the survey and all study procedures. The study protocol and the study questionnaire were approved by the ethics committee, National Healthcare Group Domain Specific Review Board (DSRB No. 2018/00463).The diabetes knowledge questionnaire was developed based on literature review and validated by a panel of healthcare professionals who were experts in diabetes care and treatment . PretestAll analyses were conducted with Stata version 15 and Mplus version 8.2. Weighted means and standard deviations are presented for continuous variables, while frequencies and weighted percentages are displayed for categorical variables. To ensure representativeness of the data to the general population, the survey sample was weighted by age and ethnicity to account for the complex survey design.A series of exploratory factor analyses (EFA) and confirmatory factor analyses (CFA) were conducted with the diabetes knowledge questionnaire. In Mplus, the CFA was first estimated and tested to evaluate the factor structure of the questionnaire. As there were items on the questionnaire measured on an ordinal or binary scale, a weighted-least-squares with a mean-adjusted and variance-adjusted (WLSMV) estimator was used to model the observed polychoric/tetrachoric correlation matrix  with a pairwise deletion of missing data. However, due to the poor fit of the initial CFA model, subsequent analyses were performed with approximately two split-half samples  randomly generated from the study sample.Using the WLSMV estimator in the factor analysis, pairwise deletion of missing data and an oblique geomin rotation were conducted to explore the dimensionality of the first half-sample (n = 1447). The following criteria were utilized to determine the number of factors in the EFA: (i) eigenvalues > 1 (ii) visual inspection of scree plot, (iii) identification of satisfactory factor loadings on each factor , and (iv) the robustness of interpretability for each solution. During each analysis, the factor loading of the questionnaire items were explored. Each rotated solution was examined in order to identify and remove items based on the following ranked criteria: (i) consistently low loadings of <0.3 across all factor models, (ii) consistently cross-loading across all models, (iii) lowest loading, and (iv) cross-loading.Derived factors from the EFA were then validated using CFA in the second half-sample (n = 1448). A WLSMV estimator was applied to examine the underlying polychoric correlation matrix. The following fit indices were utilized to compare the overall fit of the models and their complexities: (i) root mean square error of approximation (RMSEA), (ii) comparative fit index (CFI), (iii) Tucker-Lewis index (TLI). Both the CFI and TLI values range from 0 to 1, with higher values representing better fit; CFI values above 0.95 and TLI values above 0.90 were considered to be of excellent fit . With reSociodemographic characteristics and the respective weighted percentages of the sample are reported in 2 = 1685.75, RMSEA = 0.03, CFI = 0.73, TLI = 0.70, SRMR = 0.11). Descriptive information of all 29 items of the diabetes knowledge questionnaire can be found in An initial CFA was conducted on the 29-item diabetes knowledge questionnaire within the full sample, utilizing a four first-order factor structure. However, this indicated a poor fit to the data (WLSMV χ2(9) = 40.78; RMSEA = 0.05; CFI = 0.96; TLI = 0.93; SRMR = 0.03). A total score was calculated by summing all items, with higher scores indicating higher knowledge. The composite reliability value for GK was acceptable at 0.71.For Domain A, the plot of eigenvalues of the initial 10 items indicated that either a one-factor or two-factor solution was plausible. Upon examining the rotated factor models, four items were removed due to a consistently low loading of < 0.3 and cross-loadings. This led to a single factor solution of six items for the general knowledge (GK) scale, which was found to be optimal. A CFA of this six-item unidimensional model resulted in an acceptable fit (WLSMVχ2(13) = 24.34, RMSEA = 0.03, CFI = 0.94, TLI = 0.9, SRMR = 0.06). Scores on the domain were generated by summing the correct responses on the respective items, with higher scores indicating higher knowledge. The composite reliability of DK and CK was poor, at 0.50 and 0.66 respectively.For Domain B, eigenvalues for the underlying correlation matrix indicated that a one-factor to three-factor solution was plausible. After an examination of the rotated factor solutions, two items were removed due to consistently low loadings of <0.3 and cross-loadings. A two-factor solution comprising diabetes specific knowledge (DK) and knowledge of causes of diabetes (CK) was found to be optimal. A CFA of the two-factor solution indicated an acceptable fit: (WLSMVχ2(9) = 24.14, RMSEA = 0.03, CFI = 0.96, TLI = 0.94, SRMR = 0.06). A score was calculated by summing the number of correct responses of all items on the CPK scale, with higher scores indicating higher knowledge. The composite reliability of CPK was high at 0.83.For Domain C, the plot of eigenvalues for the underlying correlation matrix suggested a one-factor to three-factor solution. However, upon inspection of the EFA solutions, four items were removed due to consistently low loadings of <0.3 and cross-loadings, and a unidimensional structure for complications of untreated diabetes (CPK) was found to be most optimal. The CFA of this six-item unidimensional model indicated an acceptable fit: ; DK ] and Indians  as compared to the Chinese. DK was additionally found to be higher among those with diabetes  compared to those without diabetes. CK was particularly high among those who were single  while CPK scores were significantly higher among ethnic Malays , Indians , and Others  (vs. Chinese). GK scores were negatively associated with being single , unemployed , or having lower levels of education , secondary , vocational training  vs. degree and above).DK scores were significantly lower among those who were single , had a higher personal income  , and secondary education  or vocational training . Also, CK scores were significantly lower among Indians , those with lower personal income  , and those with secondary education  or primary education and below . Also, males , and being single  were significantly associated with lower scores for CPK.This study aimed to examine the general public’s level of knowledge of diabetes among individuals diagnosed with diabetes and those without diabetes in Singapore. In this study, participants’ knowledge was assessed based on their understanding of diabetes, which included the likely causes, risk factors, symptoms, and complications of diabetes. Overall, despite a lack of awareness in certain aspects, this study found that there was adequate knowledge of diabetes among adults with no diabetes and those with diabetes in the whole population.This finding is in line with other studies , 38–40, One possible reason for the knowledge deficiencies observed in the current study may be attributed to misconceptions surrounding certain issues like the risk factors and preventative measures related to diabetes. In this study, Singaporeans were generally able to identify the symptoms and complications of diabetes, though they were not as well versed in the risk factors that may lead to the disease. Majority of the participants in this study, believed that high blood pressure and mental stress are likely causes of diabetes, which are one of the most common misconceptions reported in other population studies as well , 41.Interestingly, while more than 80% of the general population in the current study knew that diabetes and its complications could be prevented, individuals with no diabetes did not know that it can be managed or prevented through lifestyle measures such as high fibre foods, lipid control, and good weight control. These findings are similar to a study conducted in India , and alsThis current study also revealed that a significant proportion of individuals without diabetes did not know there are different types of diabetes, and were not as aware of abnormal blood glucose levels. The findings remain consistent with a previous study conducted in Singapore , and couResearch has revealed that poor self-management is a significant barrier to effective prevention or management of diabetes complications . ParticiThis study revealed a relationship between income levels and diabetes knowledge. Other reports are in agreement with our results, that is, lower income levels were associated with poorer diabetes knowledge , 29–31. The current study found that ethnic minority groups  were significantly more knowledgeable about symptoms and complications, insulin deficiency, and abnormal blood glucose levels when compared to Chinese Singaporeans. Our results differ from a few other studies , 32. OneThe study has some limitations. Individuals who were institutionalised, hospitalised or uncontactable during the study period, as well as those with language difficulties were excluded from the study. Hence, the results may have been underestimated or overestimated. Moreover, the cross-sectional nature of the study does not allow for causal relationships to be established. Nonetheless, the current study has its strengths in that it was a nationwide population-based study with a representative public sample, ensuring high quality of data and generalizability of the findings. The factor analyses revealed a marked stability and robust factor model for the diabetes knowledge questionnaire in the study. This study has provided more precise and valuable data for the purposes of policy-making, development of diabetes literacy and health promotion programs, as well as for future research.The level of knowledge of diabetes in persons with diabetes and persons without diabetes was found to be adequate, except in one situation where both groups thought that high blood pressure and mental stress cause diabetes. Individuals without diabetes also did not know about the levels of blood glucose that were considered abnormal compared to patients with diabetes. These misconceptions can be effectively addressed through suitable diabetes health education. Knowledge regarding diabetes can vary greatly depending on one’s education, ethnicity and socioeconomic status. Understanding these variables will be important in designing prevention and management strategies for diabetes. This study reinforces the view that the main approach to managing diabetes effectively is to improve understanding and management of the disease by means of suitable widespread educational campaigns.S1 Appendix(PDF)Click here for additional data file.