P < 0.001), and 5-year recurrence rate was also lower for the RAAS inhibitor group . In our analysis, RAAS inhibitor was associated with decreased 5-year mortality in hypertensive patients who underwent cancer surgery. Prescription of RAAS inhibitor in accordance with current guidelines may be associated with improved mortality after cancer surgery.Renin–angiotensin–aldosterone system (RAAS) inhibitors are antihypertensive agents with conflicting results on protective effects against some types of cancer. In light of these controversies, we aimed to study the effects of RAAS inhibitors in patients undergoing cancer surgery. From March 2010 to December 2019, consecutive adult patients with antihypertensive drug prescription at discharge after cancer surgery were enrolled and divided into two groups according to RAAS inhibitors prescription. The primary outcome was 5-year mortality after surgery. Secondary outcomes included mortalities during 3-year and 1-year follow-ups and cancer-specific mortality and recurrence rates during 5-, 3-, and 1-year follow-ups. A total of 19,765 patients were divided into two groups according to RAAS inhibitor prescription at discharge: 8,374 (42.4%) patients in the no RAAS inhibitor group and 11,391 (57.6%) patients in the RAAS inhibitor group. In 5022 pairs of propensity-score matched population, 5-year mortality was significantly lower in the RAAS inhibitor group (11.4% vs. 7.4%, hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.64–0.83,  Interestingly, many animal studies have suggested that RAAS inhibition could play an important role in preventing cancer initiation and progression by affecting cell proliferation, angiogenesis, and inflammation3. However, results from population-based studies are controversial8.Renin–angiotensin–aldosterone system (RAAS) inhibitor is recommended as an antihypertensive agent in patients with comorbidities including heart failure, coronary artery disease, diabetes, or chronic kidney disease9. Besides, it has been reported that hypertension was present in 37% of cancer patients11, and the incidence of hypertension in cancer patients even increases up to 80% after chemotherapy13. Considering these enormous numbers of possible patients who need to be treated for hypertension after cancer surgery, more data seem to be required for evaluating the effect of RAAS inhibitors prescribed postoperatively in cancer surgery.Surgical resection is an essential modality in cancer treatment. In 2015, over 80% of newly diagnosed cancer cases required surgery, and by 2030, 45 million surgical procedures will be annually needed to treat cancers worldwideTherefore, in the present study, adult patients discharged with anti-hypertensive agent prescription after cancer surgery were enrolled and divided into those prescribed RAAS inhibitors and those prescribed the other anti-hypertensive agents. We compared the 5-, 3-, and 1-year mortalities and cancer recurrence rates between those two groups of patients.https://cris.nih.go.kr (KCT0005000). This study was conducted in compliance with the declaration of Helsinki and was reported according to the Strengthening the Reporting of Observational studies in Epidemiology guideline.This study was a retrospective cohort study using a large single-center data from the Samsung Medical Center Cancer Surgery (SMC-CanSur) registry. Approval for this study and the need for individual written informed consent were waived by the Institutional Review Board at Samsung Medical Center (SMC 2020-04-027), because the entire dataset was initially extracted in de-identified form. The cohort for this study was registered at The data in SMC-CanSur registry were extracted using the “Clinical Data Warehouse Darwin-C” of Samsung Medical Center. It is an electronic system built for investigators to search and compile anonymized medical records from the institutional electronic archive system. Our archive system contains records of more than 2.2 million surgeries, one billion laboratory findings, 100 million disease codes, and 200 million prescriptions. For cancer patients, all medical information related to cancer such as diagnosis date, cancer stage, cancer treatment, metastasis, and recurrence in this system are separately organized and updated as cancer patient data. Mortality data in this system are continuously verified with the National Population Registry of the Korea National Statistical Office using identification number of each patient for mortality statistics at institutions other than ours.14. For this study, patients without prescription of antihypertensive agents at discharge and patients with in-hospital death were excluded from this registry. The remaining 19,765 patients were divided into two groups depending on whether they were prescribed with RAAS inhibitors at discharge after cancer surgery. RAAS inhibitors were either angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB). Other antihypertensive drugs included beta blocker, calcium channel blocker, and diuretics.The SMC-CanSur registry is a de-identified cohort consisting of 87,621 consecutive adult patients who underwent cancer surgery from March 2010 to December 2019 at Samsung Medical Center, Seoul, Korea. Cancer surgery is defined as surgical removal of a solid tumor and adjacent tissue at various sites including the brain, neck, breast, thorax, abdomen, colon, and pelvis27. We applied death classification algorithm from Surveillance, Epidemiology, and End Results data which was extensively validated to improve accuracy of underlying cause of death28.The primary study endpoint was post-discharge 5-year mortality. Secondary endpoints included 3-year and 1-year mortalities and cancer-specific mortality and recurrence rates within 5, 3, and 1 years after discharge. To identify cancer-specific mortality, we used causes of death from the National Statistical Office in South Korea which was organized according to International Statistical Classification of Diseases and Related Health Problems codes. Cancer-specific mortality was defined as death due to the first primary cancer diagnosed or a diagnosed cancer other than the first primary cancer2 or Fisher’s exact test for categorical variables. Outcomes were compared using Cox regression model in entire and matched population. Hazard ratios (HR) with 95% confidence interval (CI) was reported. In entire population, covariates with a p-value less than 0.2 or clinical relevance were selected for the multivariable analysis. Following variables were retained in the multivariable Cox regression model; age, sex, diabetes, coronary artery disease, heart failure, stroke, deep vein thrombosis, chronic kidney disease, chronic lung disease, anemia, preoperative chemotherapy, preoperative radiotherapy, preoperative metastasis, the number of intraoperatively transfused red bold cell units, continuous infusion of inotropes, duration of operation and preoperative use of RAAS inhibitors. To further reduce selection bias and confounding variables between the two groups, we used propensity-score matching method to generate the groups with well-balanced covariates. Multivariable logistic regression was used to derive propensity score model with all covariates and used the model to estimate the propensity score for each patient as the probability of being included in RAAS inhibitor group. The 1:1 matching using the nearest-neighbor matching method was performed without replacement. To be specific, we matched a patient in the no RAAS inhibitor group with a patient in the RAAS inhibitor group having the nearest propensity score and was selected if the caliper was within 1.5 of the standard deviation of the propensity score logit. The optimal caliper was set in order to achieve an appropriate balance between the groups while maximizing statistical power26. An appropriate balance between the groups with an absolute standardized difference (ASD) < 10% suggested successful propensity-score matching. Kaplan–Meier survival curves were constructed and compared with the log-rank test using propensity score matched populations. We estimated the probability of dying of a cancer cause accounting for the competing risk as non-cancer cause death. In addition, we performed subgroup analysis on the association between RAAS inhibitor and 5-year mortality for each cancer types, and the results were presented in forest plot. For sensitivity analysis in the matched population, we estimated the potential impact of unmeasured confounders with an assumed prevalence of 40% on the observed association. This analysis estimates the impact of an unmeasured binary confounder on the measured causal association between a binary exposure and a binary outcome15. Statistical analyses were performed with R version 4.0.2 . All tests were two-tailed, and a p-value less than 0.05 was considered statistically significant.Baseline characteristics are presented as mean ± standard deviation (SD) or medians with interquartile range (IQRs) for continuous variables, and numbers with percentages for categorical variables. The differences were compared with the t-test or the Mann–Whitney test for continuous variables and χFrom the SMC-CanSur registry, we excluded 318 patients with in-hospital death and 67,538 patients without prescription of any antihypertensive agent at discharge. The remaining 19,765 patients were divided into two groups according to the prescription of RAAS inhibitors at discharge: 8374 (42.4%) patients in the no RAAS inhibitor group and 11,391 (57.6%) patients in the RAAS inhibitor group. The baseline characteristics of the two groups are summarized in Table The median follow-up durations for 5-year mortality from the day of discharge were 1020 (415–1818) days for the no RAAS inhibitor group and 929 (390–1800) days for the RAAS inhibitor group. The RAAS inhibitor group had significantly lower 5-year mortality . The 3-year and 1-year mortalities were also lower for the RAAS inhibitor group . For the recurrence rate, it was lower for the RAAS inhibitor group during 5- and 3-year follow-ups , but 1-year recurrence rate was not significantly different between the two groups. Cancer-specific mortalities were also significantly lower in the RAAS inhibitor group regardless of follow-up periods  . Table .Figure 1In subgroup analysis according to cancer site, 5-year mortality was significantly decreased in the RAAS inhibitor group for lung cancer . The cancer site was not significantly interacted with the association between RAAS inhibitor and mortality. However, there was a heterogeneity according to cancer site on the direction and magnitude of this association, and some of cancers may have not achieved statistical significance due to low power , critical factors in RAAS, have been associated with tumor growth by stimulating cell proliferation and neovascularization19. In contrast to AT1R, angiotensin II type 2 receptor (AT2R) activation shows anti-proliferative effects21. Although the exact mechanism for the protective effect of RAAS inhibitor against cancer is not fully known, ACE inhibitors reduce the conversion of angiotensin I to angiotensin II, and ARBs selectively inhibit the unfavorable actions of AT1R by maintaining the protective function of AT2R signaling. In this study, recurrence rate was decreased in the RAAS group, and the cumulative incidence of cacancer-specific death by accounting for competing risk was also lower for the the RAAS group. These findings support that the anti-tumor effect of RAAS inhibitor may be related to our result.To explain this favorable effect of RAAS inhibitor in patients who underwent cancer surgery, we focused on the association with tumor growth and RAAS and the RAAS inhibitors' end-organ protective effects simultaneously. The RAAS plays a vital role in cell growth, maintaining blood pressure, and stabilizing the cardiovascular system's microenvironment22. Therefore, RAAS inhibitors are highly recommended as an antihypertensive agent of choice in patients with multiple cardiovascular risk factors. Considering the 1-year recurrent rate was not different between the two groups, this protective effect of RAAS inhibitors mainly on the cardiovascular system may have also affected our results in the long term.RAAS inhibitors have suggested to provide better end-organ protection such as kidneys, blood vessels, and heart compared with the other antihypertensive agents23. Also, there is an interaction between RAAS inhibitors and epidermal growth factor receptor (EGFR) inhibitor using the crosstalk between AT1R and EGFR, the first-line treatment target for NSCLC25. Therefore, RAAS inhibitors may delay EGFR inhibitor resistance, theoretically. The heterogeneity of association between the types of surgery may also be related to the fact that power of analysis depends on number of events, so some types of surgery might have not achieved statistical significance due to low mortality.Since the surgeries for all types of cancers were included in the present analysis, we conducted the subgroup analysis according to cancer types. But we did not find the relationship between the use of RAAS inhibitors and the reduction of 5-year mortality in surgeries for specific cancer types except lung cancer. Therefore, it is hard to conclude the RAAS inhibitor's effect on survival after specific cancer surgeries in this study. However, our result of declining 5-year mortality in the RAAS inhibitor group after lung cancer surgery is consistent with the previous studies in which lung cancer prognosis was associated with RAAS inhibitors, especially in non-small cell lung cancer (NSCLC)The following limitations should be considered when interpreting the results of this study. First, as a single-center, observational study, a residual confounding factor-related bias may have persisted, despite our rigorous statistical adjustment. Unmeasured confounding variables may have affected the results even in the propensity-score matched population. Second, due to retrospective properties, it was impossible to include the blood pressure changes from discharge to follow-up in this study. So, we cannot rule out the possibility that uncontrolled hypertension or inadvertent hypotension due to RAAS inhibitors might have contributed to the death. Third, we did not consider the types and doses of RAAS inhibitors. Moreover, considering most of the patients were prescribed angiotensin II receptor blockers, our results may differ for angiotensin-converting-enzyme inhibitors. As a result, the potential effect of different and interrupted use of RAAS inhibitors and dose–response relationships could not be ascertained. In addition, our analysis may show different results according to types of surgery. Fourth, prescription from other clinics after the discharge could not be considered. So, some of RAAS inhibitor prescription after discharge might have been misclassified as no RAAS inhibitor group. Finally, our study mainly included Asians, and the findings may not be generalized to other ethnicities. Despite these limitations, we used real-world data and demonstrated that the use of RAAS inhibitors after cancer surgery was associated with reduced mortality and recurrence rate.Our study showed that the use of RAAS inhibitor decreased 5-year mortality in hypertensive patients after cancer surgery. However, large-scale, well-designed studies are needed for evaluating the relationship between the use of RAAS inhibitor and the outcomes after cancer surgeries. Based on the present evidence including our data, prescription of RAAS inhibitors as a first-line antihypertensive agent seems to be reasonable in patient who underwent cancer surgery.Supplementary Tables.


Olfactory dysfunction is one of the long-term consequences of acute SARS-CoV-2 infection in adults. This study aims to analyze the prevalence of chronic anosmia among COVID-19 children and to bring to light its impact on their families’ quality of life and wellbeing. Children younger than 18 years old, who were detected as being COVID-19-positive by RT-PCR and were assessed in a pediatric post-COVID outpatient clinic at least 28 days after the onset of the acute infection, were included in the study. The patients suffering from persisting smell disorders were asked to answer a questionnaire about their symptoms and how they influence their daily life. Out of the 784 children evaluated, 13 (1.7%) presented olfactory impairment at a mean follow-up since the acute infection of more than three months. Parents’ answers showed that they were worried about their children’s health, in particular they wanted to know if and when they would recover and if these disorders would have long-term consequences. They also wanted to share their experiences, in order to help other people who are experiencing the same disorders in everyday life. Our study highlights that smell disorders can significantly upset children’s eating habits and everyday activities. Furthermore, these findings suggest that future research should try to better understand the mechanisms causing loss of smell in COVID-19 patients and find the most appropriate treatment. Post-COVID-19 condition, or Long COVID, is now a well-established negative long-term outcome of SARS-CoV-2 infection in adults , althougThis study aims to analyze the prevalence of long-lasting loss of smell among children and to evaluate its severity, how it influences their families’ quality of life and what we can do to help them to recover.This is a retrospective study of children younger than 18 years of age with a microbiologically confirmed diagnosis  of SARS-CoV-2 infection that were assessed in a pediatric post-COVID outpatient clinic of Fondazione Policlinico Universitario A. Gemelli IRCSS in Rome, Italy. In our outpatient clinic, we evaluate children that either fully recovered from acute infection or present persisting symptoms. Children can be sent to the post-COVID unit either after discharge from our institution, or directly sent from the family pediatricians (and therefore not seen at baseline during acute infection). Data from all consecutive patients evaluated in our outpatient unit from 5 February 2021 to 1 June 2022 were included.See For each child, we collected the main demographic data, COVID-19 vaccination status, severity of acute disease according to the initial classification adapted according to our local practice  , mean tiAnosmia was defined as the loss of sense of smell, or reduced ability to smell, or distorted perception of selective smells that were normally perceived before COVID-19.Moreover, in order to understand the impact of anosmia on daily life, we asked families of children with persistent anosmia the following questions in Statistical analysis was performed using…p value < 0.05 was considered statistically significant.Categorical variables were presented as count and percentage; they were compared using Chi-squared tests or Fisher’s exact tests. Continuous variables were expressed as mean with standard deviation or median with interquartile range (IQR 25–75%), depending on the normality distribution. Mann–Whitney U test was used to compare continuous variables if not normally distributed. A The study was approved by the ethic committee of Fondazione Policlinico Universitario A. Gemelli IRCSS in Rome, Italy . Written informed consent was obtained from all participants or legal guardians for the participation in this study before beginning the study.A total of 784 children diagnosed with SARS-CoV-2 infection were enrolled in the study. The median age of our population was 7.99 years: 530/784 (67.6%) were aged 0 to 9 years and 254/784 (32.4%) were aged 10 to 18 years. Regarding sex distribution, 45.5% (357/784) were girls. Out of the infected children, 89 had known pre-existing comorbidities. The most noted pathologies were allergic asthma, autism spectrum disorders, allergies and atopic dermatitis. Only 73 patients (9.3%) completed the COVID-19 vaccination regimen before the infection, and 56 children (7.1%) received at least one dose of the vaccine. During the acute SARS-CoV-2 infection, 39 children (5.0%) were asymptomatic, 724 (92.3%) had mild disease, 19 (2.4%) had moderate disease and 2 patients (0.3%) had severe disease. Overall, 24 (3.1%) children were hospitalized and 4 (0.5%) needed pediatric intensive care unit admission. The median duration of the follow-up time since the initial diagnosis of SARS-CoV-2 infection was 106.9 days.Among the children followed up in our outpatient clinic, 13/784 (1.7%) suffered from persistent olfactory dysfunction after acute SARS-CoV-2 infection, 771/784 (98.3%) did not complain about long-lasting smell disorders. The distribution of age, gender, nationality, comorbidities, COVID-19 vaccination status, acute disease severity, mean time of follow-up and post-acute infection symptoms are reported among the different groups .p value < 0.05). One of them had allergic asthma and two suffered from allergies. Only two of them were fully vaccinated before the SARS-CoV-2 infection. All of them had mild acute disease and did not require hospitalization. The median duration of the follow-up time from the COVID-19 diagnosis was 132 days. Seven children (53.8%) suffering from olfactory dysfunction complained about taste disorders too. The most common concomitant persisting symptoms among these children were dyspnea on exertion, headache, muscle and joint pain, asthenia and palpitations. We found that the presence of altered taste, dyspnea at rest, dyspnea on exertion, chest pain, palpitations and joint pain was significantly different between the two group of patients (p < 0.05). We summarize the clinical situation of each patient in The median age of children suffering from persistent anosmia was 13.86 years: 12 of them (92.3%) were aged >10 years, 1 child was 9 years old and 8 of them (61.5%) were girls. The statistical analysis showed that the distribution of age between the anosmic and non-anosmic patients was significantly different  reported having suffered a reduced or distorted ability to smell since the acute phase of SARS-CoV-2 infection. Only 2/13 (15%) started experiencing olfactory dysfunction two months after the positive COVID test. Clinical manifestations of smell disorders can vary widely. Most of our patients (10/13) reported the inability to detect any smell. In particular, four parents firstly noticed that their children were not able to recognize cooking scents or odors. As reported by families, anosmia had a mild-moderate impact on their daily routine, and it caused an excessive use of perfumes and deodorants in four of our patients. One of our patients, a 12-year-old adolescent who cannot smell anything, is looking forward to recovering and she is constantly asking her mother when she will be able to recognize the odors again.Only one family reported that their child’s loss of smell had a slight impact on their daily activities. One patient told us that they were bothered by some smells. Two children reported a completely distorted perception of smell: for a 13-year-old adolescent, all smells were disgusting, cooking scents were not tolerated, and perfumes were not correctly perceived. Since this patient stopped eating her favorite food and lost weight, her mother told us that “her olfactory dysfunction has a devastating impact on the family’s quality of life”, they changed all their eating habits and she is worried because she does not know how to replace food that her child refuses. Another adolescent complained about an altered perception of smells as well. He said that he found human sweat disgusting. Both of them reported taste disorders as well, and they experienced these alterations two months after the acute infection. All the parents interviewed shared the same feeling—fear. They were worried about their children’s health; they want to know if and when they will recover and if these disorders will have long-term consequences. Our families trust the scientific community, encourage our clinical research and hope we will soon find an efficient treatment for anosmia. They also want to share their experiences, in order to help other people who are experiencing the same disorders in everyday life.In this study, we assessed the impact of chronic anosmia on a relatively large population of children assessed in a referral post-COVID Unit in Italy. Overall, we found that 1.7% of the assessed children still presented a smell problem at a mean follow-up of more than three months since the acute infection, and this problem had an impact on their habits and on family wellbeing. Older age and the persistence of other symptoms such as altered taste, dyspnea at rest, dyspnea on exertion, chest pain, palpitations and joint pain was significantly different between the two groups of patients, with it being more frequent in the group of chronic smell dysfunction. Specifically, nine out of the thirteen patients (69.2%) had the coexistence of multiple symptoms, making their picture more specifically related to Long COVID, while the others had either smell disjunction alone or associated taste problems.The prevalence of chronic anosmia among children has not been established. To our knowledge, there is only one study , conductOur study has limitations to address. Firstly, it is a retrospective study, and therefore, patients were not assessed at the same time of follow-up since the initial acute infection. Secondly, smell problems were defined according to a self-description of smell impairment by the patients, in the absence of a standardized diagnostic tool . ThirdlyIn conclusion, we provided the first detailed characterization of a cohort of children that developed chronic anosmia after COVID-19 and its impact on daily life. These findings highlight the need to better understand why some young people develop this problem and what its best management is.


Coronavirus disease 2019 (COVID-19) and tuberculosis (TB) are currently the two leading causes of death among infectious diseases. As we progress towards a “new normal”, more information is required regarding post-COVID-19 syndromes. We present a case of latent tuberculosis reactivation 3 months after a successful inpatient treatment of COVID-19. A 74-year-old female from the Philippines presented with a new left mid-lung infiltrate with worsening shortness of breath and lethargy for one week prior to admission. The clinical course of the patient deteriorated despite broad-spectrum antibiotics, diuretics, and high-dose steroid therapy requiring intubation and mechanical ventilation. Her sputum culture yielded the microbiological diagnosis of TB. Anti-tubercular medications were started and the patient had a favorable clinical outcome. Our case demonstrates that immunosuppression secondary to COVID-19 and its treatments may promote the development of an active TB infection from a latent infection. It is important to be aware of this potential increase in risk during and after a COVID-19 treatment. This is especially important in high-risk populations to ensure an early diagnosis and prompt management as well as to reduce transmission. With nearly 180 million cases, the novel coronavirus disease 2019 (COVID-19) has significantly strained healthcare systems worldwide. Approximately 15–30% of patients can develop acute respiratory distress syndrome, requiring prolonged mechanical ventilation and lung recruitment strategies to overcome profound hypoxemia ,5. HowevTuberculosis (TB) remains the number one infectious cause of death worldwide despite global efforts to eradicate the disease. Approximately 25% of the global population has a latent tuberculosis infection (LTBI) with an estimated 5–15% lifetime activation risk . As counA 74-year-old Filipino female with a medical history significant for hypertension, hyperlipidemia, and non-insulin-dependent type II diabetes presented to the emergency department (ED) of a South Florida hospital with a one-week history of increased generalized weakness and worsening shortness of breath. Three months prior, the patient was treated in the hospital for COVID-19 with intravenous dexamethasone and remdesivir, and was discharged home with oxygen. She fully recovered to her baseline and no longer required supplemental oxygen two months before the above onset of symptoms. On arrival to the ED, she was lethargic, but not in severe distress. She had an oral temperature of 37.5 °C, a heart rate of 97 beats/min, blood pressure of 133/78 mmHg, a respiratory rate of 20 breaths/min, and oxygen saturation of 91% on 3 L nasal cannula supplemental oxygen. She had decreased breath sounds bilaterally and rales at the bases. Her heart sounds were distant without any murmurs and she had no peripheral edema. The initial laboratory results are available in Mycobacterium tuberculosis (MTB) complex. Subsequent induced sputum cultures were also positive for MTB, confirming the diagnosis of TB.Throughout the hospitalization, her hypoxemia worsened for which she required BiPAP and subsequently developed paroxysmal atrial fibrillation with a rapid ventricular response. The acute hypoxemic respiratory failure of the patient was thought to be multifactorial and was empirically treated with diuretics, antibiotics, and steroids for a suspected pulmonary edema vs. pneumonia vs. nitrofurantoin-induced pneumonitis as the patient received nitrofurantoin for a UTI one week before arrival to the ED. She was also treated with therapeutic enoxaparin for a non-ST elevation MI although it was likely due to demand ischemia in the setting of severe pulmonary disease. She remained febrile despite optimal treatment, prompting a further workup including a lumbar puncture 15 days after admission; however, the CSF findings were unrevealing for an infectious etiology. The patient had a worsening clinical course requiring intubation and mechanical ventilation. An induced sputum culture sample obtained after intubation showed a positive AFB smear and positive PCR for a Pneumocystis jirovecii prophylaxis with atovaquone. In order to improve efficacy, rifabutin was added, but ultimately the regimen was changed to ethambutol, rifabutin, and levofloxacin due to ongoing hepatotoxicity. Eventually, the respiratory status of the patient improved so she underwent a tracheostomy placement and subsequently improved enough to have the tracheostomy closed. Finally, the patient was discharged to a specialized TB inpatient center to complete six months of MTB treatment with rifabutin, levofloxacin, and ethambutol.Initially, the treatment regimen was rifamycin, isoniazid, pyrazinamide, and ethambutol (RIPE therapy) for MTB. However, the patient developed transaminitis within a few days so she started second-line therapy . The patient was also placed on pulse-dose steroids for presumed immune reconstitution inflammatory syndrome (IRIS) and The above case illustrates the likely risk of a LTBI reactivation in a patient who had recently recovered from COVID-19 treated with steroids and remdesivir. Possible causes were the immunosuppressive sequelae of COVID-19, the effects of the treatment, or a combination of both. In any case, it is essential to consider the risk of a TB infection when treating COVID-19 patients, especially those who have emigrated from TB-endemic areas. For example, the patient presented in this case was an immigrant from the Philippines without other risk factors or known recent exposures. Therefore, the most likely conclusion was that it was a reactivation of LTBI triggered by COVID-19 rather than acute TB.Although TB is less common in the United States (US) than in the rest of the world, it is not rare, especially in areas with large immigrant populations. In 2018, the Centers for Disease Control and Prevention (CDC) reported 9029 new cases of TB in the US with two-thirds of cases in non-US-born people (a rate 14 times greater than US-born people), and 591 cases in the state of Florida .Recently, it has been shown that COVID-19 infections affect the innate immune system and T cells, which are essential to prevent LTBI reactivation. For example, studies have shown that SARS-CoV-2 can cause T cell dysfunction and cytokine storms, leading to immunosuppression. Patients with COVID-19 have decreased numbers of lymphocytes, specifically CD4 and CD8 T cells; there is evidence that these cells undergo “exhaustion”, becoming dysfunctional/ineffective, and express an increased level of immune-inhibitory factors on their surface. These patients also tend to have increased levels of cytokines such as TNF-α, IL-6, and IL-10 . One casAdditionally, the treatment for patients with COVID-19 who require supplemental oxygen is steroids, which also have immunosuppressive effects. The Infectious Disease Society of America (IDSA) guidelines for COVID-19 treatment recommend corticosteroids for a critical illness or severe non-critical illness as well as tocilizumab, which directly blocks the IL-6 receptor, for severe disease with signs of systemic inflammation . There aIn short, we present a case of TB in the US of a patient from the Philippines who recovered from a COVID-19 infection treated with corticosteroids and remdesivir and subsequently developed TB three months after recovery. Given the history and patient risk factors, this was likely a reactivation of LTBI rather than a new acute TB infection. There are currently no guidelines regarding whether screening for TB should be considered in patients with COVID-19, whether they receive treatment with steroids or tocilizumab. However, it seems that, given the increasing number of case reports regarding a co-infection with TB and the possible reactivation of LTBI, it may be prudent to begin screening high-risk patients with COVID-19, especially severe cases that require treatment. There are increasing data in the literature regarding co-infections of COVID-19 and TB, but a paucity of data regarding the possible reactivation of LTBI long after treatment and recovery from COVID-19; this will need further investigation.


Vaccination should be encouraged in elderly care institutions. Furthermore, adequate vaccination in elderly care institutions is an important consideration in current booster (third/fourth) dose schedules.We describe an outbreak of delta variant SARS-CoV-2 on a psychogeriatric ward of elderly patients. Retrospectively collected data was analysed using Fisher's exact test to assess the association between patients’ vaccination status and infection rates, severity of disease and mortality. Vaccination with two doses was shown to reduce severity of disease (5%  Prior to the emergence of the omicron variant, the delta variant was the most transmissible variant of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). Development of SARS-CoV-2 vaccinations began before the emergence of the delta variant. Age is a major risk factor for contracting SARS-CoV-2 virus, developing severe disease and mortality . Two-dosThe outbreak occurred on a psychogeriatric ward of a rehabilitation hospital in Helsinki, Finland. The hospital contains eight wards, with 200 patient beds. Patients are elderly, usually with underlying diseases requiring rehabilitation following acute care. Two of the eight wards are palliative care wards. The psychogeriatric ward consists of 28 patient beds on two different wings . At the On 18 August 2021, a frequently wandering 71-year-old patient developed a runny nose and 3 days later, following development of a fever, tested positive for SARS-CoV-2. All patients on the ward were subsequently tested. Nine patients tested positive during the first round of screening. At this point an epidemic on the ward was declared. Personnel protective equipment was upgraded to include droplet and contact precautions. During patient contact healthcare personnel used FFP2-respirator masks, eye protection (protective glasses/visors), long-sleeved protective aprons/jackets and surgical gloves. The only exception to this rule was if the healthcare worker was entering the patient's room for the sole purpose of delivering medications to the patient. In these instances, use of protective aprons/jackets was omitted. Patients were confined to their own rooms as best as possible. The ward closed to new admissions. All non-essential traffic on the ward  was restricted. The index patient had laboratory confirmation of infection with the delta variant on 22 August 2021. Six symptomatic SARS-CoV-2-positive patients were transferred to a cohort ward in another hospital. Four mildly symptomatic/asymptomatic SARS-CoV-2-positive patients were quarantined in their own rooms. Any patients with symptoms of infection were tested immediately, and all asymptomatic patients were screened a further four times. In total, 20 patients tested positive for SARS-CoV-2 during the outbreak. No new cases were identified in the final two screening rounds performed in September 2021 and the ward re-opened to new patients on 13 September 2021.Eleven inadequately vaccinated healthcare personnel  were quarantined at home. Twenty-four out of 29 healthcare personnel agreed to be screened, of which two tested positive. One was unvaccinated and the other had received only one vaccine dose.During the outbreak, patients were tested using nasopharyngeal SARS-CoV-2 RT-PCR . Genetic sequencing was performed on the index case to confirm infection with the delta variant (B.1.617.2). Further sequencing was requested for all positive samples to identify specific gene mutations and their epidemiological context.We collected data on patients and healthcare personnel on the ward after the outbreak. After determining vaccination status, infection rates and outcomes, we analysed the data using Fisher's exact test to determine whether there was a statistically significant correlation between vaccination status and contracting infection, death rates and disease severity.Two-dose vaccinated patients were defined as those having received two doses of a nationally recommended vaccine , with at least one week having elapsed since the second dose. Patients having receiving less than two doses and patients less than a week from their second dose at time of infection were defined as inadequately vaccinated.Severe disease was defined as presence of one or more of the following; breathing difficulties requiring supplemental oxygen or clinical/radiological evidence of pneumonia . These cBefore the outbreak, 19/27 patients (70%) were two-dose vaccinated and eight (30%) were inadequately vaccinated. No patient had previously been diagnosed with SARS-CoV-2 infection. Age range of patients on the ward was 70–93, mean 82. As well as dementia and psychiatric risk factors, all the patients on the ward had at least one currently recognised additional risk factor for severe disease ),Prior to vaccination, mortality from SARS-CoV-2 was close to 50% in elderly care facilities . In our


Multivariable analysis showed pre-NAT and post-NAT Ki-67 as independent predictors of survival outcomes for luminal A/B HER2 negative subtype. For TNBC, post-NAT Ki-67 was significant alone, and, for HER2 positive, the only borderline association of pre-NAT Ki-67 was observed in relation to the overall survival. Steroid and HER2 receptors were re-assessed just in a portion of the patients with aRCB. The concordance of both assessments was 92.9% for ER status, 80.1% for PR, and 92.2% for HER2. In conclusion, these real-world data of a consecutive cohort confirmed the importance of biomarkers assessment in patients with aRCB, and the need to consider specific BC subtypes when interpreting their influence on prognosis.A residual cancer burden after neoadjuvant therapy (NAT) for breast cancer (BC) is associated with worse treatment outcomes compared to patients who achieved pathologic complete remission. This single-institutional retrospective study of 767 consecutive patients, including 468 patients with assessable residual cancer burden (aRCB) after NAT, with a median follow-up of 36 months, evaluated the biomarkers assessed before NAT from a biopsy and after NAT from a surgical specimen, their dynamics, and effect on long-term outcomes in specific breast cancer subtypes. The leading focus was on proliferation index Ki-67, which was significantly altered by NAT in all BC subtypes ( Breast cancer (BC) is one of the most common malignancies, with an ever-increasing incidence, and one of the most common causes of death from cancer . The goaNeoadjuvant therapy (NAT) administered before definitive surgery is a standard treatment option in patients with BC, especially in aggressive subtypes, such as triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2) positive breast cancer . NAT purA residual cancer burden (RCB) after NAT increases the risk of disease relapse and worsens overall survival (OS) ,11,12. FThe aim of this retrospective study on a single-institution consecutive cohort of BC patients neoadjuvantly treated outside clinical trials was to evaluate biomarkers assessed from the residual cancer burden in patients who did not achieve pCR and analyze their pre-NAT and post-NAT levels and their NAT-induced changes in relation to long-term treatment outcomes.The study included female patients with histologically confirmed, nonmetastatic unilateral BC, who underwent surgery at Masaryk Memorial Cancer Institute between 2012 and 2019 and previously were treated with NAT. Patients with an unknown subtype, treated with neoadjuvant hormonal therapy, treated within clinical trials, and who underwent preoperative radiotherapy were excluded. The final analyzed group consisted of 767 consecutive patients . All patHistopathological records and results of core-cut biopsies and residual tissues after NAT were obtained from original pathological reports and reviewed. Tumor grade, expression of estrogen receptor (ER), progesterone receptor (PR), HER2 status, and Ki-67 proliferative index levels were assessed as follows: grading was determined by the Nottingham Histologic Score system in accordance with the WHO classification of breast tumors ; all immSurgical specimen obtained after NAT was assessed by pathologists as a part of routine practice. pCR was defined as the complete disappearance of all invasive carcinoma from breast and axillary lymphatic nodes, while the presence of in situ carcinoma was allowed (ypT0/is ypN0) . PatientLong-term treatment outcomes were considered in terms of relapse-free survival (RFS) and overall survival (OS). RFS was determined as the time to the first event , and OS was defined as the time to the date of death from any cause. Survival time was calculated from the date of surgery. Patients without the observed event or lost from follow-up were censored at the date of the last appropriate visit.Patient and treatment characteristics were described using standard summary statistics, i.e., median and interquartile range (IQR) for continuous variables and frequencies and proportions for categorical variables. The logistic regression model was used to evaluate the association between Ki-67 and pCR. In patients for whom retesting steroid receptors expression was indicated, the agreement of steroid receptor status between biopsy and surgical specimens was evaluated using concordance analysis and Cohen’s kappa index. The Ki-67 levels between biopsy and surgical specimen were compared using Wilcoxon paired test. Survival probabilities were calculated using the Kaplan–Meier method . Survivap = 0.260, p = 0.363, respectively). For luminal A/B HER2 negative patients, 31 patients achieving pCR had a significantly higher pre-NAT Ki-67 index (p < 0.001).The analyzed group included 767 retrospectively selected breast cancer patients treated by NAT. The median age at diagnosis was 49 years (range 17–85 years). The patient and tumor pretreatment characteristics and NAT regimens according to the BC subtypes are summarized in p < 0.001 for TNBC and HER2 positive and p = 0.019 for luminal A/B HER2 negative, p = 0.030) and TNBC patients (p < 0.001)During a median follow-up period after surgery of 36 months (95% CI 32–39), 153 (20%) relapses and 102 (13%) deaths were observed. The patients achieving pCR had a statistically significantly better RFS for all subtypes . The parameters assessed from the biopsy and surgical specimens for the aRBC group are summarized in Based on steroid receptors status assessed from the surgical specimen, concordance with the biopsy specimen was 92.9% (Cohen’s kappa 0.85) for ER status and 80.1% (Cohen’s kappa 0.59) for PR status regardless of BC subtype. The changes in steroid receptors status according to the BC subtypes are summarized in p < 0.001), while this decrease in Ki-67 expression was milder for TNBC patients (p = 0.001). Consequently, the Ki-67 levels distribution was shifted between biopsy and surgical specimens for HER positive and luminal A/B HER2 negative. Pre-NAT Ki-67 expressions were roughly uniformly distributed for these two subtypes. However, in post-NAT Ki-67 levels, the lower values predominated. In contrast, for TNBC, only a slight change in the level distribution was observed  and TNBC  patients. For luminal A/B HER2 negative patients, a statistically significant effect was also observed for pre-NAT Ki-67 . On the contrary, no significant association of Ki-67 levels with survival outcomes was noted for the HER2 positive subtype. The effect of post-NAT Ki-67 expression on long-term outcomes is shown in In the aRCB group, according to the subtype, the univariable analysis showed a prognostic effect of post-NAT Ki-67 levels and change in Ki-67 expressions between surgical and biopsy specimens for luminal A/B HER2 negative (HR = 1.24 and HR = 1.13 on continuous 10% scale, According to multivariable analyses adjusted to age and pathological tumor and nodal stage , pre-NATThis retrospective analysis of consecutive BC patients undergoing NAT focused on biomarkers commonly pathologically assessed for the biological characterization of breast tumors. The distinct biological BC subtypes respond differently to NAT, and, in addition, their prognostic and predictive factors are different ,34,35,36Patients with RCB after NAT have a worse prognosis ,11,12. TProliferative index Ki-67 is generally considered both a predictive  and progAs shown, the Ki-67 levels in RCB can be used to separate patients with better outcomes. While TNBC patients with low to intermediate Ki-67 expression in RCB had a high rate of disease recurrence, according to the results of our study, patients with luminal A/B HER2 negative subtype with very low levels had compared survival outcomes to patients who achieved pCR.One of the key observations of our study was the different dynamics of KI-67 expression between the biopsy and surgical specimen among BC subtypes. To the best of our knowledge, the previously published studies evaluated the prognostic role of Ki-67 dynamics in terms of absolute or relative differences  concordaWe are aware of the study’s limitations, mainly caused by its retrospective nature. Firstly, not all the patients with aRCB were assessed for all the considered biomarkers due to standard indications for their retesting in clinical practice. Further, in the multivariable analysis, Ki-67 was considered a continuous variable, which is not easily transferable to clinical practice. Ki-67 cut-offs and categories are also not clearly defined, and there are some issues in their reproducibility, as discussed above. It would be very useful to perform further analyses to find unambiguous cut-off values. One of the possible limitations of our study is the length of the period from which the consecutive group of patients was included because the methods of assessment of biomarkers could be updated. Finally, the patient number in pertinent cohorts was not so large, particularly in the HER2 positive subgroup with aRCB, which may affect the statistical analysis. On the other hand, the reported data reflect the real clinical experience and could be used in daily practice.Despite the above limitations, this study was performed on a large consistent cohort of patients and single-institution experience. The results may be considered both in the decision-making process for optimal treatment options and in the prognostication of patients.The evaluation of biomarkers’ dynamic in aRCB in association with long-term outcomes proved desirable. The most effective way to predict the disease prognosis in patients with RCB after NAT is to consider not only the biomarkers’ levels in residual tissue but also their baseline values, taking into account specific BC subtypes. Ki-67 expression after NAT provides relevant independent and additional information in patients who did not achieve pCR. This approach allows the identification of patients with a high risk of disease relapse and optimization of patient management after surgery.


Alzheimer’s disease (AD) is a progressive neuropsychiatric disease affecting many elderly people and is characterized by progressive cognitive impairment of memory, visuospatial, and executive functions. As the elderly population is growing, the number of AD patients is increasing considerably. There is currently growing interest in determining AD’s cognitive dysfunction markers. We used exact low-resolution-brain-electromagnetic-tomography independent-component-analysis (eLORETA-ICA) to assess activities of five electroencephalography resting-state-networks (EEG-RSNs) in 90 drug-free AD patients and 11 drug-free patients with mild-cognitive-impairment due to AD (ADMCI). Compared to 147 healthy subjects, the AD/ADMCI patients showed significantly decreased activities in the memory network and occipital alpha activity, where the age difference between the AD/ADMCI and healthy groups was corrected by linear regression analysis. Furthermore, the age-corrected EEG-RSN activities showed correlations with cognitive function test scores in AD/ADMCI. In particular, decreased memory network activity showed correlations with worse total cognitive scores for both Mini-Mental-State-Examination (MMSE) and Alzheimer’s Disease-Assessment-Scale-cognitive-component-Japanese version (ADAS-J cog) including worse sub-scores for orientation, registration, repetition, word recognition and ideational praxis. Our results indicate that AD affects specific EEG-RSNs and deteriorated network activity causes symptoms. Overall, eLORETA-ICA is a useful, non-invasive tool for assessing EEG-functional-network activities and provides better understanding of the neurophysiological mechanisms underlying the disease. These figures indicate that aging is the greatest risk factor for developing AD and the number of AD patients will sharply increase with the aging of the population in developed countries2. Regarding treatment for AD, the consensus is that drug and physical exercise treatment is more effective in the early course of the disease, even at the prodromal stage of AD [mild cognitive impairment due to AD (ADMCI)]7. Therefore, it is of great importance to find out an objective evaluation method for AD symptoms and provide appropriate medical treatment.Alzheimer’s disease (AD) is the most common type of dementia, accounting for two-thirds of all dementia cases. AD causes loss of synaptic contacts, neuronal apoptosis, and a reduction in neurotransmitter levels—finally leading to a progressive cognitive decline in memory, visuospatial, and executive functions. A recent meta-analysis study revealed that the prevalence of AD in Europe was approximately 5.0% on average, with the prevalence increasing considerably with age: 7.6% and 22.5% for community and institutional patients aged 75–84 years and 85 and older, respectively9. A recently developed automated technique for the analysis of MRI images, voxel-based morphometry (VBM), enabled us to investigate focal structural abnormalities in the brain. This technique has previously revealed that grey matter volume reductions in temporo-parietal regions in AD were related to several types of memory impairments11. Furthermore, longitudinal MRI studies using the VBM technique found that cortical atrophy begins in the medial temporal cortex and then spreads to the parietal cortex through the cingulum bundle in late onset AD, while in early onset AD, it begins in the parietal cortex and then spreads to the medial temporal cortex through the cingulum bundle14. Other brain imaging methods such as functional MRI (fMRI), Positron Emission Tomography (PET), and Single Photon Emission Computed Tomography (SPECT), which measure cerebral blood flow changes and metabolism, have shown a decrease in cortical activity in similar temporo-parietal regions in AD17. fMRI can also measure connectivity between regions  and can assess network activities. A recent meta-analysis of task-based fMRI studies revealed that, compared to healthy subjects, AD deteriorated specific network activities, namely the occipital visual network, default mode network (DMN) and ventral attention network (VAN)18. Among these networks, decreased connectivity within the DMN in the PCC and the precuneus showed correlation with cognitive dysfunction in AD21. Taking these past study results together, it is suggested that AD pathology typically begins in the medial temporal lobe and spreads to the PCC and precuneus (the posterior hub region of the DMN).Brain morphological imaging by Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) has shown typical atrophies in the medial temporal cortex  and the parietal cortex  and precuneus) in AD22. This activity, which is detected through electrodes placed on the scalp, represents a linear mixture of electrical potentials generated from different cortical areas. Thus, to assess the cortical electrical activity from EEG data, it is necessary to solve a linear inverse problem of EEG23. Exact low-resolution brain electromagnetic tomography (eLORETA) is a linear inverse solution that reconstructs cortical electrical activity from EEG data with correct localization, albeit with low spatial resolution, and visualizes cortical electrical activity on a realistic head model27. Therefore, eLORETA with EEG data has been widely used in neuroscience studies31. A number of past EEG and Magnetoencephalography (MEG) studies investigated cortical electrical activity on AD reported increased delta and theta activities in widespread areas and reduced alpha activity in the occipito-parieto-temporal areas compared with healthy subjects35. Also, a number of EEG and MEG studies investigated connectivities between cortical regions of interest (ROIs) in order to elucidate abnormalities of cortical networks38. There is a large number of past EEG and MEG studies focusing on AD using the classical connectivity method , but they reported consistent results only in the alpha frequency band , where cortical electrical activity is strongest among all frequency bands and least susceptible to artifacts38. However, the location of decreased alpha connectivity varied between studies38. Coherence is vulnerable to artifacts and many artifact-resistant connectivity methods have been invented 40. However, past studies using these artifact-resistant connectivity methods had relatively small sample sizes and the results were inconsistent41. To address this, Canuet et al.29 applied eLORETA lagged phase synchronization analysis to a large sample of EEG data from 125 AD patients for the first time. The results indicated reduced connectivity in the upper alpha frequency band between the temporal and parietal ROIs in AD patients, and increased connectivity in the theta frequency band across and within hemispheres compared to healthy elderly subjects. Furthermore, these increased theta connectivities of left temporal ROIs with several right hemisphere ROIs showed negative correlations with total scores of Mini-Mental State Examination (MMSE), suggesting involvement of the left temporal cortex in the cognitive dysfunction observed in AD29. Furthermore, using this connectivity data, recently developed graph theoretical analysis can capture the characteristics of brain networks via the clustering coefficient and average path length. Graph theoretical analysis studies of EEG and MEG connectivity data revealed that cortical networks of AD have changed from efficient ‘small-world’ networks to random networks43.Electroencephalography (EEG) is a non-invasive and affordable tool commonly used in neuroscience research to investigate cortical electrical activities. It is also used in clinical practice to support diagnoses of epilepsy, disturbance of consciousness and dementia. Unlike fMRI, PET and SPECT, which all measure blood flow changes and metabolism in response to cortical activities, EEG directly and noninvasively measures cortical electrical potentials with high temporal resolution (1–2 ms)45. The mathematical essence of this statement is that independence is a stronger requirement than uncorrelation (independence implies uncorrelation but the converse is not true in non-Gaussian data)45. In a previous study, applying ICA to the eLORETA data of 80 healthy subjects (eLORETA-ICA), we identified five EEG-RSNs across alpha, beta and gamma frequency bands and six artifact components  for the first time25. These five EEG-RSNs were occipital alpha activity  from non-Gaussian EEG data, a mathematical decomposition method—independent component analysis (ICA)—is necessaryity Fig. , visual ity Fig. , self-reDMN Fig. . TherefoIn the present study, we aimed to detect AD-specific EEG-RSN activities and attempted to reduce confounding factors by recruiting drug-free AD patients and correcting healthy age-related changes in EEG-RSN activities using eLORETA-ICA analysis in eLORETA software. Also, using Spearman’s rank correlation analysis, we aimed to investigate the relationship between the AD-specific EEG-RSN activities and cognitive dysfunctions measured by cognitive function tests. Our results reveal functional roles of EEG-RSNs and provide valuable information to better understand the neurophysiological mechanisms underlying the disease.90 drug-free probable AD patients and 11 drug-free ADMCI patients met the inclusion criteria described in the Methods section and were included in this study. Demographic and clinical characteristics of our subjects are shown in Table There were significant group differences between AD/ADMCI patients and healthy subjects regarding both age and gender. The group difference regarding age was corrected using linear regression analysis in eLORETA software in the following two analyses.90 AD and 11ADMCI patients showed significantly decreased activities in the memory network and the occipital alpha activity compared to 147 healthy subjects, with the age difference between the AD/ADMCI and healthy groups corrected by linear regression analysis Table .Table 2ZThe age-corrected EEG-RSN activities of the memory network showed correlations with the cognitive function test scores  measured in patients with AD and ADMCI. Specifically, decreased memory network activity showed correlations with worse total score of MMSE, total score of ADAS-J cog, sub-scores of MMSE , and sub-scores of ADAS-J cog  (uncorrected for multiple comparison) Table .Table 3SIn this study, using eLORETA-ICA, we measured the activities of five EEG-RSNs in drug-free AD and ADMCI patients for the first time, with healthy age-related changes of EEG-RSN activities corrected by linear regression analysis implemented in eLORETA software. Our main findings were that: (1) AD and ADMCI patients showed significantly decreased activities in the occipital alpha activity compared to healthy subjects Table , Fig. 4,34. This decreased alpha activity in the occipital cortex is thought to stem from a decrease in acetylcholine levels in the occipital cortex projecting from the basal forebrain47.Our first main finding, i.e., deteriorated activity of the occipital alpha activity in AD, has been repeatedly reported previously34. In this study, using eLORETA-ICA, we extracted decreased activities of the memory network and occipital alpha activity for the first time from the reduced alpha activity in the occipito-parieto-temporal areas in AD. In support of our result, fMRI, PET and SPECT studies with functional connectivity analysis have consistently reported hypoactivity of posterior DMN or PCC and the precuneus in AD21. In addition, longitudinal MRI studies with voxel-based morphometry found that in typical AD, cortical atrophy begins in the medial temporal cortex, and then spreads to connected regions through the cingulum bundle, resulting in disturbance of the memory network activity14. Recently, it has been pointed out that misfolded tau protein, amyloid-beta, and alpha-synuclein may propagate from neuron to neuron via the synapse and spread over connected regions of the brain50. Taken together, the notion of impairment of the network seems to be important in neurodegenerative diseases.Our second main finding, i.e., deteriorated activity of the memory network in the alpha frequency band in AD, might be expected given the memory impairment symptom of AD. However, to our knowledge, previous EEG studies have only detected reduced alpha activity in the occipito-parieto-temporal areas in AD compared to healthy subjects52. An EEG study using standardized LORETA reported that with working memory (WM) load, the precuneus showed increased activity among DAN regions, while the left temporal cortex showed decreased activity during the WM retention period in some healthy subjects53. In addition, an fMRI study, varying lags between registration and retrieval of words, reported that for longer lags, subjects became more reliant on long-term memory than WM, and activity shifted from the precuneus to medial temporal regions in an anti-correlated way51. Therefore, it would appear that the precuneus is the key region of WM. On the other hand, previous neuroimaging and lesion studies have demonstrated that the left medial temporal cortex is the key region of episodic memory and semantic memory and constitutes the left ventral attention network (VAN)57. In our previous study, by applying eLORETA-ICA to EEG data of healthy subjects, we obtained an EEG-RSN composed of alpha activity in the left temporal cortex with anti-correlated alpha activity in the precuneus and presumed the role of the network was a memory network based on its spatial and frequency configuration25. Taking into account both past and present findings, it can be said that the function of this EEG network is WM and declarative long-term memory, as we expected. Furthermore, the decreased memory network activity showed a correlation with worse ideational apraxia. Ideational apraxia is frequently associated with damage to the left posterior temporo-parietal junction, which is thought to be part of the left VAN59. Therefore, this correlation is consistent with the spatial configuration of the memory network.Our third main finding revealed that the decreased memory network activity had correlations with worse impairments of working memory and declarative long-term memory . The memory network was composed of alpha activity in the left temporal cortex with anti-correlated alpha activity in the precuneus, as shown in Fig. 38. Recently, several large-scale EEG studies of AD have been performed using artifact-resistant connectivity methods41. One large-scale EEG study using eLORETA lagged phase synchronization analysis reported reduced connectivity in the upper alpha frequency band between temporal and parietal ROIs in AD patients29. Another large-scale EEG study, using various artifact-resistant connectivity methods, reported that reproducible connectivity reduction was found only in the alpha and beta frequency bands in widespread areas41. Importantly, this reduced alpha connectivity showed correlation with deterioration of global cognitive function measured by MMSE41. Taken together, AD network anomalies examined using these connectivity methods appear to support our results.A large number of previous EEG and MEG studies investigated changes in cortical networks in AD, applying connectivity analysis methods, as outlined in the Introduction31. In particular, DLB showed significant decreased activities in the occipital alpha activity and sensorimotor network, while iNPH showed significantly decreased activities in occipital alpha activity, visual perception, and self-referential networks compared to healthy subjects. Furthermore, EEG-RSN activities showed correlations with symptoms of the diseases, suggesting that EEG-RSNs are functional networks, each with their own function31.This is the first study demonstrating that eLORETA-ICA can sensitively detect AD-specific EEG-RSN activities related to AD symptoms, in a way that has not been possible for any other EEG analysis method to date. This advantage of eLORETA-ICA is mainly due to the fact that this method can properly assess activities of EEG-RSNs from EEG data, and EEG directly detects the cortical electrical activity with high temporal resolution (1–2 ms). In our previous studies, using eLORETA-ICA, we also detected disease-specific EEG-RSN activity alterations in dementia with Lewy bodies (DLB) and idiopathic normal pressure hydrocephalus (iNPH)33. Taking this into account, we checked the basic rhythm of each AD and ADMCI patient and found that the majority of the AD patients and all of the ADMCI patients had a basic rhythm within the alpha frequency band . Moreover, in support of our assumption, a previous PET/fMRI study reported that spatial configuration of the DMN was preserved in AD21. In addition, a previous large sample size fMRI study reported that spatial configurations of the DAN, executive control network, salience network, and sensorimotor network were preserved in ADMCI and mild AD, although connectivity within all networks decreased with increasing clinical dementia rating60. A second limitation is that our correlation analysis results were uncorrected for multiple comparisons. However, the correlations of EEG-RSN activities with AD symptoms were consistent with previous findings from neuroimaging and neurocognitive studies in AD. A third limitation is that the relatively small number of electrodes (19 electrodes) may affect the source localization results by eLORETA. However, in this study, we used eLORETA results of AD patients only to extract 11 independent activities (five EEG-RSNs and six artifact activities). As each independent component configuration was the size of several cerebral lobules, we can assume that our eLORETA-ICA results are robust to some source localization errors.Our results should be interpreted with caution due to certain limitations, the first being that we assumed the same spatial and frequency configurations of EEG-RSNs in AD and healthy subjects and, accordingly, we used the five EEG-RSNs derived from our previous eLORETA-ICA study of 80 healthy subjects to calculate activities of EEG-RSN in AD. Contrary to this assumption, AD shows a slowing of basic alpha rhythm as the disease progressesOverall, our study demonstrated that eLORETA-ICA analysis could extract EEG-RSN activities from reduced alpha activity in the occipito-parieto-temporal areas in AD and revealed that AD specifically affects two EEG-RSNs . Furthermore, the decreased activity of the memory network explained the short- and long-term memory impairments—and ideational apraxia symptoms—of AD. These findings indicate that EEG-RSN activity can be a physiological marker of cognitive dysfunctions in AD and provide us with a better understanding of the physiological mechanisms underlying AD. Based on our results, eLORETA-ICA has shown itself to be a promising and powerful non-invasive tool to assess activities of brain functional networks in patients with other neuropsychiatric diseases.62 and the DSM-V63. Inclusion criteria for AD and ADMCI patients were as follows: (1) no comorbidity of other types of dementia, neurological, or psychiatric disorders; (2) not taking antidementia, antipsychotic, or antianxiety drugs; and (3) no lacunar cerebral infarct lesions or ischemic changes greater than would be expected for the patient’s age on head MRI. 91 drug-free probable AD patients and 11 drug-free ADMCI patients met the inclusion criteria. One AD patient was excluded due to the lack of 120-s resting awake artifact-free EEG segments. Finally, 90 drug-free probable AD patients and 11 drug-free ADMCI patients were included in this study. During follow-up of the 11 ADMCI patients, six patients developed AD, one patient maintained cognitive function within normal limits in MMSE and ADAS-J cog, two patients have not yet had follow-up examinations one year after diagnosis, and two patients discontinued outpatient care. The 147 healthy subjects used in the present study were obtained from our previous study64. The healthy subjects  underwent clinical tests to ensure that their memory and other cognitive functions were within normal limits . The mean age of healthy subjects (58 women and 89 men) was 49.7 ± 19.6 years This study was approved by the ethics committee of Nippon Life Hospital and conducted according to the Declaration of Helsinki. Written informed consent was obtained from all capable patients or their families.65 and ADAS-J cog66. Higher scores on MMSE indicate better performance, while higher scores on ADAS-J cog indicate worse performance.Cognitive impairment was assessed with MMSEEEG data were recorded under a resting, awake, eyes-closed condition for about 20 min at a sampling rate of 500 Hz and band-pass filtered at 0.53 to 120 Hz using a 19-channel EEG system . For each EEG recording, resting awake artifact-free segments of 120 s were selected by visual inspection using Neuroworkbench software  and imported into eLORETA-ICA.31. Briefly, eLORETA first reconstructs cortical electrical activities from scalp EEG recordings27, and then ICA decomposes cortical electrical activities into physiological RSN activities and artifact activities. eLORETA is a linear weighted minimum norm inverse solution, which has the property of correct localization albeit with low spatial resolution27. eLORETA estimates electrical activity of 6239 voxels in the cortical gray matter at a spatial resolution of 5 × 5 × 5 mm3, using a realistic head model67 with MNI152 template68. eLORETA is a freeware which can be downloaded from https://www.uzh.ch/keyinst/loreta and the version (v20171030) was used in this manuscript. eLORETA has been widely used to explore cortical electrical activities and its validity has been proven in healthy subjects and neuropsychiatric patients64. eLORETA cortical electrical activities were calculated in the following five frequency bands: delta (2–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), beta (13–30 Hz), and gamma (30–60 Hz). ICA is a mathematical method that precisely decomposes a mixture of non-Gaussian signals such as EEG and MEG data into independent signals 45. In order to decompose eLORETA cortical electrical activity into a set of maximally independent activities across a population of subjects, group ICA was applied in the eLORETA-ICA analysis69. Finally, a set of RSNs was obtained by maximizing the independence among RSNs, where independence was calculated by fourth-order cumulant45. Then, RSNs were ordered based on total power and colour coded for each frequency band. In the colour-coded map, red and blue represent an increase and decrease in power, respectively, with increasing RSN activity. In this study, in order to calculate RSN activities of AD and ADMCI patients relative to those of healthy subjects, we assumed that AD, ADMCI and healthy subjects all share the same spatial and frequency configurations of EEG-RSNs and used the 11 independent components (five EEG-RSNs and six artifact activities) derived from 80 healthy subjects in our previous study25. Once a set of independent components is determined, eLORETA-ICA can calculate the corresponding activity of each RSN for each piece of eLORETA data. The correction of healthy age-related changes in EEG-RSN activities was performed by linear regression analysis implemented in eLORETA software, where the option of log-transformation of age was selected. The output of the linear regression analysis was a z-score, which shows how much the age-corrected RSN activities deviate from the mean RSN activities of healthy subjects, with the standard deviation being used as the unit of measurement. Figures The eLORETA-ICA procedure was described in detail in our previous studyThe differences in age-corrected RSN activities of the patients (90 AD and 11 ADMCI) compared to 147 healthy subjects were assessed by independent Student’s t-test. The level of significance for t-test analysis was set at P ≤ 0.05 with Holm correction. The correlations of RSN activities with cognitive function test scores were assessed by Spearman’s rank correlation analysis. The level of significance for correlation analyses was set at P ≤ 0.05 (uncorrected). These correlation analyses were performed using the corr function in MATLAB R2022a software.


Noncommunicable diseases (NCDs) are still a major public health problem in Indonesia. Studies have shown that risk factors of NCDs are associated with coronavirus disease 2019 (COVID-19) severity and mortality. However, it is unclear whether NCD risk factors are also risks for new COVID-19 cases. This study aimed to obtain an NCD risk profile among university employees and its associations with contracting COVID-19.adj) and 95% confidence interval (CI) in multivariate analyses.A cross-sectional study was conducted in October 2021. Participants were administrative employees of Universitas Indonesia (UI), Depok City, West Java. Assessment of NCD risk factors was based on the World Health Organization STEPwise approach to NCD risk factor surveillance (WHO STEPS). Demographic, working, and medical-history data were obtained electronically by using a Google Form. Physical and laboratory examinations were done in the Integrated Post for NCDs. Risks were expressed as adjusted odds ratio  and total cholesterol level of 200–239 mg/dL  were independent risk factors, but shift work  was protective against COVID-19.A total of 613 employees were enrolled. Men were predominant (54.8%), and about 36% of them work in shift as security personnel. About 66.7% were overweight or obese and 77.8% had hypertension. There were 138 (22.8%) employees who had COVID-19. Nearly all (95.6%) had been fully vaccinated against COVID-19. At-risk waist circumference (ORThe prevalence of NCD risk factors among university administrative employees was high, increasing the risk of contracting COVID-19. A behavioral intervention program to manage NCD risk factors at the university level is urgently needed according to the Health Promoting University framework. The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is ongoing and has possibly become endemic. Currently, community transmission of COVID-19 in Indonesia has remained at a low level after a second dramatic peak in mid-July 2021  0.52, 95% confidence interval [CI] 0.34–0.80, p = 0.003), having an at-risk waist circumference , and a total cholesterol level of 200–239 mg/dl  are variables that have a significant relationship with a history of COVID-19.Univariate analyses between each risk factors with SARS-CoV-2 infection are presented in the  Tables. Our study showed that more than half of the university employees have at least one biological risk factor associated with NCDs . Having an at-risk waist circumference and a total cholesterol level of 200–239 mg/dL increased the risk of contracting COVID-19 while working in shift prevented it.Assessing the NCD risk factors was our university’s commitment to protecting health and promoting the well-being of our university members as part of the Health Promoting University framework . It seemEarly in the COVID-19 pandemic, obesity was identified as a significant risk factor for severe disease . A populA recent study found that the ratio of adiponectin to leptin (Adpn/Lep) was positively correlated with C-reactive protein level, a marker of systemic inflammation. Increased production of Adpn/Lep was caused by increased adiponectin and reduced leptin; it might be a compensatory response to systemic inflammation . Leptin A large cohort study from the general population in the UK found that modifiable risk factors for contracting COVID-19 were a higher BMI, higher glycated hemoglobin, smoking, a slow walking pace , and the use of blood pressure medication (a proxy for hypertension). A high level of HDL cholesterol was associated with lower risk. The authors concluded that lifestyle modification might reduce the risk of contracting COVID-19 . AnotherMany studies use BMI as an indicator of obesity, which delineates excessive body fat. However, a higher BMI may not represent a higher amount of body fat since it cannot distinguish between fat and lean body mass . We founp = 0.015). However, the significance was lost after adjustment for BMI. The authors concluded that overall obesity has a causal impact on the susceptibility to COVID-19 and obese people are regarded as high-risk [Clinical studies on abdominal obesity and COVID-19 are still evolving. One study found that abdominal obesity was associated with a high chest x-ray severity score better than BMI . A UK stigh-risk .The ACE2 receptor plays an important role in SARS-COV-2 infectivity as the virus uses the receptor to attach itself to the cell surface . ACE2 isIn our study, working in shift was a protective factor against contracting COVID-19. These were the security guards who work individually and mostly outdoor, thereby reducing the risk of COVID-19 transmission. On the contrary, a study in the UK found that shift work was associated with increased risk of contracting COVID-19 . More deThere were several limitations in this study. Firstly, the design was not prospective and included only people who survived COVID-19. Therefore, this study potentially suffered from selection and recall biases. Information on the history of risk factors might have also suffered from recall bias, but in the analyses, we used objective data from the current physical examination and laboratory test results. Secondly, we cannot differentiate between whether the participants had COVID-19 before or after vaccination, and most of the employees completed their vaccination schedule about three months before our data collection. Therefore, the effect of the COVID-19 vaccine on the incidence was not known. Universitas Indonesia is one of the most prominent universities in Indonesia, located in an area where the prevalence of NCDs and COVID-19 is the highest in the country. Hence, the prevalence of COVID-19 and NCD risk factors reported in this study might also be higher than other university employees in Indonesia.University administrative employees have a substantially high prevalence of NCD risk factors, and this has increased their risk of contracting COVID-19. A behavioral intervention program to manage the NCD risk factors at the university level is urgently needed according to the Health Promoting University framework.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


We searched Ovid MEDLINE, Cochrane Library, Embase, Epistemonikos, PubMed-similar-articles, clinical trial registries, journal websites, and reference lists up to February 2022. We included studies comparing the risk of CA-AKI in patients who received CO2 or ICM for peripheral angiography with or without endovascular intervention. Two reviewers screened the references and assessed the risk of bias of the included studies. We extracted data on study population, interventions and outcomes. For the risk of CA-AKI as our primary outcome of interest, we calculated risk ratios (RRs) with a 95% confidence interval (CI) and performed random-effects meta-analyses. We identified three RCTs and five cohort studies that fully met our eligibility criteria. Based on a random-effects meta-analysis, the risk of CA-AKI was lower with CO2 compared to ICM . Only limited results from a few studies were available on procedure and fluoroscopy time, radiation dose and CO2-related adverse events. The evidence suggests that the use of CO2 for peripheral vascular interventions reduces the risk of CA-AKI compared to ICM. However, due to the relevant residual risk of CA-AKI with the use of CO2, other AKI risk factors must be considered in patients undergoing peripheral vascular interventions.The aim of this systematic review was to summarise the comparative evidence on the risk of contrast-associated acute kidney injury (CA-AKI) with CO Peripheral vascular interventions (PVIs) are increasingly performed in patients with peripheral arterial disease (PAD)  and, in During PVIs, the administration of an iodinated contrast medium (ICM) has been described as a risk factor for both acute kidney injury (AKI) and subsequent clinically relevant major adverse kidney events, such as persistently impaired renal function, need for new haemodialysis and death . AlthougThe reported risk of CA-AKI varies between 7% and 11% ,9,10,11.Importantly, it cannot be excluded that other factors beyond ICM contribute to the observed renal impairment and some researchers have even questioned whether ICM plays a significant role at all for the observed deterioration in kidney function ,15, clai2) as an alternative contrast agent [2 acting as a negative contrast agent has been used for a variety of vascular procedures since the introduction of digital subtraction angiography. Because of its high solubility rate and rapid diffusibility via the lungs, CO2 is safe for peripheral intravascular use, but should not be used above the diaphragm to avoid the possibility of causing a cerebral air embolism, associated with stroke or death [For PVI, it is possible to reduce the quantity of conventional ICM or even completely avoid it using carbon dioxide  guidelines in reporting the results of this systematic review .Embase.com  (accessed on 15 February 2022). In addition, we searched the following trial registries to identify unpublished and ongoing studies: ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) (both accessed on 15 February 2022). Two sources were searched from inception to May 2021 but not updated because they had not identified any relevant studies: Epistemonikos.org (accessed on 19 May 2021) and PubMed-similar-articles  (accessed on 18 May 2021). When possible, we combined controlled vocabulary ) and free-text terms in the search strategies. We provide our full search strategies as An experienced information specialist (I.K.) conducted the following database searches from inception to February 2022: Ovid MEDLINE (accessed on 14 February 2022), Cochrane Library (Wiley) (accessed on 15 February 2022) and 2 or ICM for angiography of the lower limb arteries, kidney arteries or infrarenal aorta with or without endovascular intervention . We determined CA-AKI as our primary outcome of interest and included only studies that defined and reported CA-AKI as a binary outcome. Thus, studies reporting only continuous outcomes such as changes in creatinine or in the glomerular filtration rate (GFR) were excluded. For consistency, we will use the more current term CA-AKI throughout this manuscript instead of contrast-induced nephropathy, which was often used in the included studies. Studies that include patients receiving haemodialysis prior to the intervention were excluded. Appendix We included studies that compared the risk of CA-AKI injury in patients who received COAll references identified by our literature search were organised with Endnote X9.3 . We used the Covidence   online sTo assess the risk of bias, we used the Cochrane Risk of Bias 2 (RoB 2) tool  for RCTs2 and ICM, type of ICM, procedure and fluoroscopy time, radiation dose-area product, definition and risk of CA-AKI, additional adverse events and CO2-related side effects, and procedural outcome. One reviewer (G.W.) extracted the data into tables that a second reviewer (E.P.) checked for completeness and correctness.We used electronic extraction tables to collect the following data items from the included studies: first author, year, country, study design, follow-up duration, recruitment period, inclusion and exclusion criteria, patient characteristics, intervention description including amount of CO2 statistics [We conducted meta-analyses if the clinical heterogeneity among studies was reasonable. Based on the number of patients with CA-AKI and the number of patients at risk in each group, we calculated risk ratios (RRs) with 95% confidence intervals (CIs). We performed random-effects meta-analyses using the Paule–Mandel estimator of tau² . To asseatistics . For CA-atistics  in RStudatistics  within tatistics .After deduplication, our searches yielded 901 references. Of those, we included eight studies that fully met our eligibility criteria: three RCTs ,30,31 an2 group than in the ICM group.The included studies’ sample sizes ranged from 64 to 313 participants, and the reported mean age was between 54 and 78 years, with a majority being male. The proportion of participants with diabetes mellitus varied considerably in the individual studies, ranging from 17% to 65%. Most studies included participants with impaired renal function. Two studies only included patients with chronic kidney disease (CKD) stage 3 or higher  ,34. In f2 or ICM for angiography alone or combined with subsequent endovascular interventions. Most studies included patients with PAD as the underlying vascular condition [2 and ICM for endovascular infrarenal aortic aneurysm repair (EVAR) [2. Four publications did not provide this information. A small amount of ICM was applied in a variable number of patients in the CO2 groups in all studies. The control groups received ICM only.Study participants received COondition ,33,34,35r (EVAR)  or angior (EVAR) . One stur (EVAR) . In patiThe included studies’ authors used various definitions for CA-AKI. Commonly, an increase in serum creatinine of >25% or >0.5 mg/dL within 48 h, 72 h or even longer from baseline was considered CA-AKI. Notably, one study considered changes in creatinine up to 1 month. For the RCTs, we assessed the risk of bias as low for one trial  and as s2 group and up to 29% in the ICM group  as compared to those based on the cohort studies . No patient required haemodialysis following the procedure in any of the studies reporting this outcome.Among the eight included studies with a total of 1128 participants, the risk of CA-AKI varied considerably and ranged up to 14% in the COroup see . Based o2 were compared to 211 matched patients who received standard ICM [The largest study we identified was a recent single-centre prospective cohort study, including 313 participants with PAD and renal insufficiency (CKD stage 3 or higher) . Overalldard ICM . The per2 compared to those who received ICM , 0.47; 95% CI 0.22–0.99) and this effect remained of the same magnitude in a relatively small subgroup analysis of four studies that included patients with CKD. However, the authors also included studies in which both the intervention and control groups received CO2 angiography with different doses of additional ICM. We used more stringent inclusion criteria comparing CO2 angiography with bailout ICM administration vs. ICM only, thus reflecting clinically relevant strategies.The findings of our review support the general concept of a renoprotective role of COpatients . In this2 group in our meta-analysis, highlighting the role of additional harmful factors beyond the administration of ICM during vascular interventions.The potential mechanistic pathway of the association between CA-AKI and adverse clinical events remains to be elucidated and it is still under dispute to what extent CA-AKI represents a mediator or risk marker, especially in mild AKI cases . It cann2 with respect to renal outcomes, we cannot draw conclusions about the frequency and severity of CO2-related side effects, as reporting was not sufficient in the included trials. Importantly, data on image quality were limited, which has been reported to be inadequate for clinical decision-making with CO2 angiography, especially for infrapopliteal interventions [2 angiography for vascular interventions.Across the included studies, we observed a major difference regarding the risk of CA-AKI that could be explained by different causes. First, the different sites of peripheral angiographies  as diagnostic or interventional procedures required variable amounts of ICM. In addition, the complexity of the interventions has an impact on the amount of contrast agent. Second, the proportion of patients with diabetes mellitus and impaired renal function at baseline varied. Third, no uniform definition was used for CA-AKI. In particular, the time points and periods of post-procedural creatinine measurements were different. While our review supports a potential benefit of COventions . More reThis systematic review has the following limitations. First, we restricted our eligibility criteria to English and German publications. Second, publication bias could affect our findings since we could only rely on published data. Third, we observed heterogeneity regarding the baseline characteristics of the study participants, types of interventions and applied definition of CA-AKI.2 angiography focus on a small number of patients, further evidence from larger perspective RCTs is needed. There is also a lack of data regarding the association between ICM administration during PVI and clinically relevant composite outcomes, such as major adverse kidney events, consisting of persistently impaired renal function, need for new haemodialysis and death. The studies we identified rarely reported adverse events other than CA-AKI. If reported, the observation period was often very short.Since most published data on the benefits of CO2 for PVI may reduce the risk of CA-AKI compared to ICM. However, a relevant residual risk of CA-AKI has been described with the use of CO2, indicating the influence of other risk factors. This should be considered when patients undergo PVI with CO2 for renal protection.In conclusion, the application of CO