Objective: To characterize the evolution of healthcare workers’ mental health status over the 1-year period following the initial COVID-19 pandemic outbreak and to examine baseline characteristics associated with resolution or persistence of mental health problems over time.Methods: We conducted an 8-month follow-up cohort study. Eligible participants were healthcare workers working in Spain. Baseline data were collected during the initial pandemic outbreak. Survey-based self-reported measures included COVID-19-related exposures, sociodemographic characteristics, and three mental health outcomes . We examined three longitudinal trajectories in mental health outcomes between baseline and follow-up assessments .Results: We recruited 1,807 participants. Between baseline and follow-up assessments, the proportion of respondents screening positive for psychological distress and probable depression decreased, respectively, from 74% to 56% and from 28% to 21%. Two-thirds remained asymptomatic/stable in terms of depression symptoms and 56% remained symptomatic or worsened over time in terms of psychological distress.Conclusion: Poor mental health outcomes among healthcare workers persisted over time. Occupational programs and mental health strategies should be put in place. The COVID-19 pandemic outbreak has had substantial mental health impact on healthcare workers (HCWs), largely due to increases in healthcare capacity requirements driving job redeployments and extended working hours in combination with very high risk of contagion and death. Estimates from cross-sectional studies conducted during the initial pandemic outbreak suggest that between 25% and 50% of HCWs may have experienced clinically significant symptoms of anxiety or depression  and postThe extent to which the deleterious mental health effects brought about by the initial pandemic outbreak may have subsequently led to negative mid- and long-term mental health outcomes among HCWs, however, remains largely unexplored—despite important public health and clinical implications . For insHere we used a large sample of HCWs during the 1-year period following the initial pandemic outbreak in one of the largest COVID-19 hotspots globally to  examine https://mentalnet.cl/en/home/). We collected data through an online survey at two timepoints. Baseline assessments were performed from 24th April to 22nd June 2020 . Follow-up assessments took place between 26th January and 8th March 2021, which in Spain coincided with the third pandemic wave and with administration of COVID-19 vaccines for the majority of HCWs.We conducted a prospective cohort study in Spain as part of an ongoing longitudinal multi-national study   from healthcare facilities located in the study regions  forwarded the survey link to all HCWs. Participants were also asked to forward the survey to peers in order to enhance response rates. In addition, during the follow-up period, we sent email or telephone survey reminders to baseline participants. Participants’ personal and clinical data remained stored in separate datasets , following European General Data Protection Regulation Standards. Baseline assessments are described elsewhere . In thisAll procedures contributing to this work comply with the Helsinki Declaration of 1975, as revised in 2013. It received approval from the Hospital La Paz Ethics Committee in Madrid , study ID 4099, and was ratified by the local ethics committees from the participating sites.Baseline assessments included the following COVID-19-related exposures: direct involvement in the care of COVID-19 patients , adequate access to personal protective equipment, fear of getting infected, and fear of infecting loved ones .Both baseline and follow-up assessments included the following sociodemographic and mental health outcome variables.Sociodemographic variables: Age in years, gender , educational level , and type of job. We collapsed job types into the following categories: physicians, nurses, health technicians , ancillary workers , other HCWs , and residential support workers .Mental health outcomes: Psychological stress, as measured by the validated Spanish version of the 12-item General Health Questionnaire (GHQ-12) ; and proCronbach’s alphas were 0.87  for the GHQ-12 total score; 0.89  for the PHQ-9 total score; and 0.70  for the PC-PTSD-5. To control for region-level cumulative COVID-19 incidence, we calculated region-specific 14-day cumulative incidence rates 2, 4, 6, and 8 weeks after the start of the follow-up period and, as rates were stable over time, classified regions as “high” or “low” incidence depending on whether average cumulative incidence over time points fell under or over 750 cases per 100,000 based on visual examination of region-specific cumulative incidence rates .n = 95). We reported categorical variables as frequencies and valid percentages, and continuous and interval variables as either mean (standard deviation [SD]), or median (interquartile range [IQR]). Descriptive statistics were calculated separately for full and partial respondents.First, we removed baseline respondents who provided informed consent but did not go on to initiate the survey  and COVID-19-related exposures , and follow-up mental health outcomes , defined both as continuous questionnaire scores and dichotomous variables. We conducted sensitivity analyses adjusted by baseline assessments of the follow-up outcome under consideration. We used baseline GHQ-12 score for the model where follow-up PTSD was the outcome, as we did not have estimates for the latter in the baseline assessment. The GHQ-12 score, an instrument that has good convergent validity with the PC-PTSD-5 and accurately detects PTSD in primary care settings . To easeNext, we used baseline and follow-up mental health outcomes to categorize respondents into three mental health trajectories, separately for psychological distress and for depression, according to whether they screened negative at baseline and follow-up (asymptomatic stable), positive at baseline and negative at follow-up (recovering), or positive or negative at baseline and positive at follow-up (persistently symptomatic/worsening). For instance, if a respondent screened negative in the GHQ-12 and positive in the PHQ-9 at baseline, and subsequently screened positive in the GHQ-12 and negative in the PHQ-9 at follow-up, they would belong to the persistently symptomatic/worsening trajectory for psychological distress and to the recovering trajectory for depression. We selected these trajectory categories because of their potential implications for clinical practice.Finally, we explored the association between baseline exposures and longitudinal psychological distress and depression trajectory membership, using multinomial regression models where asymptomatic stable was considered the reference category. Baseline exposures were age group, gender, educational level, direct involvement in the care of COVID-19 patients, adequate access to personal protective equipment (adequate vs. inadequate), fear of getting infected (not or slightly afraid vs. considerably or extremely afraid), and fear of infecting loved ones (not or slightly afraid vs. considerably or extremely afraid)., psych, multinom of R Studio for Mac (Version 1.2.5042).All models were adjusted for confounding based on prior causal knowledge, using direct acyclic graphs and backdoor criteria . Region-Of 1,807 respondents who answered the survey at follow-up (between 26th January and 25th March 2021), 1,471 (81.4%) completed the entire survey, with a median response time of 21 min. Most missing data pertained to the last section of the questionnaire, suggesting that data missingness was driven by survey extension and hence largely random. Respondents who did and did not complete the survey were comparable in terms of mean age  and gender distribution . Response rates were estimated across facilities and job types and ranged from 2.7% to 100% see .There were 1,058 (59%) partial respondents  and 749 (41%) full respondents . Of note, this indicates that we retained 32% of the 2,370 original baseline respondents for follow-up assessments see . SociodeOverall, 56% of follow-up respondents screened positive for psychological distress, 21% for probable depression, and 51% for PTSD. Psychological distress, probable depression, and PTSD were more frequent among younger and female respondents, and respondents with higher educational levels—with substantial heterogeneity across specific job types see . NotablyComparisons between baseline and follow-up mental health outcomes among full respondents are shown in This study followed a cohort of HCWs from one of the earliest COVID-19 pandemic hotspots over the 1-year period after the initial pandemic outbreak. There was marked heterogeneity across individuals in terms of variation in mental health outcomes over time. While we detected general reductions in psychological distress (from 74% to 56%) and depression symptoms (from 28% to 21%), the overall burden of poor mental health among HCWs remained substantial 8 months after the pandemic onset . Our analysis of mental health outcome trajectories revealed that psychological distress and depression symptoms persisted or worsened over time for 56% and 19% of respondents, respectively. We identified prospective associations between certain baseline characteristics, such as being female, reporting inadequate access to personal protective equipment, or being afraid of getting infected and of infecting loved ones, and follow-up psychological distress, depression symptoms, and PTSD symptoms. These results highlight the importance of adapting, implementing, and scaling-up evidence-based public, occupational, and mental health interventions for HCWs to prevent their mental health from further deteriorating during the ongoing pandemic and its aftermath.Early cross-sectional studies from high-incidence COVID-19 areas, such as the Chinese region of Wuhan , Italy , 5, or SOther prospective studies have sought to describe the evolution of HCWs’ negative mental health outcomes over time using a variety of outcomes and follow-up periods , 27–30. To our knowledge, only one study has described the trajectories of mental health problems among HCWs during the COVID-19 pandemic . Notably In addition to confirming associations previously reported in cross-sectional reports, our findings expand existing evidence in impactful ways for public health and clinical decision-making. First, by including a heterogeneous sample of HCWs with and without clinical duties, our study may serve to inform strategies aimed at non-clinical workers such as administrators or cleaners—largely overlooked in most studies examining mental health outcomes among HCWs during the COVID-19 pandemic. Second, our finding of scarce evidence of reliable baseline predictors of mental health outcome trajectories over time suggests that all HCWs should be offered easy-to-access mental health resources tailored to their needs , regardless of profile in terms of sociodemographic characteristics and baseline clinical features.Our study has limitations. First, we used a non-random sample that increases probability of some degree of collider bias and hinders transportability of study results across settings. Also, and in line with other multi-center studies , 4, respThis is the first study to describe the trajectories of change of a large sample of HCWs from an early pandemic hotspot over a long follow-up period. Our results suggest preventative and restorative strategies at various levels , and outlines modifiable factors that might inform resource allocation, such as provision of protective equipment or being in direct care of COVID-19 patients. Further studies exploring the long-term impact of the pandemic among HCWs are warranted.


Though evidence on the detrimental impact of the COVID-19 pandemic in nursing homes is vast, research focusing on general practitioners’ (GP) care during the pandemic in nursing homes is still scarce.A retrospective online survey among 1,010 nursing home managers in Germany was conducted during the first wave of the COVID-19 pandemic between November 2020 and February 2021. Associations between perceived deficits in GP care (routine and acute visits) and both general and COVID-19-related characteristics of nursing homes were analysed using multiple logistic regression analyses.The majority of nursing home managers reported no deficits in GP care . Logistic regression analyses revealed that deficits in GP care (routine visits) were significantly associated with visiting restrictions for GPs and nursing home size. Small nursing homes (1–50 residents) were significantly more likely to report deficits in GP care (routine visits) compared to medium (51–100 residents) and large nursing homes (> 100 residents). Further, deficits in GP care (acute visits) were significantly associated with dementia as a focus of care and the burden of insufficient testing for SARS-CoV-2 among residents. Moreover, visiting restrictions for GPs were significantly associated with dementia as the focus of care and the COVID-19 incidence at the federal state level. Finally, COVID-19 cases in nursing homes were significantly associated with size of nursing homes, COVID-19-incidence on the federal state level and the burden of insufficient testing capacities for SARS-CoV-2 among residents.We found structural factors associated with GP care deficits during the pandemic. New concepts for GP care should be implemented in pandemic preparedness plans to ensure high quality, consistent, and reliable GP care as well as effective infection prevention measures in nursing homes. The novel coronavirus, initially called 2019-nCov . The firDuring the pandemic, structural deficits in the long-term care system in Germany gained visibility. Staffing shortages, frequent staff turnover, low preparedness for infection control, and inadequate infection prevention were all observed by researchers –13. GeneAs with structural deficits, the frequency of consultations between nursing home residents and GPs and medical specialists was inconsistent and less frequent for residents of long-term care facilities than for the general population of the same age even before the pandemic began –20. For Infection prevention measures against the coronavirus, i.e. visiting restrictions at hospitals and nursing homes, were enacted in many countries , 22. In Therefore, the primary aim of the present study is to investigate whether nursing home managers perceived deficits in GP care during the first wave of the pandemic. Further, this study evaluates COVID-19-related and structural factors associated with perceived deficits in GP care.A retrospective online survey was conducted between November 15, 2020, and February 28, 2021, using the Research Electronic Data Capture System (REDCap), a secure web application. The targeted time frame of the survey was between March 1, 2020, and June 30, 2020, so as to collect information about the first wave of the pandemic and the following “lockdown” in Germany. The survey is part of the interdisciplinary COVID-Heim project, which aims to draw lessons from the pandemic for structural developments in the nursing home setting in Germany by combining various data sources.In Germany, there is a total of 15,380 long term care facilities, including daytime inpatient nursing care and permanent inpatient nursing care for older people . For theWe asked nursing home managers to report on the general characteristics of homes they managed, including size  and ownership . Furthermore, we inquired about the existence of a cooperation or contract with a GP (yes/no) and the presence of an employed GP in the facility (yes/no). In Germany the primary healthcare in nursing homes is almost exclusively provided by GPs , 25, 26,Bundesstaat) in Germany , beginning with the first report from March 4, 2020, [COVID-19 incidence on the state level. For local COVID-19 incidence in the general population, we used RKI daily situation reports for each state , moderate burden (1), strong burden (2), and very strong burden (3). The items presented for evaluation were: 1) acquisition and utilisation of infection control equipment ; 2) compliance with RKI hygiene guidelines; 3) economic problems ; 4) insufficient testing for SARS-CoV-2 infections among residents; and 5) concerns about SARS-CoV-2 infections among residents. The single items were adapted from Hower et al. .st of March, 2020 to 30th of June 2020. Possible answers were that GPs had 1) unrestricted access; 2) access with limitations; meaning that GPs were only granted access in the event of an emergency 3) no access; or 4) not applicable; meaning that there is no external GP visiting residents [COVID-19 impact on GP care (outcome). COVID-19 cases among residents or staff were assessed by asking nursing home managers whether there were any COVID-19 cases among residents or staff since March 2020 (yes/no). Further, visiting restrictions for GPs were assessed by asking nursing home managers how access to facility was regulated for GPs during the 1esidents . Furtherp < 0.05.Descriptive statistics were used to generate frequencies and percentages for general characteristics of nursing homes, COVID-19 related characteristics of nursing homes and COVID-19 impact on GP care. We used multiple logistic regression analysis to regress COVID-19 impact on GP care (outcome) on potentially associated factors, which were COVID-19 cases in nursing homes (yes vs. no), visiting restrictions for GPs (no access/access with limitations vs. unrestricted access), and deficits in GP care for routine visits  and GP care for acute visits . Missing values were excluded from the analysis. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 27.0 . Statistical significance was assumed at n = 279, 27.6%) or medium-sized . Likewise, about half of participating nursing homes were in non-profit ownership  and four in ten nursing homes were in private ownership . Further, 866 out of 1,010 (85.7%) participating nursing home managers reported having cooperation contracts with GPs. An additional 2% (n = 20) managers reported employing in-house GPs. Furthermore, 119 (11.8%) of nursing homes reported dementia as their focus of care. The greatest COVID-19-related burden was ‘concerns about SARS-CoV-2 infections among residents’ , followed by ‘compliance with hygiene guidelines of Robert Koch- Institute’ . Approximately two-fifths of the nursing homes perceived ‘economic problems ‘  and ‘insufficient testing for SARS-CoV-2 infections among residents’  as strong or very strong burdens. General and COVID-19-related characteristics of nursing homes are shown in detail in Table The majority of participating nursing homes were either small  of all nursing homes COVID-19 cases among residents or staff occurred. In about two-thirds  of nursing homes, GPs had unrestricted access to the facility. In the remaining third (33.8%) of participating nursing homes, access for GPs was limited or not possible at all. Nursing home managers reported more deficits in GP care for routine visits  than for the provision of GP care for acute visits . Most nursing homes reported no deficits in GP care for routine visits (84.3%) or acute visits . In addition, COVID-19 cases in nursing homes were associated with the COVID-19 incidence on the state level in Germany. Facilities located in states with a COVID-19 incidence rate of 200 or higher were more likely to report COVID-19 cases in their facility compared to facilities in states with an incidence of 1–99 . Finally, COVID-19 cases in nursing homes were associated with a strong/very strong burden due to insufficient testing for SARS-CoV-2 infection among residents .Multiple logistic regression analysis were performed to identify factors associated with COVID-19 cases in nursing homes (yes vs. no), visiting restrictions for GPs (no access/access with limitations vs. unrestricted access), and deficits in GP care for routine visits  and GP care for acute visits . Results showed that COVID-19 cases in nursing homes (yes) were linked to the size of nursing homes, whereas medium and large nursing homes were more likely to report COVID-19 cases in their facility compared to small nursing homes  experienced significantly less deficits in GP care for routine visits  than in smaller nursing homes. Furthermore, deficits in GP care for routine visits were linked to visiting restrictions for GPs . Moreover, deficits in GP care for acute visits  was associated with dementia as the focus of care  and a strong/very strong burden due to insufficient testing for SARS-CoV-2 infections among residents .Moreover, logistic regression analysis revealed that deficits in GP care for routine visits  – but not acute visits – were significantly linked to the size of nursing homes. Large-sized nursing homes  and dementia as focus care . Results from the multiple logistic regression analysis are shown in Table Lastly, visiting restrictions for GPs (no access/access with limitations) were associated with a COVID-19 incidence of at least 300 on the state level . Still, deficits in GP care (routine visits) were associated with visiting restrictions for GPs and the size of the nursing homes. Small nursing homes (1–50 residents) were more likely to report deficits in GP care (routine visits) compared to medium (51–100 residents) or large nursing homes (> 100 residents). Further, deficits in GP care (acute visits) were associated with dementia as the focus of care and the burden of insufficient testing for SARS-CoV-2 among residents. Visiting restrictions for GPs were associated with dementia as the focus of care and COVID-19 incidence at the state level. Finally, COVID-19 cases in nursing homes were associated with the size of the facility, COVID-19-incidence at the state level, and the burden of insufficient testing for SARS-CoV-2 among residents.Prior evidence indicated major challenges for nursing homes and in GP healthcare due to the pandemic , 31–34. In line with similar results from previous studies , 35, ourP < 0.001). Soldevila and colleagues [In contrast to previous findings from Rothgang et al. , our reslleagues  argued tlleagues . FurtherIn our sample, almost one-third of nursing homes implemented visiting restrictions for GPs. This is comparable with previous findings by Rothgang and colleagues , who desFurther, our data imply that nursing homes with dementia as a focus of care were particularly burdened by the impacts of the pandemic, which is in line with prior research conducted by Gordon et al. , who higFurthermore, the association found between local COVID-19 incidence and COVID-19 cases in nursing homes in our data is also reflected in recent research out of the USA , Canada Our study has both strengths and limitations. Strengths include the population-based design of the sampling. To our knowledge, the sample of the present study is the largest and most comprehensive sample of German nursing homes used to investigate the first wave of the COVID-19 pandemic; moreover, compared to all nursing homes in Germany our sample was comparable distributed in terms of ownership, but medium and large nursing homes were overrepresented in our sample . FurtherMoreover, the present study only investigates perceived deficits in GP care by managers in nursing homes; this does not cover inadequacies in the utilisation of other aspects of the healthcare system, such as medical specialists –20, whicFinally, even though we took the cumulative incidence of COVID-19 cases from the state level into account, we were not able to differentiate between urban and rural areas, which could provide valuable context in the light of previous research  that fouThe results of the present study provide new and valuable information on GP care in nursing homes during the first wave of the COVID-19 pandemic that helps to illuminate the diverse impacts of this extended health crisis. In particular, our data indicate that perceived deficits in GP care for routine and acute visits are more frequent in nursing homes with dementia as a focus of care; these homes should be supported by policymakers and legislation in the context of infection control, staffing and structural expansion and strategies to improve care should be enhanced as such. For example, new concepts of interprofessional collaboration between all care providers for nursing home residents could reduce negative outcomes. The development of nationwide recommendations for nursing homes during periods of elevated risk — like a pandemic — could provide reassurance and represents an important task for the RKI, the Federal Ministry of Health, and nursing care insurance companies. More broadly, structural factors were related to care deficits and therefore need to be considered when establishing pandemic action plans in the future. Mandatory training in geriatric medicine and gerontopsychiatry for GPs, consistent availability of GPs and medical specialists, and telemedicine techniques should be promoted so as to maintain high-quality primary care even during protection measurements like visiting restrictions. Likewise, structured guidelines for behaviour and hygiene standards need to be established and utilised for infection control during periods of increased disease transmission and beyond. Further, personal protection equipment and testing devices are needed to contribute to the improvement of GP care for this vulnerable group of patients who are especially in need of reliable and compassionate care.


Bioactive adrenomedullin (bio-ADM) is a vasoactive peptide with a key role in reducing vascular hyperpermeability and improving endothelial stability during infection, but it also has vasodilatory properties. Bioactive ADM has not been studied in conjunction with acute respiratory distress syndrome (ARDS), but it has recently been shown to correlate with outcomes after severe COVID-19. Therefore, this study investigated the association between circulating bio-ADM on intensive care unit (ICU) admission and ARDS. The secondary aim was the association between bio-ADM and ARDS mortality.We analysed bio-ADM levels and assessed the presence of ARDS in adult patients admitted to two general intensive care units in southern Sweden. Medical records were manually screened for the ARDS Berlin criteria. The association between bio-ADM levels and ARDS and mortality in ARDS patients was analysed using logistic regression and receiver-operating characteristics analysis. The primary outcome was an ARDS diagnosis within 72 h of ICU admission, and the secondary outcome was 30-day mortality.n = 132) developed ARDS within 72 h. We found that elevated admission bio-ADM level was associated with ARDS independently of sepsis status and of organ dysfunction as measured by the Sequential organ failure assessment (SOFA) score. Both lower levels (< 38 pg/L) and high (> 90 pg/L) levels of bio-ADM were independently  predictive of mortality. Patients with indirect mechanisms of lung injury had higher bio-ADM levels than those with a direct mechanism of injury, and bio-ADM increased with increasing ARDS severity.Out of 1224 admissions, 11% (High levels of bio-ADM on admission are associated with ARDS, and bio-ADM levels significantly differ depending on the injury mechanism. In contrast, both high and low levels of bio-ADM are associated with mortality, possibly due to the dual action of bio-ADM in stabilising the endothelial barrier and causing vasodilation. These findings could lead to improved diagnostic accuracy of ARDS and potentially lead to new therapeutic strategies.The online version contains supplementary material available at 10.1186/s40635-023-00494-7. Acute respiratory distress syndrome (ARDS) is a clinical diagnosis associated with hypoxic respiratory failure often caused by pulmonary endothelial damage and inflammation. Since first described by Ashbaugh et al. in 1967 , 3. The For example, in a large international multicentre prospective cohort study in the intensive care unit (ICU) published in 2016 only 60% of ARDS patients were properly recognised, including those with severe disease, and the diagnosis was frequently delayed with only 34% of cases recognised at the time of ARDS criteria fulfilment  days for mild ARDS, 2.1 [1.0–5.1] days for moderate ARDS, to 4.17 [1.24–7.9] days for severe ARDS, where the difference between mild to moderate and severe ARDS was significant (p = 0.023). The SOFA score and the SAPS-3 increased with the severity of ARDS. Bio-ADM values were higher in severe ARDS than in mild or moderate ARDS , see Fig. Demographics and comorbidities did not differ with ARDS severity. Mortality was the highest in patients with severe ARDS (56%) compared to 40% and 15% for moderate and mild ARDS, respectively (p <  0.001), and cardiac arrest was more common . Fewer had ARDS  and mortality was higher , Sepsis-3 criteria  and all five types of non-respiratory organ dysfunction measured by SOFA were associated with ARDS. See Fig. In univariate logistic regression analyses, bio-ADM , as was sepsis  was also associated with ARDS.In a multivariable logistic regression analysis of ARDS with bio-ADM, sepsis, and the non-respiratory SOFA scores as independent variables, bio-ADM was independently associated with ARDS  for the presence of ARDS.p = 0.21).The non-respiratory SOFA scores and Sepsis-3 had an AUC of 0.76 (95% CI 0.71–0.80), and the addition of ADM yielded an AUC of 0.77 . Both groups had median bio-ADM values higher than that of the control group.The median bio-ADM value for ARDS solely caused by direct (pulmonary) risk factors was 66  pg/L and 84 [75–180] pg/L for ARDS patients with any indirect risk factor of ARDS (low levels (< 38 pg/L) and high (> 90 pg/L) levels of bio-ADM were positively associated with mortality (ORp = 0.027 and ORp = 0.040).Thirty-day mortality vs admission bio-ADM levels are presented in Fig. In this study of intensive care patients, we used a rigorous and structured approach to manually identify all ARDS patients in the cohort without relying on diagnoses set by the treating clinician, as this is unrealiable . We founAs expected from the properties of bio-ADM and a study in COVID-19 patients , we founBio-ADM levels were higher in indirect lung injury mechanisms compared to direct lung injury. Considering that sampling was done within hours of ICU admission, and since bio-ADM is primarily produced in endothelial cells, this difference makes sense from a pathophysiological perspective. Direct mechanisms of lung injury initially have a more severe epithelial injury, while indirect mechanisms primarily have an endothelial or vascular injury in the early stages of the disease . Indeed,low levels (defined as < 38 pg/L) and high levels (> 90 pg/L). Conversely, the lowest mortality in ARDS was seen in bio-ADM levels, around 60 pg/L. As bio-ADM is known to have a stabilising effect on the endothelium, the connection between mortality in ARDS and low levels of bio-ADM could be due to inadequate ADM production leading to endothelial dysfunction and vascular leakage in the context of widespread endothelial injury. The link between high levels of adrenomedullin and mortality has previously been shown for sepsis and may be due to marked vasodilation and hypotension, as described earlier. In various studies of sepsis and bio-ADM, cut-offs of 70, 102 and 108 pg/L have been shown to distinguish survivors from non-survivors [The U-shaped relationship between bio-ADM and ARDS mortality was an unexpected finding. However, the present study was not designed to investigate this non-linear relationship. Mortality was high for urvivors –18. HoweInterestingly, apart from the obvious connection between respiratory SOFA and ARDS, neurological SOFA was the organ failure most correlated with ARDS in multivariate regression models. Whether this is due to affected lungs or an increased risk of aspiration in patients with an altered level of consciousness, or if it is caused by brain-lung organ cross-talk , is beyoThere were several limitations to our study. First, clinical data were collected retrospectively, and thus missing data could lead to the misclassification of patients. In particular, the limiting factors are missing chest imaging in patients who fulfil the other ARDS criteria and the lack of echocardiography in patients without a known risk factor. However, since the ARDS criteria were rigorously applied, we assess that this would primarily lead to erroneously classifying ARDS patients as controls, thus introducing bias towards the null hypothesis.Among excluded patients, ARDS was less common. Since mortality was also significantly higher in excluded patients, it is possible that some of these patients were so critically ill on arrival that there was not enough time or resources to take the study samples or perform the necessary investigations needed to screen for ARDS.Since bio-ADM was analysed within 6 h of ICU admission and many patients had or developed ARDS within the same time frame, this study cannot determine if high bio-ADM levels can predict ARDS development. It can only show a strong association between high bio-ADM and the presence of ARDS in critically ill patients.The rationale for the deviation from the timing criteria of the Berlin definition (onset within 7 days) was that the majority of patients develop ARDS within 72 h  and thatRespiratory SOFA was excluded from the regression model since it is a part of the outcome of interest, i.e. respiratory SOFA is determined by the PThe non-linear association between admission bio-ADM and mortality was interesting but had weak prognostic significance for 30-day mortality. This is unsurprising since bio-ADM was analysed at the start of intensive care, sometimes weeks before the patient died. In addition, the cut-offs for high and low bio-ADM in ARDS mortality were decided entirely ad-hoc, and further studies are needed to establish these levels.Serial blood samples would be helpful in further elucidating the role of bio-ADM in ARDS pathophysiology and mortality. Our current samples are limited to ICU admission only.The findings of this study have potential implications for a better understanding of the pathophysiology of ARDS and for managing ARDS patients in a general ICU population and possibly other critically ill patients with conditions characterised by endothelial injury and elevated levels of bio-ADM. If bio-ADM at a later date is shown to be predictive of ARDS development, it could be integrated into standard critical care since it is currently available as a bedside analysis. However, additional research is needed before this is feasible, especially serial sampling of bio-ADM and sampling before ICU admission  to elucidate further the role of adrenomedullin in the pathogenesis of ARDS and to properly evaluate bio-ADM as a predictor of ARDS development and mortality. The safety and efficacy of treatment with adrenomedullin or adrecizumab in sepsis and ARDS also need further confirmation. Furthermore, serial studies in both classic ARDS and severe COVID-19 would help to further determine the role of ADM in the pathophysiology of severe respiratory disease.High levels of bio-ADM are positively associated with ARDS in a general ICU population, whereas both high and low levels of bio-ADM are associated with mortality in ARDS, possibly due to the dual action of bio-ADM in stabilising the endothelium and causing vasodilation. Further studies are needed to elucidate the role of bio-ADM in ARDS development and studies targeting bio-ADM for treatment and possibly prevention of ARDS.Additional file 1.Table S1. Characteristics of control population and patients fulfilling ARDS critera but lacking radiology. Data regarding general characteristics, outcomes, organ dysfunction and illness severity are presented below. Patients included in the study were compared to those excluded, and the p-values refer to that comparison.Proportions (%) are within their subgroups unless otherwise specified. SD: standard deviation; IQR: interquartile range; CCI: Charlson Comorbidity Index; SAPS3: Simplified Acute Physiology Score III; SOFA: Sequential Organ Failure Assessment; bio-ADM: circulating bioactive adrenomedullin; CRP: C-Reactive Protein; ICU: intensive care unit. IMV: invasive mechanical ventilation. Table S2. Characteristics of included and excluded patients. Data regarding general characteristics, outcomes, organ dysfunction and illness severity are presented below. Patients included in the study were compared to those excluded, and the p-values refer to that comparison.Proportions (%) are within their subgroups unless otherwise specified. SD: standard deviation; IQR: interquartile range; CCI: Charlson Comorbidity Index; SAPS3: Simplified Acute Physiology Score III; SOFA: Sequential Organ Failure Assessment; bio-ADM: circulating bioactive adrenomedullin; CRP: C-Reactive Protein; ICU: intensive care unit. IMV: invasive mechanical ventilation.


After exclusion due to image quality, outlier values or missing data, DWI was analyzed for ten subjects; BOLD for eight subjects. The diffusion coefficient ADCD decreased in the CsA-treated group over time, whereas it increased in the EVE group . The change in ADCD from months 4.5 to 12 significantly differed between groups in the cortex (p = 0.033) and medulla (p = 0.019). In BOLD, cortico-medullary transverse relaxation rate R2* increased (decreased tissue oxygen) in the CsA-treated and decreased in EVE-treated groups over time. Similarly, R2* values at month 12 were higher in the CsA-treated group compared to the EVE-treated group. There was no significant difference for the perfusion fraction FP. In conclusion, this prospective sub-study of the ZEUS trial suggests an impact of immunosuppressive regimen on fMRI parameters of the kidney graft.The ZEUS study was a multi-center randomized controlled trial investigating the effect of early conversion from a ciclosporin-based to an everolimus-based regimen on graft function twelve months post-transplantation. In this investigator-initiated sub-study, functional magnetic resonance imaging (fMRI) of kidney grafts was prospectively performed to non-invasively assess differences in graft oxygenation, diffusion and perfusion between groups and time-points using diffusion-weighted imaging (DWI) and blood oxygen level-dependent (BOLD)-MRI. Sixteen patients underwent DWI and BOLD-MRI at months 4.5 and 12 post-transplantation on a 3 Tesla and 1.5 Tesla ( Kidney transplantation is the treatment of choice for patients with end-stage kidney disease, prolonging survival . Thanks The ZEUS study was a multi-center, open-label randomized controlled trial designed to investigate the effect of an early conversion from a calcineurin inhibitor-based immunosuppression with ciclosporin (CsA) to a mammalian-target-of-rapamycin inhibitor-based regimen with everolimus (EVE) on graft function twelve months post-transplantation . An imprFunctional magnetic resonance imaging (fMRI) techniques represent an attractive diagnostic tool for renal investigations allowing the non-invasive simultaneous assessment of several aspects of kidney function, such as tissue structure, perfusion and oxygenation, in addition to morphological imaging, without the need for contrast media ,9.Diffusion-weighted imaging (DWI) evaluates organ diffusivity and microperfusion, while blood oxygen level-dependent (BOLD)-MRI assesses tissue oxygenation. Whereas DWI has been investigated as a non-invasive marker of kidney function, BOLD has proven particularly useful to study the acute and chronic effects of various interventions ,10,11,12The purpose of this investigator-initiated local sub-study of the ZEUS trial was the evaluation of additional aspects of kidney graft function according to the immunosuppressive regimen using fMRI methods. With the exception of one study performing BOLD after acute intake of ciclosporin, this question has not been addressed so far to the best of our knowledge . Due to The protocol of the present investigator-initiated, prospective, single-center sub-study of the ZEUS trial was approved by the local ethics committee  and conducted in accordance with the Declarations of Helsinki and Istanbul ,16.All kidney transplant recipients included in the ZEUS trial from our study center were eligible for the current study . SpecifiThe ZEUS study was a 12-month multi-center randomized controlled parallel-group trial, the protocol of which has been published previously . Patient®; Siemens Healthcare, Erlangen, Germany) for all subjects except three who underwent MRI on a 1.5 T MR scanner . During each of the two MRI sessions, anatomical MRI, DWI and BOLD-MRI were performed.MRI data were acquired on a 3.0 T whole body MR Scanner , field of view (FOV) = 400 × 400 mm2, matrix = 128 × 128, six averages, bandwidth = 2300 Hz/pixel and partial Fourier 6/8. Ten diffusion gradient b-values were applied (in s/mm2): b = 0, 10, 20, 50, 100, 180, 300, 420, 550 and 700. The gradients were applied in three orthogonal directions and subsequently averaged, minimizing effects of diffusion anisotropy. Parallel imaging  with a reduction factor of 2 was applied. A TE of 64 ms was used. Acquisition time for DWI was 8:06 min.Intravoxel incoherent motion (IVIM)-DWI yielded the perfusion-cleared apparent diffusion coefficient ADC* , which correlates to tissue oxygen content provided that confounding factors such as blood volume or hydration state are excluded [2 and a matrix size of 256 × 256, on average. Other parameters were: TR of 65 ms, TE of 6–52 ms, inter-echo spacing time of 4.2 ms, flip angle of 30° and bandwidth of 330 Hz/pixel. Twelve T2*-weighted images, corresponding to 12 different echoes, were acquired for each slice within a single breath-hold of 17 s.BOLD-MRI takes advantage of deoxygenated hemoglobin as an endogenous contrast agent, which influences the relaxation time T2*, yielding the transverse relaxation rate R2excluded ,9. For B® and MATLAB®. The obtained values were read into MS Excel® for further statistical processing. GraphPad Prism 9® and MS Powerpoint® were used for figure preparation.A maximum of three regions of interest (ROIs) traced in medulla and cortex were analyzed in every slice  for each medulla and cortex. ROIs were manually defined by the same blinded investigator on images handed over in a random fashion. ROIs were traced in the medulla and cortex. Data were analyzed using in-house custom-scripts written in IDL® machine. Recorded parameters were resistive indices (RI) measured at intralobar arteries .Duplex ultrasound scan (DUS) was performed at both study visits by the same experienced nephrologist on a Siemens Acuson Sequoia 512® device . Recorded variables were the overall mean arterial systolic, diastolic and mean pressures and dipping effect (in mmHg).Ambulatory blood pressure measurement was performed at both study visits using a Profilomat IILaboratory analyses were performed according to the ZEUS study protocol as specified in Histopathological analysis of renal tissue obtained from protocol graft biopsies was performed according to clinical routine in the department of pathology of the University of Bern. Pathologists were not blinded to patient treatment. Biopsy reports were retrospectively assessed for the presence of IFTA, arteriolar hyalinosis and rejection in a semi-quantitative manner. There was no study-specific histological re-analysis.D, FP, R2* and medulla/cortex ratios (MCR) MCR ADCD, MCR FP and MCR R2* at month 12; as well as in the changes in ADCD, FP, R2* and the MCR from month 4.5 to month 12. Secondary outcomes were the changes in ADCD, FP, R2* and cortico-medullary ratios from month 4.5 to month 12 in each medication group; the differences in mean RI and overall mean systolic, diastolic and mean blood pressure and dipping values between time-points for medication groups and the difference in changes from baseline to month 12 between groups; and the correlations of fMRI parameters and their changes over time across and within medication groups for eGFR, RI, overall mean systolic, diastolic and mean blood pressure and dipping values.Primary outcomes were the differences between the CsA-treated and EVE-treated patient groups in ADC® and MS Office 2007®.Continuous variables are expressed as means with standard deviation (SD) or medians and range . Wilcoxon-signed-rank-test was used for cortico-medullary differences and longitudinal changes in fMRI, RI and ABPM parameters within groups. Mann–Whitney U-test was performed for comparisons across groups of absolute fMRI, RI and ABPM values and of longitudinal changes in these parameters. Correlations between fMRI absolute values and changes over time and differences across groups in eGFR, medication levels, RI and ABPM were determined by Kendall’s Tau correlation coefficient analysis. Data were analyzed using IBM SPSS Statistics 24From September 2005 until December 2006, 70 patients received a kidney transplant in our center and were screened at the outpatient University Clinic for Nephrology and Hypertension in Bern for participation in the ZEUS trial and the MRI substudy. A total of 37 subjects were enrolled in the ZEUS trial, 16 of which were included in the current study and underwent MR measurements. One patient was subsequently excluded because of lack of randomization, one patient resigned from participation .Clinical characteristics of the subjects are shown in The MRI protocol, including morphological sequences, DWI and BOLD, could be performed in all of the patients at baseline and in 12 patients on study day 2. Subjects without a second measurement were not included in the analysis . Data ofD as a marker of pure diffusion are shown in D was noted . In the CsA-treated group, medullary and cortical ADCD values decreased in all but one subject from month 4.5 to month 12 (p = 0.14 and p = 0.14), whereas in the EVE-treated group, medullary and cortical ADCD values increased from month 4.5 to month 12, reaching statistical significance for the medulla . At baseline, there was a tendency for higher ADCD values in the group randomized to CsA as compared to the group randomized to EVE. In contrast, at month 12, ADCD values were higher by trend in the EVE-treated group vs. the CsA-treated group  or medication groups.Mean overall medullary and cortical values for the apparent diffusion coefficient ADCed group . This waed group . There wP are shown in D, no significant cortico-medullary differences were found for FP at either time-point . There was no difference in FP or MCRFP between medication groups at baseline nor at twelve months , in the cortex  or in the MCRFP .Mean medullary and cortical values for the fraction of perfusion Fe months  Furthermp = 0.012) with lower cortical R2* values, compatible with the known relative medullary hypoxia. Inverse trends were noted according to medication assignment, including increasing medullary R2* values  in all of the CsA-treated patients and decreasing medullary and cortical R2* values in five and four of six EVE-treated patients, respectively .Mean resistive indices measured by duplex ultrasound scanning are shown in Mean ABPM-derived blood pressure values are shown in Mean serum creatinine values and estimated glomerular filtration rates are shown in The number of available biopsies was six and five at baseline and five and five at month 12 in the groups randomized to CsA and EVE, respectively. No difference in the degree of IFTA (reaching from none to mild) or arteriolar hyalinosis (reaching from none to severe) was revealed between nor within medication groups .To investigate medication-induced changes in fMRI parameters and correlations of fMRI parameters with selected clinical, biological and histological parameters, exploratory correlation testing was performed.D over time were not correlated with changes in eGFR or histological parameters. Cortical ADCD at twelve months correlated negatively with the resistive indices measured by DUS .Changes in ADCP correlated positively with eGFR at twelve months . A negative correlation was found between FP and the diastolic and mean blood pressure by ABPM .The perfusion fraction FNo correlation of R2* with blood pressure, RI or graft function was noted.In this investigator-initiated study, we tested the hypothesis that diffusivity, perfusion and tissue oxygenation as measured by fMRI techniques differ between kidney transplant recipients included in the ZEUS trial randomized to continuing ciclosporin or to being switched to everolimus. The results show an improvement in graft diffusivity after switch to everolimus as compared to patients maintained on ciclosporin.D significantly differed between the medication groups showing increase in EVE-treated patients while decreasing in CsA-treated patients. (2) Medullary ADCD significantly increased after switching to everolimus. (3) Medullary and cortical R2* values showed inverse trends in medication groups with increasing values  in the CsA-treated group and decreasing values in the EVE-treated group.The main findings are the following: (1) The mean changes in medullary and cortical ADCD as a marker of perfusion-free diffusion, decreased in patients maintained on CsA, whereas it increased in patients converted to everolimus. The ADCD has previously been shown to be reduced in various states of acute and chronic kidney diseases and to correlate to biological kidney function markers and interstitial fibrosis [P was not affected in this study, possibly due to lack of statistical power; moreover, in addition to capillary perfusion, this parameter is believed to reflect tubular processes. Lastly, an influence of the higher proportion of recipients of living donor kidneys in the EVE-treated group together with a higher number of transplantations from extended criteria donors in the CsA-treated group cannot be excluded.First, ADCfibrosis ,22,23,24Second, R2*, as a marker of tissue oxygenation—if confounding factors are excluded—increased (lower tissue oxygenation) in CsA-maintained patients, whereas it decreased (higher tissue oxygenation) in EVE-treated patients. This may suggest ameliorated graft tissue oxygenation under everolimus as compared to ciclosporin, possibly due to the expected vasoconstrictor effect of calcineurin inhibitors . HoweverP showed no significant changes over time nor between medication groups. Studies in kidney grafts have suggested lower FP values in cases of decreased graft function and acute rejection and a correlation with chronic tubulo-interstitial damage [P correlated positively with eGFR at month 12, which corresponds to previous reports [The DWI-derived fraction of perfusion Fl damage ,23,26. I reports .D and FP. This is in accordance with previous studies from our center showing a loss of cortico-medullary differentiation over time in transplanted kidneys from living donors [In this study, no cortico-medullary differences were found for ADCg donors ,21,22.D values at month 12. Similarly and expectedly, mean blood pressure values as measured by ABPM increased by trend in the CsA-treated group over time but remained stable in the EVE-treated group.Other relevant findings include significantly higher resistive indices as measured by DUS in the CsA-treated group as compared to the EVE-treated group at month 12, possibly in the context of calcineurin vasculopathy. Baseline RI values 4.5 months after transplantation corresponded to reference values in kidney grafts . HoweverD are nominally independent from field strength, whereas for FP the sequence can be adapted so that values are comparable even at different field strengths; in contrast, BOLD-derived parameters are not comparable across different field strengths. Consequently, these data were excluded for BOLD-MRI. Lastly, post hoc correction for multiple comparisons was not carried out in this exploratory analysis of clinical correlations.There are important limitations to our study: First, the number of subjects available for final analysis was limited, precluding formal statistical analysis of the BOLD data and multivariate analysis of clinical correlations. Second, for technical reasons, three patients underwent MRI at 1.5 T , as opposed to 3 T for the other patients. For DWI, the results for ADCIn conclusion, this prospective small cohort from the ZEUS trial suggests early MRI modifications following CsA to EVE switch. Whether these modifications are linked to the absence of vasoconstrictive effects of calcineurin inhibitors or reflect an early signal of allograft protection needs to be clarified by further studies involving a larger number of patients with systematical and standardized histological analysis.


We performed this study to explore the pattern of anti-HTN medications and to identify factors that are associated with the changes in anti-HTN medications. To this end, we used a clinical database of Seoul National University Hospital, extracted, transformed, and loaded by the observational medical outcomes partnership common data model. Demographic and all recorded clinical diagnoses, medications, and procedures data of eligible subjects were collected. Of 636 subjects who were eligible for this study, 297 subjects with a record of ≥1 anti-HTN medication changes and other 297 subjects without a record of medication change were selected for the study population. High diastolic blood pressure (adjusted odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.001–1.040,  Hypertension (HTN) is a major risk factor for cardiovascular diseases . The numSuboptimal adherence to the anti-HTN medications is a major reason for the reduced benefit of the treatment . FrequenTherefore, it is recommended to minimize changes in anti-HTN medications to maximize the benefit of the treatment by increasing adherence. In this regard, identifying factors that can potentially lead to changes in anti-HTN medications may help clinicians optimize treatment strategies for individual patients.Factors that are associated with anti-HTN medication changes have not been fully evaluated –13. PrevThe objectives of our study were (a) to explore the pattern of anti-HTN medications, and (b) to identify factors that are associated with the changes in anti-HTN medications. To this end, we tested a hypothesis that patients with certain medical conditions are significantly associated with the changes in anti-HTN medications.We used a clinical database of Seoul National University Hospital (SNUH), Seoul, South Korea, extracted, transformed, and loaded using by the observational medical outcomes partnership common data model . The OMOP CDM of SNUH was screened for the period of January 2004 to December 2020. SNUH is a university-affiliated, tertiary-care hospital, the OMOP CDM of which contains 2.3 billion medical records from 3 million Korean patients . This stEligible subjects were those who had been diagnosed with HTN and received ≥1 anti-HTN medications. The index date was defined as the first date of prescription for anti-HTN medication with ≥365 days of prior clinical history identified. On the other hand, the cohort exit date was defined as 1,095 days after the index date . We excl2 using the modification of diet in renal disease (MDRD) equation, or having any diagnosis of renal failure or chronic kidney disease  <40 mg/dL, low density lipoprotein (LDL) ≥160 mg/dL, triglyceride (TG) ≥200 mg/dL, or having any diagnosis of dyslipidemia-related diseases ( disease –19.We categorized anti-HTN medications into the following six classes: angiotensin-converting-enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), beta-blockers (BB), calcium channel blockers (CCB), diuretics (DU), and others  . A changThe patterns of anti-HTN medications were characterized by anti-HTN medication classes. To this end, a Sankey plot was generated using networkD3 package in R version 3.5.1  to visualize the use of anti-HTN medications over time . We alsot-tests and Pearson χ2 tests or Fisher's exact tests, respectively.Continuous variables were described using mean ± standard deviation (SD). Categorical variables were presented as proportion (%). Continuous and categorical variables were compared between the changed and unchanged groups by using Student's p-value < 0.05 was considered statistically significant.The association between a covariate and change in anti-HTN medications was assessed using univariate and multivariate logistic regression analyses. The logistic regression models included the main effects and all of the 2nd order interactions between the main effects. To select variables for multivariate logistic regression analyses, stepAIC function from the MASS package in R was used. The stepAIC function selects variables from the initial logistic regression model by identifying the model with the lowest Akaike's An Information Criterion . We alsoA total of 25,715 subjects with anti-HTN medications were identified, of whom 636 were eligible for this study . After 1The frequency of changes in anti-HTN medications ranged from 0 to 7, with a median of 2. About two-thirds (63.2%) and one-fourth (27.5%) of subjects received one and two anti-HTN medications, respectively, as the initial treatment . A smallThe proportion of combination therapies increased when anti-HTN medications were changed, while the proportion of monotherapy decreased. The proportion of monotherapy reduced from 63.2 to 37.1% when anti-HTN medications were changed . On the For the second choice of anti-HTN medication, ARB+CCB combination was most frequent (54.3%), followed by ARB+DU combination (16.8%). Adding another class of anti-HTN medications that were not part of their previous regimens was observed most frequently when anti-HTN medications were changed 29.2%, .p = 0.049, p = 0.030) more likely to have their anti-HTN medications changed than those without arrhythmia. Lastly, subjects with angina pectoris who also had received antianginal agents were 4.85 times  more likely to have their anti-HTN medications changed than those without angina pectoris and antianginal agents.Subjects with higher diastolic blood pressure were 1.02 times more likely to have their anti-HTN medications changed than those with lower diastolic blood pressure  of subjects started treatments using one anti-HTN medication . In addiOur study results were consistent with those of a previous study in Korea using a claims database, which reported ARB (51.6%), CCB (45.0%), and BB (18.5%) were the most frequently used anti-HTN medications regardless of usage as mono- or combination-therapy . SimilarFor the initial monotherapy between 2010 and 2018, ARB and CCB were consistently highly used , whereas the uses of ACEi and DU were steadily low  . A much Multiple pathophysiological dysregulations involving the renin-angiotensin-system, autonomic nervous system, and endothelium contribute to the development of essential HTN . For thiChanges in anti-HTN medications other than dose increase, dose decrease or removing ≥1 medication may represent a clinical setting where the previous treatment regimen was not adequate for the patient. Particularly, patients might have other medications added after previous treatments because the previous dosage regimen was not sufficient to reduce elevated blood pressure. Our results showed that 200 or 29.2% patients had other medications added after previous treatments to further reduce an elevated blood pressure, 162 (81.0%) of whom were treated with monotherapy before the addition . This inFrequent changes in anti-HTN medications can result in various problems including reduced adherence to the prescribed drug, increased hospitalization risk, new adverse events, and concerns about the new treatment , 29, 30.https://github.com/chung7k/Treatment-pathway_anti-HTN-medication). Unlike other studies where only the use of monotherapies was explored, we also identified the use of combination therapies . This research was supported by the BK21FOUR Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education (5120200513755).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.


Escherichia coli (E. coli), among others. Herein, we present a rare case of acute necrotizing pancreatitis complicated by emphysematous necrosis with hemorrhagic conversion and E. coli septicemia in a 60-year-old morbidly obese male patient without any underlying risk factors. He presented with respiratory failure in the setting of COVID-19 and was subsequently diagnosed with acute necrotizing pancreatitis complicated by emphysematous necrosis. To our knowledge, emphysematous pancreatitis in the setting of COVID-19 with no other attributable causes for pancreatitis was not previously reported in the literature. This article aims to report an unusual association between COVID-19 infection and acute emphysematous pancreatitis with evidence of hemorrhagic conversion. Furthermore, given the neoteric nature of this viral infection, we hope to promote sensitivity toward capturing additional clinical features associated with active COVID-19 infection, with the goal to keep clinicians abreast with its many possible sequelae.The COVID-19 global pandemic continues to wreak havoc on a number of affected patients and poses a significant burden on the healthcare system. Even though it has been over two years since the pandemic emerged, clinical presentations in affected patients continue to appall clinicians. Emphysematous pancreatitis is a rare, fatal complication of acute necrotizing pancreatitis presenting with a high mortality rate. This rare entity stems from superinfection of acute necrotizing pancreatitis with gram-negative bacteria, most commonly from  Approximately 80% of acute pancreatitis cases in the United States are due to alcohol consumption and cholelithiasis -3. ViralA 60-year-old male with a past medical history of class III obesity status post-gastric sleeve surgery, and cholecystectomy, presented to the emergency department with a chief complaint of intractable nausea and vomiting with worsening acute epigastric abdominal pain one day prior to admission. He also developed a non-productive cough and non-bloody diarrhea at around the same time. The patient denied any history of trauma, recent medication changes, chronic diseases, smoking, or alcohol use. On physical examination, he was afebrile, tachycardic, and hypertensive, and had an oxygen saturation of 92% on room air. He had epigastric tenderness with normal bowel sounds and no evidence of guarding, rebound tenderness, or distention. Laboratory investigations were significant for leukocytosis at 13,000 µL and lipase of 9,989 IU/L. Liver function tests revealed transaminemia with aspartate transaminase (AST) of 158 IU/L, alanine transaminase (ALT) of 161 IU/L, total bilirubin of 2.1 mg/dL, and alkaline phosphatase of 520 IU/L. A comprehensive metabolic panel revealed an acute kidney injury with a creatinine of 1.42 mg/dL and normal calcium of 9.5 mg/dL. Lipid panel was within normal limits. The patient was also tested for COVID-19 given his respiratory symptoms and was subsequently found to be positive. Computed tomography (CT) of the abdomen and pelvis with contrast revealed evidence of moderate-to-severe pancreatitis with extensive peripancreatic inflammatory changes, extending to the adjacent pylorus and duodenum. There was also an increased size of the intrahepatic and extrahepatic biliary ducts with a surgically removed gallbladder with no evidence of gallstones , and empiric antibiotics were de-escalated to intravenous meropenem. Wound cultures came back positive for Bacteroides fragilis. Repeat chest X-ray revealed worsening bilateral airspace disease, suggestive of acute respiratory distress syndrome in the setting of COVID-19 and pancreatitis. The palliative team was consulted, and given the patient's rapid deterioration over the prior 24 hours, the family opted to undergo compassionate extubation.On hospital day 3, the patient’s condition continued to deteriorate as he now required three vasopressors, an intravenous infusion of sodium bicarbonate, and stress dose steroids. Day 3 labs were drawn, which revealed worsening multi-organ dysfunction, as summarized in Table In the United States, around 80% of acute pancreatitis cases are caused by alcohol use and cholelithiasis -3. In exE. coli, as seen in the case above [E. coli septicemia. To our knowledge, emphysematous pancreatitis in the setting of COVID-19 with no other attributable causes for pancreatitis has not been previously reported in the literature. Our patient had a history of cholecystectomy 12 years prior to his presentation and did not have any evidence of biliary stones on ultrasound or CT scan. In addition, his lipid panel was within normal limits. Based on our patient’s history and laboratory findings, alcohol-induced, hypertriglyceridemia, and biliary stones as possible etiologies of his patient’s pancreatitis were ruled out. The rapid progression of necrotizing pancreatitis to fulminant emphysematous pancreatitis in under 24 hours makes this case more compelling.Emphysematous pancreatitis is a rare, fatal complication of acute necrotizing pancreatitis with a mortality rate as high as 50% . This rase above . We presEmphysematous pancreatitis can be further divided into two main subtypes: the first being the aggressive type with acute onset and the second being a less aggressive type with a delayed onset . Some imCOVID-19 is a known hypercoagulable disease increasing the risk of thrombosis and thromboembolism. Initial cases early on in the pandemic have revealed that this infection results in a unique, profoundly prothrombotic milieu causing both venous and arterial thrombosis ,12. PropA study published by Wang et al. reported the presence of angiotensin-converting enzyme (ACE2) receptors on pancreatic islets and exocrine cells. ACE2 and transmembrane protease serine 2 are thought to play a pivotal role in the pathophysiology of acute pancreatitis by COVID-19 . HoweverLastly, the coexistence of COVID-19 and acute pancreatitis leads to a higher incidence of mortality and multi-organ failure. A study comparing outcomes of acute pancreatitis between patients with and without a positive COVID-19 polymerase chain reaction (PCR) result showed higher morbidity and mortality in patients with positive PCR results, suggesting a deleterious relationship between the two processes . AnotherCOVID-19 and its sequelae continue to remain a conundrum due to its unique, novel impact globally and the many different complications it can impose on affected patients. In this article, we herein report one of the first incidences of acute necrotizing pancreatitis with severe hemorrhage as a sequela of active COVID-19 infection to our knowledge. Being cognizant of the various complications of COVID-19 including this highly deleterious sequela should help clinicians in promptly recognizing and managing patients affected by this entity.


Herpes Simplex Virus Type 2 (HSV-2) is one of the primary causes of genital ulcers. In addition, HSV-2 infection multiplies the risk of acquiring HIV. Men who have sex with men (MSM) are at particularly high risk of contracting both diseases. Unfortunately, little information is available with regarding to the comprehensive prevalence of HSV-2 among MSM in mainland China. The objective of this manuscript was to determine the composite prevalence of HSV-2 among MSM in mainland China via systematic review and meta-synthesis.As one of the most prolific sexually transmitted infections (STIs) in the world, We systematically searched PubMed, Embase, Chinese National Knowledge Infrastructure, WanFang Database for Chinese Periodicals, and the VIP Database for Chinese Technical Periodicals for relevant articles published from the database’s inception to 28 April 2022 that reported data on the prevalence of HSV-2 within the MSM population in mainland China. We considered publications to be eligible for inclusion if they satisfied these conditions: (1) publication participants were MSM in China mainland. Studies were excluded if participants were exclusively all HIV-positive MSM, all HIV-negative MSM, injection-drug users, or MSM sex workers. These studies would have introduced selection bias and skewed pooled prevalence estimates higher or lower; (2) proportion of HSV-2 virus among MSM in China mainland were reported; (3) HSV-2 diagnosis was conducted in a laboratory based on a strict type-specific glycoprotein-G based assays diagnostic method or PCR method; and (4) had a sample size over 20. Exclusion criteria included: (1) not being an original manuscript, such as a review article; (2) being a guideline, correspondence, and/or conference abstract; (3) the publication population did not reside in China mainland when the study was carried out; and (4) if the same epidemiological data were printed in both English and Chinese journals, English articles were preferred. We assessed the risk of bias in each individual publication using the modified quality assessment tool for systematic reviews of observational publications (QATSO). This meta-analysis was conducted by using R software. Due to extensive heterogeneity between various publications, we employed a random effect model to calculate the composite prevalence and corresponding 95% confidence intervals. We then conducted meta-regression to investigate the potential causes of observed heterogeneity. Lastly, we employed subgroup analysis based on characteristics of studies to compare the prevalence estimates across the groups. Publication bias was evaluated by funnel plot, Begg’s test and Egger’s test. Sensitivity analysis was also performed by removing each single study separately.This study included 31 articles (9 published in English and 22 in Chinese) in our meta-synthesis. The pooled prevalence of HSV-2 among MSM in China mainland was 0.094 (95%CI:0.074 to 0.116). Prevalence of HSV-2 among MSM in Southwest China was higher than other regions, prevalence of HSV-2 among MSM that recruited from VCT (Voluntary Counseling and Testing) was lower than other ways, respectively. Compared to 2000–2010, the prevalence of HSV-2 among MSM in mainland China showed a downward trend during 2011–2020, however, the difference was not statistically significant .Prevalence of HSV-2 among MSM in China mainland is high, around 0.094. It indicated HSV-2 needed to be screening for MSM population among China mainland and proper actions should be taken to curve the trend of HSV-2 among MSM in China.Trial registration CRD42020180361. Herpes Simplex Virus Type 2 (HSV-2), the one of the most common causes of genital ulcers, is a sexually transmitted infection of global concern , 2. It eEvidence suggested that HSV-2 increases the risk of HIV acquisition and transmission, , 13and mIn May 2016, the World Health Assembly (WHA) adopted a global health sector strategy on sexually transmitted infections (STIs) for 2016–2021, which adopted alongside linked global health sector strategies on HIV and viral hepatitis, to eliminate STIs as a main public health concern by 2030 through integration of preventive and control measures. Considering that controlling HSV can also have a beneficial effect on the transmission of HIV at the same time,  the deteThis systematic review followed the recommendations of the PRISMA statement where relevant. The protocol was filed with the International Prospective Register of Systematic Reviews (PROSPERO reference CRD42020180361).Our team searched for all studies reporting the prevalence of HSV-2 among MSM population in Mainland China by utilizing PubMed, Embase, Chinese National Knowledge Infrastructure, WanFang Database for Chinese Periodicals and VIP Database for Chinese Technical Periodicals from their inception up to 28 April 2022. The search strategy is presented in Appendix We considered publications to be eligible for inclusion if they satisfied these conditions: (1) publication participants were MSM in China mainland. Studies were excluded if participants were exclusively all HIV-positive MSM, all HIV-negative MSM, injection-drug users, or MSM sex workers. These studies would have introduced selection bias and skewed pooled prevalence estimates higher or lower; (2) proportion of HSV-2 virus among MSM in China mainland were reported; (3) HSV-2 diagnosis was conducted in a laboratory based on a strict type-specific glycoprotein-G based assays diagnostic or PCR method; and (4) had a sample size over 20. Exclusion criteria included: (1) not being an original manuscript, such as a review article; (2) being a guideline, correspondence, and/or conference abstract; (3) the publication population did not reside in China mainland when the study was carried out; and (4) if the same epidemiological data were printed in both English and Chinese journals, English articles were preferred.We imported all search results using Endnote X9, identified duplicates, and excluded them. We then filtered the titles and abstracts of remaining records for relevance by two independent authors (SHI and CHEN). The full texts of potentially relevant records were then assessed for eligibility. We based our judgement to include publications on previously defined inclusion and exclusion criteria. If the two reviewers disagreed on whether or not to include a particular publication, its fate was decided by a third party (ZHANG). The two reviewers (SHI and CHEN) extracted data from relevant publications. The following was obtained from each paper: first author, publication year, study period, region, area, age, sample size, positive number, HSV-2 detecting method, study design, sampling procedure. Again, disagreements were settled by investigator three (ZHANG). We entered this information into an Excel spreadsheet.We conducted a thorough quality-related assessment of the relevant papers incorporated by the meta-analyses utilizing the modified quality assessment tool for systematic reviews of observational publications (QATSO). The original QATSO tool comprises five quality-related sections: external validity (sampling strategy used), reporting (response rate and objectivity of measurement), confounding factors, bias (privacy), and a final, cumulative score based on the aforementioned parameters. The primary health outcome of focus in this meta-synthesis was prevalence of HSV-2. We did not assess confounding in this analysis, as the publications did not offer adaptable information on the risks for HSV-2 prevalence. Two reviewers (SHI and CHEN) conducted quality assessment independently. If the two independent reviewers disagreed on an individual publication, a third reviewer (ZHANG) made the decision.2 statistic. The I2 values of 25%, 50%, and 75% were considered as low, moderate, and high degrees of heterogeneity, respectively. Pooled prevalence and 95% CI of HSV-2 among the MSM population in China mainland was calculated using a random-effects model if heterogeneity was present and a fixed-effects model if heterogeneity was absent. Single raw prevalence was transformed via the Freeman-Tukey Double arcsine method to stabilize variances, all estimates were presented after back transformation.We carried out the meta-synthesis of proportions by using R 4.2.0 statistical software. Heterogeneity across the studies was assessed using Cochran’s Q test, and heterogeneity was considered to be present when p < 0.05. The degree of heterogeneity was assessed using the IWe conducted subgroup analysis and meta-regression to explore potential sources of heterogeneity by area , sampling procedure , study design , study period  and QATSO .The publication bias was assessed using Begg’s test and Egger’s test and visually inspecting the funnel plot. To examine whether single study had a disproportionally excessive influence, sensitivity analysis was also conducted, in which 1 study at a time was removed and the others analyzed to estimate whether the result could have been affected markedly by a single study. P < 0.05 was considered statistically significant.The comprehensive search for published epidemiological researches into HSV-2 among MSM conducted on the China mainland yielded 1115 hits, of which 108 were duplicates. Thus, 1007 publications were screened for titles and abstracts. These articles went through two stages of screening. Firstly, we precluded the articles failed to meet the inclusion criteria by reading the titles and abstracts. After conducting titles and abstracts screening, we identified 75 full-text articles for detailed review. When papers were excluded, it was primarily because the participants of study were not relevant population, or that it is unavailable to separate the prevalence rate of HSV-2 or studies based on same data source. Finally, we included 31 articles (9 published in English and 22 in Chinese) in our meta-synthesis. A flowchart of the selected publications is presented in Fig. Table 2 = 96.2%, Q = 779.56, P < 0.01) among the 31 studies. The forest chart is illustrated in Fig. Prevalence estimates of HSV-2 among MSM in mainland China ranged from 0.011 to 0.247, with the most estimates between 0.05 and 0.15. The random-effects pooled prevalence was 0.094  with high heterogeneity . However, the result didn’t fully clarify the high level of heterogeneity. Table . We founThus far, there is a lack of pooled estimation regarding the prevalence of HSV-2 among MSM population in mainland China and even the results of different studies vary greatly. This study therefore aimed to determine, through a systematic review and meta-analysis, the prevalence of HSV-2 among the MSM population in mainland China. Our systematic review of the observational study included 31 studies that involved a total of 24,858 participants in mainland China and covered 14 provinces or municipalities of the country. The aggregate prevalence of HSV-2 among MSM in mainland China was 0.094, suggested that nearly one of ten MSM have infected HSV-2 in mainland China. This result was higher than the study reported in general populations in mainland China . When coIn view of the extreme heterogeneity observed, subgroup analysis of the prevalence of HSV-2 among MSM was conducted on different characteristics and obtain some information from analysis. The prevalence of HSV-2 among MSM varied from region to region. Specially, the prevalence of HSV-2 among MSM in Southwest China was higher than the other regions. The Open-Door Policy in 1979 not only brings globalization to the China economy, but also has an impact on the sexuality of the Chinese population. Homosexuality that was once obscured by the contemporary Chinese society also emerged to become a legitimate lifestyle choice . SouthweIn our estimation, this is the first meta-synthesis regarding the prevalence of HSV-2 among the MSM population in mainland China. This publication was, however, vulnerable to several shortcomings. First, both subgroup and meta-regression analyses provided limited explanation of heterogeneity. This suggests that there may be other factors that could explain the differences between studies. This may also be related to the specificity of the MSM population, which is still not widely accepted in China, although its acceptance has increased, making it a relatively hidden population and therefore difficult to obtain a sample through probability sampling, as well as a complex group where multiple factors such as age, income and marital status. All these details are not available through existing studies, which may lead us to conclude that there is no source of heterogeneity in the results based on the available material. This also poses a challenge for our future research efforts; it is expected to make use of probability sampling or conduct further accurate research on MSM population with a certain demographic characteristic. Second, there are more cross-sectional and fewer longitudinal publications of HSV-2 infection among MSM, which cannot describe incidence of HSV-2 among MSM. Also, as the publications included in this meta-synthesis only covered 14 provinces and municipalities in mainland China, there was a distinct lack of data from other provinces and municipalities. Therefore, the results we ascertained may not be applicable to all geographic areas of China. However, this publication covered most parts of the county, so the results are still reliable. Furthermore, we could not discern the survey population’s age, which rendered additional analysis of the age-based connections impossible.This meta-analysis provides a comprehensive synthesis of HSV-2 prevalence in literature targeting Chinese MSM population. The study concluded that MSM are at particularly high risk of contracting HSV-2 infection in China’s mainland. Sustainable, holistic, and efficacious prevention efforts must be implemented for assisting this vulnerable population. Additional, comprehensive epidemiological examinations should be conducted to acquire a more exact estimate of the status of HSV-2 infection epidemics among the MSM population in China.


A 26-year-old primipara woman with COVID-19 performed an emergency Cesarean section due to further hypoxemia at 28 weeks 5/7 days gestation. The female neonate was born weighing 1,347 gram with an Apgar score of four at 1 min, three at 5 min, and eight at 10 min. RT-PCR from nasopharyngeal swabs for COVID-19 were performed at birth, 24 h, and 48 h after birth, all of which were negative. On head ultrasound bilateral cystic lesions were found in the anterior horn of the lateral ventricles at birth. A brain magnetic resonance imaging (MRI) test at 56 days of life (corrected 36 weeks and 6/7 days) revealed cystic lesions with T1 low signal, T2 high signal, and T2 Flair high signal around the anterior horn of the lateral ventricle and We diagnose it as Grade 2 periventricular leukomalacia (PVL). She was discharged on day 64 of life, with no abnormality on exam. While the majority of neonates born to women with COVID-19 during pregnancy have favorable outcome, we report a case of a neonate with Grade 2 periventricular leukomalacia and this should prompt clinicians to monitor fetal cerebral function and structure shortly after birth. Coronavirus disease 2019 (COVID-19) affected millions of people worldwide since early 2020  from a sample done via nasopharyngeal swab two days later (The threshold cycle was 20.5), and was admitted to the hospital. She didn’t diagnose premature rupture of the membrane and had no medical history, except for obesity. Treatment on day four of admission included oxygen with nasal cannula and her clinical condition deteriorated. A thoracic computed tomography (CT) scan revealed bilateral ground glass opacities and consolidation  based on increased oxygen demand and a chest X-ray, and immediately thereafter surfactant was administered intra-tracheally. rRT-PCR from nasopharyngeal swabs for COVID-19 were performed at birth, 24 h, and 48 h after birth, all of which were negative. Toxoplasma gondii, rubella, cytomegalovirus (CMV), and herpes simplex virus (HSV) testing (TORCH) were negative. On head ultrasound bilateral cystic lesions were found in the anterior horn of the lateral ventricles at birth and 4 days of life . A brain1 The neuropathologic hallmarks of PVL are microglial activation and focal and diffuse periventricular depletion of premyelinating oligodendroglia. Premyelinating oligodendroglia are highly vulnerable to death caused by glutamate, free radicals, and proinflammatory cytokines  early in the pandemic revealed that pregnant individuals with COVID-19 infection had substantial increase in severe maternal morbidity and maternal mortality, as well as neonatal complications, compared to non-infected women . VerticaSeveral reports described increased rate of preterm birth, up to 22% in a recent systematic review . Currentn = 1), delayed myelination and brain dysplasia (n = 1), and abnormal signal in bilateral periventricular areas (n = 1)  .Engert et al. reported a case of severe brain damage after SARS-CoV-2-mediated hyper inflammation during pregnancy. In the report, intracranial inflammation and coagulopathy were documented as well as petechial bleeding  and highly elevated D-dimer and White Blood Cell (WBC) count .We suggest that the neonate we report had a post-COVID-19 systemic inflammatory response during pregnancy that resulted in pathological fetal circulation, followed by a coagulopathy and preterm labor. It is possible that placental over expression of angiotensin-converting enzyme 2 which can critically modulate the SARS-CoV-2 receptor caused modulated hemodynamics within the utero-placental unit. Secondly, the pro-inflammatory cytokine storm invoked by SARS-CoV-2 may have induce severe inflammation with deleterious consequences on the fetal brain  .Favre et al. reported two cases of decreased fetal movements and abnormal fetal heart rhythm five days after mild maternal COVID-19, requiring emergency Cesarean section at 29 weeks and 3/7 days and 32 weeks and 1/7 days of gestation, leading to brain injury. Placental examination revealed extensive and multifocal chronic inter-villositis, with intense cytoplasmic positivity for SARS-CoV-2 spike antibody and SARS-CoV-2 detection by RT-qPCR. Vertical transmission was confirmed in one case, and both neonates developed extensive cystic PVL .We report a case of a neonate with Grade 2 periventricular leukomalacia and this should prompt clinicians to monitor fetal cerebral function and structure shortly after birth under careful monitoring of cardio respiratory condition during investigation following approved guidelines.The datasets for this article are not publicly available due to concerns regarding participant/patient anonymity. Requests to access the datasets should be directed to the corresponding authors.The studies involving human participants were reviewed and approved by the Institutional Review Board of Yodogawa Christian Hospital. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.KS and RH consulted in mother. KK, NY, HO, and AM consulted in the prenatal period and designed. KK ang MN wrote the draft. KK, NY, and AM provided medical care at NICU. KK participated in the data collection and provided histology analysis. RG reviewed the literature and participated in the publication. All authors contributed to the article and approved the submitted version.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. The handling editor TM declared a past co-authorship with one of the authors MN.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.


Introduction: Remote pulmonary artery pressure (PAP)-guided heart failure (HF) therapy for NYHA class III patients has been shown to reduce hospitalizations and increase survival. We aimed to assess whether PAP monitoring allows for the increase in HF directed medication in an elderly German cohort of advanced HF patients already receiving clinically optimized HF medication. Methods: We analyzed PAP and HF medication dosage, including diuretics, in 24 patients  using implanted PAP-sensors during the first 12 months of PAP-guided HF care in an interdisciplinary HF unit. Results: During 12 months of PAP-guided HF therapy, PAP decreased significantly . 16% of patients had an unplanned HF hospitalization. There was no significant change over time with respect to the dosage of RAAS inhibitors (ACE-I/ARB/ARNI), Beta blockers, or MRA treatments. In contrast, the dosage of loop diuretics increased significantly (2.1 ± 0.5-fold) over time. In the comparison of a “responder” (patients with PAP and diuretic dose decline) and “non-responder” (patients with PAP and diuretic dose increase) group, there were no significant differences between any of the baseline, medication, or HF hospitalization characteristics between the two groups. Conclusions: In elderly patients treated with clinically optimized HF medication, no further evidence-based medication increase could be achieved using PAP-guided HF care. However, by individual adjustment of diuretic dosage, a significant decline in PAP over time occurred, which could not be predicted by any of the baseline characteristics. With 15 million patients, chronic heart failure (HF) HF is a very common disease in Europe and is the most frequent reason for a hospitalization due to illness. Because of progressive aging in Western societies, the prevalence increases steadily and leads to a high financial burden ,3,4,5. SDuring the last 15 years, with the development of a battery-free sensor for the wireless transmission of PAP values by remote access from the patient’s home , clinicaThe most detailed medication analysis so far comes from the randomized CHAMPION trial , where tThe aim of the present early single center study was to assess whether in advanced elderly HF patients with already clinically optimized medical HF therapy at a tertiary care center in Germany, a further increase in evidence-based HF medication is possible with the support of PAP hemodynamic information during a period of 12 months. Patients in the HF outpatient department, with chronic HF in functional NYHA class III, individually optimized HF medication, and a cardiac decompensation within the last 12 months, were offered implantation of the PAP sensor CardioMEMS™ and participation in a single center telemonitoring registry. A total of 31 patients received implantation of a CardioMEMS™ sensor via right heart catheterization between 2015 and 2017 and were repeatedly trained in HF care by a European Society of Cardiology-certified HF nurse. However, only 30 patients were compliant after implantation and regularly (≥5 times per week) transmitted their data by 12 a.m. each day within 12 months of follow-up, or until initiation of palliative care or death. A total of 24 patients survived 12 months of follow-up and thus represent the present analysis cohort. Regular telephone contact was initiated by HF nurses with all patients, using a standardized questionnaire [adopted from the INH (Interdisciplinary Network for HF) trial] . The nurFor comparison of the diuretic dose, torasemide was converted into a furosemide equivalent by assuming a ratio of 1:4. All neurohormonal antagonist dose changes, which were collected via telephone contact or during office visits, were transformed into % of guideline recommended dose.All patients provided written informed consent for participation in the single center registry (NCT03020043). The study complies with the Declaration of Helsinki and was approved by the local ethics committee.t-test. A Spearman’s statistical correlation analysis was performed for changes in loop diuretic dose and PAP diastolic values. Statistical significance was assumed if p < 0.05, and all reported p values are two-sided. All the statistical analyses, calculations, and graphs were performed using GraphPad Prism software (version 9.0) for MS Windows .This study is a retrospective analysis of the first German experience with the hemodynamic-guided HF care in an advanced HF cohort of a university hospital. Patient baseline characteristics were calculated as mean and standard deviation. Dose changes for guideline-directed evidence-based HF medication and changes in PAP values at baseline and follow-up (6 and 12 months after the implant) were compared using a one-way ANOVA; for △PAP, a two-way ANOVA was used. Dose changes for loop diuretics and functional NYHA class at baseline and follow-up values (6 and 12 months after the implant) were compared using a paired The patient baseline characteristics in N-terminal pro brain natriuretic peptide (NT-proBNP) values were elevated, and kidney function was moderately impaired in most patients. All patients received hemodynamic telemonitoring with the CardioMEMS™ system for severe NYHA class III HF. Only 21 of 24 patients were tolerating the RAAS blockade: one patient suffered from angioedema and two patients were intolerant of any RAAS inhibition due to hypotension, in addition to high potassium levels in one of these patients. A total of 92% of the patients took beta blockers, and 75% were on MRA . Overall, systolic blood pressure was within the normal range, despite advanced HF, but the baseline PA pressure (PAP) was significantly elevated. Hemodynamic analysis showed that a total of 17 patients suffered from pulmonary hypertension (defined by mean PAP ≥ 25 mm Hg) . FurtherAt 12 months follow-up, there was no significant change in the neurohormonal blockade dose, when compared to baseline medication A.p = 0.034) and increased further until 12 months of follow-up , followed by ARNI/ACE-I/ARB (n = 24/28/18), BB (n = 57 changes), and MRA (n = 45 changes C).Most medication changes occurred within the first 3 months after implantation, demonstrating the efforts to uptitrate medication and achieve optimized diastolic PAP D. p = 0.015) and up to 12 months of follow-up  and an absolute decline in diastolic PA-pressure of 4 mmHg  were possible with PAP-guided monitoring in advanced elderly HF patients already receiving clinically optimized HF-medication. According to the inclusion criteria of our registry, in close association with the CHAMPION trial , the PAPSecond, as expected, the average dosage of ACE-I and ARB declined over time, whereas ARNI dose and frequency increased non-significantly. This is due to the stepwise integration of ARNI since 2016, which is within the observation time of the present analysis. In a previously published report of the MEMS-HF trial, ARNI use was associated with less use of loop-diuretics compared to non-ARNI use at baseline . In addiWith respect to other HF medication, only 50% of the recommended dose of MRA could be achieved in 16 HF patients, whereas 2 patients could not even tolerate an MRA. In 16 patients, a non-significant increase in MRA dose could be detected from baseline to 6 months, but this was followed by a subsequent decline until 12 months of follow-up due to recurrent hyperkalemia episodes. Currently, one would expect that improved results with a higher percentage of MRA treatment and doses can be expected, because SGLT2 inhibitors reduce the risk of MRA-associated hyperkaliemia , and novMost medication changes occurred within the first 3 months, and the frequency of changes decreased during 12 months of follow-up. This is in line with previous studies (CHAMPION and MEMS-HF) ,25, whicThe drug class of SGLT-2-inhibitors were not included as antidiabetic nor HF therapy because patients were included into the registry in parallel to the publication of the EMPA-REG-OUTCOME trial  and prioFinally, our results show that a significant reduction in PAP values could be achieved, despite the fact that we could not increase evidence-based HF medication in individually optimized NYHA class III elderly HF patients. The reduction in PAP was not directly correlated with diuretic or other medication dosage, suggesting that the decline in PAP values may be due to better adherence to HF care. The present single center registry comprises only 24 patients with hemodynamic telemonitoring, with analyses of the changes of evidence-based HF medication during the 12 months of follow-up. The limited patient number is most likely responsible for our inability to identify a clear patient profile associated with a positive response to hemodynamic-guided heart failure therapy. However, the study represents a careful individual analysis of advanced HF patients being treated in a university outpatient setting.