Background: The COVID-19 pandemic has induced demanding work situations in intensive care units (ICU). The objective of our study was to survey psychological reactions, the disturbance of social life, work effort, and support in ICU nurses, physicians, and leaders. Methods: From May to July 2020, this cross-sectional study included 484 ICU professionals from 27 hospitals throughout Norway. Symptoms of anxiety and depression were measured on Hopkins Symptom Checklist-10 (HSCL-10). Symptoms of post-traumatic stress disorder (PTSD) were measured on the PCL-5. Results: The study population were highly educated and experienced professionals, well prepared for working with COVID-ICU patients. However, 53% felt socially isolated and 67% reported a fear of infecting others. Probable cases of anxiety and depression were found in 12.5% of the registered nurses, 11.6% of the physicians, and 4.1% of the leaders. Younger age and <5 years previous work experiences were predictors for high HSCL-10 scores. Reported symptom-defined PTSD for nurses 7.1%; the leaders, 4.1%; and 2.3% of physicians. Conclusions: ICU health care professionals experienced talking with colleagues as the most helpful source of support. The COVID-ICU leaders reported a significantly higher mean score than physicians and nurses in terms of pushing themselves toward producing high work effort. In March 2020, The World Health Organization (WHO) declared that the 2019 coronavirus (with COVID-19) outbreak had reached the level of a pandemic, due to a rapid worldwide spread with a significant threat to health ,4. In NoA key question is to what extent this first wave will affect the psychological reactions, the disturbance of social life, work effort, and support in health care professionals (HCPs): ICU nurses, physicians and leaders.Worldwide, the health care system and HCPs in COVID-ICUs experienced a massive psychological burden, especially in Italy  and ChinManagers and head (leaders) of ICU-departments are, according to World Health Organization (WHO), facing similar forms of stress as the HCPs working bedside them. In addition, they may experience pressure relating to the responsibilities of their role . In a French study of critical care clinicians in 21 ICUs (n = 1058), six independent factors were associated with psychological reactions: fear of being infected; inability to rest; inability to care for family; struggling with difficult emotions; regret about the restrictions in visitation policies; and witnessing hasty end-of-life decisions . MoreoveAt work, HCPs could experience a lower level of work satisfaction, or the opposite if management appreciated the individual efforts in the care of COVID-19 patients . Kramer Social support is recognized as an important protective factor to reduce mental health problems ,26. In aEven though there are several studies on psychological distress among health care professionals, there is a lack of studies from Scandinavia and especially including leaders working in COVID-ICUs. What was the prevalence of probable clinical cases of anxiety, depression, and symptom-defined PTSD among COVID-ICU health care professionals, i.e., nurses, physicians, and leaders in Norway?What demographic characteristics were associated with the probable mental health disorder in COVID-ICU health care professionals?To what extent did COVID-ICU health care professionals in Norway suffer from disturbance of their social life during the first wave of the pandemic?How did COVID-ICU health care professionals in Norway self-assess their work effort, and what kind of support was received and perceived as useful?Our research aims were to survey symptoms of anxiety, depression, and PTSD in the sub-groups of nurses, physicians, and leaders in COVID-ICUs. Moreover, we aimed to survey satisfaction with the respondents’ own professional work effort, disturbance of social life, and support measures. This report represents part II of a national COVID-19 intensive care study focusing on both data on physical preparedness and working conditions , and psyhttps://www.uio.no/english/services/it/adm-services/nettskjema/about-nettskjema.html, accessed on 1 May 2020).This observational cross-sectional study investigated self-reported psychosocial reactions and support measures in a nationwide cohort of ICU health care personnel in Norway during the first wave of the COVID-19 pandemic in 2020. Respondents were defined as frontline HCPs actually caring for COVID-19 patients in centralized 28 hospitals, satisfying the criterion of having a COVID-ICU. Nurses, physicians, and their leaders in 28 were invited to participate when their local leader redistributed the invitation including general information about the study with a direct link available for voluntary participation from 6 May to 14 July 2020. The HCPs could voluntarily follow a direct link for electronic signature to the informed consent, and could continue to respond the study questionnaire. The survey was administered online through the University Information Technology Center (USIT) at University of Oslo (The baseline study questionnaire was a composite package of 181 questions divided into eight parts. A previously published paper presents the ICU-HCPs’ preparedness and working conditions . For theThe Hopkins Symptom Checklist-10 (HSCL-10) measures 10 items of anxiety- and depression-related symptoms on a four-point Likert scale (1 = Not bothered to 4 = Very much bothered) . Four itThe PTSD checklist for DSM-5 (PCL-5) is a 20-item self-report measure that examines symptoms of PTSD using 5-point Likert scale  ‘during the last month’ ,32. In tCurrent symptoms of anxiety and/or depression and probable symptom-defined PTSD were assessed with two international recognized checklists, previously translated, and validated into Norwegian ,11:The HThe assessment of individual work effort, support measures from the employer, professional satisfaction and proficiency during work, recognition and support during the pandemic, and appreciation of effort from hospital, family or friends and the responsible authorities were scored using a 5-point Likert scales . In the present study, the Cronbach’s alpha of work effortwas 0.42 and for recognition and support 0.49. Then, a multiple-choice question regarding support from the employer during the COVID-19 effort gave the possibility to choose one or more of these options: no special support, group meetings ; professional support by a dedicated person ; follow-up by leader after completed shifts. There were also options of “support offered but declined” and “not applicable”.Three questions focused on more personal areas: (1) disturbance on the respondent’s social life, fear of infecting family, colleagues, or patients; (2) social contacts outside working hours, use of social media  and phone calls to colleagues. Both questions one and two were assessed with Yes/No or N/A (“not applicable”); 3) social contact in terms of meeting people outdoors or indoors at distance wearing a mask, or alternatively in violation with these recommendations from the Norwegian Institute of Public Health (NIPH) [ social cAge, sex, marital status, name of the hospital, occupation  and length of work experience were assessed . One quep = 0.05). Analysis with the Kruskal–Wallis test was used to compare groups where we had skewed data. For the test of correlation coefficients, Spearman’s rho  was used for categorical variables. Quantile regression analyses for skewed original scores in dependent variables were performed [The data are presented as the mean, standard deviation (SD), range (min–max) or 95% confidence interval (CI), or a percentage, as appropriate. The significance level is set at 5%  and the Data protection officer at Oslo University Hospital (20/09438). Moreover, at each hospital and each COVID-ICU in Norway, approvals for the study were obtained from the Data Protection Officer, the Head of Research and the leaders. Online signed informed consent, and data from the study questionnaire were stored on a secured server. Results from the study were processed without names or other recognizable information. A code connects the informants’ information to a code list. A link key (name and study ID) is stored separately on a secured server at Services for Sensitive Data at the University of Oslo. The respondents had the possibility of contacting the project manager for answers to any questions or for support of any kind. The study was registered in Clinicaltrials.gov, NCT04372056.In total, 484 health care professionals, working in COVID-ICUs at 27 hospitals throughout Norway completed the survey . One ICUAnxiety symptoms, measured with the HSCL-10 during the COVID-ICU work, were present in 10.7% of RNs, 11.6% of physicians, and 4.1% of leaders, whereas the corresponding incidence of depression were 13.0% (RNs), 9.3% (physicians), and 4.1% (leaders). When symptoms of anxiety and depression, i.e., mental health disorder were merged, the incidence was 12.5% in RNs, 11.6% in physicians, and 4.1% in leaders .p = 0.017), and limited previous work experiences  were the only significant factors associated with high HSCL-10 scores.A quantile regression analysis  indicatep < 0.001) (p < 0.001) (Spearman’s rho) was found between respondents with high scores in both the HSCL-10 and the PCL-5 checklists.RNs had a significantly higher prevalence of symptom-defined PTSD (7.1%) versus leaders (4.1%) and physicians (2.3%), (< 0.001) . The quaMore than half of all the responding health care professionals  reported fear of infecting others, especially family members in their own household. Moreover, many reported a fear of infecting other family members , colleagues , or patients , but also friends . Fifty-three percent (n = 257) felt socially isolated, whereas one out of three (n = 150) felt lonely during the first wave of the pandemic. Three out of four (n = 363) reported increased contact via social media, telephone, or at work. Outside working hours, social contact was challenged, but partly compensated by frequent use of social media  , video chats with family and friends , and phone calls to colleagues . Social contact was also maintained by meeting people outdoors , or indoors with a mask, and physical distance . Only 32 HCPs (6.6%) reported having social contact indoors in violation with the recommendations from the Norwegian Institute of Public Health. The work efforts for RNs, physicians, leaders, and subsequent professional satisfaction and proficiency are summarized in p < 0.001) and physicians. The variable overextending, i.e., in a large effort, was expected from the team, managers or colleagues results showed significant differences between groups physicians (0.012) to RNs, versus leaders (p < 0.001).Three out of four  HCPs were expressed in recognition of the work effort , and through recognition and in addition support from family or friends . MoreoveSupport at work: almost all respondents (93.6%) perceived talking with colleagues as the most supportive measure in the COVID-ICU setting and outside of work hours. Receipt of organized support measures was reported by 39.5% (n = 191), while 37% (n = 177) did not receive any such support measures during the pandemic. Support in group meetings  was reported by 30.4% (n = 147) and professional support  by 28.9% (n = 140). Support phone calls from the Department of Human Resources were reported by 5.4% (n = 26) and follow-ups from a manager after a completed shift by 4.8% (n = 23). In addition, 8% (n = 39) were offered supportive talks but declined to participate.The personal economy was improved for 30.8% (n = 149), unchanged in 66.5% (n = 332), and worsened in 2.7% (n = 13) during the pandemic.Alcohol consumptions were reported by the majority, “as usual” , whereas 25.2% (n = 122) reported “less” use, and 10% (n = 48) “more” use. For those reporting “more than usual”, the purpose of use was “calming”, “as a mood enhancer”, or “to sleep”. Very few of the respondents reported daily use of psychoactive drugs, such as sleep medications  or tranquilizers . Sporadic use was reported for sleep medications , antidepressants , and anxiolytic medications .A majority  were determined to continue in their present job, while one out of four (26%) had considered quitting their job during the first wave of the pandemic as illustrated in The main results of this prospective, observational cross-sectional study are that HCPs as both clinicians (nurses and physicians) and leaders in Norwegian COVID-ICUs were experiencing low symptom levels of anxiety, depression, and PTSD during the first wave of the pandemic (May–July 2020). In quantile regression analysis, younger age, and limited work experiences (<5 years) significantly increased the symptoms of anxiety and depression. The leaders reported that they extended their limits of work effort to a higher degree relative to physicians and nurses. HCPs perceived their individual work effort as satisfying, successful, and meaningful, which may have protected them against stress reactions . The phyHCPs working in critical care settings across the world during COVID-19 report different symptom levels of psychological reactions ,23,38, wInterestingly, in a general Dutch population study during the first four months of the pandemic, no increase in the prevalence of anxiety and depression symptoms was found, but emotional loneliness increased significantly . The preHealth fears were significantly associated with worse mental health outcomes in HCPs during the outbreak as concluded in a review . In the Similarly, to the levels of anxiety and depression symptoms, we found low levels of symptom-defined PTSD, and nurses with the highest prevalence rate (7.1%), which may have triggered psychological reactions due to feeling overwhelmed and/or perceiving fear of being infected or infecting their family. This may be related to the high level of education and professional experience , but intNurses, physicians, and leaders in our study perceived their individual work effort as satisfying, successful, and meaningful, and this attitude may have protected them against stress reactions . Kramer In the present study, the COVID-ICU leaders were significantly more satisfied professionally with their own professional work effort and had a significantly higher mean score compared to physicians and RNs in terms of extending themselves to high work effort. This controversy was unexpected but may have to do with the personal characteristics and preferences of those who choose to become leaders. However, caring for psychosocial well-being in pandemic situations is recommended for both the hospital clinical staff, the general population, and the leaders to prevent distress over time ,29. Disturbance of social life was experienced during work in cohorts (large areas of many patients) without breaks for a long period of time, but also in private life. We found that 53% (n = 257) felt socially isolated. HCPs in the present study reported suffering from social isolation and reduced possibilities to have social contacts indoors (7%) but reported increased contact via social media (75%). The Norwegians have smartphones and are used to social media. Similar findings from social isolation and fewer contacts are described in literature reviews worldwide ,49.During the first wave, the private life resulted in sleep problems and in New York reported 26% on disturbance of sleep (severe or very severe) and an additional 45% reported moderate sleep problems . Some peIn the present study, only 5% of the respondents reported follow-up briefings with their leaders after a shift in the ICU. The physicians had perceived sufficient advice and support to a higher degree relative to the other groups, in addition to perceiving the work as meaningful. Another helpful form of support was talking with HCP colleagues at work or of duty, as many of our respondents preferred. In another study, nurse leaders were described as “anchors” in facilitating frontline nurses’ psychological adaptation . In a CoThe strength of the present study is the nationwide survey including 27 of the 28 COVID-ICUs in Norway. Another strength is that it includes HCPs from three sub-groups working in the ICU-context. Two internationally recognized and validated checklists, HCL-10 and PCL-5 were part of the questionnaire, and some of the items in the questionnaire were developed by the research group using a modified Delphi method. We also consider the pilot study (n = 5) of the questionnaire package for face validity, reliability, and feasibility as a strength, leading to a minor revision before implementation of the main study. A limitation, due to performing a sample calculation ahead of the study, is the lack of a completely national registry of employed HCPs in ICUs. At the present time, the Norwegian directorate of health has initiated a national mapping. On a national level, 96% (27 of 28) of the hospitals with COVID-ICUs participated. The sample size and result will not be representative for all ICUs in the country, and there may be a risk for selection bias, since the head of each hospital ICU decided to whom the invitations would be forwarded. Another limitation of the study is that it includes relatively few physicians. Despite the above limitations, our findings from the first wave are of international interest, and the work will continue with analyses in the longitudinal project. The ICU health care professionals in Norway providing care for COVID-19 patients during the first wave of the pandemic generally had a low level of anxiety, depression, and symptom-defined PTSD. More symptoms were found in the youngest HCP with a few years of work experience. The HCPs experienced isolation in their social life due to the lockdown, in addition to fear of infecting others. Support from colleagues was perceived as the most helpful psychosocial support. The leaders reported a higher mean score than physicians and RNs regarding the experience of extending themselves to a high work effort, which they felt was expected at work in ICUs, from managers and colleagues.


The use of erythrocyte sedimentation rate (ESR) in coronavirus disease 2019 (COVID-19) to determine disease severity and prognosis is limited. This study aimed to interrogate the diagnostic and prognostic role of ESR compared to other acute-phase reactants.  This retrospective cross-sectional study included 493 confirmed and hospitalized adult COVID-19 patients. Pneumonia, radiological severity, oxygen, intensive care requirements, mortality, ESR, and other acute-phase reactant values were recorded. Logistic regression and ROC analysis identified the effect of ESR on mortality and the sensitivity and specificity of the optimal cutoff values of ESR for the prediction of pneumonia, intensive care needs, and mortality and compared these with values for CRP. p < 0.001), requiring oxygen (p < 0.001), and requiring intensive care (p=0.003) compared to those without these, and in exitus patients (p=0.043) compared to survivors. Logistic regression analysis identified that ESR did not impact mortality. ROC analysis found the AUC, cutoff, sensitivity, and specificity results of ESR for pneumonia were 0.827, 37 mm/h, 77%, and 78%; for intensive care were 0.625, 50 mm/h, 74%, and 52; and for mortality were 0.606, 51 mm/h, 71%, and 49%, respectively. However, ROC analysis values for CRP were superior to ESR for all these categories.  Of patients, 346 (70.2%) had pneumonia, 98 (19.9%) required intensive care, 183 (37.1%) required oxygen support, and 62 (12.6%) died. ESR data were obtained for 278 patients. Among patients, 80.2% had ESR above 20 mm/h, with a median value of 53 (interquartile range: 49). ESR was higher among those with pneumonia ( ESR increased in COVID-19 patients in the presence of pneumonia and severe disease; however, it was not prognostic. Sensitivity and specificity values for pneumonia, intensive care requirements, and mortality were lower than those for CRP. Due to coronavirus disease 2019 (COVID-19), a process deeply affecting the whole world in terms of individual and public health and social and economic aspects has lasted nearly two years, and it was declared a pandemic by the World Health Organization. More than 250 million people have been infected, and more than 5 million have died , 4. AlthThe study included patients over 18 years admitted to the hospital with COVID-19 diagnosis confirmed with polymerase chain reaction (PCR) or with COVID-19 diagnosis using PCR after admission for other reasons from 15 March 2020 to 31 April 2021. PCR test was performed with real-time reverse transcriptase . Patient age, sex, ward of admission , presence of pneumonia, oxygen requirements, pulmonary imaging, laboratory findings, and outcome (discharge or exitus) were retrospectively determined from the hospital information system and the national health data records system.Pneumonia diagnosis was decided with pulmonary radiography and computed tomography (CT) for those with the radiological investigation and clinical and biochemical findings for those without imaging. Patients with pneumonia identified on tomography had radiological severity rated from 1 to 5. Ratings were 1 for the involvement of less than 10% of pulmonary parenchyma, 2 for 10–30% involvement, 3 for 30–50% involvement, 4 for 50–75% involvement, and 5 for more than 75% involvement. This rating was made by a single clinician who was not a radiologist (infectious disease expert assigned to diagnosing and treating COVID-19 patients). The scoring did not note the nature of involvement (like ground glass and consolidation). Radiological scoring was performed before examining the patients' biochemical and clinical features. Additionally, severe pneumonia was assessed as having more than 50% involvement (rating 4 and 5), while mild pneumonia was assessed as less than 50% involvement .Sedimentation, CRP, procalcitonin, and ferritin maximum values and definite lymphocyte count minimum values were recorded from laboratory data.t-test, while the comparison of two independent groups without normal distribution was made by the nonparametric Mann–Whitney U test. The comparison of more than two groups was made by the Kruskal–Wallis test, and the comparison of dependent groups was made by the nonparametric Wilcoxon test. The level of significance was defined as p < 0.05. Univariate logistic regression analysis was performed to identify independent variables affecting the dependent variable of mortality, and multivariate binary logistic regression analysis was performed to identify variables significant in this analysis. The Spearman correlation test was performed for correlation analysis of groups not abiding by the normal distribution. Cutoff values, sensitivity, and specificity values for CRP and sedimentation parameters were calculated with receiver operating characteristic curve (ROC) analysis.The Statistical Package for Social Sciences (IBM SPSS for Mac 26.0) program version 26 and Jamovi software version 2.2.3 were used for the statistical analysis. The chi-square analysis was used to compare categorical variables, and the normality test for quantitative variables was performed with the Shapiro–Wilk test. A comparison of two independent groups with normal distribution was made by Student's The study was approved by Ordu University Clinical Research Ethics Committee and conducted according to the principles of the Helsinki Declaration.The study included 493 patients. The median age of patients was 58 years (range 18–100), with 247 women included in the study (50.1%). Of patients, 346 (70.2%) had pneumonia diagnosis. Ninety-eight patients (19.9%) required intensive care, and 183 (37.1%) required oxygen support. All patients with pneumonia diagnosis had tomography. Of the 147 patients without pneumonia, 107 had tomography taken. Among the 40 patients without CT, 10 had pulmonary radiographs and 30 had no pulmonary imaging.p < 0.001). 5 patients died without pneumonia; 4 had advanced malignancy, while 1 was an immobile patient with an advanced neurological disease who died due to gastrointestinal hemorrhage.Of the patients, 62 (12.6%) died. The distribution of exitus patients is shown in The comparison of laboratory data for patients according to outcome is given in Among patients, only 278 had sedimentation data. These 278 patients had a median ESR of 55.5 ± 33.2, with a median value of 53 : 49). When the normal upper limit is accepted as 20 mm/h, 223 patients (80.2%) had high ESR values. Among those with ESR data, 23 of 47 patients without pneumonia (48.9%) had ESR above 20 mm/h, with a mean ESR of 25.1 ± 21.1 and median value of 20 mm/h . Of the 231 patients with pneumonia, 200 (86.6%) had ESR above normal.p < 0.001, Spearman correlation coefficient: 0.224). ESR values were significantly higher for those with pneumonia, severe pneumonia, oxygen requirements, and intensive care needs compared to patients without these and among exitus patients compared to surviving patients. The group with cancer and rheumatological diseases that may affect ESR did not have significant differences compared to the group without these factors. The comparison of ESR values in various groups is given in There was a positive, significant, low correlation between ESR value and age (p < 0.001). Among the 64 patients with ESR examined more than once, 12 entered intensive care and only one died. There was a significant difference between the maximum ESR values for patients requiring and not requiring intensive care, with no difference identified between final ESR values .Of the 278 patients with ESR examined, 64 had more than one result. Of these, 35 had the ESR test twice and 29 had it three times. For all patients tested twice, the final test was lower than the first, while for all patients tested three times, the final ESR value was lower than the maximum value. The final ESR median value was 44 (IQR: 38), while the maximum ESR median value for the same patients was 77 (IQR: 41)  which were significant in univariate logistic regression analysis to identify factors affecting the outcome  underwent multivariate logistic regression analysis. Sex and oxygen requirements were not significant in univariate analysis and not included in the model for multivariate analysis. Intensive care needs, low lymphocyte count, and high ferritin had significant correlations with mortality; however, age, pneumonia, CT severity, CRP, and sedimentation were not significant .As a result of the ROC analysis, it was seen that the predictive value of ESR was the highest in the presence of pneumonia. However, lower AUC values than CRP were found in this subject and other subjects, such as the need for intensive care and death. Cutoff, AUC, sensitivity, and specificity values of ESR and CRP are shown infigures 1p < 0.001). Multivariate binary logistic regression analysis found that lymphocyte count, ferritin level, and intensive care needs were significant parameters predicting death, while CRP, ESR, age over 60 years, and severe involvement in CT were not significant.In our study, ESR was significantly higher in patients with COVID-19 having pneumonia, oxygen requirements, and intensive care needs than in those without. There was no significant difference identified between the sexes. The mean ESR values of exitus patients and those with widespread pneumonia involvement (>50%) on CT were higher than survivors and those with milder involvement, respectively. Among the other parameters for exitus and surviving patients, mean CRP, procalcitonin, ferritin, and lymphocyte counts were higher than ESR with a significant degree of difference . However, even for this topic, CRP was identified to be more beneficial. In terms of mortality and intensive care requirements, ESR achieved a low AUC value, and CRP predicted higher sensitivity and specificity in these situations.p < 0.001). In this study, ESR was identified to be an independent factor in predicting severe disease and death, with the cutoff value of 52.5 mm/h having sensitivity and specificity of 65.5% and 76.3% for severe disease and the cutoff value of 56.5 mm/h having sensitivity and specificity of 66.7% and 72.5% for mortality [Despite several studies assessing acute-phase responses in COVID-19 disease since the start of the pandemic, including ESR data, the number of studies investigating ESR in depth is very few. Our study investigated ESR values in different stages and radiological severity levels of the disease and revealed new findings in comparing diagnostic benefits with other acute-phase reactants. In daily practice, parameters like CRP, which is more dynamic with a shorter half-life, ferritin, fibrinogen, procalcitonin, and d-dimer, are more commonly used , 6. Howeortality .In China, a meta-analysis of 28 studies by Zhang et al., including 4663 cases, identified ESR increases in 61.2% of cases (95% CI 41.3–81.0%). In this study, CRP, LDH elevation, and lymphopenia were compared in groups with and without severe disease and found to comprise risk for severe disease. However, sedimentation was not investigated between the groups . A revieA simple, cheap, and rapid laboratory test has been commonly used for nearly one hundred years to identify the sedimentation rate of erythrocytes, and the discovery of ESR dates back to 1897 . It is bp > 0.01), and a score of 38 was identified to predict severe disease [p < 0.001).Apart from hematological and biochemical parameters, radiological methods are used to determine the disease severity of COVID-19. As the severity of the disease increased, along with the disruption of laboratory values, there was an increase in radiological involvement scores. CT is accepted as the most effective method to identify pulmonary abnormalities. Various radiological weighted scoring systems are used for CT assessment, and these were found to have sensitivity from 80 to 83 and specificity from 82 to 100 for the detection of disease severity . Another disease . In our This study has several significant limitations. Being a retrospective study prevented the study's prospective design and planning for laboratory parameters in this way.Additionally, different pandemic clinics in our hospital were managed by different branches and specializations , which caused differences in the use of laboratory tests. For this reason, it appears that the differences in individual approaches of some specialist branches and clinicians caused data loss, especially about ESR. ESR tests were from the periods when patients were monitored in the ward and were admitted to primary intensive care. The tertiary intensive care clinical follow-up protocol does not include ESR, so data come from the period when patients were monitored on the ward. This situation prevented serial ESR monitoring of many patients and detecting values from the most severe period of the patient's clinical progression.Additionally, the frequency of requesting acute-phase reactants was variable according to the clinical severity of the patient and the doctor. These prevented the chronology for ESR and other acute-phase reactants from being simultaneous. The most pathological values obtained during the duration of follow-up for the patients were assessed. ESR data were obtained in the first 15-day monitoring duration according to most patients' admission and hospitalization duration. The days when disease symptoms were noted and microbiological diagnoses were received are unclear. As ESR is a test with low specificity affected by many physiological and pathological situations, it is necessary to be careful when interpreting data. When anemia, comorbid inflammatory, and other chronic diseases that may affect ESR are commonly seen at advanced ages, COVID-19 is more severe and deadly, which may overestimate the ESR and COVID-19 relationship. Despite all these limitations, it is considered that the degree of benefit of ESR compared to other acute-phase reactants, especially CRP, was revealed to determine the severity and progression of the disease. However, there is a need to identify laboratory parameters with more specific and prognostic features that can be used to determine the severity of COVID-19.In conclusion, increases in acute-phase reactants, disruptions in hematological and coagulation parameters, and nonspecific tissue injury markers are observed in COVID-19. The disruptions in laboratory parameters are more pronounced in severe patients. Along with radiological methods, mostly CRP, ferritin, procalcitonin, d-dimer, fibrinogen, interleukin-6 levels, leukocyte, lymphocyte, and platelet counts are used for the detection of disease severity and follow-up. Many publications report that ESR increases in COVID-19 and the changes are more pronounced with other laboratory values in severe diseases. However, the extra contribution in addition to other parameters was not questioned. In our study, although ESR was shown to be significantly increased in groups with COVID-19 pneumonia, severe pneumonia, and intensive care requirements and who died, it was not prognostic and had less benefit for diagnosis and follow-up than CRP. It will be beneficial to follow up along with other parameters in selected nongeriatric COVID-19 patients without comorbid disease; however, it was concluded that it does not provide additional contributions in routine use.


Anemia in the postpartum period remains a considerable public health problem in developing countries, particularly in sub-Saharan Africa. It is the most common indirect cause of maternal morbidity and mortality. It is also a major health problem in women of reproductive age, affecting their quality of life, occupational capacity, lactation, and immunological function. Immediate postpartum anemia has a significant impact on women's quality of life, although its predictors have received little attention in Ethiopia, notably in Harari Regional State. Therefore, this study aimed to determine its magnitude and contributing factors in Eastern Ethiopia.st to August 30th, 2021, among 484 postpartum women admitted to two public hospitals in Harari Regional State, Eastern Ethiopia. Data were collected using a pre-tested, structured interviewer-administered questionnaire. About 2 mL of blood samples were collected and analyzed using the cell-Dyne 1,800 machine. The collected data were entered into Epi-Data version 4.6 and analyzed using SPSS version 25. A multivariable logistic regression analysis was conducted to estimate the effect of independent variables on immediate postpartum anemia. An adjusted odds ratio (AOR) with a 95% confidence interval (CI) was computed to report the presence of the association. Statistical significance was declared at a p-value of < 0.05.A facility-based cross-sectional study was conducted from June 1The overall magnitude of immediate postpartum anemia was 28.1% [95% CI ]. Lack of formal education , having antenatal care < 4 visits , a history of cesarean delivery , a history of maternal blood loss , pre-delivery Hgb level < 11 g/dl , and having no iron-folate supplementation  were factors statistically associated with immediate postpartum anemia.In this study, nearly one-third of mothers admitted for postpartum care developed anemia within 48 h of giving birth. Women's educational level, frequency of antenatal care, mode of delivery, a history of maternal blood loss, pre-delivery hemoglobin level, and iron-folate supplementation status were identified as immediate postpartum anemia risk factors. Therefore, promoting the benefits of adequate antenatal care and iron-folate supplementation during pregnancy is crucial to avoiding the risks of postpartum anemia. Anemia is a condition characterized by a reduction in the number and/or size of red blood cells below cut-off values, thereby impairing the blood's ability to transport oxygen to meet physiologic needs . Even thAlthough hopeful progress has been made in lowering maternal mortality in many countries, there is still evidence of a continuous increment in the rate of indirect causes of maternal mortality . GloballIn 2019, anemia caused 1.74 billion cases and 58.6 million years of disability worldwide . More spFurthermore, researchers have shown that postpartum anemia (PPA) has been found to be one of the most common causes of morbidity in the early postpartum period. In addition, it is also a major health problem in women of reproductive age, affecting their quality of life, occupational capacity, lactation, and immunological function , 14, 15.Studies have revealed that socio-demographic factors, obstetric-related factors, and nutritional and maternal health status are associated with PPA. For instance, various research reports have found that the age of the mother , 20, areIn Ethiopia, although few studies have been conducted in the last decade, almost all previous studies focused on assessing lactating women after they were discharged from the facility –31, whicst to August 30th, 2021, in two public hospitals in Harari Regional State, Eastern Ethiopia. The Harari region is one of the 11 regions in Ethiopia, which are found in Eastern Ethiopia. Harar is the capital city of the Harari Regional State, located 526 km east of the capital city, Addis Ababa. According to the Ethiopian census projection for 2019/2020, the region has an estimated population of 263,656, including 60,667 reproductive-age women  and Jugal Regional Hospital (JRH). HFCSH is the tertiary health care level , and Jugal Regional Hospital (JRH) is the only regional hospital in Harari Regional State. Both hospitals currently provide comprehensive care for more than five million people in their catchment area. Hiwot Fana Comprehensive Specialized Hospital (HFCSH) and Jugal Regional Hospital (JRH) have 60 and 23 beds in the maternity ward, respectively. According to Health Management and Information System (HMIS), the estimated annual maternal delivery services of HFCSH was 4,680 , and JRHIn this study, all postpartum women admitted to the maternity wards of two public hospitals (HFCSH and JRH) were enrolled within the first 48 h of delivery. However, women who delivered by cesarean hysterectomy or laparotomy after uterine rupture and multiple pregnancies were excluded to reduce the overestimation of immediate postpartum anemia. Moreover, all postpartum women with the following preconditions  were excluded from the study.p = 24.2%) taken from a study conducted at Mekele, Ethiopia (α/2 = 1.96), and 10% contingency for non-response rate. The final sample size for this study was 484.In this study, the sample size was calculated by using statistical software Epi-info version 7.2.4.0  by considering the following assumptions: A proportion of immediate postpartum anemia  was proportionally allocated to 292 and 192 women from HFCSH and GRH, respectively. We also calculated the Kth interval for both hospitals (Kth = 1314/484 ≈ 3). Therefore, every third eligible postpartum woman was selected and interviewed until the required samples were obtained  report (6-month report), 2,380 and 1,560 women were admitted to the maternity wards of HFCSH and JGH, respectively, for postnatal care services, including those who gave birth at home or other health facilities. The data collection period was adjusted for 2 months to get the required sample size. Therefore, the total number of the 6-month report was divided into three to get 2 months' report. Thus, the total number of 2-month postpartum women at both hospitals became 1,314. Proportionally, we allocated 794 and 520 women to HFCSH and JRH, respectively. Then, the total sample size , which was recommended by food and nutrition technical assistance (FANTA) to stratify individuals as food secure or food insecure . It is vA combination of data collection methods was used. The data from mothers were collected using a pre-tested structured and face-to-face interviewer-administered questionnaire with reviews of maternal charts for clarity of diagnosis and intervention. The data collection tool for maternal  was prepInitially, all medical records/charts of mothers were screened for the presence of any diagnosed medical and/or obstetrical complications, pre-delivery Hgb level, newborn weight, and other clinical characteristics. The laboratory technician collected approximately 2 mL of blood from each study participant, especially after 8 h of delivery. Hgb concentration was determined using the automated blood analyzer Cell-Dyne1800  by the laboratory technician. Hemoglobin levels were collected and attached to the participants' folders before they were discharged from the hospitals. Finally, anemic mothers were managed based on their Hgb levels according to national guidelines with IFA or blood transfusion and counseled on iron-rich diet intake after being informed by the focal person of the unit (ward).An outcome variable was immediate postpartum anemia. If a woman's Hgb level was <10 g/dl, it was considered to be anemic (yes), and if the Hgb level was 10 g/dl or above, it was considered non-anemic (no) . We recoIn this study, the explanatory variables include socio-demographic-related characteristics , obstetrics or reproductive-related factors , and nutritional related factors .food insecurity is a lack of consistent access to a sufficient amount of healthy, nutritious, and culturally appropriate food for every person in a household due to a lack of money and other resources to live an active, healthy life. It is measured by the Household Food Insecurity Access Scale (HFIAS) based on nine occurrence questions developed by NATA and validated in Ethiopia  , 42, andEthiopia . It is cStructured and pre-tested tools were used. The final version of the questionnaire for maternal information was translated from the English language into the local language by experts. The training was given to data collectors and supervisors. A pre-test was conducted on 5% of the sample size at another public hospital  with simp-value < 0.25 were considered for the multivariable analysis model to control for potential confounders. During multivariable analysis, the model fitness was checked by the Hosmer-Lemeshow model fitness test, and the result was insignificant (p = 0.828). Moreover, multi-collinearity was also checked using the variance inflation factor  and standard error < 2. Finally, an adjusted odds ratio (AOR) with a 95% CI was used to indicate the relationship between the independent variables and the immediate postpartum anemia. The statistical significance was declared at a p-value less than 0.05.The collected data were coded, cleaned, and entered into Epi-Data version 4.6 and then exported to SPSS version 25  for further analysis. Descriptive statistics were carried out using frequency tables, proportions, and summary measures. Bivariable and multivariable logistic regression analyses with a 95% Confidence Interval (CI) were used to identify factors independently associated with immediate PPA. From the bi-variable analysis, variables with a significant level of The study protocol was approved by the Institutional Health Research Ethics Review Committee (IHRERC) of the College of Health and Medical Sciences, Haramaya University (IHRERC/091/2021). All participants were informed about the procedure and purpose of the study, and informed, written, and signed voluntary consent was obtained before participation. Additionally, informed, written, and signed voluntary assent was taken from the parent, husband, or guardian using normal disclosure processes for participants less than 18 years of age. Other additional data needed were extracted from medical records; confidential information about the identity of individual patients was not collected. The standard safety measures for the prevention and transmission control measures of COVID-19 were strictly followed and carried out during the data collection period as per the WHO 2021 standard.SD± 5.24) years. Nearly one-third of the study participants, 134 (28.1%), had no formal education. Slightly more than half (51.8%) of the participants' income was less than 2,500 ETB, with a median income of 2,500 ETB and IQ ± 2500 ETB , were multiparous, and 126 (65.8%) had short inter-pregnancy intervals (<2 years). More than half (56.7%) of the participants had <4 ANC visits, and about one-eighth (11.9%) of the participants had a history of maternal blood loss in recent pregnancy .Among all study participants, 132 (27.7%) had clinical or diagnostic tests that confirmed medical and/or obstetric complications during recent pregnancy. Pregnancy-induced hypertension was the most reported condition (14.8%), whereas a history of malaria was the most minor medical disease reported in this study (0.6%) .In this study, nearly three-fourths (73.8%) of the study participants started iron-folate during the most recent pregnancy, and more than half (57.4%) of them had poor adherence to iron-folate. The majority, 397 (83.2%), of the study participants' mid-upper arm circumference was 23 cm or above .The overall magnitude of immediate postpartum anemia was 28.1% [95% CI (23.7–32.1%)]. The postpartum hemoglobin concentration of the participants ranged from 3 g/dl to 14.8 g/dl, with median values of ± 10.5 g/dl .In bivariable analysis, mothers' age, place of residence, educational level, maternal parity, inter-pregnancy interval, frequency of ANC follow-up, mode of delivery, gestational age at delivery, a history of maternal blood loss, pre-delivery Hgb level, iron-folate supplementation, and MUAC level of the mothers were independently associated with immediate postpartum anemia among postpartum mothers. However, in the final model of multivariable logistic regression analysis, the educational level of the mother, frequency of ANC follow-up, mode of delivery, a history of maternal blood loss, pre-delivery Hgb level, and IFA supplementation during recent pregnancy were factors that remained statistically associated with immediate postpartum anemia.Accordingly, the likelihood of immediate PPA was four times higher among women with no formal education than among those with at least secondary education or above . Likewise, women who had fewer than four ANC visits were three times more likely to be anemic than those who had at least ≥ 4 ANC visits during their current pregnancy . Similarly, the odds of immediate PPA were three times higher among women who gave birth through cesarean section (C/S) than among those who delivered vaginally . Moreover, the likelihood of immediate PPA was nearly five times higher among women with a history of blood loss than their counterparts . Likewise, women with a pre-delivery Hgb level of <11 g/dl were 5.5 times more likely to be anemic than those whose Hgb levels were ≥ 11 gm/dl . Furthermore, women with no history of iron-folate supplementation during their current pregnancy were three times more likely  to be anemic than those with a history of iron-folate supplementation during their most recent pregnancy .In this study, the overall magnitude of immediate postpartum anemia was 28.1%, 95% CI: (23.7–32.1%), which is comparable with findings from similar studies reported in Mbarara, Uganda 30.0%) ; Coastal.0% ; CoaOn the contrary, the number of postpartum anemia reported in the current study is higher when compared to the previous studies conducted in different parts of the world, like in Germany (22%) ; MariakaIn the final model of the multivariable analysis, the educational status of the women was independently associated with immediate PPA. Accordingly, women without formal education had a significantly higher likelihood of developing anemia than women who had attended secondary and above-secondary education. This result is in agreement with a study conducted in Northern Ethiopia  and NairLikewise, the frequency of antenatal care visits was found to be an independent predictor of immediate PPA. Thus, women who had fewer than four ANC visits were more likely to develop immediate PPA when compared to those who had four or more ANC visits. This finding is in line with studies conducted in Debra Markos, Northern Ethiopia  and Jimmvia cesarean section compared with those who gave birth via SVD. This finding is congruent with previous studies investigated in developing countries such as Southern Ethiopia  of the College of Health and Medical Sciences, Haramaya University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Myelodysplastic syndromes (MDS) are heterogeneous groups of clonal myeloid disorders characterized by unexplained persistent peripheral blood (PB) cytopenia(s) of one or more of the hematopoietic lineages, or bone marrow (BM) morphologic dysplasia in hematopoietic cells, recurrent genetic abnormalities, and an increased risk of progression to acute myeloid leukemia (AML). In the past several years, diagnostic, prognostic, and therapeutic approaches have substantially improved with the development of Next Generation Sequencing (NGS) diagnostic testing and new medications. However, there is no single diagnostic parameter specific for MDS, and correlations with clinical information, and laboratory test findings are needed to reach the diagnosis. The secondary causes of PB cytopenia occur far more often than the primary BM neoplasms. Various nonclonal disorders affecting the BM, including viral , bacterial and parasitic infections, autoimmune disorders , nutritional deficiencies , medication exposures, drugs, toxins , chronic kidney and liver diseases, and endocrinopathies, need to essentially be ruled out first, before a diagnosis of MDS can be made [Cytopenia is a “sine qua non” for any MDS diagnosis; however, specific cytopenias have only a minor impact on the classification. Moreover, the lineage manifesting significant morphologic dysplasia frequently does not correlate with the specific cytopenia in individual MDS cases .9/L, and an absolute neutrophil count of <1.8 × 109/L [9/L), if unequivocal morphologic dysplasia and/or cytogenetic abnormalities are present [The recommended threshold of cytopenia as per the risk stratification guidelines, defined in the International Prognostic Scoring System (IPSS), include hemoglobin of <10 g/dL, a platelet count of <100 × 10 × 109/L ,5. Howev present . In addi present .The morphologic classification of MDS practically depends on several diagnostic approaches, which include the presence of an increased blast population in both the BM and PB, the evaluation of cytologic abnormalities and dysplastic changes among the hematopoietic elements, the evaluation of cellular topography and cellularity, and the presence or absence of fibrosis.Traditionally, the World Health Organization (WHO) defined the MDS categories depending on the blast percentage in the PB and BM, but a threshold of less than 20% is a mandatory cut-off. The presence of an increased blast population of 2–4% in PB or 5–9% in BM is categorized as MDS with excess blast 1 (MDS-EB-1), whereas the presence of a higher number of blasts, with 5–19% in PB or 10–19% in the BM, or the presence of unequivocal Auer rods by morphologic examination are categorized as MDS with excess blast 2 (MDS-EB-2) . HoweverMorphologic dysplasia may occur in one or more of the hematopoietic lineages. Erythroid dysplastic features occur in the form of megaloblastoid changes, multinuclearity in erythroid precursors, nuclear lobulation, the presence of pyknosis or chromatin condensation in the nuclei, cytoplasmic fraying involving 50% of the cellular membrane, internuclear bridging, cytoplasmic vacuolization, and the presence of ringed sideroblasts described as five or more granules encircling one third or more of the nucleus by iron stain A. On the+ events is optimal [Alterations in the hematopoietic stem cells were generally regarded as one of the disease-initiating events in MDS, either in primary de novo disease or secondary therapy-related causes, both of which ultimately result in disrupted hematopoiesis. Even though the morphology is considered to be one of the key features in the diagnosis, flow cytometry (FC) has also been considered to be an important tool for the diagnosis, prognostication, and monitoring of the disease course . The Int optimal ,13. The  optimal . There i optimal ,16. The + myeloid precursors among the entire viable nucleated cells (% of CD34+ myeloblasts); (3) percentage of CD34+ precursor B-cells (hematogones) among the entire CD34+ cells (% of CD34+ B-cells); and (4) CD45 antigenic expression of CD34+ myeloid progenitors as ratio to lymphocytes (lymphocyte/myeloblast CD45 ratio). The established reference values were identified, and deviations from the references are scored as one point with a maximum of four points. A score of ≥two points indicated MDS, and high scores of three or four are associated with a high probability of MDS, [A four-parametric scoring system (referred to as the Ogata score) is widely used as a simple FC criterion for MDS diagnosis, which contributes only a minimal inter-observer variability, and with a reported specificity of 93% and sensitivity of 70% ,18. The  of MDS, ,18. Howe of MDS, . + erythroid progenitor cells, have been reported to provide the best discriminating parameters between MDS and non-clonal cytopenias [Since dyserythropoiesis is a common feature of MDS, the integration of erythroid aberrancies in flow cytometric panels led to an increased sensitivity in detecting MDS. Aside from evaluating antigen expression aberrancies on immature myelo/monocytic cells in MDS, the analysis of immunophenotypic aberrancies of nucleated erythroids further aid in supporting the diagnosis of MDS . The ELNtopenias . It has topenias .Additionally, many of the investigations of the immunophenotypic alterations identified by MFC can lead to discoveries of newer targets for future drug development .Cytogenetics has been an important and a necessary parameter in the diagnosis of MDS. The WHO relies heavily on cytogenetic aberrations in MDS. In addition to establishing a clonal process in patients with peripheral blood cytopenia, cytogenetics plays a major role in the prognostication, clinical-morphologic correlation, theragnostic strategies, and in predicting the likelihood of progression to AML. In contrast to other myeloid malignancies, in which the diagnosis is defined by a single cytogenetic event (such as chronic myeloid leukemia and acute promyelocytic leukemia), there is a vast spectrum of cytogenetic-defining lesions in MDS, making diagnosis very challenging. Nevertheless, roughly 50% of MDS has normal cytogenetics. The cases with borderline dysplasia and normal cytogenetics present with diagnostic challenges. Various combinations of chromosomal lesions contribute to the large spectrum of clinicopathologic features of MDS. According to the WHO, MDS may still be diagnosed in a patient with unexplained cytopenia, when all of the other secondary causes of refractory cytopenia are essentially and exhaustibly ruled out, and as long as there are MDS-defining cytogenetic abnormalities identified (with some exceptions) .The results from cytogenetic studies, both by conventional karyotyping (G-banding) and fluorescence in situ hybridization (FISH) assays, serve as strong parameters included in the revised International Prognostic Scoring System (IPSS-R) score for MDS. As such, the IPSS-R has been proven to be beneficial for predicting the clinical outcomes for untreated MDS patients and aiding in the design of clinical trials for the disease . The comIn contrast to AML, balanced structural abnormalities, such as translocations and inversions, are relatively rare in MDS . In geneSequential cytogenetic analysis (both karyotyping and FISH) of follow-up samples has been established as identifying the possible clonal evolution of MDS clones leading to greater understanding of the heterogenous acquisition or loss of these genetic events in MDS . DemonstMonosomy 7 (-7) and deletions of the long arm of chromosome 7 (del(7q)) are found in several myeloid neoplasms, suggesting its crucial role in disease pathogenicity. They occur either in isolation or as part of a complex karyotype, and are generally associated with unfavorable prognosis in certain disease entities. In MDS, the isolated cytogenetic abnormality of del(7q) has been categorized in the intermediate prognostic subgroup, whereas isolated cytogenetic abnormality of -7 has been classified as belonging in the poor prognostic subgroup. Among the patients with del(7q), there was a tendency toward better survival compared with the patients with complete -7 as an isolated abnormality and as a noncomplex aberration. However, because the survival difference between these related cytogenetic lesions are not statistically significant, they are then regarded as a single cytogenetic category . The chrCUX1, EZH2, LUC7L2, MLL3, and SAMD9/9L [The deletion breakpoints in chromosome 7 are heterogeneous and the deletions are often interstitial. The majority of the cases had proximal breakpoints in 7(q11) or 7(q22). The commonly deleted regions on 7q identified in MDS are located at positions 7q22, 7q32-33, and 7q35-36 . MonosomSAMD9/9L . HoweverCUX1 is a conserved, haplo-insufficient tumor suppressor frequently deleted in myeloid neoplasms. It encodes a homeodomain-containing transcription factor, which is located in chromosome band 7q22.1. In the RNA-sequencing data, a CUX1-associated cell cycle transcriptional gene signature was identified, suggesting that CUX1 exerts tumor suppressor activity by regulating the proliferative genes [ve genes .EZH2 acts as a tumor suppressor for myeloid malignancies. It is located at chromosome 7q36, which encodes a member of the polycomb group family, that forms multimeric protein complexes which are involved in maintaining the transcriptional repressive state of genes. It encodes a histone methyltransferase which functions in the epigenetic silencing of the genes involved in stem cell renewal [EZH2 gene [ renewal . HoweverZH2 gene .The 5q- syndrome was first reported in 1974 . CurrentNPM1 or MAML1 and APC genes, have been related to a higher risk of MDS and an earlier risk of transformation to AML [The most common abnormality includes the interstitial deletion of the long arm of chromosome 5. Larger losses of the 5q arm, by deletion of the centromeric or telomeric regions or mutations involving the n to AML ,36. The n to AML . Howevern to AML .RPS14 allele, for example, can recapitulate the dyserythropoiesis seen in MDS del(5q). The loss of this protein has been shown to upregulate p53, primarily in erythroblasts, and therefore to promote apoptosis from these cells. The mutations of p53 are significantly associated with the loss of del(5q) and a complex karyotype, and this has not been associated with del(7q) [RPS14 are also found in about 25% of the patients with Diamond–Blackfan Syndrome, which leads to haploinsufficiency of RPS14 [HSP9, CTNNA1, and EGR1 [TRAF6, resulting in thrombocytosis, neutropenia, and megakaryocytic dysplasia [It was discovered that the haploinsufficiency of several genes located in this region are capable of generating the clinical phenotype in patients with MDS. The loss of one  del(7q) . Mutatioof RPS14 . The hapand EGR1 . On the and EGR1 . The losysplasia .Lenalidomide is a thalidomide analog, which shows a dramatic therapeutic effect in patients with low-risk MDS. Its response rate was significantly higher among those with interstitial deletion involving chromosome 5q . It can The deletion of the long arm of chromosome 20 (del(20q)) is a recurrently identified cytogenetic abnormality in myeloid neoplasms, including myeloproliferative neoplasms (MPN), MDS/MPN, MDS, and AML. However, unlike del(5q), del(20q) is not recognized by the WHO as a unique entity in MDS. Del(20q), as an isolated cytogenetic abnormality, can be seen in the bone marrow specimens of patients without morphologic diagnostic features of any of the myeloid neoplasms, and this may also be seen in patients with non-myeloid malignancies or unexplained cytopenias. Therefore, the WHO emphasizes that the presence of isolated del(20q) is not considered to be definitive clonal evidence of MDS in patients with unexplained cytopenia, in the absence of morphologic evidence of MDS . This maU2AF1, ASXL1, SF3B1, TP53, and SRSF2. In MDS, del(20q) may cause deletion of the ASXL1 gene, and ASXL1 alteration exerts a negative impact on MDS with del(5q). This has also been correlated with a lower platelet count and a poor response to azacytidine (AZA) [ASXL1 mutations are found in 11 to 21% of patients with MDS and are a predictor of poor OS [MDS with isolated del(20q) are categorized in the good cytogenetic prognostic subgroup by the IPSS-R. The breakpoints of del(20q) are heterogeneous. The most frequently mutated genes identified include ne (AZA) . The ASX poor OS ,46,47. T poor OS .The deletion of the Y chromosome (-Y) belongs to the very good prognostic subgroup in MDS, as categorized by the IPSS-R, but has also been attributed to an age-related phenomenon. It is noteworthy that, although it has been associated with better prognosis in MDS, the exact mechanism remains unknown. It was also known that the loss of X in women and the loss of Y in men increases with age . DeletioTrisomy 8 (+8) is the most common chromosomal gain in MDS, and is seen in about 11% of de novo MDS with an abnormal karyotype . It beloKMT2A gene (previously referred to as MLL or mixed lineage leukemia gene) is located at the 11q23 breakpoint. It was shown that del(11q) is heterogenous at the molecular level and may signify cryptic rearrangements involving chromosome 11 or the KMT2A gene. Unlike in AML with del(11q), which harbors the cryptic KMT2A rearrangements, it was reported that MDS with del(7q) lacks this cryptic rearrangement, and therefore may potentially explain the biological differences between AML and MDS with del(11q) [MDS with isolated del(11q) is associated with a very good prognosis (similar to -Y) characterized by the IPSS-R. It is a rare cytogenetic abnormality, which is reported to occur in 0.7% in de novo and secondary AML and MDS . The KMTdel(11q) .KMT2A gene is the CBL gene. Being a signal transduction gene, the mutations in the CBL gene constitute important pathogenic lesions associated with AML progression, due to the impaired degradation of the activated tyrosine kinase [Another gene located at chromosome 11q23 telomeric to the e kinase ,59.ETV6/TEL gene [ETV6 deletion is seen to be higher in AML than in MDS [Deletion in the short arm of chromosome 12 is a rare event in MDS, and occurs in 0.6 to 5% of the cases at diagnosis . This waTEL gene . Howevern in MDS .TET2 mutations, and the association was more pronounced when TET2 was the sole abnormality, with a frequency of 45% [NPM1 and biallelic CEBPA mutations [The deletions in the long arm of chromosome 9 are more commonly seen in AML than in MDS or MPN. The IPSS-R categorizes del(9q) in the intermediate risk subgroup with a median OS of 32 months. The myeloid neoplasms with del(9q) were identified as having a high prevalence of y of 45% . Recent utations .TP53) [TP53 mutations, due to its favorable response to hypomethylating agents (HMA), particularly decitabine [TP53 is the most commonly mutated gene in human cancer. It functions as a transcription factor for cell cycle arrest, DNA repair mechanisms, apoptosis induction, and cellular differentiation. In MDS, the TP53 mutation was significantly associated with del(5q) syndrome, with its diverse roles in cell cycle, DNA repair and apoptosis leading to chromosomal instability, and AML transformation [TP53 in the pathogenesis of MDS was also seen in the context of therapy-related MDS (t-MDS), as defined by the WHO’s classification in 2016, wherein an exposure to cytotoxic or radiation therapy for a previous unrelated malignancy or autoimmune disease was documented [The presence of a chromosome 17 abnormality in MDS has been correlated with poor prognostic features and very low OS, except for isochromosome 17q (i(17q)), which is associated with the intermediate risk prognostic subgroup by the IPSS-R. The association between a poor prognosis and a chromosome 17 abnormality in patients has also been found in the context of a complex karyotype. This was also correlated with the loss of 17.13.1, which contains the genetic loci of the tumor suppressor gene p53 (TP53) . The sigcitabine . TP53 isormation . The assKMT2A gene (previously known as the MLL gene) has been mapped in the 11q23 locus and this gene forms fusion transcripts with more than 70 translocation partner genes. The KMT2A gene translocation results in the formation of a chimeric protein in its amino-terminal and fused in the carboxy-terminal portion of the fusion partner gene [CBP gene encodes a transcriptional adaptor/coactivator protein in the 16p13 locus, and is involved in the regulation of the cell cycle [CBP to regulate the cell cycle by its structural alteration when fused with KMT2A [The balanced translocation of chromosome 11 and 16 occurs in approximately 3% of the therapy-related MDS cases [ner gene . On the ll cycle . It was EVI1 at 3q26.2.2 or the longer form MECOM and RPN1, resulting in ectopic and overexpression of EVI1, or MECOM or the RPN1/EVI1 fusion transcripts, with RPN1 acting as an enhancer of EVI1 expression [EVI1 has been associated with several signaling pathways, leading to cell growth, cell differentiation impairment, and cell survival [GATA2 was also implicated and was observed to be overexpressed in these cases, suggesting its role in the development of chromosome 3 rearrangements [MDS with inversion 3 (inv(3)) and balance translocation of chromosome 3 ) are observed in approximately 1% of the cases, and has been categorized in the poor prognostic subgroup . Myeloidpression ,74. EVI1survival . GATA2 wDEK/NUP214 in der(6). This cytogenetic event has been associated with a poor prognosis in myeloid neoplasms. This abnormality is predominantly occurring as a sole karyotypic aberration, but a subset has been associated with a complex karyotype [FLT3-ITD mutations in patients with t [The translocation of chromosome 6 and 9 ) is a rare occurrence in MDS, occurring in 1% of all of the MDS cases [aryotype . In AML,h t . It was h t .Over the past decade, the explosion of identified molecular signatures in MDS has been defined, with the development of high throughput sequencing studies. These major technological advances and breakthroughs in genetics unraveled the previously hidden mysteries of disease drivers that led to a drastic paradigm shift, not only in disease classification, but also in prognostication and therapeutic guidelines in myeloid malignancies. In the most recent WHO classification, clonal evidence in MDS mainly focuses on cytogenetic alterations; however, approximately 40 to 50% of MDS cases have normal cytogenetics, leaving diagnostic challenges for the diagnosing physician. This has been complicated by the discovery of clonal hematopoiesis of indeterminate potential (CHIP), wherein certain somatic pathogenic leukemia-associated variants are identified in healthy elderly individuals who have never had any evidence of cytopenia or cytologic dysplasia in the bone marrow or peripheral blood samples ,79,80. HAside from CHIP, other entities have been described as being potential pre-MDS conditions. A spectrum of clinico-pathological and molecular entities has been continuously reported in the literature and have been adapted in daily clinical practice. Idiopathic Cytopenia of Undetermined Significance (ICUS) is defined as the presence of persistent and unexplained peripheral cytopenia(s) in one or more lineage with no documented evidence of MDS-related mutations, while failing to demonstrate significant cellular dysplasia and marrow blast count of <5%. ICUS was also categorized into four subgroups, based on which particular cytopenic lineage is affected. Entities such as ICUS-A (anemia), ICUS-N (neutropenia), ICUS-T (thrombocytopenia), and ICUS-PAN (bi/pancytopenia) have been used. It was reported that ICUS-PAN may harbor a higher risk of transformation to an overt hematologic neoplasm, as compared to ICUS-A or ICUS-N . The diaDNMT3A, TET2 and ASXL1 genes (DTA genes), have largely been implicated with CHIP, especially with a variant allele frequency (VAF) of ≥2% [DTA mutations, other genes have also been implicated with CHIP mutations, such as RUNX1, IDH1/2, and JAK2, among others. On the contrary, certain spectrum of the mutations in AML have already been implicated to possibly arise from an underlying MDS clone, or after a leukemogenic therapy (t-AML), in particular, the presence of the splicing gene mutations , has been established to be more than 95% specific for the diagnosis of secondary AML (s-AML) [It has been demonstrated that approximately 10% of what are supposed to be healthy individuals aged 70–80 years carry one or more somatic variants indicating the presence of CHIP. The specific variants, particularly those in the ) of ≥2% ,79. In a (s-AML) .DNMT3A mutation is present in approximately 15% of MDS cases, and its presence is associated with a shorter OS in de novo MDS, as well as a higher tendency to evolve to sAML [TET2 is another recurrently mutated gene, identified especially during the early events of MDS pathobiology, and is reported to occur in about 20–30% of the cases [TET2 gene also provide significant therapeutic value. The response rate using HMAs, such as AZA and decitabine (DEC), were reported to be higher in the subset of MDS patients with TET2 mutations compared to the TET2 wildtype, especially when the major disease clone is identified [ASXL1 mutation is another epigenetic modifier which is identified in approximately 10–20% of MDS, with frameshift mutations and heterozygous point mutations being identified in about 70% and 30%, respectively, both of which are associated with adverse prognostic outcome and shorter OS [IDH1 and IDH2 are seen in 5–12% of MDS patients and are thought to also represent an early driver of disease progression [IDH variants suggests that it is less frequently involved in the ancestral myeloid neoplastic clone [IDH1/2 mutations in MDS are associated with lower absolute neutrophil count, higher bone marrow blast percentage, higher platelet counts, and with survival not significantly different when comparing IDH1 vs. IDH2 [IDH mutations is associated with an unfavorable prognosis in MDS [IDH1 (ivosidenib) and IDH2 (enasidenib) inhibitors for cytoreduction for patients with high-risk MDS, who have been refractory with HMA inhibitors [The growing interest in and understanding of the complex biology and genetic sequences of genes have substantially changed the diagnosis and treatment of MDS. Although there is no molecular signature that is entirely specific and sensitive for the diagnosis of MDS, and although several mutations seen in CHIP are also diagnostic for MDS, many of these gene mutations have significant predictive and prognostic values in MDS. The  to sAML ,46,86. The cases ,87. The entified . The ASXorter OS ,88,89. Igression ,91. The ic clone . It was vs. IDH2 . Howevers in MDS . Emerginhibitors .SF3B1 is the most frequently mutated gene reported in MDS, occurring in about 25–35% of patients [Aside from epigenetic modifying genes described above, splicing gene mutations are reported to occur in almost half of MDS cases and are strikingly common in those with normal cytogenetics (CN-MDS), and often represent early events in the pathogenesis ,58,95. Spatients ,87. It hpatients .BCOR, KMT2a, RUNX1, WT1, and CREBBP), signaling gene mutations , and repair mechanism pathways (such as TP53) have all been described [A spectrum of other molecular pathways has also been reported and have significant biological affects in clinical behavior and disease progression in MDS. Transcription factors  traditionally require 15% ring siderblasts from the entire erythroid precursors; however, in the presence of the SF3B1 mutation, the cutoff requirement goes down to only 5% [SF3B1 mutation in MDS is 0.97, either as an isolated mutation or in the presence of other co-mutations [At least one or two somatic mutations are identified in MDS  37,58,8,858,88.  only 5% . It was utations .TP53, EZH2, ETV6, RUNX1, ASXL1, and SRSF2, whereas the presence of SF3B1 has been implicated in better outcomes [SF3B1 (associated with a better outcome) and TP53 (associated with a worse outcome), there is no other defined variant that has been implicated in having an independent prognostic value. The presence of mutations in either SRSF2 and U2AF1, or the co-mutation of both, showed 100% specificity for myeloid neoplasm in the presence of myelodysplasia [The outcomes of MDS patients progressively worsen as the number of the acquired somatic mutations increases. A number of these somatic mutations have been implicated in predicting a lower OS in univariate analyses, in particular outcomes ,87. Asidysplasia .SF3B1) have not yet been concretely included by the WHO as evidence of clonality or for the prediction of outcome in MDS.However, currently other mutations , and the loss of the Y chromosome) . In a suThe traditional understanding that the presence of higher VAF levels at diagnosis has been implicated to be the early acquired somatic clones in MDS or AML, and therefore CHIP mutations have been proven to be one of the earliest events in the pathogenesis of these myeloid neoplasms. This process can lead to further genetic instability, and make the neoplasms more prone to acquisition of additional mutations until a malignant driver clone is acquired A. The emSF3B1, SRSF2, U2AF1, and ZRSR2 [Whole exome sequencing studies reveal complex and novel pathways in MDS. The frequent mutations of the spliceosome machinery were also identified to be one of the most frequently affected pathways in MDS, particularly the mutations in nd ZRSR2 .PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11, can now be detected through targeted RNA sequencing, which may further aid in discriminating between AML and MDS in equivocal blast-count cutoff threshold.Aside from the novel DNA mutations, reciprocal balanced gene rearrangements can now be detected by the NGS platforms. The AML-defining recurrent genetic alterations, involving NPM1, CEBPA, RUNX1, SF3B1, and others) at diagnosis. NGS generally can detect as low as 1% VAF, and therefore can play a complementary role with targeted quantitative real-time PCR (qPCR) or digital droplet PCR (ddPCR) approaches. Error-corrected or barcoded sequencing, using molecular identifiers, can increase the sensitivity of NGS to 10−5 for MRD purposes [With a multitude of detectable mutational markers in MDS and AML, NGS offers the opportunity and leverage for measurable residual disease (MRD) monitoring, especially in the presence of somatic driver mutations , using a combination of clinical, cytogenetic, and genetic parameters, in which the primary endpoint is leukemia-free survival, was presented. The IPSS-M model is a refinement of the IPSS-R, in which the variables consist of hemoglobin levels, platelet count, bone marrow blast count, IPSS-R cytogenetic category, and the presence of mutations in 31 genes . Using this model and cut-offs, a six-risk category was redefined: very low; low; moderate low; moderate high; high; and very high .Artificial intelligence (AI) is a field that focusses on automating intellectual tasks normally performed by humas, while machine learning (ML) and deep learning (DL) are the specific methods for achieving this goal. ML is a subfield of AI, which allows pattern recognition in high-dimensional space. DL, on the other hand, is a subset of ML, in which artificial neural networks (ANNs) are utilized in learning complex functions . The conDue to several unavoidable issues related to interobserver variability in the morphologic evaluation of MDS, ML strategies can provide a supplementary tool to minimize the degree of inherent subjectivity. The identification of BM dysplasia to diagnose MDS can sometimes be challenging, and therefore the ML approach may aid in establishing the diagnosis. AKIRA is the first CNN-based AI system that was developed to identify the decreased granules in neutrophils, which is one of the most common forms of dysplastic change seen in MDS . The sysAs a corollary to advances in molecular genetics and the morphological assessment of dysplasia, quantitative image analysis improves the accuracy and reproducibility of MDS diagnosis. One approach is the use of real-time deformability cytometry (RT-DC) imaging, to standardize and measure the morphological and mechanical properties of single cells in the blood or bone marrow. It utilizes automated image analysis and ML to characterize thousands of cells. The images are captured by a high-speed camera and each of the cell images are analyzed in real-time to obtain the cell area, length and height, aspect ratio, deformation, inertia ratio, and porosity, and therefore aid in cellular designation . AnotherMDS is a clonal myeloid neoplasm which can be difficult to diagnose by conventional methods. Screening clinical and morphologic evaluation, as well as flow cytometric findings, and the detection of genetic lesions by newer technical approaches and modalities, in particular, cytogenetics/FISH and mutational testing by NGS platforms, provide a comprehensive step-wise approach for the diagnosis, prognostication and therapeutic decisions. All in all, the hematologists, oncologists and the hematopathologists should remain in close coordination and in constant interaction for holistic patient care. Such combined efforts can lead to an optimized use of the newer diagnostic modalities for the benefit of patients with myeloid malignancies and their overall welfare.


N = 1467; 71.4% females) and 14 universities in Taiwan  completed the English and Chinese PhoPhiKat-45 measures, respectively. Item response theory and differential item functioning analyses demonstrated that most items were well-distributed across the latent continuum. Five of 45 items were flagged for DIF, but all values had negligible effect sizes (McFadden’s pseudo R2 < 0.13). The Canadian sample was further subdivided into subsamples who identified as European White born in Canada (n = 567) and Chinese born in China, Hong Kong, or Taiwan (n = 180). In the subgroup analyses, no evidence of DIF was found. Findings support the utility of this measure across these languages and samples.The PhoPhiKat-45 measures three dispositions toward ridicule and laughter, including gelotophobia , gelotophilia , and katagelasticism . Despite numerous cultural adaptations, there is a paucity of cross-cultural studies investigating measurement invariance of this measure. Undergraduate students from a Canadian university ( Humour is a multidimensional phenomenon that encompasses a function  and fulfills complex needs for the individual  . Ruch 11 proposeIn terms of measurement, these dispositions are commonly measured using the self-report instrument named PhoPhiKat  and differential item functioning (DIF) to be the first to investigate the psychometric properties of the measure and its relation to different samples. The present study aims to investigate: (1) the item response parameterization of the English and Chinese version of the PhoPhiKat-45; (2) evaluate uniform and non-uniform DIF for individual items with these two groups; and (3) further subdivide Canadian individuals to those who identified as European White and Chinese to evaluate whether DIF represents differing cultural perceptions within the same geographical region. The first objective employs IRT, a technique to determine how much information a particular item on a measure or questionnaire may provide to the researcher ,35,36,37N = 1467; 71.4% females) participated in the study online through the undergraduate participant research recruitment pool. Qualtrics, a web-based survey tool, was used for anonymized data collection. The sample identified as European White , Asian/Pacific Islander , Black/African American , Hispanic/Latino , Native American , and other identity or prefer not to say . Students’ ages ranged from 16 to 54 years . Study participation was voluntary, and participants received a credit towards a psychology course. Participants were provided with informed consent and debriefed.In the Canadian sample, undergraduate students  between the ages of 18 to 29 years . Students participated voluntarily and were debriefed after participation. In the Taiwanese Chinese sample, data were collected using paper and pencil from undergraduate students from 14 universities located in Northern, Central, Southern, and Eastern areas in Taiwan , gelotophilia , and katagelasticism  [strongly disagree to strongly agree. The measure has demonstrated evidence of strong internal consistency, test-retest reliability, and structural, convergent, and discriminant validity [ others) . Each revalidity ,45,46. FX2 statistics were reported for item fit [Q3 statistics for excess item covariation when the latent trait is controlled for [Q3 values showed no evidence for the violation of the assumption of local item independence for all items in the Canadian English Sample. In the Taiwanese Chinese sample, most items showed no evidence for the violation of the assumption of local item independence; however, items 1 and 7 showed a residual correlation of 0.46. Specifically, these two items shared overlap in content regarding being paranoid about being the person laughed at when overhearing strangers laughing. As such, method variance may lead to residual correlations that the latent trait cannot explain [The marginal maximum likelihood estimation method was used to evaluate gelotophobia, gelotophilia, and katagelasticism through Samejima’s graded response model (GRM) . Orlandoitem fit . Local dlled for . Marais lled for  recommen explain . a) and three category threshold (bi) function values were produced for every item. Discrimination values were categorized as follows: ≤0.24 as very low, 0.25 to 0.64 as low, 0.65 to 1.34 as moderate, 1.35 to 1.69 as high, and ≥1.7 as very high [ib) were presented as z-scores  and indicate the amount of latent trait required for a 50% probability of endorsing the following response category.In Samejima’s graded response model, a single item discrimination value  and a group who identified as Chinese born in China, Taiwan, or Hong Kong . The same criterion threshold of McFadden’s R2 > 0.035 and 10% change in proportional β was used to examine DIF. No significant DIF was identified across the three subscales of gelotophobia, gelotophilia, and katagelasticism. To ascertain whether DIF biases existed when Chinese participants completed the English version of the PhoPhiKat-45, subgroup analyses were conducted within the English Canadian sample. This group was further divided into a group who identified as European White born in Canada  with the largest only at 0.13 in pseudo R2 between Models 1 and 3 for item 21. For a proportional 10% β change, item 21 was the only item with a change greater than 10%. In the item response function of item 21, for every response category, the solid line (Canadian English) was located to the left of the corresponding dashed line (Taiwanese Chinese), suggesting that over θ, the Canadian English sample have a greater probability of selecting a higher response option than the Taiwanese Chinese sample for this particular item  was excluded from the gelotophobia latent trait analysis due to a negative slope identified that precluded further analyses. The English PhoPhiKat-45 measure was translated from the German version and this item may be read by English speakers as making a funny impression or appearing hilarious or amusing in front of others naturally. Although the Taiwanese Chinese version was translated from the English version, the item performed well in the Taiwanese sample. Future studies should investigate whether this item may be removed or modified for the English measure of the PhoPhiKat-45. The purpose of this study was to provide evidence for the psychometric properties of the PhoPhiKat-45 in English and Chinese in two independent samples collected from Canada and Taiwan. Using IRT parameters for the Canadian English and Taiwanese Chinese versions, items were well-distributed across the latent continuum and showed high discrimination parameters allowing differentiation across different levels of gelotophobia, gelotophilia, and katagelasticism. Item characteristic curves for each individual item demonstrated high discrimination parameters that were well spread across the latent continuum for gelotophobia, gelotophilia, and katagelasticism, respectively measured. Notably, one item  analyzed has 10% change in β and over 0.13 in McFadden’s pseudo R2. Following an approach by Lau, Chiesi, and Saklofske [Measurement invariance using DIF was also conducted to investigate whether meaningful interpretation of mean group comparisons may be made without significant biases. At the single-item level, five items were flagged for DIF in the Taiwanese Chinese version against the original English version. Only one item , clinical status , and socioeconomic background. Second, although the present study included an extensive assessment of individual item performance of the PhoPhiKat-45, future studies will benefit from investigating whether these variables have the same predictive validity across cultures. Specifically, Chinese individuals conceptualize the value of humour in everyday life differently than those from Western cultures given the early historical and cultural influences of Confucianism, Taoism, and Buddhism (for a review see Yue ). With COverall, IRT and DIF analyses conducted on the English and Taiwanese Chinese versions of the PhoPhiKat-45 demonstrated strong psychometric properties for assessing gelotophobia, gelotophilia, and katagelasticism. With the exception of one item, cross-cultural comparisons of the measure did not present biases with significant effect sizes for the individual item characteristics. Through a subgroup analysis, it is suggested that translations may alter item meanings rather than cultural concepts. However, variance across cross cultural groups may result in comparison biases, such as differences in the conceptualization of humour, including cultural influences, trait representation, and personal coping methods. Findings from this investigation support the utility of the PhoPhiKat-45 English and Chinese versions, and support the generalizability of gelotophobia, gelotophilia, and katagelasticism measures across different languages.


Signal Amplification by Reversible Exchange (SABRE) and hydrogeneable Parahydrogen Induced Polarization (hPHIP) can enhance weak NMR signals, and thus increase the range of NMR applications. Here, using an N-heterocyclic carbene Ir-based catalyst, simultaneous SABRE and hPHIP was achieved for the compound with an N-donor site and an acetylene triple bond. It was demonstrated that the interplay between SABRE and hPHIP can be manipulated. Specifically, it was found that the hPHIP effect could be almost completely suppressed, while stable SABRE was observed in subsequent consecutive experiments. The presented results have the potential to increase the numbers of parahydrogen hyperpolarizable molecules. Signal Amplification by Reversible Exchange (SABRE) and hydrogeneable Parahydrogen Induced Polarization (hPHIP) can enhance weak NMR signals, and thus increase the range of NMR applications. Precisely, MR suffers from inherently low sensitivity, which results from low nuclear spin polarization.12,13 As a consequence, MR methods cannot be employed for the investigation of important systems in which investigated nuclei are at low concentrations. MR methods are also usually expensive due to the high costs of the equipment and their maintenance. Thus, since the early days of NMR, the low sensitivity of this method has been one of the main concerns, and many approaches have been developed to overcome the low sensitivity of NMR.13–16 One of the most powerful approaches is hyperpolarization, in which nuclear spin polarization is enhanced via polarization transfer from the degree of freedom, where the polarization is high, to the nuclear spins.12,14 For example, the p-H2 hydrogen gas mixture enriched in a parahydrogen isomer in relation to the mixture from thermal equilibrium at room temperature is a reservoir of hyperpolarization.17 This hyperpolarization can be relocated to another molecular system. Two variants of Parahydrogen Induced Polarization (PHIP) transfer are possible: irreversible and reversible. The first variant, a hydrogenable Parahydrogen Induced Polarization (hPHIP) involves metal-catalyzed hydrogenation or hydroformylation reactions of unsaturated bonds via p-H2.18–20 According to the reversible variant of PHIP, the NMR signal is amplified by reversible exchange (SABRE).21,22 In SABRE, a labile ternary complex between the p-H2, the pre-catalyst and the to-be-hyperpolarized ligand is created. In this complex, the hyperpolarization is transferred to the ligand via the freshly activated metal catalyst. Thus, when the ligand is released from the labile structure, it is hyperpolarized.Analytical methods that can deliver comprehensive information about broadly understood molecular and biological systems, and materials which are built from them, are of central importance for progress in various fields of science, medicine, and industry. There is no doubt that NMR is one of the most powerful analytical methods. It would be a challenge to enumerate all of the applications and advantages of NMR. It particularly offers in-depth insight into the molecular structures of both small organic molecules and complex functional biomolecular systems.23,24 Both techniques have become very efficient methods for hyperpolarization of various molecular systems with biological relevance.25–29 In particular, several PHIP hyperpolarized molecular systems can be; for example, employed as MRI contrast agents.30–32 PHIP also has potential in the field of metabolomics and the monitoring of chemical reactions where traces of various analytes can be detected.33–36hPHIP and SABRE have already been demonstrated to be capable of enhancing the analytical potential of NMR.via one individual method alone. Simultaneous SABRE and PHIP hyperpolarization may deliver a higher NMR signal enhancement per molecule unit. This could enhance the NMR sensitivity.SABRE and hPHIP are considered to be separate methods. However, the combination of different scientific approaches or analytical techniques can very often culminate in interesting results, or deliver information that cannot be obtained via SABRE and hPHIP  molecule simultaneously PHIP see . 1 was c37–40As a pre-catalyst, we employed [Ir(COD)(IMes)Cl] imidazol-2-ylidene and COD = 1,5-cyclooctadiene), which is used in the vast majority of the research concerned with SABRE, but which can also facilitate hydrogenation (for the sake of convenience it is referred to here as Ir-IMes).4, we started hyperpolarization experiments immediately , 8.55 (H4), 7.95 (H2), 7.46 (H3) ppm were negative, and their enhancement factors (EF) were 5.2, 5.0, 4.1 and 1.1 for H1, H4, H2, and H3, respectively , 5.97 (HB) and 5.45 (HC) ppm. The position of these signals are the same as for three vinyl protons from 3-vinylpyridine (2)  see . Thus, 11H NMR pattern has typical hPHIP features.17 Thus, hydrogenation occurred when the sample was shaken at the Earth's magnetic field, i.e., at the same time when SABRE took place. The hPHIP enhancement factors for the hyperpolarized 2 were 9.7, 21.1, 27.8 for HA, HB, HC, vinyl protons, respectively.The p-H2 atmosphere without mixing for 30 minutes, and also for 1 hour . The analysis of several consecutive cycles revealed, however, that both SABRE and hPHIP decreased step-by-step in the consecutive cycles unit. Finally, we were not able to observe either SABRE or hPHIP, despite the fact that the substrate for hydrogenation was still present in the sample. Afterwards, the sample was kept under the r 1 hour . Surprise see ESI.It seems that some deactivation processes took place in the sample, and as a result, no Ir SABRE and also no hPHIP active species were present in the sample after some time.i.e., the interaction between Ir-IMes pre-catalyst and the ligand before the administration of hydrogen gas. The nature of this interaction is similar to the previously reported cases, i.e., the Ir-IMes pre-catalyst coordinates the ligand. It was observed that not all Ir-IMes were involved in the formation of the complex, even though the ligand is used quite excessively. This situation was also observed for some ligands  when they were used for SABRE, and they were efficiently hyperpolarized without the deactivation processes that we observed in the case of 1.35,43 Thus, at this step, no adverse effect occurs which could result in SABRE deactivation.In order to gain insight into this unexpected situation, we have taken a closer look at the first step of the process which is concerned with the activation of the catalyst, 44–46 For example, it was observed that for 5-(tributylstannyl)pyrimidine and 5-(trimethylsilyl)pyrimidine, a typical ternary labile SABRE complex was formed, and hyperpolarization was observed.44 However, the ternary labile SABRE complexes can conglomerate into tri-metal-center structures which are SABRE inactive . This is important, because the co-ligand can limit the number of 1 molecules within the coordination sphere; as one or two coordination positions will be occupied by the co-ligand. Thus, the modification of the coordination sphere can potentially minimize the adverse effect of the SABRE deactivation process.Thus, there is the interesting question of what will happen when the Ir coordination sphere in which unwanted deactivation occurs is modified by additional ligands (H)2 (DMSO)2] complex . DMSO does not have any NMR signals in the vinyl and aromatic region. Therefore, it can be considered as SABRE and hPIHP “silent”, but it can participate in the hPHIP and SABRE mechanisms.plex see . This co2(L)(DMSO)] is created, in which only one molecule of that ligand will be in the coordination sphere of iridium atom. Importantly, in this complex, the SABRE of the ligand is possible.As a result, , in which a polarization was transferred to 1 2Cl].47,48The analysis of hydride region revealed two hydride signals at −23.5 and −23.7 ppm. These signals can be assigned to the complex [Ir(IMes)(H)to 1 see . It is ws see ESI. Apart fvia the polymerization of Ir SABRE and hPHIP active species, as the multimeric species usually do not induce reversible exchange and hydrogenation. The mechanism of simultaneous SABRE and hPHIP, and thus the interplay between SABRE and hPHIP, can be manipulated via the initial activation of the catalyst. This activation procedure almost entirely suppresses hPHIP efficiency, whereas SABRE can be carried out multiple times. These results also demonstrate that additional molecules which do not undergo any reaction within the catalytic cycle can modify the properties of metal-based catalysts towards new functions. Finally, the interplay between SABRE and hPHIP in the context of molecular structures and pre-catalyst activation poses an issue for further investigation. This can be of importance for further SABRE and hPHIP applications in hyperpolarization of more biorelevant molecules containing motifs similar to that in 1. The presented results can also be helpful during the SABRE hyperpolarization of systems in which unsaturated bonds cause a suppression of the SABRE effect. Our work in this area is steadily progressing.In conclusion, the Ir-IMes catalyst can simultaneously deliver SABRE and hPHIP for a molecule that contains N-donor units which are suitable for reversible exchange, and unsaturated bonds which make hydrogenation possible. Such a structure can potentially facilitate deactivation Authors declare no conflict of interests.RA-012-D2RA02872G-s001