Yoga is well‐thought‐out as an all‐inclusive approach globally and can be administered in clinical care as an integrative or alternate approach to regular treatment. Yoga exercise has been disclosed to influence remission from cancer cells over a long period of time and also reverses epigenetic alterations. Applications of Yoga in the management of oral oncology patients are scarce, hence the need for a scoping review of the literature. Hence, this study aimed to conduct a scoping review of the existing empirical evidence on the applications of yoga in oral oncology.The review methodology was informed by Joanna Brigg's Institute guidelines for systematic scoping reviews, and the review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses extension for Scoping Reviews. Ten databases were searched. The records of all the literature retrieved from the search were imported into the Rayyan software for deduplication. After the full‐text screening, only two were found eligible for inclusion in the scoping review. Data obtained in the included literature were extracted and synthesized.p‐values > 0.04). However, it was found that Yoga significantly reduced anxiety, saliva stickiness, and episodes of falling ill  while it improved mental well‐being, cognitive functioning, emotional functioning, and head and neck pain of those oral cancer patients that received it .This review found that Yoga was not significantly effective in the management of stress among oral cancer patients (An integrative care approach that considers nonpharmaceutical techniques such as yoga could help to reduce care cost while improving care outcomes and quality of life of oral cancer patients. Hence, it is imperative to consider yoga along with its potential benefits, and we recommend gradual incorporation of yoga into oral cancer care. Consequently, the key aim of this scoping review is to find out about existing literature on applications of Yoga in oral oncology management.2The Joanna Briggs Institute's guidelines for systematic scoping reviews (ScRs) informed the design of this ScR.To address this question, we conducted a systematic search of 10 electronic databases , on the January 27, 2023, to identify literatures relevant to the question using a combination of the terms “yoga,” “oral cancer” and their synonyms, and with the aid of Boolean operators (“OR” and “AND”) and truncation (“*”). The search strings generated from these search combinations are depicted in Tables The records of all the literature retrieved from the scoping search were imported into the Rayyan software for deduplication.Only those literatures that met all of the following criteria were included in the ScR: peer‐reviewed journal papers; papers published in English; papers reporting empirical findings on the application of yoga in the field of oral oncology; and papers with accessible full texts. However, all those literatures that do not meet all the above criteria were excluded from the ScR.p‐values, with a p‐value < 0.05 considered to be of statistical significance. Quantitative data analysis  was intended to be done; however, this could not be done due to the multiple heterogeneities in the methodology  of the included articles.From the included literature, data were extracted using a customized data extraction sheet Table . The ext3From the 10 electronic databases searched, a total of 55 publications were retrieved. From these publications, six were duplicated copies and were all removed. After the screening of the titles and abstracts of the remaining 49 publications, 42 publications were excluded. After the full text screening of the remaining seven publications, only two publications were finally included into the scoping review  for a duration of 2 weeks; and Phase 2  for a duration of 2 months.3.5The study by Bakshi and GoyalThe study by Pattnaik et al.3.6Both studies reported that yoga interventions had some impacts on some domains of health of oral cancer patients.3.6.1p‐value = 0.074) and experimental group (baseline data ‐ 89.39 (M) ± 29.13 (SD); endline data ‐ 125 (M) ± 36.13 (SD); p‐value = 0.107); however, the level of increase was reportedly lower among those that received yoga compared with those patients who received it not. Furthermore, from the exploration of the various subdomains of quality of life explored, only the subdomains of cognitive functioning , emotional functioning , head and neck pain , saliva stickiness , and falling ill  ± 92.75 (SD); endline data [control group] – 0 [M] ± 0 [SD], p‐value = 0.001; endline data ‐ 8.33 (M) ± 15.07 (SD), p‐value < 0.001]) were significantly improved through yoga therapy, and the degree of improvements observed in these domain were higher than those observed among those who did not receive yoga therapy . However, no significant improvement or worsening of other sub‐domains in the EORTIC‐H&N‐35 questionnaire were recorded in the study.Only one study, by Bakshi and Goyal,3.6.2p‐value = 0.884; endline data [experimental group] ‐ 58 (M) ± 23.40 (SD), p‐value = 0.995).Only one study, by Bakshi and Goyal,3.6.3p‐value = 0.977; endline data [experimental group] ‐ 14 [M] ± 5.657 [SD], p‐value = 0.259). In fact, as shown in the statistics narrated in the preceding sentence, the endline data on general health, compared to that of the baseline, of both the control group and the experimental group decreased; however, the level of decrease was more pronounced in the experimental group than in the control group.Only one study, by Bakshi and Goyal,3.6.4p‐value = 0.915; endline data [experimental group] ‐ 17.17 [M] ± 4.6 [SD], p‐value = 0.181). However, it is noteworthy that the endline stress level among the intervention group is lower than that recorded among the control group.Both studies explored the role of yoga on the perceived stress of oral cancer patients.p‐value < 0.001). Also, the study did not report any change of effect size across different subgroups.However, in the study by Pattnaik et al.,3.6.5p‐value = 0.739; endline data [experimental group] ‐ 38.50 [M] ± 10.82 [SD], p‐value = 0.004).Only one study, by Bakshi and Goyal,3.6.6p‐value = 0.358; endline data [experimental group] ‐ 50.67 [M] ± 7.68 [SD], p‐value = 0.010).Only one study, by Bakshi and Goyal,3.6.7p‐value = 0.522), diastolic blood pressures  and pulse rates  of the investigated oral cancer patients. In the study, yoga therapy did not cause any significant change in the these observed parameters .Only one study, by Bakshi and Goyal,4Medical pluralism, a combination of western and traditional medicine is a global practice.This scoping review found that yoga could be effective in the management of stress among oral cancer patients. Other studies have found that yoga practice may assist cancer patients and survivors in managing symptoms such as anxiety, fatigue, insomnia depression, and pain.In addition, an integrative care approach that considers a nonpharmaceutical approach could help to reduce care cost while improving care outcomes and quality of life.However, this scoping review has its limitation. The search strategy did not include gray literature and print‐only journals; hence, this may have limited the robustness of the search strategy. The exclusion of gray literature was deliberate because they are not peer reviewed. Also, print‐only journals were excluded due to inaccessibility.5Since yoga therapy significantly increased the mental wellbeing of the population with cancer, it is important to integrate yoga in the prevention and treatment of cancer. For a population with cancer, any therapy that would enhance their quality of life, especially without therapeutic complications should be embraced. Yoga targets fundamental concerns, especially stress and anxiety in cancer treatment. It is important that the health workers are familiarized with non‐pharmaceutical therapy such as yoga. It is imperative to consider yoga along with its potential benefits, and we recommend a gradual incorporation of yoga into oral cancer care.Kehinde K. Kanmodi: Conceptualization; data curation; formal analysis; funding acquisition; investigation; methodology; project administration; resources; software; supervision; validation; visualization; writing—original draft; writing—review & editing. Ramat O. Braimah: Resources; software; writing—original draft; writing—review & editing. Jimoh Amzat: Resources; writing—original draft; writing—review & editing. Afeez A. Salami: Data curation; investigation; methodology; resources; software; validation. Lawrence A. Nnyanzi: writing—review & editing.Kehinde Kazeem Kanmodi is an Editorial Board member of Health Science Reports. and a coauthor of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication. Other authors have no conflict of interest to declare.Not applicable. This study did not collect data from human or animal subjects but an open research repository.The lead author Kehinde Kazeem Kanmodi affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.


In hemophilia patients undergoing cardiac surgery, ROTEM® and Quantra® viscoelastic tests are useful to monitor perioperative hemostatic status and a single dose of rIX‐FP is safe and avoids any hemorrhagic or thrombotic complication.Cardiac surgery poses a high hemostatic risk in patients with hemophilia. We present the first case of an adult patient with hemophilia B on treatment with albutrepenonacog alfa (rIX‐FP) who underwent surgery for acute coronary syndrome. Treatment with rIX‐FP made it possible to perform the surgery safely. In fact, HB accounts for 15% of all diagnosed cases of hemophilia, with a prevalence of 1 per 40,000 live males.The availability of new treatments, such as extended half‐life recombinant factors, has dramatically changed the clinical landscape for hemophilia patients.Cardiac surgery alone poses a high hemostatic risk, due to the need for total heparinization, surgical trauma, extracorporeal circulation (ECC), hypothermia, increased fibrinolysis, and cardiac arrest.Viscoelastic tests (VET) have also proven to be a very useful tool in the monitoring of patients during surgical procedures.In general, HB patients who undergo surgery need to maintain hemostasis with recombinant FIX. The World Federation of Hemophilia (WFH) guidelines recommend FIX activity levels of 60–80 IU/dL prior to major surgery and continuous FIX replacement during the 14‐day postoperative period .2Our patient was a 48‐year‐old man with a diagnosis at 5 months of age of mild HB with a mutation in exon 6 of FIX and severe hemorrhagic phenotype; no history of inhibitor. He had a history of smoking, dyslipidemia, HIV  and treated HCV. The patient was receiving FIX on demand, although due to recurrent bleeding, he started tertiary prophylaxis with nonacog alfa . The patient also had severe hemophilia‐associated arthropathy. Subsequently, he was switched to rIX‐FP (37.5 UI/kg per week) with the aim of improving his quality of life.Two weeks after starting rIX‐FP, he attended the emergency department with abdominal pain in the right renal fossa, oppressive chest pain, and mild hypotension (104/76 mmHg). Laboratory tests were significant for elevated troponins at 23,161 ng/mL. The electrocardiogram showed ST segment elevation of 1 mm in II, III, avF and a decrease in aVL, and a diagnosis of acute coronary syndrome was given. On admission (D0) the patient presented a slight increase in activated partial thromboplastin time (aPTT) of 31.4 s , coinciding with a trough FIX level of 27.3% (6 days since the last infusion). VET analysis with ROTEM  and Quantra®  showed a normal profile.The patient started anticoagulation with enoxaparin at therapeutic doses (1 mg/kg every 12 h) and antiplatelet therapy with clopidogrel 75 mg every 24 h. An adverse thrombotic event related to prophylactic treatment was ruled out. FIX levels were closely monitored and maintained above 30% by rIX‐FP supplementation, avoiding very high levels due to concerns about thrombosis  artery with long severely calcified plaque in the proximal‐middle segment compromising the outflow of 2 well‐developed diagonal branches that also revealed proximal disease Figure . The cirA coronary artery graft with cardiopulmonary bypass by cardiac surgery with ECC was proposed. Arterial/venous conduits used were : saphenous vein graft to right coronary, saphenous vein graft (right) to first diagonal and left internal mammary artery to anterior descending coronary. Just before surgery D14), the patient received 37.5 IU/kg of rIX‐FP, achieving FIX levels of 86.5%. Factor levels were maintained at 74.5% post‐ECC Figure . D‐dimer4, the paAfter surgery, the patient started treatment with antiplatelet therapy  and FIX levels remained at around 60% (D15 – D23). Eight infusions were administered in the 2‐week postoperative phase for a total of 147.5 IU/kg. After hospital discharge, the patient continued antiplatelet therapy. The patient's pharmacokinetics (PK) parameters showed a half‐life of rIX‐FP of 135.5 h, so we decided to prescribe 37.5 IU/kg once a week, with the aim of maintaining FIX levels above 30%. WAPPS‐Hemo V.5.4. was used to determine the individual PK profile of the patient at 4 FIX plasma levels  with no washout period: 30 min pre‐dose, and 3‐, 96‐ and 168‐hours post‐infusion. To date, the development of FIX inhibitors has not been observed.3In this article we report the case of a patient with a diagnosis of mild hemophilia B and severe hemorrhagic phenotype, who required surgery with ECC after being diagnosed with acute coronary syndrome.The patient attended the emergency service due to an acute coronary syndrome just 2 weeks after changing treatment to rIX‐FP (37.5 IU/kg per week). Catheterization revealed a coronary tree with severe, diffuse, calcified disease, suggesting that this was not an adverse event associated with the prophylactic rIX‐FP. According to the literature, increasing numbers of hemophilia patients are requiring cardiac surgery because of longer life expectancies and accompanying age‐associated comorbidities such as cardiovascular disease.The indications for cardiac surgery in patients with hemophilia are the same as in patients without hemophilia, that is, there are no changes in surgical and anesthetic protocols.Cardiac surgery with and without ECC has been shown to be effective and safe. However, in expert hands, surgery without ECC has been shown to reduce morbidity and, in nonrandomized adjusted studies, mortality in high‐risk patients.Most experts agree that cardiac surgery in patients with hemophilia requires a multidisciplinary and highly individualized approach for each patient, with the participation of hematologists, anesthesiologists, surgeons, intensivists, and laboratory specialists.With regard to therapeutic interventions during the surgical process, we found that optimization of factor levels before, during and after surgery was essential to obtain results similar to those obtained in non‐hemophiliac patients.VETs with ROTEM and Quantra were especially useful to evaluate the global hemostatic status during the perioperative process, allowing us to analyze components such as platelet and fibrinogen levels, beyond the effect of FIX levels. In addition, VET proved very useful for monitoring the effect of heparin during surgery. These tools have been widely used in the surgical setting, especially for the differential diagnosis of post‐surgical bleeding in disorders such as hypofibrinogenemia or thrombocytopenia.In summary and to the best of our knowledge, this is the first report of cardiac surgery with ECC in a patient with hemophilia B receiving treatment with rIX‐FP. Based on the success of this patient's surgery and the suggestions of other authors regarding cardiac surgery in patients with hemophilia, we consider that there are a series of considerations that are essential for the management of this type of patient in these situations: (1) surgery should be scheduled under the supervision of a multidisciplinary team with experience in this field, (2) treatment should be individualized following current WHO recommendations, (3) treatment should be closely monitored to ensure good hemostatic protection during and after surgery, (4) viscoelastic testing during the perioperative process is very useful to assess the patient's overall hemostatic status, and (5) treatment with EHL FIX, such as rIX‐FP, in patients with HB is safe and effective in this type of surgery. In fact, a single administration of rIX‐FP pre‐intervention was successful in our case in maintaining elevated FIX levels and preventing bleeding during surgery and even in the 24 h after the intervention.4In a patient with hemophilia B, cardiac surgery with extracorporeal circulation was performed safely without hemorrhagic or thrombotic complications after a single preoperative dose of rIX‐FP. Viscoelastic tests proved to be very useful in monitoring the patient during surgery.Francisco José López‐Jaime: Conceptualization; funding acquisition; project administration; supervision; writing – review and editing. Ihosvany Fernández‐Bello: Investigation; writing – review and editing. Eva Calavia‐Aranda: Data curation; writing – review and editing. Begoña Reina Monsó: Investigation; supervision; writing – review and editing. Adrián Montaño: Conceptualization; data curation; funding acquisition; writing – original draft; writing – review and editing.Francisco J. López Jaime has participated as consultant or speaker for Amgen, Bayer, CSL Behring, Leo Pharma, Novartis, Novo Nordisk, Pfizer, Roche, Sobi and Takeda. The rest of the authors declare that they have no interests that could be perceived as a conflict or bias.Written, informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.


Previous trials suggest that older adults with non‐small cell lung cancer (NSCLC) derive benefit from platinum doublet combination therapy, but its superiority is controversial. Although geriatric assessment variables are used to assess the individual risk of severe toxicity and clinical outcomes in older patients, the standard first‐line treatment is still debated. Therefore, we aimed to identify the risk factors for clinical outcomes in older patients with NSCLC.Patients aged ≥75 years with advanced NSCLC treated at any of 24 National Hospital Organization institutions completed a pre‐first‐line chemotherapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. We evaluated whether these variables were the risk factors for progression‐free survival (PFS) and overall survival (OS).n = 90) or monotherapy (n = 58). Median PFS was 5.3 months and OS was 13.6 months. We identified that hypoalbuminemia  was a risk factor for PFS and monotherapy , lactate dehydrogenase , and high C‐reactive protein  were risk factors for OS. The median OS was significantly longer in patients treated with combination therapy than in those who received monotherapy .A total of 148 patients with advanced NSCLC were treated with combination therapy (Platinum doublet combination therapy may be beneficial in older patients with NSCLC. Identification of risk factors will assist in the development of a personalized treatment strategy. Here, we report that platinum doublet combination therapy may be beneficial in older patients with NSCLC. The OS was significantly longer in patients treated with platinum doublet combination therapy than in those who received monotherapy. Moreover, we identified several laboratory values that reflect prolonged exhaustion owing to inflammation and might be predictors of outcomes in older patients with NSCLC. Lung cancer is the leading cause of cancer‐related deaths worldwide, and the majority of patients diagnosed with the disease have non‐small cell lung cancer (NSCLC).Age is an important factor in management decisions because of the complex interplay between normal age‐related decline and comorbidities. The Karnofsky performance status or Eastern Cooperative Oncology Group performance status (ECOG‐PS) is used in patients to predict treatment toxicity and survival.Although the CGA is too complicated for use in daily clinical practice, it has been validated among oncologists.In total, 354 patients from any of 24 National Hospital Organization institutions were enrolled in this prospective study between April 2013 and March 2017. A total of 148 of these patients were aged ≥75 years and had histologically or cytologically proven advanced NSCLC  and were treated with cytotoxic chemotherapy (platinum doublet therapy or a single agent) as first‐line therapy. Patients were excluded from the study if they had had active malignancy within the previous 5 years, a history of chemotherapy, had massive pleural or pericardial effusion or ascites, or had received radiation therapy to the lung. The study was approved by the National Hospital Organization Central Review Board and conducted in accordance with the Declaration of Helsinki and ethical guidelines for clinical research (UMIN000010384). All patients provided their written informed consent before enrollment.All patients completed a pre‐first‐line chemotherapy assessment, which included the characteristics of the cancer , treatment variables, laboratory test values, and geriatric assessment variables. The ability to perform activities of daily living was assessed using the Barthel Index.t‐test for continuous variables and the chi‐squared test for categorical variables. PFS and OS were estimated using the Kaplan–Meier method, and the survival curves were compared with the log‐rank test and a Cox proportional hazards model. The risk factors for PFS and OS were evaluated using a Cox proportional hazards model. In the multivariable analysis, all variables were evaluated for univariate analysis were selected. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc.). A two‐sided p‐value of ≤ 0.05 was considered statistically significant.Patient characteristics are summarized using descriptive statistics or contingency tables. Associations between treatments and patient characteristics were examined using the unpaired A total of 148 patients were included in the analysis (Table 2) ranged from 15.5 to 32.9, with about half (54.7%) of the patients having a BMI ≥22. Twenty‐three patients (15.5%) had experienced weight loss of ≥5% within the previous 6 months. Although most patients had good performance status , patients with poor performance status  were also enrolled. Twenty‐three patients (15.5%) were limited in their ability to perform activities of daily living. Twelve patients (8.1%) had a Barthel Index score of <85 points. About one‐third of the patients (35.1%) scored <27 points on the Mini‐Mental State Examination.A total of 23 patients (15.5%) were at high risk of complications (Charlson Comorbidity Indexp = 0.3077)  , which was not significantly different from the median PFS of 4.0 months (95% CI: 2.8–5.7) in patients who received monotherapy  Figure . However) Figure .The overall response rate was higher in the combination cohort than in the single‐agent cohort (31.1% vs. 13.8%). The disease control rates were similar between these cohorts Table .A total of 62 patients developed severe hematological toxicity . The frequency of severe hematological toxicity was higher in patients treated with single‐agent chemotherapy than in those treated with platinum doublet combination therapy (51.7% vs. 35.6%). In terms of nonhematological toxicity, adverse events emerged in most cases at any grades. The frequency of severe nonhematological toxicity was not high and was similar between the combination and monotherapy groups (Table p = 0.0264) (Table p = 0.0217), high LDH , and high CRP  (Table The median follow‐up duration was 11.9 months. Median PFS was 5.3 months 95% CI: 4.4–6.3) and median OS was 13.6 months (95% CI: 10.5–17.3) for all patients Figure . Patient.4–6.3 anThe correlation between CGA and clinical outcomes in older patients with cancer has previously been investigated.Two recent randomized Phase III trials that compared docetaxel with platinum doublet combination chemotherapy  found that combination chemotherapy was tolerable and highly effective for “fit” older adults.In this study, we also identified high LDH and CRP levels as risk factors for OS. However, LDH is elevated not only in patients with cancer but also in those with other diseases, so the prognostic role of LDH in patients with lung cancer is not conclusive.This study had several limitations. First, there was a degree of bias in the treatment variables because the decision regarding selection of the first‐line chemotherapy regimen or dose de‐escalation was made by the physicians, as in clinical practice. Second, patients with NSCLC treated with immune checkpoint inhibitors (ICIs) as first‐line therapy were not included. As previously reported, pembrolizumab has a clinical benefit in patients with advanced NSCLC, regardless of patient age.In conclusion, our study has identified several laboratory values that reflect prolonged exhaustion owing to inflammation and might be predictors of outcomes in older patients with NSCLC. Moreover, platinum doublet combination therapy may be of benefit in this population in the clinical setting.Conceptualization: Mototsugu Shimokawa, Masaki Kanazu, Shinji Atagi. Data curation: Ryusei Saito, Masahide Mori, Atsuhisa Tamura, Yoshio Okano, Yuka Fujita, Takeo Endo, Mitsuru Motegi, Shohei Takata, Toshiyuki Kita, Noriaki Sukoh, Mitsuhiro Takenoyama, Shinji Atagi. Formal analysis: Mototsugu Shimokawa, Masaki Kanazu, Fumitaka Mizuki. Funding acquisition: Masaki Kanazu. Investigation: Mototsugu Shimokawa, Masaki Kanazu. Methodology: Mototsugu Shimokawa, Masaki Kanazu, Shinji Atagi. Supervision: Fumitaka Mizuki, Shinji Atagi. Validation: Fumitaka Mizuki, Mototsugu Shimokawa. Visualization: Mototsugu Shimokawa, Masaki Kanazu. Writing: Mototsugu Shimokawa, Masaki Kanazu. Review and editing: Ryusei Saito, Masahide Mori, Atsuhisa Tamura, Yoshio Okano, Yuka Fujita, Takeo Endo, Mitsuru Motegi, Shohei Takata, Toshiyuki Kita, Noriaki Sukoh, Fumitaka Mizuki, Mitsuhiro Takenoyama, Shinji Atagi.This study was supported financially by the National Hospital Organization in Japan.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.Table S1. Detail of regimenClick here for additional data file.


Hay fever is a common allergic disease, with an estimated worldwide prevalence of 14.4% and a variety of symptoms. This study assessed the minimal clinically important difference (MCID) of nasal symptom score (NSS), non‐nasal symptom score (NNSS), and total symptoms score (TSS) for app‐based hay‐fever monitoring.MCIDs were calculated based on the data from a previous large‐scale, crowdsourced, cross‐sectional study using AllerSearch, an in‐house smartphone application. MCIDs were determined with anchor‐based and distribution‐based methods. The face scale score of the Japanese Allergic Conjunctival Disease Standard Quality of Life Questionnaire Domain III and the daily stress level due to hay fever were used as anchors for determining MCIDs. The MCID estimates were summarized as MCID ranges.A total of 7590 participants were included in the analysis . The anchor‐based method produced a range of MCID values  for NSS , NNSS , and TSS . The distribution‐based method produced two MCIDs  for NSS , NNSS , and TSS . The final suggested MCID ranges for NSS, NNSS, and TSS were 1.8–2.1, 1.2–1.3, and 2.4–3.3, respectively.MCID ranges for app‐based hay‐fever symptom assessment were obtained from the data collected through a smartphone application, AllerSearch. These estimates may be useful for monitoring the subjective symptoms of Japanese patients with hay fever through mobile platforms. The following two distribution‐based methods were used as an additional confirmation of the MCID.2.7r was the recommended PRO test‐retest reliability.The formula used for calculating the standard error of measurement (SEM) was “standard deviation (SD)*√(1 − r)”, where ICCs were calculated by comparing baseline and subsequent measurements of NSS, NNSS, and TSS from patients who indicated no change in the face scale score and stress level.2.8Half a standard deviation (SD) at baseline was assumed to be equal to the MCID.2.9Ranges of MCID were recommended rather than single MCID estimate values.33.1n = 4331) of the participants were women. Both the face score and stress level scale showed that the more severe the category, the higher the proportion of younger and female participants. Participants in the more severe group were more likely to state their medical history as unknown.In total, 7590 participants were analyzed in Tables 3.2A summary of subjective symptom scores is shown in Tables 3.3The Spearman's correlation coefficients between anchor groups and NSS, NNSS, and TSS were higher than 0.3 for anchors of face scale score and stress level scale . A total of 24 MCIDs, eight each in NSS, NNSS, and TSS, were calculated by the anchor‐based method . MCIDs based on the anchor‐based method were summarized using median with IQR: NSS , NNSS , and TSS . The summary of MCID estimates is shown in Table 3.4The results of the distribution‐based analysis are shown in Table 3.5The estimated SEM of 1.8 for NSS was larger than the 25th percentile of median anchor‐based estimates of 1.5, and the SEM was selected as the lower boundary of the MCID range for NSS. The estimated SEM of 1.2 for NNSS was equal to the 75th percentile of median anchor‐based estimates, and the MCIDs of NNSS calculated by the anchor‐based method were replaced by the SEM. The final suggested MCID ranges for NSS, NNSS, and TSS were 1.8–2.1, 1.2–1.3, and 2.4–3.3, respectively .In this study, two methods were utilized to calculate MCID: (1) distribution‐based method and (2) anchor‐based method. Among the two approaches, results from the anchor‐based method, which utilizes an external clinical marker termed the “anchor”, are prioritized in current practices.This study had several limitations. First, the designated anchors were selected based on results from a cross‐sectional study and may not be strongly correlated with the fluctuating hay‐fever symptoms assessed in a longitudinal fashion. Future studies should validate the accuracy of the suggested MCID values with changing symptoms when followed long‐term.In conclusion, our study results suggest MCID ranges of 1.8–2.1, 1.2–1.3, and 2.4–3.3 points for NSS, NNSS, and TSS, respectively. The MCID ranges from this study were based on data from a smartphone app‐based, large‐scale clinical research in the Japanese population, and were calculated utilizing a multi‐faceted approach. This may have implications as a useful standard in the global shift toward incorporating mHealth when evaluating hay‐fever symptoms and monitoring treatment effectiveness in practice and research.Ken Nagino: Conceptualization (lead); data curation ; formal analysis (lead); methodology (lead); software (lead); validation (lead); visualization (lead); writing—original draft preparation (lead). Jaemyoung Sung: writing—original draft preparation ; writing—review & editing . Akie Midorikawa‐Inomata: funding acquisition ; resources ; writing—review & editing . Atsuko Eguchi: funding acquisition ; resources ; writing—review & editing . Keiichi Fujimoto: funding acquisition ; resources ; writing—review & editing . Yuichi Okumura: project administration ; writing—review & editing . Alan Yee: original draft preparation ; writing—review & editing . Kenta Fujio: data curation ; writing—review & editing . Yasutsugu Akasaki: data curation ; writing—review & editing . Tianxiang Huang: data curation ; writing—review & editing . Maria Miura: data curation ; writing—review & editing . Shokirova Hurramhon: funding acquisition ; resources ; writing—review & editing . Kunihiko Hirosawa: data curation ; writing—review & editing . Mizu Ohno, data curation ; writing—review & editing . Yuki Morooka, data curation ; writing—review & editing . Hiroyuki Kobayashi: project administration ; resources ; supervision . Takenori Inomata: Conceptualization ; funding acquisition (lead); investigation (lead); project administration (lead); resources (lead); supervision (lead); writing—review & editing (lead).The AllerSearch application was created using Apple's ResearchKit . Takenori Inomata, Yuichi Okumura, and Akie Midorikawa‐Inomata are the owners of InnoJin, Inc., Tokyo, Japan, which developed AllerSearch. Takenori Inomata report receiving grants from Johnson & Johnson Vision Care, SEED Co., Ltd., Novartis Pharma K.K., and Kowa Company, Ltd., outside the submitted work, as well as personal fees from Santen Pharmaceutical Co., Ltd., and InnoJin, Inc. Ken Nagino, Yuichi Okumura., and Akie Midorikawa‐Inomata received personal fees from InnoJin, Inc. outside the submitted work. The remaining authors declare no competing interests.Supplementary MaterialClick here for additional data file.


GSE54129 and GSE161533 datasets, immunohistochemistry, and western blotting. The association between BASP1 and clinicopathological characteristics, as well as its predictive value, were examined using the STAD dataset. Cox regression analysis was performed to determine whether BASP1 can be used as an independent prognostic indicator for GC, and a nomogram was constructed to predict OS. The association between BASP1 and immune cell infiltration, immune checkpoints, and immune cell markers was confirmed by enrichment analysis, as well as analysis based on the TIMER and GEPIA databases. BASP1 was observed to be highly expressed in GC and was associated with a poor prognosis. The expression of BASP1 was positively correlated with the expression of immune checkpoints and immune cell markers, as well as immune cell infiltration. Thus, BASP1 may serve as a standalone prognostic indicator for GC. BASP1 is highly correlated with immune processes, and its expression is positively correlated with the degree of immune cell infiltration, immune checkpoints, and immune cell markers.BASP1 is a membrane‐bound protein that plays a promotional or inhibitory role in a variety of tumors; however, its role in gastric cancer (GC) and in the immune microenvironment has not been reported. The objectives of this study were to determine whether BASP1 is a valuable prognostic marker for GC and to explore its role in the immune microenvironment of GC. The expression level of BASP1 in GC was analyzed based on the TCGA dataset and further verified using  BASP1 is highly expressed in gastric cancer and can be used as an independent indicator to predict poor overall survival in patients with gastric cancer. BASP1 is highly correlated with immune processes, and its expression is positively correlated with the degree of immune cell infiltration, immune checkpoints, and immune cell markers. ACCadenoid cystic carcinomaBASP1brain acid‐soluble protein 1BLCAbladder urothelial carcinomaBRCAbreast invasive carcinomaCESCcervical squamous cell carcinoma and endocervical adenocarcinomaCHOLcholangiocarcinomaCOADcolon adenocarcinomaDEGsdifferentially expressed genesDLBClymphoid neoplasm diffuse large B‐cell lymphomaDSSdisease‐specific survivalESCAesophageal carcinomaGBMglioblastoma multiformeGCgastric cancerGEOGene Expression Omnibus databaseGOgene ontologyGSEAgene set enrichment analysisGTExgenotype‐tissue expressionHNSChead and neck squamous cell carcinomaHPAThe Human Protein AtlasKEGGKyoto Encyclopedia of Genes and GenomesKICHkidney chromophobeKIRCkidney renal clear cell carcinomaKIRPkidney renal papillary cell carcinomaLAMLacute myeloid leukemiaLGGbrain lower grade gliomaLIHCliver hepatocellular carcinomaLUADlung adenocarcinomaLUSClung squamous cell carcinomaMESOmesotheliomaOSoverall survivalOVovarian serous cystadenocarcinomaPAADpancreatic adenocarcinomaPCPGpheochromocytoma and paragangliomaPFIprogression‐free intervalPRADprostate adenocarcinomaREADrectum adenocarcinomaROCreceiver‐operating characteristic curveSARCsarcomaSKCMskin cutaneous melanomaSTADstomach adenocarcinomaTCGAThe Cancer Genome AtlasTGCTtesticular germ cell tumorsTHCAthyroid carcinomaTHYMthymomaUCECuterine corpus endometrial carcinomaUCSuterine carcinosarcomaUVMuveal melanomaHelicobacter pylori infection, high salt intake, low vegetable, and fruit fiber intake [Globally, gastric cancer is the third most prevalent cause of cancer mortality and the fifth most common cancer . Althougr intake , 3, and r intake , 4. Convr intake . Althougr intake  because r intake  and the r intake , 9. TherBrain acid‐soluble protein 1 (BASP1), also known as NAP22 or CAP‐23, was originally thought to be a membrane‐bound protein belonging to the family of neuronal growth‐associated proteins  and is pIn this study, we found that BASP1 is highly expressed in GC, acts as an independent prognostic indicator in GC, and is associated with poor prognosis by univariate and multifactorial Cox regression analysis, as well as analysis of clinicopathological characteristics and prognosis. Immune cell infiltration analysis revealed a significant positive correlation between the expression of BASP1 and the infiltration levels of immune cells, such as CD8+ and CD4+, as well as the expression of immune checkpoints such as PD‐1 and PD‐L1, suggesting that BASP1 may play an important regulatory role in GC tumor immunity.https://portal.gdc.cancer.gov/) dataset  and the normal tissue transcriptome dataset from GTEx  were processed by the Toil process [GSE54129  and GSE161533 . The protein expression of BASP1 in GC cell lines was analyzed using the Human Protein Atlas (HPA) database (www.proteinatlas.org) [The Cancer Genome Atlas ). Written informed consent was obtained from all the patients.imagej software .Proteins extracted from GC and paracancerous tissues were separated by 10% SDS/PAGE, transferred to PVDF membranes, and treated with anti‐human BASP1  and β‐ACTIN  at 4 °C overnight. The membrane was incubated with the corresponding peroxidase‐linked secondary antibody for 1 h at 25 °C. Finally, the signal was detected using the ECL system. Intensity was measured using r software (version 4.1.0) and tested using the Wilcoxon rank‐sum test. The r package ‘survival’ was used to analyze the relationship between BASP1 expression and overall survival (OS), progression‐free interval (PFI), and disease‐specific survival (DSS) in patients with GC. Independent prognostic indicators were determined using one‐way and multiway Cox regression analyses. On this basis, a nomogram was created to integrate multiple indicators for predicting 1‐, 3‐, and 5‐year OS, and was validated with calibration curves. The effectiveness of the OS predictive capability was verified using a receiver operating characteristic (ROC) curve.The correlation between differential expression of BASP1 in GC and age, sex, pathological stage, histological grade, and TNM stage was analyzed using http://www.linkedomics.org) database [https://cn.string‐db.org/) database [cytoscape software, and enrichment analysis of GO function and KEGG pathway analysis were conducted [Differentially expressed genes (DEGs) associated with the BASP1 gene in GC were analyzed using the LinkedOmics (database . DEGs widatabase . Moreoveonducted .https://cistrome.shinyapps.io/timer/) database [https://kmplot.com/analysis/) was used to analyze the correlation between BASP1 expression and prognosis of patients with GC at different levels of immune cell infiltration [http://gepia.cancer‐pku.cn/) databases [The relationship between BASP1 expression and immune cell infiltration and somatic cell copy number in GC was analyzed using the TIMER  for 12 h at 4 °C and secondary antibody for 30 min at room temperature. Finally, the slides were developed with diaminobenzidine (DAB) kit , counterstained with hematoxylin, and observed under a microscope.r software (version 4.1.0). The r packages involved include: ‘survival’, ‘rms,’ ‘pROC’, ‘ggplot2’, ‘clusterProfiler’, ‘org.Hs.eg.db’, and ‘GSVA’. The results of the western blot experiments were statistically analyzed using graphpad prism 9.0.0 program, and quantitative results were expressed as mean ± standard error of the mean. Statistical significance was set at P < 0.05.Statistical analysis, data processing, and visualization in bioinformatics were performed using GSE54129 and GSE161533 datasets verified that the expression of the BASP1 gene was markedly increased in GC . The expression was significantly downregulated in seven cancers  were identified by screening GC samples from TCGA dataset using the LinkedOmics website, and the top 50 DEGs in terms of correlation were visualized Fig. . Then, tnse Fig. .Based on the results of the above enrichment analysis, we investigated the relationship between BASP1 expression and immune cell infiltration in depth. Immune cell infiltration analysis of the TIMER database showed that BASP1 expression in GC was favorably associated with infiltration of CD8+ and CD4+ T cells, macrophages, neutrophils, and dendritic cells Fig. . SubsequFinally, we analyzed whether the degree of immune cell infiltration affected patient prognosis. The results revealed that patients with high BASP1 expression combined with reduced infiltration of B cells, macrophages, CD4+ memory T cells, CD8+ T cells, and increased infiltration of regulatory T cells and type 2T helper cells had a poorer overall prognosis Fig. .To further explore the role of BASP1 in tumor immunity, we analyzed the correlation between BASP1 expression levels and those of immune checkpoints and immune cell surface markers in GC. An investigation based on TCGA database showed a significant positive correlation between BASP1 expression and the expression of PD‐1 (PDCD1), PD‐L1 CD274), CTLA‐4, LAG‐3, TIGIT, Tim‐3 (HAVCR2), BTLA, and SIGLEC‐15 Fig. . Analysi74, CTLA‐In recent years, despite the optimization of both diagnostic and therapeutic strategies for GC, patients still have an unfavorable prognosis, with a 5‐year survival rate of only 10% for advanced GC , 37. EffIn the present study, we confirmed the high expression of BASP1 at the transcriptional level in GC using TCGA and GTEx data and obtained consistent conclusions by validation of the GEO database. Immunohistochemical results and western blotting experiments further confirmed this conclusion. Cox regression and Kaplan–Meier analyses showed that BASP1 could be used as an independent prognostic factor for patients with GC. The higher the pathological stage, histological grade, and T and N stages of GC, the higher the expression level of BASP1, which was closely correlated with poor prognosis. The nomogram constructed based on clinicopathological characteristics and indicators can predict the 1‐, 3‐, and 5‐year OS of patients with GC with high accuracy in clinical practice. In addition, GO, KEGG, and GESA enrichment analyses suggested that BASP1 may be involved in ‘regulation of T‐cell activation’, ‘primary immunodeficiency’, and other processes that are highly related to the immune response. In the analysis of immune cell infiltration, we also found that BASP1 expression was positively correlated with the infiltration of most immune cells. Previous research has demonstrated that the expression of BASP1 is higher in germinal center B cells generated by T‐cell‐dependent (TD) immune responses than in germinal center B cells generated by T‐independent (TI) immune responses . Howeverin vivo and in vitro.In conclusion, this study suggests that BASP1 is highly expressed in GC and can be used as an independent indicator to predict poor OS in patients with GC. BASP1 is highly correlated with immune processes, and its expression is positively correlated with the degree of immune cell infiltration, immune checkpoints, and immune cell markers. However, this study is based on bioinformatics and clinical samples and has certain limitations. The mechanism by which BASP1 regulates tumor immunity needs to be further verified The authors declare no conflict of interest.https://www.webofscience.com/api/gateway/wos/peer‐review/10.1002/2211‐5463.13654.The peer review history for this article is available at MZ and TongW contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by XL and LZ. The first draft of the manuscript was written by TaoW.


In immediate serial recall, a canonical short-term memory task, it is well established that performance is affected by several sublexical, lexical, and semantic factors. One factor that receives a growing interest is valence, whether a word is categorised as positive  or as negative . However, contradictory findings have recently emerged. Tse and Altarriba in two experiments with one set of stimuli and fixed lists concluded that valence affects serial recall performance, while Bireta et al. in three experiments with three sets of stimuli and randomised lists concluded that valence does not affect serial recall performance. Two experiments assessed the experimental discrepancy between Tse and Altarriba and Bireta et al. For both experiments, in one block, every participant saw the exact same lists as those used in Tse and Altarriba, and in the other block, each list was randomly constructed for each participant, as was done in Bireta et al. In Experiment 1, with concrete words varying in valence, we replicated the results of Tse and Altarriba with fixed lists and the results of Bireta et al. with randomised lists. In Experiment 2, with abstract words with both fixed and randomised lists, we replicate the absence of effect valence like Tse and Altarriba and Bireta et al. Overall, we conclude that valence does not affect serial recall and the discrepancy was attributed to the peculiarity of the fixed lists used by Tse and Altarriba. It has only recently been shown that arousal affects immediate serial recall when valence and dominance are equated  = 2.008, p = .051, d = 0.296, BF10 = 1.000, and for the effect of valence on abstract words, t(45) = 1.664, p = .103, d = 0.245, BF10 = 0.573. In their Experiment 2, they added a neutral condition, but we focus again on the difference between positive and negative words. This time, they did observe a significant effect of valence on the concrete words, t(45) = 2.745, p = .009, d = 0.405, BF10 = 4.382, but not on the abstract words, t(45) = 0.762, p = .451, d = 0.112, BF10 = 0.210. Thus, of four comparisons, only one Bayes factor (BF) provides evidence for the idea that valence affects performance on immediate serial recall tests.The second result, that valence affects serial recall, is the focus of this comment. In their Experiment 1, 01 = 9.22, 8.76, and 9.19 for Experiments 1, 2, and 3, respectively).In contrast to  Importantly, the statistical analyses that support the statement that the words do not differ on these dimensions were done comparing the 35 words in one group to the 35 words in the other. The potential problem, as we see it, is that Tse and Altarriba then used fixed lists rather than random lists: Every participant saw the exact same lists. The reason that this is a potential problem is that the individual lists were not equated.We suspect the differing conclusions of US as the measure of frequency  = 1.293, p = .200, the positive concrete lists nonetheless tended to be of higher frequency than the negative concrete lists because of how the words were allocated to each list. Given that high-frequency words are better recalled on immediate serial recall tests than low-frequency words, it is not clear whether the observed difference between positive concrete and negative concrete words is due to frequency or valence or some combination of the two.Here is a specific example of the type of unwanted systematic variation that can occur when the participants all see the same lists but the lists (as opposed to the set of words as a whole) were not equated. Using SUBTLEXrequency , we rankLike The suggestion that the different results of In Experiment 1, we examined whether the discrepancy between the results of d = 0.405). For the null hypothesis, an absence of effect was used (Cohen’s d = 0.000). For both sample size analyses, 10,000 simulations were conducted via a non-directional Bayesian paired sample t-test and the default priors.The Bayes factor design analysis BFDA;  was usedd = 0.405), our results revealed that with 44 participants, 7.5% of the samples showed evidence for the null hypothesis (BF < 0.3333), 37.5% were inconclusive (0.3333 < BF < 3), and 55% showed evidence for the alternative hypothesis (BF > 3). For the null hypothesis simulation (Cohen’s d = 0.000), our results revealed that with 44 participants, 1.4% of the samples showed evidence for the alternative hypothesis (BF > 3), 20.5% were inconclusive (0.3333 < BF < 3), and 78.1% showed evidence for the null hypothesis (BF < 0.3333). Overall, we conclude that 44 participants would allow us to detect a similar difference to For the alternative hypothesis simulations (Cohen’s https://www.prolific.co/). All 44 participants met the following eligibility criteria: (1) native speakers of English, (2) American nationality, (3) normal or corrected-to-normal vision, (4) no cognitive impairment or dementia, (5) no language-related disorders, (6) ages between 18 and 30 years, and (7) had an approval rating of at least 90% on prior submissions at Prolific. They were paid £9.00 per hour (pro-rated) for their participation. The mean age was 25.64 years . Twenty-four self-identified as female, 19 as male, and one preferred not to specify their gender. This research was approved by the research ethics committee of the Université de Moncton.The participants were recruited from Prolific  × 2 list type (fixed lists vs randomised lists) repeated-measures factorial design. The experiment was divided into two blocks of 20 trials  each corresponding to a list condition  preceded by two practice trials. The order of the blocks was counterbalanced across participants so that half of the participants began with the fixed lists and the other half with randomised lists. For both blocks, valence (negative lists or positive lists) varied randomly from trial to trial and the order of the words within a list was randomised for each participant.The procedure was based on The responses were scored as in the work of R  or BF01 (BF01 = 1/BF10) corresponding to the strength of evidence in favour of the null hypothesis.All analyses were conducted with the statistical software R . We compR  and the R . For BF The data and the R markdowns associated with this and the subsequent experiment are available on the Open Science Framework (OSF) project page of this project.F = 0.660, p = .421, 01 = 5.276.To allowed direct comparison between our experiment and the work of M = 0.70, SD = 0.19) than for concrete negative words . This difference was significant by the frequentist test, t(43) = 2.345, p = .024, d = 0.353, although the Bayesian test revealed only anecdotal evidence, BF10 = 1.897. This result replicates Tse and Altarriba.As shown in M = 0.66, SD = 0.21) and concrete negative words , t(43) = 0.231, p = .818, d = 0.035, BF01 = 5.972. This result, including the evidence in favour of the null hypothesis from the Bayesian test, replicates As shown in Although these results are clear, given the theoretical importance of the absence of an effect of valence on serial recall, we conducted a second experiment using the abstract positive and abstract negative words of Experiment 2 was identical to Experiment 1 except that we used the abstract positive and abstract negative words of SD = 3.22, range = 18–30). Twenty-seven participants self-identified as female and 17 as male.Forty-four different participants were recruited from Prolific. The eligibility criteria were the same as in Experiment 1. The mean age was 25.59 years  = 1.543, p = .221, 01 = 3.358.As in Experiment 1, there was no effect of block order M = 0.58, SD = 0.23) and abstract negative words , t(43) = –0.542, p = .591, d = 0.082, BF01 = 5.333.As shown in M = 0.59, SD = 0.22) and abstract negative words , t(43) = .000, p = 1.000, d = 0.000, BF01 = 6.126.As shown in Experiment 2 was identical to Experiment 1 except for the stimuli: Whereas Experiment 1 used concrete positive and negative words, Experiment 2 used abstract positive and negative words. As in Experiment 1, there was no evidence that valence affected serial recall when each participant received randomly generated lists, replicating As noted in the introduction, it is well known that concrete words are better recalled than abstract words on immediate serial recall tests even when the stimuli are controlled for valence (The two papers used different designs. These results have important methodological implications. First, if fixed lists are used, then it is the lists that should be equated rather than the entire pool of words. If this is not done, then it is possible that one or more unwanted systematic differences may be introduced that affect the results. Second, researchers should always include their stimuli in their papers because it allows other researchers to investigate stimulus properties. The reason we know that concreteness effects obtain even when valence is controlled is because previous researchers published their stimuli and we could then compute valence using the The results of the current article, along with those of In conclusion, although many long-term memory/lexical factors do affect immediate serial recall, including whether the words are abstract or concrete, valence does not when the lists of positive and negative words are appropriately equated.


In animals, the success of particular lineages can be measured in terms of their number of species, the extent of their geographic range, the breadth of their habitats and ecological niches, and the diversity of their morphological and life‐history traits. Here, we review the distribution, ecology, morphology and life history of skinks, a diverse lineage of terrestrial vertebrates. We compared key traits between the three subfamilies of skinks, and between skinks and non‐scincid lizards. There are currently 1743 described species of skink, which represent 24% of global lizard diversity. Since 2010, 16% of lizard descriptions have been of skinks. The centres of skink diversity are in Australia, New Guinea, southeast Asia, Oceania, Madagascar and central Africa. Compared with non‐scincid lizards, skinks have larger distributional ranges, but smaller body sizes. Sexual size dimorphism is rare in skinks. Almost a quarter (23%) of skinks exhibit limb reduction or loss, compared with just 3% of non‐scincid lizards. Skinks are more likely to be viviparous (34% of species) compared with non‐scincids (13%), and have higher clutch/litter sizes than non‐scincids. Although skinks mature later than non‐scincids, their longevity is similar to that exhibited by other lizard groups. Most skinks (88%) are active foragers, and they are more likely to be carnivorous than non‐scincids. Skinks are more likely to be diurnal or cathemeral than other lizard groups, but they generally have lower field body temperatures compared with non‐scincids. The success of skinks appears to be both a result of them hitting upon a winning body plan and ecology, and their capacity to regularly deviate from this body plan and adapt their ecology and life history  to prevailing conditions. There are currently 1743 described species of skink, which represents 24% of global lizard diversity. The success of skinks appears to be both a result of them hitting upon a winning body plan and ecology, and their capacity to regularly deviate from this body plan and adapt their ecology and life history  to prevailing conditions. The most diverse terrestrial vertebrate groups are non‐avian reptiles  has been an important step in improving our understanding of their biology and ecology , minimum convex polygons  or buffered using a 1.78 km radius, as described in detail in Roll et al. . DistribBody size data were collected as snout‐vent length , we averaged the smallest and largest reported means if more than one value was available. If no means were available, we averaged the smallest and largest observed values.2.110 error structures) or chi‐squared tests. Since we compared the three monophyletic skink subfamilies to each other, or skinks to all non‐skink lizards, phylogenetically informed analyses are irrelevant, and we did not use them. Thus, while conclusions regarding differences between subfamilies are valid, we do not infer them to mean that such differences evolve independently  are, on average, larger than those of non‐scincid lizards . There are no significant differences in the range sizes among skink subfamilies  :Reduced‐limb skinks (Lygosominae and Scincinae):Limbless (Lygosominae and Scincinae):Acontiinae :SD mm; versus 99.6 ± 90.1 for non‐scincids  and lower mean maximum body mass . The smallest skink species is the limbless Paracontias fasika, with a max mass of 0.23 g, which is the 6th smallest lizard overall . The largest skink, Bellatorias major, is only the 74th largest lizard overall ; Tiliqua scincoides and the extinct Chioninia coctei are tied in #77 (max 1405 g), Tiliqua nigrolutea is #87, Corucia zebrata and T. rugosa are tied in #99, and T. gigas, with a max weight of 1019 g, is the only other skink that can grow larger than 1 kg. The limbless Acontias plumbeus is the longest skink , Bellatorias major is the longest limbed skink (max 391 mm) and Scincella macrotis is the shortest .Skinks are relatively small lizards Figure , with a SD mm, n = 31) comprises, on average, of the longest species, Lygosominae  of the shortest, and Scincinae  is intermediate  is uncommon in skinks and within each subfamily Figure . The oven = 398; 112 limbless; 286 limb‐reduced, of which 4 with forelimbs only, 52 with hindlimbs only), compared with only 3.0% of non‐scincid lizards  are limbless, 43.7% (n = 129) of the Scincinae are limb‐reduced and 21.7% (n = 64) are limbless, but only 10.9%  of the Lygosominae species are limb‐reduced and 1.1%  are limbless.Skinks exhibit substantial variation in body shape Figure . Applyin3.3n = 5012; χ2 = 72.4, p < .0001). Only including those species with known reproductive modes, 34.3% of skink species are viviparous (vs. 12.6% for non‐scincids), 64.7% are oviparous (vs. 87.2% for non‐scincids), and 1.0% have a mixed reproductive mode (vs. 0.2% for non‐scincids). Thus, skinks are more likely to be viviparous than non‐scincid lizards . The percentage of viviparous species is highest in Acontiinae , lowest in the Lygosominae  and intermediate in the Scincinae (65.6%). Viviparous species are more common in southern and alpine Australia, New Zealand, northern Asia, Europe, northern and southern Africa, and central and South America  is unknown, less than the knowledge gap for non‐scincid squamates  is lower than that of non‐scincid lizards . However, after correcting for mass and reproductive mode (log10‐transformed brood sizes are higher by 18% for viviparous species and increase with log10‐transformed mass with a slope of 0.25), skink broods are actually 14% higher . Among skinks the mean clutch/litter size is highest in the Scincinae (4.4 ± 2.9SD), lowest in the Acontiinae (2.4 ± 1.5SD) and intermediate in the Lygosominae (3.2 ± 1.9SD)  is older than that for non‐scincid lizards . This difference intensifies when body mass  is accounted for. Acontiine skinks take the longest to mature , whereas Lygosominae and Scincinae mature at similar ages  is similar to that of other lizards  regardless of whether mass is corrected for  or not . Within skinks, differences between lygosomines  and scincines  are small and not statistically significant whether we correct for mass  or not   Figure . The sin3.4Microhabitat varies substantially among skink subfamilies Figure . All acoχ2 = 77.23, p < .0001). Members of the Acontiinae are all carnivorous, while 6.2% of scincine species with known diet are omnivorous (the others are carnivorous). In the Lygosominae, 9.5% of species with known diets are omnivores and 1.2% (n = 10) feed mostly on plants  is unknown, which is comparable to the knowledge status for non‐scincids . Of these 814 skink species, 90.1% are carnivorous, 8.8% are omnivorous, and 1.1% are herbivorous . For the species where activity patterns are known, skinks have a higher incidence of diurnal (78.0% vs. 67.9%) and cathemeral (13.8% vs. 4.3%) species compared with non‐scincid lizards. In contrast, there are relatively few nocturnal skinks (8.2%) compared to nocturnal non‐scincid lizards . Acontiinae is the most unusual skink subfamily in terms of activity pattern, with all species either nocturnal (5) or cathemeral (6)  of skinks  is slightly lower than that of non‐scincid lizards . When activity times are taken into account, diurnal skinks are active at slightly lower body temperatures  than non‐scincid lizards, but nocturnal and cathemeral skink body temperatures are higher than those of other lizards with similar activity times (Table Acontias meleagris) is active at a low 21.8°C. There is relatively little difference between Scincinae  and Lygosominae  in their field body temperature: these are not statistically significantly different whether activity times are taken into account  or not . Preferred body temperatures in a thermal gradient are positively correlated with field body temperatures ; however, the slope (0.74 ± 0.08) is significantly shallower than 1, suggesting that skinks preferring cold temperatures may have difficulty getting warm enough, while species preferring warm temperatures can barely keep cold enough. However, the model predicts that body temperatures will equal preferred temperatures at 30.64°C – remarkably close to the 30.58°C average Tb for active skinks as a whole.The mean field body temperature , lack sexual dimorphism, are active foraging carnivores and exhibit diurnal or cathemeral activity patterns. Skink species generally have larger geographic ranges than other lizards and display both areas of high species diversity  and species paucity . Ironically, although the standard skink body plan appears to have been highly successful, part of the success of skinks lies in their ability to frequently deviate from their typical body plan, with repeated transitions from oviparity to viviparity and from fully limbed species to limb‐reduced or limbless species. The three skink subfamilies are inconsistent in their expression of these distributional, morphological, life history and ecological attributes, with the Acontiinae deviating substantially from most of the broader trends in skinks.4.1Skinks currently comprise almost a quarter (24%) of the known lizard fauna globally, and as approximately 20 new species are described each year Figure , this nuPlestiodon are thought to have been present in North America for around 18–30 million years , their centres of diversity are in Australia, New Guinea, southeast Asia, Oceania, Madagascar and southern and central Africa. Apart from the hotspot in Oceania and New Guinea, which are disproportionately dominated by skinks , than the smallest known limbed skink, Scincella macrotis. Unlike many endothermic lineages, squamate body size does not appear to be driven by climatic factors  than any other vertebrate group, and this has been largely driven by skinks, which alone account for at least 31 transitions from oviparity to viviparity , successful because they are uniform in their morphology, ecology and life history or are they successful because they exhibit variation in key traits? Our study indicates that skinks are on the one hand uniform—exhibiting a great propensity for small body size , diurnality, active foraging and carnivory. But despite this tendency for uniformity, skinks are the poster child for key evolutionary transitions in limb reduction and the evolution of viviparity. As a lineage, skinks appear to be evolutionarily ‘malleable’, filling every available ecological niche by either staying as close as possible to their standard body plan and ecology (which appears to be a good design that works the majority of times) or evolving rapidly in different directions to exploit extreme environments—that is limb reduction and loss in fossorial environments ; data curation ; funding acquisition (lead); investigation ; methodology ; project administration ; writing – original draft . Alex Slavenko: Data curation ; formal analysis ; visualization ; writing – review and editing . Reid Tingley: Conceptualization ; formal analysis ; methodology ; visualization ; writing – review and editing . Jules E. Farquhar: Data curation ; formal analysis ; visualization ; writing – review and editing . Marco Camaiti: Data curation ; formal analysis ; methodology ; visualization ; writing – review and editing . Uri Roll: Data curation ; formal analysis ; methodology ; visualization ; writing – review and editing . Shai Meiri: Conceptualization ; data curation ; formal analysis ; funding acquisition ; investigation ; methodology ; visualization ; writing – original draft .The authors declare no conflicts of interest.Appendix S1Click here for additional data file.Appendix S2Click here for additional data file.Data S1Click here for additional data file.


Milk replacer is recommended as an effective substitute when sow milk is insufficient or unavailable to meet the requirements of neonates, and the protein sources of milk replacer are vital for the intestinal maturation and health of neonates. In this study, we investigate the effects of SDPP or SPI partially substituting WPC in milk replacer on the growth performance, ileal morphology, nutrient digestion, immunity and intestinal microbiota of neonatal piglets. Our results confirm the efficacy of SDPP in milk replacer for improving the growth and intestinal health of neonatal piglets.p = 0.05), ADG (p = 0.05) and F/G (p = 0.07) compared with WPC– and SPI–fed piglets, and SDPP–fed piglets had a lower diarrhea index (p < 0.01) from PND 2 to PND 8. SDPP–fed piglets had an increased ileal villus height (p = 0.04) and ratio of villus height to crypt depth (VCR) (p = 0.02), and increased activities of sucrase (p < 0.01), lactase (p = 0.02) and trypsin (p = 0.08) in the jejunum, compared with WPC– and SPI–fed piglets. Furthermore, SPI–fed piglets had an increased mRNA expression of IL-6 (p < 0.01) and concentration of plasma urea (p = 0.08). The results from LEfSe analysis showed that SDPP–fed piglets had a higher abundance of beneficial Butyricicoccus compared with WPC– and SPI–fed piglets, in which higher abundances of pathogenic bacteria such as Marinifilaceae, Fusobacterium and Enterococcus were observed. Moreover, SDPP–fed piglets had an increased concentration of butyric acid (p = 0.08) in the colonic chyme compared with WPC– and SPI–fed piglets. These results suggest that neonatal piglets fed milk replacer with SDPP partially substituting WPC had improved growth performance and intestinal morphology and function, associated with higher digestive enzyme activity and fewer pathogenic bacteria.Appropriate protein sources are vital for the growth, development and health of neonates. Twenty–four 2–day–old piglets were randomly divided into three groups and fed isoenergetic and isonitrogenous diets. The experimental diets included a milk replacer with 17.70% whey protein concentrate (WPC group), a milk replacer with 6% spray–dried porcine plasma isonitrogenously substituting WPC (SDPP group), and a milk replacer with 5.13% soy protein isolate isonitrogenously substituting WPC (SPI group). Neonatal piglets were fed milk replacer from postnatal day 2 (PND 2) to day 20 (PND 20). The growth performance, intestinal morphology, activities of digestive enzymes, plasma biochemical parameters, immunity–related genes, short–chain fatty acids (SCFA) and intestinal microbiota in the colonic chyme were determined. The results showed that SDPP–fed piglets had higher final BW ( Genetic selection for highly prolific sows has been found to largely increase litter size . HoweverAs a dairy–based protein, whey protein concentrate (WPC) has been widely used as a major protein source in milk replacer ,11. It hIn this study, therefore, we aimed to investigate the effects of partially substituting the dairy–based protein WPC in milk replacer with the animal–based protein SDPP or the plant–based protein SPI on the growth performance, intestinal morphology, activity of digestive enzymes, immunity–related parameters, intestinal microbiota composition and metabolites in neonatal piglets.n = 8), a milk replacer with 6% SDPP isonitrogenously substituting WPC , and a milk replacer with 5.13% SPI isonitrogenously substituting WPC . The nursery room temperature was controlled at 28~31 °C. The intake of milk replacer was converted into dry matter intake using a dry matter–to–water ratio of 1:4, and piglets were weighed individually at the start and end of the study to calculate the average daily feed intake (ADFI), average daily gain (ADG) and ratio of ADFI to ADG (F/G). Visual diarrhea scores were assessed three times daily and the diarrhea index was calculated [Twenty–four Landrace/Yorkshire crossbred piglets (2 days old) with an average initial body weight of 1.55 ± 0.23 kg, including a mix of females and males, were selected for this experiment. After birth, piglets were allowed to suckle from their respective sows for 48 h prior to being transported to a nursery room, and were housed individually in stainless steel metabolic crates (0.6 × 0.9 × 0.6 m). Piglets were randomly divided into three treatment groups receiving experimental diets, including a milk replacer with 17.70% WPC . Similarly, chyme samples from the colon were collected, frozen in liquid nitrogen and stored at −80 °C for 16S rRNA sequencing to assess the microbial community composition.Prior to slaughter, milk replacer and water were withheld from piglets for 12 h. Once their final body weight was recorded, blood was collected from the anterior vena cava. Plasma samples were obtained by centrifuging blood samples stored in heparin anticoagulated tubes at 3000× Pieces of ileum were fixed in 4% paraformaldehyde solution for histomorphometric analysis. Ileum samples were dehydrated and embedded in paraffin. Sections 5 μm thick, cut using a Leica RM2235 microtome , were stained using the periodic acid–Schiff (PAS) method. Image Pro Plus 6.0 software  was used to acquire images and to measure the villus height, the depth of crypts and the area of goblet cells in the tissue.Jejunum samples were homogenized using 4 °C pre–cooled 0.9% saline for further analysis. The protein content of the samples was determined using the Coomassie brilliant blue method, and the test kit was purchased from Nanjing Jiancheng . The activities of sucrase, maltase, lactase and trypsin were determined according to the instructions for the Nanjing Jiancheng kit . The optical density values of disaccharidase and trypsin were measured at 505 nm and 253 nm, respectively, using a SpectraMax190 microplate reader ; then, the activities of the enzymes were calculated according to the change in absorbance.2O, 4× gDNA Wiper Mix, 5× HiScript III qRT SuperMix). Quantitative PCR  was carried out using the QuantStudio5 instrument . Data were normalized using β-actin and the relative expression was calculated using the 2−ΔΔCt method [Extracted ileal RNA with a concentration of 500~1000 ng/μL was used to synthesize cDNA, according to the instructions for the reverse transcription kit (Vazyme) (RNase-free ddHt method . The pri® High–Fidelity PCR Master Mix with GC buffer (New England Biolabs) and high–efficiency high–fidelity enzymes were used to perform PCR. The NEBNext® Ultra™ IIDNA Library Prep Kit  was utilized for library construction. Then, the constructed library was qualified and sequenced using the NovaSeq6000 instrument . After careful processing and analysis, the effective tags were obtained and denoised using QIIME2 software (2019.1) to generate ASVs (Amplicon Sequence Variants) and feature tables. The species information for each ASV was determined by comparing it to a database. Finally, QIIME2 software was used to conduct alpha and beta diversity analysis.Colonic chyme samples were used for 16S rRNA amplicon . Genomic DNA was extracted using either the CTAB or SDS method. Specific primers with barcodes, the Phusiong for 15 min. After centrifugation, 0.2 mL of 25% (w/v) metaphosphoric acid and 23.3 μL of 210 mmol/L crotonic acid were added to 1 mL of supernatant, mixed well, and left to stand at 4 °C for 30 min, and then, centrifuged at 8000× g for 10 min. After centrifugation, 0.9 mL of chromatographic methanol (1:3 dilution) was added to 0.3 mL of supernatant, and mixed well. Finally, the supernatant was filtered using a 0.22 μm filter membrane into a 1.5 mL EP tube for later use. SCFA concentrations were measured using GC CP3800 gas chromatography .Briefly, 0.5 g of colonic chyme sample and 1.2 mL of ultrapure water were added to a centrifuge tube after thawing, allowed to stand for 30 min and centrifuged at 10,000× p < 0.05 and a tendency at p < 0.10.The Shapiro–Wilk test and UNIVARIATE procedures of SAS 9.4  were used to analyze variance homogeneity and normality, respectively. Data were analyzed using one–way analysis of variance (ANOVA), and the LSD method was used for multiple comparisons. Data are presented as mean ± pooled standard error (SEM) and considered significant at p = 0.05) and ADG (p = 0.05), and lower F/G (p = 0.07), compared with WPC– and SPI–fed piglets  compared with WPC– (21.08%) and SPI–fed piglets (28.55%).Venn analysis identified 1244, 1104 and 1219 unique OTUs in the WPC, SDPP and SPI groups, respectively . Firmicunt phyla a. SDPP–ff__Marinifilaceae, f__Rikenellaceae, g__JG30_KF_CM66, f__Anaerovoracaceae and g__A21b in the WPC group, g__Butyricicoccus in the SDPP group, and g__Fusobacterium, g__Enterococcus, g__Sumerlaea and f__Rubritaleaceae in the SPI group (LEfSe (LDA Effect Size) is used to find biomarkers with statistical differences across groups. The most abundant phylotypes contributing to the differences across the intestinal microbiota of the WPC, SDPP and SPI groups were found to be PI group .p = 0.08, SDPP–fed piglets tended to have a higher concentration of butyric acid in the colonic chyme compared with WPC– and SPI–fed piglets (Whey protein concentrate (WPC) is a commonly used dairy–based protein in milk replacer for piglets . HoweverIn the present study, the higher final BW and ADG, and the lower F/G, in SDPP–fed piglets indicated the crucial role of SDPP in improving the growth performance of piglets, which is consistent with previous results from studies that include SDPP in weaning diets in which it increased post–weaning growth rate ,30,31. AIL–6 and anti-inflammatory factor IL–10 play an important role in regulating the inflammatory response system. In this study, both IL–6 and IL–10 were over-expressed in the ileum of SPI–fed piglets. This finding seems paradoxical considering the anti–inflammatory effects of IL–10. However, previous research has found that an increased level of IL–10 is a protective mechanism for the body against the release of a large number of pro–inflammatory cytokines [IL–6 can also stimulate the release of IL–10 in local tissues [In contrast, SPI–fed piglets had the lowest growth rate, which may be associated with poor digestive capability, immunity and bacterial structure. Our study found that SPI–fed piglets had higher plasma urea, indicating a potential increase in protein breakdown or lower protein utilization, because urea is the main end product of amino acid and protein metabolism, which is negatively correlated with amino acid utilization and protein retention . Immunitytokines . In addi tissues . TherefoFirmicutes, Bacteroidetes and Proteobacteria were the most abundant bacterial phyla in the colonic chyme. SDPP-fed piglets had lower Proteobacteria levels compared with WPC– or SPI–fed piglets. Interestingly, previous research demonstrated that breast–fed infants had lower Proteobacteria levels (3.29%) compared with formula–fed infants (13.85%) [Proteobacteria has been linked to inflammation and intestinal dysbiosis [Butyricicoccus, a high butyrate–producing probiotic [Marinifilaceae, Fusobacterium and Enterococcus, was increased in the colonic chyme of WPC– and SPI–fed piglets. It has been reported that Marinifilaceae was enriched in the lumen of colitis and infection animal models [Fusobacterium, F. nucleatum has been recognized as an opportunistic pathogen that plays an important role in intestinal diseases, which promotes the inflammatory response and induces the release of the pro–inflammatory cytokines IL–6 and IL–8 [IL–6 in SPI–fed piglets.The normal intestinal microbiota is essential for intestinal homeostasis . Dietary(13.85%) . Furtherysbiosis ,47. In trobiotic , was incrobiotic . In addil models ,51. One and IL–8 ,53,54. TThe use of SDPP to partially substitute WPC in milk replacer improved the growth performance and intestinal function of piglets, associating with increased activities of digestive enzymes, decreased expressions of inflammatory genes, and the lower presence of pathogenic bacteria compared with the WPC and SPI groups. However, further research is needed to investigate the long-term implications of these outcomes.


The overall risk of colorectal cancer in Crohn's disease (CD) is higher than in the general population, and CD‐associated cancer (CDAC) has poorer prognosis than sporadic cancer. Developing treatment strategies for improving the prognosis of CDAC, we evaluated the characteristics of CDAC according to the underlying disease behavior, namely stricturing and penetrating.This multicenter retrospective study comprises 316 CDAC patients who underwent surgery between 1985 and 2019. Clinicopathological findings including disease behavior and oncological outcomes were investigated.p = 0.02; relapse‐free survival [RFS]: p = 0.002) whereas stricturing had no effect. Furthermore, penetrating behavior was identified as one of the independent risk factors for poor OS and RFS .There was no association between the preoperative course of CDAC patients and disease behavior; however, postoperative information revealed distinctly different characteristics between CDAC patients with stricturing behavior and those with penetrating behavior . Oncological outcome of patients with CDAC was distinctly different according to disease behavior, as penetrating provided a poor outcome (overall survival [OS]: Our study highlights the different characteristics of CDAC according to the underlying disease behavior and substantiates the poor prognosis of CDAC patients with penetrating behavior. Treatment planning including screening, surgical procedures, and postoperative treatment, with awareness of these findings, may contribute to improved prognosis for CDAC patients. Time‐to‐event analysis showed that disease behavior affected the oncological outcome of CDAC patients. Although stricturing behavior was not associated with OS and DFS, penetrating behavior was identified as bringing about a poor oncological outcome for both OS and DFS. Accumulating evidence has shown the increased risk of cancer for patients with Crohn's disease (CD) who have had extensive, long‐standing, unresected involvement.Disease behavior such as stenosis and fistula, which is one of the features of CD, is considered to be one of the phenotypes of chronic persistent inflammation in the local environment. According to the Montreal classification, CD consists of three components: age at diagnosis, location, and behavior.The factors responsible for either B2 or B3 complications as a result of chronic persistent inflammation remain unclear, although B2 is thought to occur through fibrosis when regeneration and repair cannot restore normal structure.Considering that disease behavior can represent phenotypes of chronic persistent inflammation, B2 or B3 lesions may affect carcinogenesis, known as the dysplasia‐carcinoma sequence. Therefore, we hypothesized that different disease behaviors can provide differing clinical phenotypes of CDAC, which has carcinogenic predisposition against the background of chronic inflammation. In this study, we evaluated the characteristics of CDAC according to the underlying disease behavior and examined the possibility of clinical applications for improving the prognosis of CDAC.22.1A total of 316 CDAC patients who underwent surgery between 1985 and 2019 were enrolled in the project study led by the Japanese Society for Cancer of Colon and Rectum, which collected the data from 39 participating institutions.2.2In this study, the disease behavior was basically classified at the time of surgery that led to cancer diagnosis. Stricturing was defined as fibrostenotic features and penetrating as intra‐abdominal or perianal fistula, perianal ulcer, inflammatory mass, and/or abscess. Although these behaviors were mainly determined from intra‐operative findings, but also comprehensively from preoperative diagnostic studies such as small bowel series, enterographic contrast, as well as magnetic resonance imaging or from postoperative pathological evidence.2.3p values were two‐sided, and p < 0.05 was considered statistically significant. Statistical analyses were performed using JMP Pro 13.1 (SAS Institute).Comparisons of patients' and clinical characteristics between groups were evaluated using the Kruskal–Wallis test for continuous variables (expressed as median ± interquartile range) and Pearson's chi‐squared test or Fisher's exact test for categorical variables, as appropriate. A survival analysis was performed using the Kaplan–Meier method and was compared using the log‐rank test. Overall survival (OS) was measured from the date the patient underwent surgery until the date of death resulting from any cause, or until the last known follow‐up in patients who were still alive. Relapse‐free survival (RFS) was measured from the date the patient underwent surgery to the date of disease recurrence, death from any cause , or until last contact with the patient. In survival analysis, we excluded 33 patients because of a lack of follow‐up information. Cox's proportional hazards model was used to estimate hazard ratio (HR) for OS and RFS. Clinical variables that were considered for univariate and multivariate analyses, in addition to disease behavior, were previously identified confounding factors with an impact on clinical course of CD: onset age, disease duration, smoking history, ileum lesion, colon lesion, use of 5‐aminosalicylic acid, use of steroids, and use of anti‐tumor necrosis factor‐α drugs; and factors with an impact on prognosis in patients with colorectal cancer: sex, age at diagnosis of cancer, histological differentiation (well to moderately differentiated or others), pathological T stage (T1/2 or T3/4), lymphatic invasion (present or absent), venous invasion (present or absent), and lymph node metastasis (present or absent). All 33.1Patients' characteristics and clinical courses before diagnosis of cancer are shown in Table 3.2p = 0.002), presence of lymphatic invasion (p = 0.03), and high TNM stage (p = 0.002). Penetrating behavior was associated with poorly differentiated cancer (p = 0.02) and high T stage (p = 0.03). Interestingly, the recurrence type in patients with CD‐associated cancer was shown to be different for each behavior. Specifically, stricturing behavior was associated with recurrence of peritoneal dissemination (p = 0.04), whereas penetrating behavior was associated with local recurrence (p = 0.008).Postoperative information, which included pathological findings and recurrence type, are shown in Table 3.3p = 0.02; RFS, p = 0.002; log‐rank test).We next investigated the impact of CD behavior on the oncological outcomes. Time‐to‐event analysis showed that disease behavior affected the oncological outcome of CDAC patients Figure . Althoug3.4p = 0.01; Table p = 0.004; Table We further evaluated the predictive factors for oncological outcomes of CDAC. Variables to be evaluated comprised CD characteristics and the clinical course, including disease behavior and well‐known risk factors for poor oncological outcome. Notably, along with cancer histology of poor differentiation, high T stage, venous invasion, and node involvement, penetrating behavior was identified as an independent risk factor for poor OS , and those with B2 + B3 also had poor RFS compared with those with B1  behavior. As the number of CDAC cases is expected to increase in the future, physicians may contribute to improved prognosis by developing a treatment plan for each case based on the individual's disease behavior.Conception and design, acquisition of data, and analysis and interpretation of data: Akira Yamamoto, Yuji Toiyama, Hiroki Ikeuchi, Motoi Uchino, Kitaro Futami, Kinya Okamoto, Takayuki Ogino, Soichiro Ishihara, Yoichi Ajioka, and Kenichi Sugihara; drafting the work critically for important intellectual content: Akira Yamamoto, Yuji Toiyama, Hiroki Ikeuchi, Motoi Uchino, Kitaro Futami, Kinya Okamoto, Takayuki Ogino, Soichiro Ishihara, Yoichi Ajioka, and Kenichi Sugihara; final approval of the version to be published: Akira Yamamoto, Yuji Toiyama, Hiroki Ikeuchi, Motoi Uchino, Kitaro Futami, Kinya Okamoto, Takayuki Ogino, Soichiro Ishihara, Yoichi Ajioka, and Kenichi Sugihara; agreement to be accountable for all aspects of the work: Akira Yamamoto, Yuji Toiyama, Hiroki Ikeuchi, Motoi Uchino, Kitaro Futami, Kinya Okamoto, Takayuki Ogino, Soichiro Ishihara, Yoichi Ajioka, and Kenichi Sugihara.This work was supported by the Japanese Society for Cancer of Colon and Rectum.The authors declare no conflicts of interest for this article.Approval of the research protocol: This multicenter retrospective study was approved with the permission of The University of Tokyo Ethics Review Board (2019220NI‐(2)).Informed Consent: N/A.Registry and the Registration No. of the study/trial: N/A.Animal Studies: N/A.Data S1Click here for additional data file.


Post‐COVID‐19 condition affects patients on various aspects. This 41‐year‐old female presented to the outpatient clinic complaining of severe insomnia characterized by inconsistent 2 h of sleep per day despite taking sleep aid pills after being infected with COVID‐19 and persisting for 6 months after recovery. She is a nonsmoker and does not consume any alcohol. RA is allergic to NSAIDs.She had COVID‐19 in November 2020 and was treated with oxygen therapy at home. She presented to the outpatient clinic in May 2021 complaining of persistent severe insomnia for 6 months after COVID‐19 infection.2.1The patient had insomnia for 6 months which exacerbated in the last 2 weeks , headache , occasional slurred speech and nausea (these attacks occurred once daily and resolved spontaneously), and fibromyalgia exacerbation, including burning sensation of the spine that affects her daily performance and sleeping. Her pain was stronger and stiffer at mornings to the extent that she sometimes needed help getting out of the bed. Also, she complained of pain in the shoulder, spine, and hip at multiple trigger points. In addition to chronic and dry cough associated with shortness of breath (SOB) and chest pain, general fatigue, low appetite, and anhedonia. Her relationship with her daughters was affected too, and she felt detached from them. She even had death thoughts.2.22. In addition, she was calm and cooperative but she had a low tone of voice and talked slowly. Although she had a depressed mood, her thoughts were clear, logical, concentrated and goal‐directed without perceptual disturbances.Upon physical evaluation, the patient was conscious, oriented and alert. She weighed 78 kg and her height was 169 cm. Her body mass index was 27.3 kg/cmShe did not have any fever and her vital signs were normal and stable, with intact reflexes and cranial nerves. She was not cooperative in performing power test but intact power performance and positive pain pressure points over all joints were performed.2.3Before being infected with the coronavirus, the patient was a socially active person and an athlete. She was humorous and outgoing. She also had regular sleep schedule with an excellent memory. In 2013, when RA was pregnant, she was diagnosed with migraine and fibromyalgia. She was on pregabalin 75 mg once daily for 3–4 months. Her muscle pain had improved completely since then. She is also an asthmatic patient on inhalers and nebulizers once needed.2.42 sat was 84%–90%. Her pulmonologist performed a chest X‐ray. The report revealed bilateral infiltrates. She was treated with dexamethasone 8 mg intramuscular injection for 2 days, prednisolone syrup, azithromycin 500 mg for 6 days, bilastine, montelukast, inhaled corticosteroids, enoxaparin 6000 IU for 10 days, and oxygen therapy for 2 months. Additionally, after 2 weeks of the mentioned respiratory symptoms, she started experiencing GI symptoms, including severe diarrhea, vomiting, loss of appetite, and blood in stools. She had lost 10 kg but was tested negative for Helicobacter pylori and amoebae. After 2 weeks of these GI symptoms, she started to experience severe memory impairment; she was not oriented to place nor time especially after waking up at mornings. She felt detached emotionally from her family members.At the beginning of RA's COVID‐19 disease, she complained of a severe headache with burning sensation . Her pain score, according to the patient, was 10. She also reported that she had auditory hallucinations about voices of wolves for 3 weeks. Additionally, RA had developed severe back pain along her spine, and she was treated by a rheumatologist who prescribed her the following medication: pregabalin 75 mg twice daily, etoricoxib 120 mg once daily, duloxetine 30 mg once daily, and a one shot of dexamethasone 8 mg intramuscular injection. Ten days later, she started to complain of mild respiratory symptoms including nasal congestion, runny nose, anosmia, and ageusia. Symptoms were later exacerbated to severe SOB; her O2.5The patient has reported that since she was infected with SARS‐CoV‐2, she had inconsistent sleep patterns with only 30–120 min of sleep per day. She tried different sleep medications, including diazepam 10 mg and flupentixol/melitracen. None was beneficial. She also reported that she had difficulty sleeping due to muscle and joint pain. She was presented to a neurologist who prescribed her mirtazapine. It helped her fall asleep but was associated with severe agitation and uncontrolled nervousness. RA had violent behavior toward her children; she was still on pregabalin, etoricoxib, and duloxetine.33.1At first, RA was prescribed melatonin 2 mg seven tablets before bedtime for her insomnia. After no noticeable improvement, she was prescribed bromazepam 3 mg two tablets once daily. It increased her sleep duration to 2–4 h per day inconsistently. She was also prescribed citalopram and continued on pregabalin 150 mg once daily.3.2The patient was admitted to JUH on August 1, 2021 and discharged on August 4, 2021. During this period, laboratory testing, imaging modalities, sleep study, and specific consultations were done for proper evaluation of her condition, as the following.3.2.1Chest X‐ray: no infiltrates, no hyperlucency, and appears normal  was 94% in the awake state and was below 90% for 0.1% of the total sleep time, and finally, snoring time of 34 min (20% of sleep time).The patient's Epworth Sleepiness Scale score was 12/24. The sleep efficiency was 44% with a total sleep time of 169 min. Sleep onset was 13 min and rapid eye movement (REM) latency from sleep onset was 239 min with REM time of 29 min. The patient had 31 hypopnea attacks with a sleep distribution of 14% N1, 60% N2, 9% N3, 17% REM, and an overall arousal index of 34 events per hour of sleep. The apnea–hypopnea index was elevated at 11 events per hour of sleep. On the other hand, arterial oxygen saturation . She also reported headaches, slurred speech, nausea, low energy, low appetite, anhedonia, family detachment, and occasional death wishes.2 was 94%, 0.1% total sleep time spent with spaO2 less than 90%, and snoring time was 20% of sleep time.It was critical to conduct sleep studies as soon as possible and take steps to prevent it from worsening. Sleep studies revealed decreased sleep efficiency at 44% with a total sleep time of 169 min, sleep onset was 13 min, and REM latency from sleep onset was 23 min with REM time of 29 min. Furthermore, the arousal index was elevated at 34 events per hour of sleep, 31 hypopnea attacks, awake spaOThe majority of COVID‐19‐confirmed patients reported at least one symptom even after 6 months of infection.Subjective sleep quality, length, latency, effectiveness, sleep disruption, consumption of hypnotic medication, and daytime functionality were substantially elevated in COVID‐19 survivors. Females have a greater frequency of mental problems including posttraumatic stress disorder and anxiety than males, which may be connected to variations in gonadal hormone levels in response to stress and gender disparities in brain areas.The authors of a study of 35 individuals surviving the COVID‐19 discovered a correlation between sleep quality and a specific gender.13 FemIn the present case report, the quality of life (QoL) was decreased with depressed mood, anhedonia, and death wishes. A study conducted by El Sayed et al. reported statistically significant positive connections between the insomnia severity index scale and various domains of the QoL scale, including general well‐being, role constraints due to poor physical health, and role restrictions due to emotional burdens, and overall health.Our case report presented a vital problem for post‐COVID patients, which affected all domains of life and it is not a common complaint to have insomnia for 6 months (2 h/day) after being diagnosed with COVID‐19. The current literature lacks extended follow‐up of insomnia symptoms in COVID‐19 patients. It is worth mentioning that the studied case lacked history of smoking, alcohol, caffeine, and substance use.We recommend conducting extensive longitudinal studies with a sufficient follow‐up period of confirmed COVID‐19 patients to test the severity of insomnia and its impact on different domains of QoL.5Post‐COVID‐19 condition can affect patients on many aspects, including the psychiatric level. Insomnia can be developed following COVID‐19. Further analysis is required to assess the prevalence and cause of post‐COVID insomnia.Asma Salameh Albtoosh: Conceptualization; formal analysis; methodology; writing – original draft; writing – review and editing. Sajeda Ghassan Matar: Methodology; writing – original draft; writing – review and editing. Shatha Nizar Bishtawi: Writing – original draft; writing – review and editing. Alaa Ahmed Elshanbary: Methodology; writing – original draft; writing – review and editing. Lara Ibrahim Ramadan: Writing – original draft; writing – review and editing. Andrew Bradbeer: Writing – original draft; writing – review and editing. Elfatih A. Hasabo: Writing – review and editing. Iman A. Basheti: Writing – review and editing.The study was funded by the authors themselves.The authors have no conflict of interest to declare.Verbal and written consents were obtained from the patient before writing the case or using investigations to participate.Written consent to publish this information was obtained from the patient. This patient has not been reported in any other submission by the authors or anyone else.