Management of prostate cancer relies heavily on accurate risk stratification obtained through biopsies, which are conventionally performed under transrectal ultrasound (TRUS) guidance. Yet, multiparametric MRI has grown to become an integral part of the care of males with known or suspected prostate cancer. This article will discuss in detail the different MRI-targeted biopsy techniques, their advantages and disadvantages, and the impact they have on patient management. Yet, multiparametric MRI has grown to become an integral part of the care of males with known or suspected prostate cancer. This is in large part due to the development of the Prostate Imaging-Reporting and Data System (PI-RADS)7 While it is still considered by many as the gold standard, systematic TRUS-guided biopsies have important limitations .22 The negative predictive value of PI-RADS for clinically significant prostate cancer is high, with reported values of 83%, 91.7%, and 98.0%.23–25 When a prostate cancer is not detectable with MRI, it is generally lower grade (GS ≤6), a satellite lesion, or apical in location.26Until the publication of PI-RADS, acquisition protocols, interpretation, and reporting were not standardized, and the data describing the accuracy of MRI was heterogeneous and difficult to compile.Multiparametric MRI is used to identify lesions that likely represent high-grade prostate cancer. Once identified, these lesions can then be targeted using one of three strategies: (1) TRUS-guided cognitive MRI targeting, (2) MRI-TRUS fusion targeting, and (3) in-bore MRI targeting.With cognitive MRI targeting, a provider performs a conventional systematic TRUS-guided biopsy, but also attempts to mentally map the location of the target lesion identified on MRI to the real-time TRUS images. As it requires no specialized equipment aside from the usual ultrasound scanner and transducer, TRUS-guided cognitive MRI targeting is the cheapest form of MRI targeting, and is widely available to patients.The cognitive co-registration of TRUS and MRI can at times be challenging, and its accuracy is to a great extent reliant on the skill and experience of the operator. The accuracy of co-registration can be impacted by different positions of the patient, and therefore prostate, during the procedures. The patient lays supine in the MRI scanner, while he typically assumes a left lateral decubitus during the TRUS-guided biopsy. Another factor that may impact the co-registration of images is the different obliquity with which MRI and TRUS images are obtained . Transvei.e. targets) from the MRI data and then projects them onto real-time TRUS images. Typically, a radiologist interprets the MRI scan and identifies the target lesions prior to the biopsy.Fusion targeting employs a computer algorithm to map the prostate and regions of interest  or elastic . Based on experiments on a phantom, these two registration methods perform similarly, except at the edges where rigid registration seems to be more accurate.27Most systems require the biopsy operator to first perform a two-dimensional sonographic scan of the prostate, as prescribed by the vendor of the fusion device, which is then post-processed into a three-dimensional (3D) volume. Once the 3D ultrasound image is constructed, the biopsy operator will also contour the gland, as done with the MRI. Co-registration of the MRI and TRUS maps may be rigid , in addition to maintenance.31MRI-TRUS fusion targeting therefore still requires significant subspecialty expertise on the part of both the interpreting radiologist and the urology operator, both of whom must have training in compatible targeting systems and must devote time to prostate gland segmentation and target definition.32,33 even when the cognitive targeting is performed by an experienced provider, the recent randomized controlled FUTURE trial demonstrated no such difference in the detection of overall prostate cancer or of GS ≥3 +4 disease.34 One indisputable advantage of MRI-TRUS fusion targeting, however, is that it can record the locations of biopsies performed on the 3D fusion model, allowing them to be re-biopsied at future visits (“tracking”), the important clinical utility of which will be reviewed later  or the needle insertion location in the template  is determined using proprietary software. Direct MRI visualization of needle placement into the target lesion allows for high accuracy, needle tracking, and immediate visual confirmation that the desired lesion was sampled. Proponents of this technique also highlight the need for fewer samples to characterize the lesions seen on MRI. Its opponents say it does not completely evaluate the disease status of the patients, as only three or four targets can be sampled per procedure, and tumors that are not clearly visible on MRI will not be detected. Furthermore, in-bore targeting is extremely costly. It not only requires the use of expensive MR-safe equipment, but due to the long amount of magnet time, it affects the workflow of most radiology departments and is uncomfortable for the patient (particularly in closed MR systems). A recent study by Friedl et al showed no significant correlation between operator experience and cancer detection rate, although the biopsy time required and the number of cores taken—both key drivers of cost and patient discomfort—fell significantly between the operators’ first and second year of experience.36,37 concluded that all MRI-targeted biopsy techniques have a higher rate of clinically significant cancer detection (91% vs 76%)37 and a lower rate of clinically insignificant cancer detection (44% vs 83%)37—in other words, lower rates of both underdiagnosis and overdiagnosis.Two meta-analyses evaluating MRI-targeted biopsy techniques versus conventional TRUS-guided biopsy38 In this study, MRI-targeted biopsies could be performed either with cognitive targeting or MRI-TRUS fusion, and either transrectally or transperineally, reflecting the variations in approaches that exist in the community. The study corroborated the findings of the meta-analyses, finding that MRI-targeted biopsy detected significantly more clinically significant cancer, and significantly less insignificant cancer, than conventional TRUS-guided biopsy.38Additional validation of the use of MRI-targeted biopsy was provided by the prospective PRECISION study, which randomized males with clinically suspected prostate cancer but no prior biopsy to either MRI-targeted biopsy or conventional TRUS-guided biopsy.36 and in the randomized controlled FUTURE trial,34 both times finding no significant difference in detection of prostate cancer between any of the three MRI-targeting techniques. This argues that the simple use of MRI for target identification is more important than the method of targeting itself. That being said, reproducibility of the biopsy may be highest with MRI-TRUS fusion given its “tracking” capability, of particular import in the setting of AS.Wegelin et al further analyzed the performance of the individual MRI-targeting techniques both in a metanalysis39 Although MRI-targeted procedures are individually more costly than conventional TRUS-guided biopsies, MRI tends to detect more clinically significant than insignificant cancers, leading to fewer biopsies, unnecessary treatments and complications, ultimately providing a cost savings.A study of MRI-targeted biopsies by Pahwa et al found that all approaches were more cost-effective than conventional TRUS-guided biopsies, even if a conventional TRUS-guided biopsy was performed when MRI showed no lesions suspicious for cancer.40 More recently, however, Diamand et al found a significant reduction in upgrading at prostatectomy when combining systematic and MRI-targeted biopsy , for only a modest increase in downgrading (12.9% vs 9.3%).14 With regards to cost-effectiveness, Pahwa et al.’s found that performing systematic biopsy in the event of a negative MRI result remains more cost effective than conventional TRUS biopsy alone, but less cost effective than performing only MRI-targeted biopsy.39 Nevertheless, ACR guidelines continue to recommend MRI-targeted biopsy as a supplement to systematic biopsy, rather than a replacement.41One of the few remaining areas of controversy is whether or not biopsy-naïve males undergoing MRI-targeted biopsy should undergo any systematic sampling in addition to the targeted sampling of the lesions seen on MRI. Siddiqui et al.’s study, in which the same patients underwent concurrent MRI-targeted and conventional TRUS biopsy, showed that systematic sampling detected GS ≥4 +3 cancers missed by MRI-targeting in 5 out of 542 patients thought to have no cancer based on MRI-targeted biopsy—but that for every 1 such case, 17 additional cases of clinically insignificant cancer were diagnosed: the overdiagnosis problem returned.42,43—the number of males who drop AS for therapy is significant: 37%, 50% and 57% at 5, 10 and 15 years in a study published by Tosoian et al.43 A biopsy technique that more accurately characterizes disease would improve patient selection and allow for closely monitored intermediate-risk patients to be eligible for AS.While prostate cancer-specific mortality is very low in patients on TRUS-guided biopsy AS protocols— between 0.15 and 1.5% depending on eligibility criteria14,44 For example, Hu et al report that a MRI-targeted confirmatory biopsy performed in males thought to be eligible for AS by conventional biopsy upgraded disease 36%.45 Similar studies have confirmed this high number, with a range in the literature of 26–42%.46Multiparametric MRI has shown itself to be such a technique. By purposefully oversampling suspicious lesions, MRI-targeted biopsy can improve the detection rate of high-risk foci disease, improving the correlation between the biopsy cores and whole-organ pathology.47 Clinically, tracking is highly important as it may double the sensitivity for tumor upgrading on repeat biopsy.48In addition, repeat biopsies using conventional TRUS are insensitive at detecting the progression of a known cancer to higher-grade disease. By contrast, MRI-TRUS fusion biopsies have the ability to precisely track and re-biopsy the same lesion across many visits, providing important longitudinal data on a patient’s prostate cancer. Palapattu et al demonstrated the accuracy of lesion tracking by showing that the same clone of cells could be extracted on both initial and repeat biopsy of a given lesion in 96% of cases.49 excluded any male with GS four pattern, the inclusion of males with low-volume GS 3 + 4 disease is now considered appropriate,50 following studies showing that they were no more likely to develop high-risk disease than males with GS 3 + 3 disease.51 Nevertheless, intermediate-risk patients should be closely monitored and may undergo further risk-stratification, including on the basis of MRI findings (such as PI-RADS five lesion) or molecular markers.52Together, the improved correlation with whole-organ pathology and the lesion-tracking capabilities of MRI-targeted biopsy techniques provide more accurate initial and longitudinal grading of disease. This has resulted in a liberalization of AS selection criteria to include intermediate-risk disease: whereas the initial Epstein criteria for AS46 Initial biopsies should ideally performed using MRI-TRUS fusion targeting, and confirmatory biopsies should always be performed using MRI-TRUS fusion targeting, with expedited timing for males with GS 3 + 4 disease. If the confirmatory biopsy upgrades the patient’s cancer to GS ≥4 +3, definitive treatment is usually recommended. Otherwise, patients are followed with MRI-TRUS fusion biopsies every 12–24 months with tracking biopsies of the cancerous lesions. If GS 3 + 4 disease is present, MRI-TRUS fusion biopsies are performed every 6–12 months.Taking these technological developments into account, authors such as Elkhoury et al have proposed updated management pathways that make use of MRI-TRUS fusion biopsies and their tracking ability.68Ga-PSMA) positron emission tomography (PET) has been shown to be useful in detecting prostate cancer both within the prostate gland53 and in recurrent and metastatic disease.54 In addition, it has more recently been shown to increase sensitivity for localized cancer when performed in conjunction with multiparametric MRI as 68Ga-PSMA PET/MRI. A study by Hicks et al of 32 patients with known prostate cancer ahead of radical prostatectomy found that 68Ga-PSMA PET/MRI detected prostate cancer in 97% of patients with the disease vs 79% by multiparametric MRI alone, using whole organ pathology as the gold-standard.55 Particularly with the increasing prevalence of PET/MR scanners, this modality may provide not only increased sensitivity for prostate cancer, but also a "one-stop shop" in which both localized disease and regional or distant metastases are diagnosed in a single study.Gallium 68-labeled prostate-specific membrane antigen-11 (13C-MRS). Hyperpolarized 13C produces >10,000-times greater signal on MRI than 12C.56 Using MRI, one can thereby generate spectral arrays showing the metabolites of a given hyperpolarized 13C-labeled biomolecule. In particular, hyperpolarized 13C-labeled pyruvate has been shown to be of particularly utility in the imaging of cancers, including prostate cancer, which are more reliant on anaerobic respiration than normal cells and so metabolize a much greater proportion of pyruvate into lactate, resulting in a high 13C-lacate/13C-pyruvate ratio. Early human trials of this metabolic MRI have already begun, with promising results.56Another promising variation of multiparametric MRI in the diagnosis of prostate cancer is hyperpolarized Carbon 13 MR spectroscopy (13C-MRS are co-registered to the conventional MRI with which they are concurrently acquired. As a result, both of these advances may ultimately serve as new "parameters" in multiparametric MRI and may be used in the same way to identify and target suspicious lesions, with greater sensitivity and prognostic value than is currently possible.Notably, data from both PET/MR and The increasingly wide adoption and standardization of multiparametric MRI, as well as the development of MRI-TRUS fusion techniques, have had a significant impact in the imaging and tissue diagnosis of prostate cancer. As the GS of MRI-TRUS fusion biopsy cores more closely matches that from whole-organ pathology, males with prostate cancer are being risk-stratified more accurately. Suspicious lesions can also now be tracked and biopsied reproducibly over time. In turn, criteria for eligibility for AS are being liberalized and AS management protocols are evolving.


Patients with novel coronavirus disease 2019 (COVID-19) experience various degrees of liver function abnormalities. Liver injury requires extensive work-up and continuous surveillance and can be multifactorial and heterogeneous in nature. In the context of COVID-19, clinicians will have to determine whether liver injury is related to an underlying liver disease, drugs used for the treatment of COVID-19, direct effect of the virus, or a complicated disease course. Recent studies proposed several theories on potential mechanisms of liver injury in these patients. This review summarizes current evidence related to hepatobiliary complications in COVID-19, provides an overview of the available case series and critically elucidates the proposed mechanisms and provides recommendations for clinicians. Altered liver function tests are reported in up to half of the patients with COVID-19 infection.Disease severity, pre-existing liver disease and older age present a risk for liver injury.Drug-induced liver injury is an important consideration in patients with COVID-19.Hepatotoxic antiviral medications require careful monitoring of adverse effects.SARS-CoV-2 may directly bind to ACE2 positive cholangiocytes and can cause hepatic injury.Activation of the immune system and ‘cytokine storm’ may contribute to an immune-mediated process of hepatic injury in COVID-19.The control of cytokine dysregulation at an early stage could be beneficial to curb the disease progression.In the current pandemic coronavirus disease (COVID-19), almost every country in the world has now registered COVID-19 cases, and the confirmed cases have exceeded one million to date. While initial clinical studies, especially from China, the USA and Italy, have highlighted the dominant clinical symptoms including fever, cough, fatigue and shortness of breath, the later research unveiled shreds of evidence on the extrapulmonary manifestations of the disease. These reports highlighted that beyond severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a complicated course of the disease or even viral infection itself can lead to involvement of other organs and multi-organ failure. The liver is the primary organ for detoxification and metabolism, and maintaining an optimal function is imperative to engage all available therapeutic modalities in the treatment of COVID-19. Abnormal liver function requires clinical evaluation, continuous surveillance and, potentially, specific therapy. To support clinical decision making and optimize the outcome in the treatment of COVID-19, it will be crucial to clearly understand the possible mechanisms involved in liver injury. The current review summarizes the pathophysiology and potentially specific role of COVID-19 in liver disease based on the available data and case series published, ahead of print and non-peer-reviewed preprints as of 2 April. The search strategy is detailed in the Supplementary Material online.Emerging data from small clinical case studies have proposed that liver injury in COVID-19 is frequently seen, but the extent and underlying mechanisms remain undetermined. 1 Autopsy studies in patients revealed that SARS-CoV was detectable in 41% of the liver tissue, with a maximum viral load of 1.6 × 106 copies/g of tissue.2 The pathological findings of liver biopsy specimens from SARS patients showed hepatocellular necrosis, mitoses, cellular infiltration and fatty degeneration. In a recent autopsy analysis of liver tissue from a patient with COVID-19, moderate microvesicular steatosis and mild inflammation in the lobular and portal area was observed. However, this pattern of histological injury is not specific for one etiology but can also be observed during sepsis or drug-induced liver injury (DILI).3The liver exerts a crucial function in host defense against microbes and is involved in most systemic infections as it receives both the portal and systemic circulation. Certain viruses exert a direct cytopathic effect on hepatocytes and cholangiocytes although, in most cases, the pathogenesis seems multifactorial. Yang et al. reported that SARS-CoV could cause direct cytopathic liver injury rather than inducing cellular stress from low oxygen supplies or cytokines as seen in sepsis.4 The cell entry receptor, ACE2, is widely expressed across the human body, including the lungs , gastrointestinal tract , hepatobiliary system (hepatocytes and cholangiocytes), cardiovascular system , the renal system  and the pancreas.5 Recent studies have observed that ACE2 expression in the cell clusters of cholangiocytes was significantly higher than that in the hepatocytes population (59.7% vs. 2.6%).6 The authors conclude that SARS-CoV-2 may directly bind to ACE2 positive cholangiocytes, but not hepatocytes, to exert a cytopathic effect. Cholangiocytes are involved in many aspects of liver physiology, including regeneration and adaptive immune response mechanisms, and the disruption of cholangiocyte function can cause hepatobiliary damage. This is supported by cholestatic markers, including gamma-glutamyl transferase (GGT), that can be found in some, but not all, case series of COVID-19.79 Notably, a recent review reported unpublished data with GGT elevations in 54% of cases.8 In a human organoid model of liver ductal organoids, permissiveness to SARS-CoV-2 infection was observed. Here viral infection impaired the barrier and bile acid transporting functions of cholangiocytes through dysregulation of genes involved in tight junction formation and bile acid transportation, supporting the susceptibility of cholangiocytes in SARS-CoV-2-related liver injury.10Similar to SARS-CoV, SARS-CoV-2 uses the angiotensin-2 converting enzyme (ACE2) receptor protein to attack the host system.8,1113 These mechanisms may contribute to pulmonary and extrapulmonary injuries12,14 and the control of cytokine dysregulation at an early stage could be beneficial to curb the disease progression.15Dysregulation of the innate immune response can be one aspect of liver injury in COVID-19. Patients with COVID-19 exhibit marked activation of inflammatory markers, including abnormal levels of C-reactive protein (CRP), lymphocytes, neutrophils and cytokines, in particular interleukin-6 (IL-6).16 In some of the available case series of COVID-19, a correlation between lymphopenia and liver injury was observed and CRP ≥20 mg/L and a lymphocyte count <1.1 × 109/L were independent risk factors for liver injury. Notably, lymphopenia in COVID-19 studies was reportedly observed in 63% to 70.3% of patients and those with lower lymphocyte counts more susceptible to fatal outcomes.11Hepatic inflammation involving activation of innate immune cells and the release of cytokines is a well-established driver of liver injury from various causes.7--9,1113,2936 A recent systematic review and meta-analysis on LFT abnormalities provided a pooled elevation of aspartate aminotransferase (AST) in 33.3% and alanine aminotransferase (ALT) in 24.1% of cases.39 Various investigators across different studies reported a correlation between the severity of COVID-19 and the degree of liver dysfunction.8,11,25 In one retrospective study, one patient experienced severe hepatitis with ALT of 7590 U/L and AST of 1445 U/L.17 In a report from Shanghai, 50.7% of patients presented with elevated LFTs at the time of hospitalization. Interestingly, these were more likely to have a moderate-to-high-grade fever when compared with the patients with normal LFT .7 On the other hand, mild and moderate cases experienced only discrete abnormal LFT values. These reports support the concept that the disease severity and an older age predispose to more severe liver injury from COVID-19. Based on these case series, patients with severe COVID-19 and pre-existing liver conditions8 – but also elderly patients11 – should undergo surveillance and individually tailored therapeutic approaches for potential liver injury.More than 20 publications to date reported abnormal levels of aminotransferases in patients with COVID-19.28 and thus more prospective data related to the clinical relevance COVID-19 and liver injury is required.A recently published article by Bangash et al. argues after careful review of seven relevant studies that elevated ALT and AST may not necessarily be of hepatic origin alone. The authors have given a timely reminder that it is common for other respiratory viruses to create similar LFT elevations39 More generally, non-hepatotropic viral infections may affect the liver and induce hepatitis or fulminant acute liver failure. However, in the majority of cases, recovery from viral illness is often sufficient to resolve liver injury.40The previous pathogenic coronaviruses, such as SARS-CoV and the Middle East respiratory syndrome coronavirus (MERS-CoV), were also reported to manifest with elevated levels of ALT and AST.17 It is important to remember that LDH and AST elevation could be from muscle damage and not necessarily reflect liver injury.Like in SARS-CoV and MERS-CoV infections, abnormal levels of albumin and lactate dehydrogenase (LDH) were also reported in SARS-CoV-2 infection, with the maximum of 98% and 76% of the patients affected as reported in the study by Chen et al.The current armory of therapeutic agents explored against SARS-CoV-2 includes several antiviral agents, supportive therapy and trials of alternative medicines in many regions of the world. Given the fact that the liver is involved in the metabolism of many drugs, including nucleoside analogs and protease inhibitors that are currently used to treat COVID-19, hepatotoxicity from these drugs can arise.41 Another case series from Wuhan reported that 55.4% of patients experienced liver injuries after treatment with lopinavir and ritonavir.26 Fan et al. published a retrospective study on COVID-19 and observed that the utilization rate of this drug combination was significantly higher in patients with abnormal LFTs compared with patients without LFT elevations . In this study, 47.3% of the discharged patients showed elevated LFTs at baseline, and 23.7% developed abnormalities during hospitalization, suggesting emerging liver injury from drugs or during the course of the infection. Importantly, LFT elevation during the hospital stay was associated with prolonged length of hospitalization.7A recent randomized controlled trial of lopinavir and ritonavir in severe COVID-19 reported that elevated levels of AST, ALT and total bilirubin occurred as adverse effects in a few patients.42 The pharmacodynamic activity of this drug in COVID-19 may involve the arresting of cytokine storms or the activation of CD8+ cells or by preventing endocytosis-mediated uptake of the virus.43 Importantly, hepatotoxicity related to chloroquine or hydroxychloroquine has rarely been reported.Chloroquine, an old drug with a potential of repositioning for new treatment indications, has recently been tried in patients infected with SARS-CoV-2. After a profound success in inhibiting viral replication in vitro, concurrent clinical trials (>20) on chloroquine conducted at 10 hospitals across China have demonstrated superior efficacy in viral control.37In severe cases of COVID-19 with cytokine release, tocilizumab, an IL-6 antagonist, which is humanized IgG1 monoclonal antibody to the IL-6 receptor, has been used as a potential therapy for SARS-CoV-2. In previous clinical trials for other indications tocilizumab was reported to cause mild elevations of LFTs which were usually transient and commonly resolved within 2–6 weeks from exposure.44 that is currently being trialed for SARS-Cov-2 infection. Safety data from ongoing studies will guide on its use in patients, but so far no reports of liver toxicity have emerged.Remdesivir is an experimental antiviral nucleotide analog with broad activity against coronaviruses45 Therefore, it has to be expected that the patients with COVID-19 are also more vulnerable to hepatic injury.9 In a case series from the Zhejiang province, a prevalence of 11% of underlying liver disease was reported. About half of them experienced symptoms for more than 10 days after the illness onset.21 In another study from Wuhan, 9% of patients had the underlying liver disease of cirrhosis or hepatitis.23 Li et al., who investigated risk factors involved with hepatic injury, stated that two patients had presented with alcoholic liver disease at baseline. One of them had a moderate elevation of ALT (120 U/L) within a week of hospitalization, while the other showed no such abnormalities.11 In the initial cohort described from China, 2.7% exhibited hepatitis B virus infection with no mention of worsening outcomes.26 Therefore, the association of the pre-existing liver conditions with disease prognosis and outcomes in COVID-19 will have to be evaluated by comprehensive data registries which recently started enrolling patients (e.g. COVID-Hep Registry and SECURE-Cirrhosis Registry).Scare data has been published for COVID-19 infection in patients with pre-existing liver disease. Experience from previous episodes of coronavirus infection can guide on the extent of hepatic involvement and on the management of patients with pre-existing liver disease. In SARS, the highest mortality rates were observed in the elderly and adults with underlying liver disease.29 Lowering immunosuppression to the most acceptable level appears reasonable in infected liver transplant patients, in particular, in the setting of lymphopenia or clinical worsening of infection.46Management of post liver transplant recipients during the COVID-19 pandemic presents a special challenge for clinicians because of the limited data available and the crucial need to continue immunosuppressive drugs in these patients, which puts them at risk for more severe courses of COVID-19 infection and possible prolonged viral shedding. Case reports from China did not reveal an increased mortality in organ transplant recipients. Qin et al. reported the first case of SARS-CoV-2 infection in a patient with hepatocellular carcinoma who underwent liver transplantation.In addition clinicians have to be aware of drug–drug interactions in the transplant setting. In particular immunosuppressive drugs and ritonavir-boosted antiviral therapies exhibit relevant interactions through CYP34A which lead to increased levels of calcineurin and mTOR inhibitors. Accordingly, chloroquine-based regimes or remdesivir (compassionate use program only) appear to be safe, while boosted protease inhibitors should be avoided see . Additio46Liver function abnormalities – predominantly AST elevation – in COVID-19 appear to be frequent but not severe in most cases. Direct viral hepatotoxicity, DILI, ‘bystander effects’ during a systemic viral infection and potentially sepsis, or exacerbation of an underlying liver disease have to be considered. Ex vivo studies offer that SARS-CoV-2 can selectively target the liver, in particular cholangiocytes through ACE2, and thus hepatobiliary injury appears plausible. Irrespective of the mechanisms involved in the hepatic injury of patients with COVID-19, activation of the immune-mediated pathway seems to be critical. Special high risk populations require close monitoring. These include the elderly population, patients with end-stage liver disease and liver transplant recipients. Symptomatic treatment with acetaminophen and avoidance of non-steroidal anti-inflammatory drugs in cirrhosis is recommended. Cautious use of antiviral agents in patients with decompensated liver disease and drug–drug interactions in post liver transplant patients has to be considered. As emphasized by a recent position paper of the European Study of Liver Disease, elective procedures and routine tests should be postponed according to the risk–benefit at the given time. On the other hand, emergency medical care needs to be done with appropriate measures to prevent infection.Click here for additional data file.Supplemental material, sj-pdf-1-ueg-10.1177_2050640620924157 for Liver injury in COVID-19: The current evidence by Saleh A Alqahtani and Jörn M Schattenberg in United European Gastroenterology Journal


Overall, appropriate empiric treatment was prescribed in only 48/217 encounters (22%) during the pre-intervention period, but this increased to 73/83 encounters (88%) in the post-intervention period (p < 0.001). The results indicate that the treatment protocol was successful in changing prescribing practices and decreasing the use of inappropriate antimicrobials at the LTCF.Urinary tract infections (UTIs) are a commonly diagnosed problem in long-term care facilities (LTCFs), but antimicrobial treatment is often incorrectly prescribed. Although bacterial resistance to antimicrobials commonly used for UTIs, such as trimethoprim/sulfamethoxazole and fluoroquinolones, has been dramatically increasing, they are still commonly prescribed. The purpose of this project was to determine if implementation of a standard treatment protocol for UTIs, which emphasized correct UTI diagnosis and use of nitrofurantoin and cefpodoxime/ceftriaxone as empiric therapy per the institutional antibiogram, changed clinician prescribing practices. This quasi-experimental model utilized two years of pre-intervention and two years of post-intervention data. Three hundred patient encounters were included. Antibiotics prescribed in the pre-intervention period included: trimethoprim/sulfamethoxazole (32%), ciprofloxacin (14%), amoxicillin (13%), levofloxacin (9%), cefpodoxime (9%), ceftriaxone (8%), amoxicillin/clavulanate (5%), nitrofurantoin (4%), and other (6%). By contrast, antibiotics prescribed in the post-intervention period included: cefpodoxime (46%), nitrofurantoin (30%), ceftriaxone (10%), trimethoprim/sulfamethoxazole (8%), amoxicillin/clavulanate (1%), and other (5%). These differences in prescribed drug between the pre-intervention and post-intervention encounters were statistically significant ( Clostridioides difficile infection  vs. 70 [84%]) or White race (n = 58 [27%] vs. n = 13 [16%]), and with a mean age of 71.1 years (SD = 10.49) vs. 73.5 years (SD = 10.58) (age was recorded at the patient’s first encounter during the four-year study period). These demographic differences in race/ethnicity between the pre- and post-intervention period encounters were statistically significant (p < 0.001). A comparison of the antibiotics prescribed in both the pre- and post-intervention periods can be seen in Ciprofloxacin was prescribed for 30 pre-intervention encounters (14%) and one post-intervention encounter (1%), while levofloxacin was prescribed in 20 pre-intervention encounters (9%) and 0 post-intervention encounters . Trimethp < 0.05); there was no statistically significant difference in conducting a culture (p > 0.05). Further, the duration of antimicrobial therapy ordered was statistically significantly different between the pre-intervention and post-intervention periods (p < 0.001), ranging 5-14 days in the pre-intervention period (most often 10 days [57%]) and 7–10 days in the post-intervention period (most often 7 days [86%]). In addition, 134 encounters (62%) that were treated for UTI had catheters in the pre-intervention period vs. 34 (41%) in the post-intervention period ; among tp < 0.001). Overall, bivariate results show that the appropriate empiric treatment was prescribed in only 48 encounters (22%) during the pre-intervention period, but this increased to 73 encounters (88%) in the post-intervention period. This difference was statistically significant (p < 0.001). This indicates the treatment protocol is largely being followed, and it was effective in changing prescribing practices and decreasing the use of inappropriate antimicrobials at the LTCF. For every one-year increase in patient age, the probability of prescribing an appropriate empiric therapy decreased by 0.4%; however, this did not reach statistical significance (p > 0.05). Because this sample was predominantly composed of male African American patients, sex and race/ethnicity were not included in the final model and thus could not be assessed as independent predictors of appropriate empiric therapy. The presence of local signs/symptoms, systemic signs/symptoms, or an indwelling catheter and conducting a urinalysis or culture were not statistically significant predictors of appropriate empiric therapy . The results of adjusted logistic regression models with average marginal effects show that, during the post-intervention period, UTI patient encounters were 66.8% more likely to be prescribed appropriate empiric treatment compared to UTI encounters during the pre-intervention period . This diThe correct diagnosis and treatment of UTIs in patients who reside in LTCFs is challenging, and the literature to help improve practices is limited. Clinical practice guideline recommendations are not available for this population, which makes the selection of appropriate antimicrobial therapy challenging. Antimicrobial resistance to drugs historically used for the treatment of UTIs, such as trimethoprim/sulfamethoxazole and the fluoroquinolones, is increasing, and may vary widely by location . At our p < 0.001 for both). Zabarsky and colleagues evaluated the use of an education intervention to decrease both urine culture collection and antimicrobial treatment of UTIs in a LTCF [p < 0.0001) as did treatment of ASB (p < 0.0017) compared to the three-month period prior to the intervention. Additionally, the reductions persisted for 30 months after the start of the intervention. As part of the implementation of our protocol, education regarding appropriate treatment of both ASB and UTIs was provided to the primary prescribing clinicians. In most of the studies described in the literature, the treatment algorithm or protocol focused primarily on whether or not to prescribe an antibiotic. Unlike previous literature, our protocol incorporated recommendations to reduce inappropriate prescribing in addition to recommendations of selecting a specific empiric antibiotic for those patients with true suspicion of UTI. Numerous reports in the literature describe antimicrobial stewardship interventions to decrease inappropriate antimicrobial prescribing for UTIs. Many studies have involved educational interventions in the acute care setting ,18,19,20n a LTCF . The eduC. difficile infection and increased incidence of extended-spectrum beta-lactamase (ESBL) producing organisms. Therefore, the protocol limits the use of these agents to patients with systemic infections or those with poor renal function. In some cases where cephalosporins were used, there was no clear documentation of systemic signs and symptoms of infection. In other cases, prescribers sometimes considered non-definitive parameters to be signs/symptoms of systemic infection, such as abdominal pain, which may be unrelated to a UTI. In other instances, the only documented abnormality in the patient was “cloudy urine” and a cephalosporin was used for empiric treatment. In addition, although the protocol resulted in a significant increase in appropriately changing urinary catheters, more than two-thirds of patients who should have received a catheter change did not. Finally, the prescribing habits of individual providers was not formally assessed, although there did not appear to be one outlier prescriber but rather collective inappropriate prescribing across the three primary providers within the LTCF. Efforts are currently underway to provide further education to the LTCF practitioners on the appropriate use of cephalosporins and the importance of changing indwelling catheters in patients suspected of having a UTI.Although the protocol can largely be considered a success, areas for improvement were noted. In particular, the use of cephalosporins was questionable in a number of cases, and these patients likely could have been placed on nitrofurantoin empirically. Although cephalosporins have high susceptibility based on the antibiogram, the protocol is designed to limit their use as they are associated with untoward adverse effects, such as the development of The evaluation of this project does have certain limitations that must be addressed. First, this was a retrospective chart review with limitations inherent to this type of study design. Part of the purpose of implementing the protocol was to decrease the number of patients being inappropriately treated for UTIs, which is why the protocol emphasizes obtaining urinalysis results first, prior to initiation of antimicrobial therapy. Although there were fewer courses of therapy in the post-intervention period, it cannot be conclusively determined if this was due to practitioners obtaining urinalyses but not prescribing antibiotics. Because urinalyses are ordered for reasons besides assessment of infection, patients had to be identified for inclusion based on receipt of antibiotic therapy rather than performing a chart review on all patients for whom a urinalysis was obtained. In addition, hospitalizations and deaths from UTIs were not specifically assessed as part of this project. Finally, the ultimate goal of changing prescribing practices would be to see changes reflected in the institutional antibiogram. However, changes in an antibiogram often take years to reflect, so this could not be adequately assessed during the study period, but it will be assessed in the future. The implementation of this UTI treatment protocol was successful and resulted in more appropriate empiric treatment of UTIs. Use of agents with poor susceptibility to uropathogens at our facility, such as trimethoprim/sulfamethoxazole and the fluoroquinolones, decreased after implementation of the protocol, while use of agents with excellent susceptibility, such as nitrofurantoin and cefpodoxime, increased. The use of a standard treatment protocol for UTIs should be considered in other LTCFs as an antimicrobial stewardship initiative to improve empiric antibiotic use.


Statins can decrease hepatocellular carcinoma (HCC) occurrence, but the magnitude and the predictors of these effects remain unclear. This meta-analysis provides a pooled estimate of the impact of statin use on HCC occurrence. Pooled effects were calculated using a random-effects model by means of the DerSimonian and Laird test. Primary endpoint was the time-dependent correlation between statin use and HCC incidence expressed as hazard ratio (HR), both crude and adjusted. The crude and adjusted odds ratios (OR) for HCC occurrence between statin users and non-users were analyzed. Twenty-five studies with 1,925,964 patients were included. Crude OR for HCC incidence was 0.59 (95% CI: 0.47–0.74), confirmed in adjusted analysis . Adjusted HR was 0.73 (95% CI: 0.69–0.76). This effect was more pronounced in HBV patients  and with a cumulative daily dose beyond 365 . Lipophilic statins were associated with reduced HCC incidence . Atorvastatin determined the greater magnitude of effect . This meta-analysis demonstrates the beneficial chemopreventive effect of statins against HCC occurrence. This effect is dose-dependent and more pronounced with lipophilic statins. Hepatocellular carcinoma (HCC) is the fifth most commonly occurring type of cancer and the leading cause of mortality in cirrhotic patients . DespiteThree-hydroxy-3-methyl-glutaryl-coenzyme A (HMG co-A) reductase inhibitors (statins) are effective and commonly used worldwide as a treatment for dyslipidemia, and increasing evidence shows that statins also have anti-inflammatory and anti-oncogenic effects ,6.A previous meta-analysis, based on 10 studies, shed light on the beneficial role of statins in preventing HCC occurrence ; howeverIn the last years, several cohort and case–control studies have been published in the field, hence the need to update the previous data in order to better define the eventual chemopreventive role of statins in hepato-oncology.The aim of this meta-analysis was to provide a pooled estimate of the impact of statin use on HCC occurrence. Primary endpoint was defined as the time-dependent correlation between statin use and HCC incidence . Secondary outcome was the correlation between the overall incidence of HCC and statin administration expressed in terms of the odds ratio (OR), again both crude and adjusted.As shown in Finally, 25 studies reporting 21,576 cases of HCC in 1,925,964 patients were included in the meta-analysis ,30,31,32The main characteristics of the included studies are reported in The recruitment period ranged from 1988 to 2018. Nine studies ,18,20,22Five studies ,20,26,27Baseline clinical and demographical characteristics were well balanced between statin users and the control group. Variables adjusted for were mainly age, sex, and etiology of the underlying liver disease; other comorbidities; and the use of other medications.Quality was deemed mainly high with five observational studies assessed as low-quality articles ,19,23,29Details on methodological characteristics and quality of included articles are shown in p < 0.001). Of note, high evidence of heterogeneity was observed (I2 = 92%).As reported in Adjusted analysis, considering the aforementioned baseline confounders, confirmed the anti-oncogenic effect of statins, with a reported adjusted OR (aOR) as high as 0.74 (95% CI: 0.70–0.78). Heterogeneity slightly decreased to 79% in adjusted analysis B.2=37%; 2=96%).Crude HR was reported only in two studies ,29, confThere was no evidence of publication bias (data not shown).2 = 0%) while only a non-significant benefit was observed in HCV patients, although this result should be interpreted with caution due to the low number of studies and the high heterogeneity  and 0.27 (95% CI: 0.11–0.67) in patients administered a cumulative defined daily dose (cDDD) below or beyond 365, respectively .2 = 19%) incidence while an association between hydrophilic statins  and reduced risk for HCC was not found   were associated with significantly reduced HCC  .2=17%), although further studies are warranted to provide definitive results in this regard.Analysis conducted according to single agents found a significant beneficial effect only with atorvastatin , design , and location (Asia versus western).The only exception was the sub-analysis restricted to RCTs, where an OR around 1 was observed; of note, two out of three studies included as RCTs represented individual patient data analysis of patients enrolled in prospective controlled trials of cholesterol in heart disease  ,32 whereHeterogeneity in the sensitivity analysis was mainly moderate.HCC is one of the most common cancer types and the leading cause of tumor-related deaths in cirrhotic patients .Statins have been shown to consistently reduce liver fibrosis progression, mainly due to their immunomodulatory effects , to mitiA previous meta-analysis found a 37% decreased risk of HCC occurrence in statin users [Through a meta-analysis of 25 studies, we made several key observations. First, we found a 26% decreased incidence of HCC in patients treated with statins, after adjustment for several variables. When considering a time-dependent outcome, such as HR, not influenced by the imbalance in follow-up length between the studies, we confirmed a 27% decreased incidence of HCC when adjusting for several clinical and demographical parameters.Second, this effect was more pronounced and consistent in HBV patients (56% decrease in HCC incidence) and it was found to be linearly correlated to the dose, with a 73% decreased HCC risk in patients administered a cDDD beyond 365.Third, as already observed in previous individual studies ,27, lipoThis preventive effect of statins is likely to be independent of its lipid-lowering effects, because lipid-lowering agents other than statins were not associated with reduction in the risk of HCC in previous reports ,30.The chemopreventive effect of statins in Asian populations, mainly affected by HBV hepatitis/cirrhosis, is well recognized and it was strongly confirmed in our analysis. In fact, HBV genome integration determines several DNA modifications and microdeletions that can target cancer-relevant genes, potentially providing hepatocytes with a growth advantage . StatinsOn the other hand, the anti-oncogenic effect of statins in HCV patients is less evident, probably due to modification of metabolic syndrome, insulin-mediated cell proliferation, and obesity-associated inflammation ,38. A clOne of the novel findings in our study is the clear dose-dependent effect of statins in decreasing HCC occurrence, with 365 cDDDs as the cut-off to observe the highest preventive effects, as already reported in previous individual studies . SeveralThe greater chemoprotective effect of lipophobic statins, clearly outlined by our analysis, is likely due to greater lipid solubility and membrane permeability which enhance their pharmacological effects . FurtherOf note, sensitivity analysis restricted to RCTs did not show a significant preventive benefit with statins although the result should be interpreted with caution due to the low number of RCTs included. It is evident that the limited number of RCTs was insufficient to detect a significant effect of statins, in particular considering that these RCTs were conducted in non-cirrhotic patients, hence with a very low HCC incidence.There are some limitations to our study. First, the limited number of studies in many subgroups does not allow a strong comparison between statins users and non-users in several subsets of patients, in particular concerning single pharmacological agents or based on the use of specific antiviral treatments. Second, several comparisons were weakened by the high heterogeneity. We performed different sensitivity analyses that confirmed the main results and, noteworthy, the heterogeneity decreased when several subgroups were considered separately. To take into account the potential baseline confounders, we considered in our primary analysis the aHR. However, even if the heterogeneity decreased, it remained significant, probably none of the studies adjusted for the same confounders. Other eventual source of heterogeneity could be represented by the different populations enrolled in the included studies, with different risk of HCC occurrence and probably uneven screening campaigns in the different geographic areas. Finally, most of the included studies were retrospective series, hence prone to selection bias.In conclusion, despite these weaknesses, our meta-analysis demonstrates the beneficial chemopreventive effect of statins against HCC occurrence. This effect is dose-dependent and more pronounced with lipophilic statins.Further studies are warranted to confirm these results and to identify the exact setting where this anti-oncogenic effect could be enhanced.Only studies meeting the following criteria were included: (1) RCTs or observational studies recruiting >10 patients with clear exposure to statin therapy; (2) studies published in English; (3) articles reporting HCC occurrence; and (4) studies reporting OR, HR, or data useful for their calculation. Case reports, non-clinical studies, review articles, and animal models were excluded.Bibliographic research was conducted on PubMed, EMBASE, Cochrane Library, and Google Scholar including all studies fulfilling inclusion criteria published until December 2019.The search was conducted by two study investigators (AF and MAA) independently and keywords used were “HMG-CoA reductase inhibitor(s),” “statin(s),” “atorvastatin,” “fluvastatin,” “lovastatin,” “pravastatin,” “rosuvastatin,” or “simvastatin” combined with “liver cancer” or “neoplasm(s).”Relevant reviews and meta-analyses on the use of statins and HCC occurrence were examined for potential suitable studies. Authors of included studies were contacted to obtain full text or further information when needed.The quality of included studies was assessed by two authors independently (AF and MAA) according to the Cochrane Collaboration’s tool for assessing the risk of bias  for RCTsPrimary endpoint of the current meta-analysis was the comparison of HCC occurrence between statin users and non-statin users. Data of HCC occurrence were compared through a random-effects model based on the DerSimonian and Laird test, and summary estimates were expressed in terms of both HR and OR along with their relevant 95% CIs.To partially obviate the bias due to the different follow-up length among the studies and, within each study, between the two treatment arms and to consider not only the number of events but also their timing and the follow-up of censored patients, HRs were considered in the analysis when reported in the included studies.Two separate analyses were conducted for crude and adjusted summary estimates (both OR and HR) and aHR was considered the primary endpoint in the meta-analysis.p < 0.10 for chi-square test and I² <20% were interpreted as low-level heterogeneity.Chi-square and I² tests were used for across studies comparison of the percentage of variability attributable to heterogeneity beyond chance. Probability of publication bias was assessed using funnel plots and with Begg and Mazumdar’s test.Sensitivity analysis was conducted according to the quality of included studies (high versus low), location of the studies (Asia versus western), and study design .A subgroup analysis based on several statin molecule and class (lipophilic versus hydrophilic), etiology of liver disease, presence of diabetes, and cumulative defined daily dose (cDDD: ≤365 versus >365) was performed.All statistical analyses were conducted using RevMan 5.3 software . For all calculations a two-tailed p-value of <0.05 was considered statistically significant.Our meta-analysis demonstrates the beneficial chemopreventive effect of statins against HCC occurrence. This effect is dose-dependent and more pronounced with lipophilic statins. Further studies are warranted to confirm these results and to identify the exact setting where this anti-oncogenic effect could be enhanced.


Respiratory syncytial virus (RSV) is the predominant viral cause of childhood pneumonia. Little is known about the role of viral-coinfections in the clinical severity in children infected with RSV.We conducted a systematic literature review of publications comparing the clinical severity between RSV mono-infection and RSV co-infection with other viruses in children under five years (<5y). Clinical severity was measured using the following six clinical outcomes: hospitalisation, length of hospital stay, use of supplemental oxygen, intensive care unit (ICU) admission, mechanical ventilation and deaths. We summarised the findings by clinical outcome and conducted random-effect meta-analyses, where applicable, to quantitatively synthesize the association between RSV mono-infection/RSV co-infection and the clinical severity.Overall, no differences in the clinical severity were found between RSV mono-infection and RSV co-infection with any viruses, except for the RSV-human metapneumovirus (hMPV) co-infection. RSV-hMPV coinfection was found to be associated with a higher risk of ICU admission (odds ratio (OR) = 7.2, 95% confidence interval (CI) = 2.1-25.1; OR after removal of the most influential study was 3.7, 95% CI = 1.1-12.3). We also observed a trend from three studies that RSV-hMPV coinfections were likely to be associated with longer hospital stay.Our findings suggest that RSV-hMPV coinfections might be associated with increased risk for ICU admission in children <5y compared with RSV mono-infection but such association does not imply causation. Our findings do not support the association between RSV coinfections with other viruses and clinical severity but further large-scale investigations are needed to confirm the findings.PROSPERO CRD42019154761. Respiratory syncytial virus (RSV) is the predominant viral cause of childhood pneumonia -3. It isAs new diagnostic techniques for respiratory pathogens became more widely available in research and clinical settings, co-detection of RSV with another respiratory virus is not uncommon. Studies have shown that co-detection of RSV with other respiratory viruses could account for 35%-40% of all RSV infections in young children -9. HowevThis systematic review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines  admission, mechanical ventilation and deaths. The search strategy  independently screened titles, abstracts and full-texts of the retrieved records from the literature search. For data extraction, a questionnaire was tailored to collect relevant information and results from included studies. The questionnaire consists of two forms, data cataloguing and data extraction. Data cataloguing form collects general information of the study design, study subjects, diagnostic test and statistical method. Data extraction form collects results of comparisons in the outcomes between mono-infection group and coinfection group. More details on the data cataloguing and extraction forms are available in Appendix S3 in the Quality assessment was conducted for all included studies independently by two reviewers (PP and FM). The questionnaire used for the quality assessment was modified based on the Critical Appraisal Skills Programme (CASP) checklist for cohort studies. The questionnaire contained the following seven questions: 1. Did the study address a clearly focused issue?, 2. Were the subjects recruited in an acceptable way?, 3. Was the exposure accurately measured to minimise bias?, 4. Was the outcome accurately measured to minimise bias?, 5. Have the authors taken account of any confounding factors in the design and/or analysis?, 6. Can the results be applied to the local population?, 7. Do the results of this study fit with other available evidence? Answer to each of the question could be “Yes”, “No”, or “Can’t tell”.For each outcome, a narrative summary of results was conducted comparing mono-infection group and co-infection group. The summary was further stratified by pathogen pair if two or more studies were available for a specific pathogen pair. For the outcome length of hospital stay, no meta-analysis was conducted due to the reporting variability . For outcomes other than length of hospital stay, crude odds ratios (OR) were either extracted or calculated from the original results; a random-effect meta-analysis of ORs was conducted if three or more studies were available per co-infected virus and outcome. The choice of conducting a random-effect meta-analysis  was based on the anticipation that populations included in the studies differed by ethnicity, age, clinical diagnosis and hospital setting . Ad hoc sensitivity analysis was conducted for statistically significant meta-analysis results by taking out one study each time from the analysis . Publication bias was assessed by visual inspection of the funnel plot and was tested by Egger’s regression method . All staAfter removal of duplicates, we screened 1720 studies by title and abstract and screened 235 studies by full-text for eligibility. The percentage of agreement between the two reviewers during the full-text screening stage was 93% 218/235). A total of 27 studies /235. A t were incThree studies ,31,36 coSeventeen studies ,38,40,41Nine studies ,38,40,41Twelve studies ,33-37,39Outside the meta-analysis above, RSV coinfections with adenovirus , witNine studies ,27,38,41Four studies ,28,36,39To our knowledge, this is the first systematic review and meta-analysis focusing on the role of viral co-infections in the clinical severity among RSV infected young children. Our findings suggest no association between viral co-infections with RSV and clinical severity, except for RSV and hMPV co-infections, in which this specific pair is found to be associated with higher risk of ICU admission.Similar to the findings of previous reviews on non-RSV-specific viral-coinfections -13, we fWe found that common confounders of the respiratory virus and disease association, such as age, sex, prematurity and comorbidity, did not seem to substantially affect the findings of the association between RSV-coinfections and the clinical severity ,23,30. NOur study is not without limitations. First, although our results did not support the association between other virus pairs with RSV and clinical severity in young children, we lacked the power to reach a firm conclusion of no association. The numbers of RSV-coinfections in most studies were less than 50. More large-scale studies are warranted to confirm our findings. Second, we were unable to differentiate co-detection from co-infection. Co-detection of RSV with the other virus does not necessarily implicate pathogenic effect of either virus. Detection of RSV in the respiratory tract was found to be highly associated with ALRI in children whereas other viruses, such as adenovirus and rhinovirus, when presented alone, were less associated with ALRI and were more often detected in healthy children . This miDespite these limitations, our study is the first systematic review that compares the effects of RSV-specific coinfection on the clinical severity in children <5y. Our study results suggest that RSV-hMPV coinfections are associated with higher risk of ICU admission and this could have relevance to the clinical management of paediatric patients with RSV-hMPV coinfection. No firm conclusions can be made regarding RSV coinfections with other viruses. Further well-designed studies are necessary to confirm our findings.


The relative cerebral blood volume (rCBV) was assessed in the tumor-suspect FLAIR and contrast-enhancing (CE) lesions. We analyzed how a multilevel classification using a molecular subtype, the presence of a CE lesion, and two rCBV histogram parameters performed for PD prediction compared with a decision tree model (DTM) using additional rCBV parameters. Results: The PD rate was 69% in the whole cohort, 86% in Astro-IDHwt, 52% in Astro-IDHmut, and 55% in oligodendrogliomas. In the presence of a CE lesion, the PD rate was higher with 82%, 94%, 59%, and 88%, respectively; if there was no CE lesion, however, the PD rate was only 44%, 60%, 40%, and 33%, respectively. The additional use of the rCBV parameters in the DTM yielded a prediction accuracy for PD of 99%, 100%, 93%, and 95%, respectively. Conclusion: Utilizing combined information about the molecular tumor type, the presence or absence of CE lesions and rCBV parameters increases PD prediction accuracy in diffuse glioma.Rationale and Objectives: Advanced adjuvant therapy of diffuse gliomas can result in equivocal findings in follow-up imaging. We aimed to assess the additional value of dynamic susceptibility perfusion imaging in the differentiation of progressive disease (PD) from pseudoprogression (PsP) in different molecular glioma subtypes. Materials and Methods: 89 patients with treated diffuse glioma with different molecular subtypes (IDH wild type (Astro-IDH The differentiation of diffuse gliomas by their histologic and molecular characteristics enables targeted adjuvant therapeutic management and a better estimation of prognosis. However, classical MR imaging tools such as T2 signal and contrast enhancement (CE) are often insufficient for the initial differentiation between tumor subtypes and in the post-therapeutic evaluation. Therapy-related changes include radiation necrosis (RN), pseudoprogression (PsP), and pseudoresponse (PR) . PR can Our study aimed to estimate the value that DSC-MRI adds to conventional MR imaging for the differentiation between PD and PsP in different glioma molecular subtypes, by using a multilevel classification and a machine learning-based analysis of nine rCBV histogram parameters in two tumor VOIs.wt) or IDH mutated (Astro-IDHmut)) and oligodendrogliomas  were included (n = 95). Finally, patients with incomplete imaging or missed follow-up were excluded, leading to a final patient number of 89  were used as reference standards by retrieving the patients’ electronic health records within 6–9 months from the time of the analyzed MRI. Clinical data included the disease’s further course, clinical examination notes and follow-up imaging. Therapy regimes preceding the DSC-MRI examination  were also noted. The individual outcome for both high grade and low grade glioma was defined in accordance with the RANO  and if awt (31 WHO grade IV), 27 had Astro-IDHmut (5 WHO grade IV), and 20 had oligodendroglioma , 42 had Astro-IDHroglioma . 61/89  with an automatic definition of the arterial input function and model-based post-processing leakage correction. For rCBV histogram analysis, we used an in-house Matlab®-based software , as described in [MRI examinations were acquired using a 3T MRI scanner  according to the standardized brain tumor imaging protocol, including DSC-MRI . DSC-MRIribed in . Two boaAfter automatic distortion corrected transfer of the VOIs to the CBV maps, we normalized all CBV values to a VOI in the contralateral normal-appearing white matter, resulting in relative CBV values (rCBV) and retrieved nine parameters from the corresponding rCBV histogram: the mean, minimal, and maximal rCBV, the standard deviation, skewness, and kurtosis, as well as the 25th, 50th, and 75th percentiles.p-value of less than 0.05 was considered statistically significant.We used the Fisher exact test to assess if the presence of a CE lesions (binary non-parametric variable) could identify PD vs. PsP (binary dependent variable). Univariate logistic regression was used for the continuous variables of mean and maximal rCBV. For the combined assessment of all rCBV parameters in both VOIs we used a machine learning-based approach with a decision tree model , where the input parameters were the presence of a CE lesion and the corresponding nine rCBV histogram parameters (2 × 9 parameters). We included missing rCBV values as a separate category representing the absence of CE as input information. We evaluated the diagnostic imaging performance by receiver operating characteristics (ROC) analysis, including calculation of the 95%-confidence intervals. Statistical calculations were performed with the software JMP 13.0  and on statpages.org. A wt subgroup (+17% compared to the whole group), in 52% in the Astro-IDHmut subgroup (−17%), and in 55% in the oligodendroglioma subgroup (−14%). Astro-IDHwt tumors had a higher prevalence of PD when the MGMT promoter was unmethylated (92% compared to 81% in methylated MGMT promotors).The rate of PD  was 69%. PD occurred in 86% (36/42) in the Astro-IDHwt (74%), followed by Astro-IDHmut (63%), and oligodendroglioma (40%). The presence of a CE lesion raised PD probability in the whole cohort to 82% vs. the initial 69% (+13%), more so in oligodendroglioma  than in Astro-IDHwt  and in Astro-IDHmut . A significant association between the presence of a CE lesion and a higher prevalence of PD was found in Astro-IDHwt (p = 0.0214) and oligodendroglioma (p = 0.0281) with the highest accuracy in Astro-IDHwt  compared to Astro-IDHmut (48%) and oligodendroglioma (45%), in agreement with prior reports [The rate of PsP 31%) in our cohort was comparable with the literature 1% in our. We foun reports ,33.Also, the presence of a CE lesion had a predictive value for PD, as has been described previously ,35. The mut lower rCBV values than Astro-IDHwt [Our results confirmed previous findings of the predictive value of mean and maximal rCBV―parameters that are easily obtainable in the clinical routine. We found that rCBV performed better within the CE lesion (if present) than in the whole suspect FLAIR area, which aligns with the hypothesis that elevated rCBV reflects vessel sprouting with an impaired vascular function (concomitant with blood-brain barrier breakdown) within tumor infiltration zones in PD rather than ischemia-related scar tissue or immune-response related hypercellularity seen in PsP . In the ro-IDHwt ,38. Thesro-IDHwt .wt, PD probability is per se high and increases by the presence of a CE lesion; rCBV does not add much information. In Astro-IDHmut, with a chance of 52% for PsP, the presence of a CE lesion is of minor importance but an elevated rCBV speaks highly in favor of PD. In oligodendrogliomas, the presence of a CE lesion or an elevated rCBV raises the probability of PD from 45% to >80%. Cases without a CE lesion or a high-CBV-lesion are more challenging in all subgroups. However, DTM yields very high accuracy even in these groups, reflecting the added value of all rCBV histogram parameters. It is known that Astro-IDHwt have an inherently worse prognosis than Astro-IDHmut, part of which is that these tumors tend to recur rather than show PsP. It has also been shown that Astro-IDHmut glioma consistently demonstrated less aggressive imaging features than Astro-IDHwt [The multilevel classification with associated probabilities  might sero-IDHwt . We hypomut are not significant, while the rare WHO grade IV Astro-IDHmut still have a significantly worse outcome [wt” does probably not exist and should be designated as “molecular glioblastoma” [wt were WHO grade IV and 18% of Astro-IDHmut were WHO grade IV tumors, which is a good representation of the generally known distributions. It has also been shown that IDH mutation status―along with other factors such as MGMT methylation, overexpression of p53 and 1p/19q codeletion―has a predictive value for PsP, with IDH-mutant tumors being more prone for PsP, which could also be reproduced in our cohort (14% PsP-rate in Astro-IDHwt vs. 48% in Astro-IDHmut and 45% in oligodendroglioma). MGMT methylation has also been shown to correlate with a higher occurrence of PsP [Our results interpretability is inherently limited by the retrospective design of the study with inhomogeneous data. We included both patients who were directly post-treatment, as well as patients with treatment more than 2 years ago; while most PsP occur in the months directly after treatment, there are reports of late onset PsP ,41, supp outcome . Also, ilastoma” . In our e of PsP , which cUtilizing combined information about molecular tumor subtype, the presence of a contrast-enhancing lesion and multiple perfusion imaging parameters can increase diagnostic certainty in the differentiation of tumor recurrence vs. pseudoprogression in diffuse gliomas. DSC-CBV is especially helpful for the prediction of pseudoprogression in IDH-mutated glioma and oligodendroglioma.


M2012, LCRAT, Bach) and the UK (LLP2008) in the German population, comparing with standard eligibility criteria based on age limits, minimal pack years of smoking  and maximum years since smoking cessation. The eligibility criterion recommended by the United States Preventive Services Taskforce (USPSTF) would select about 3.2 million individuals, a group equal in size to the upper fifth of ever smokers age 50–79 at highest risk, and to 11% of all adults aged 50–79. According to PLCOM2012, the model showing best concordance between numbers of lung cancer cases predicted and reported in registries, persons with 5-year risk ≥ 1.7% included about half of all lung cancer incidence in the full German population. Compared to eligibility criteria (e.g. USPSTF), risk models elected individuals in higher age groups, including ex-smokers with longer average quitting times. Further studies should address how in Germany these shifts may affect expected benefits of CT screening in terms of life-years gained versus the potential harm of age-specific increasing risk of over-diagnosis.As randomized trials in the USA and Europe have convincingly demonstrated efficacy of lung cancer screening by computed tomography (CT), European countries are discussing the introduction of screening programs. To maintain acceptable cost-benefit and clinical benefit-to-harm ratios, screening should be offered to individuals at sufficiently elevated risk of having lung cancer. Using federal-wide survey and lung cancer incidence data (2008–2013), we examined the performance of four well-established risk models from the USA (PLCOThe online version of this article (10.1007/s10654-020-00657-w) contains supplementary material, which is available to authorized users. Following results from the earlier US National Lung Cancer Screening trial (NLST) , recent An alternative to concise inclusion criteria is the use of more refined models for the prediction of an individual’s absolute lung cancer risk. Several models have been developed on the basis of an individual’s age and detailed smoking history, presence of pulmonary disease , emphysema), family or personal history of cancer, body-mass-index and socio-economic background indicators. Major models (reviewed in –12) haveIn view of the possible introduction of lung cancer screening in Germany, we analyzed data from federal-wide health surveys and cancer registries to examine screening eligibility according to selected  criteria or risk models, and to describe the risk factor profiles of individuals eligible by these different criteria as compared to those eligible by model thresholds.German Health Update study  is a health monitoring program consisting of cross-sectional surveys conducted by the Robert Koch Institute to provide data on health and disease, health determinants and health behaviors from nationally representative samples of adults in Germany  lung cancer incidence ratios between 0.92 and 1.15), Bach (P/O ratios of 0.88–1.03) and LCRAT (P/O ratios of 0.97–1.17), and more variable results for LLP2008 (P/O ratios of 0.96–1.72) [We examined the performance of eligibility criteria and risk models in German federal-wide health survey and lung cancer incidence data. Predicted risks showed high correlations between all US models, whereas the LLP96–1.72)   .Projected to the overall German population , about one third  of ever smokers in the age range of 50–79 years would be eligible for screening by the NELSON criteria for both age and smoking (55-75-10 × 30/15 ×  255-10) versus about one fifth  by the USPSTF (55-80-30-15) criteria, and 11% by the 55-80-40-10 criteria. Based on risk models, calibrated-in-the-large to federal-wide annual lung cancer incidence  to about 5.0 in the highest decile (5-year risk ≥ 6.5%) [False-positive screen tests can cause major harm especially when they lead to further, invasive medical investigations. An analysis of NLST trial data showed that, even within the limits of NLST eligibility criteria, the ratio of true-positive lung cancer diagnoses over invasive diagnostic work-up  triggered by a false-positive screen-test can still vary substantially according to individuals’ 5-year lung cancer risk, from about 1.35 in the lowest risk deciles of the PLCO ≥ 6.5%) . These fM2012, LCRAT and Bach models, especially, could identify individuals developing lung cancer over the next 5–6 years with up to 10 to 19% greater sensitivity than with the NLST/USPSTF criteria based on minimum age and cumulative smoking history and maximum time since quitting, and similar findings were made in cohorts in Germany [M2014 to 2.32% and 2.49% for LCRAT and BACH, respectively or 3.85% for LLP2008. For the PLCOM2012, LCRAT or Bach models, comparable risk thresholds were reported in ever-smokers in the same age range in the US general population, based on data of the National Health Interview Survey (NHIS) [Analyses in prospective population cohorts in North America , 15, 16  Germany  and Aust Germany . For theM2012), including ex-smokers with longer average quitting times. The most extreme shift towards higher age  was observed for the LLP2008 model, a model that ignores the progressive attenuation of lung cancer risk after smoking cessation.For this German adult population we found that the prevalence of smoking varies quite strongly with age and by sex, with more current smokers in the younger age groups, more long-term quitters (ex-smokers) in older age groups, and overall a higher prevalence of ever smoking among men than among women. The different prevalence of long-term smoking habits in younger and older age groups can be explained by an increasing percentage of long-term quitters (ex-smokers) in the older age groups, plus, for women, a well-documented trend of increasing smoking prevalence in more recent birth cohorts. Reflecting these age-related differences in the prevalence of current and past smoking, screening eligibility by the NELSON (55-75-10 × 30/15 × 25 − 10), USPSTF/NLST (55–80-75-30-15) or also the more stringent 55-80-40-10 criteria was found to be higher in younger and lowest amongst the oldest age groups. Our analyses show that, compared to using the USPSTF/NLST, NELSON or other criteria selection based on risk estimates shifts eligibility towards individuals with older age and with higher prevalence of self-reported COPD  when CT screening may be introduced in Germany.Recommended criteria for lung cancer screening eligibility so far have been defined mostly in terms of lower and upper age limits, combined with basic summary measures of lifetime cumulative smoking exposure and maximum time since smoking cessation, and have been defined mostly as extensions from criteria used in randomized screening trials, in particular the National Lung Screening Study in the USA (NLST). Judging by the good overall balance between projected reduction in lung cancer mortality and gain in life years (LYG) versus expected biopsies or surgeries for benign lesions and cases of over-diagnosis  the US PCompared to standard criteria based on age limits and summary indices for minimal lifetime smoking exposure, such as USPSTF, NLST or NELSON, studies in North America and Germany have shown that risk prediction models more accurately identify the individuals with the highest lung cancer risks in a given study population. Thus, at equal numbers of individuals to be screened, risk-based strategies identify screening participants with 10–20% greater average risk and hence a smaller number to be screened per lung cancer case. Especially in North America this possible gain in screening efficiency is evoked as key argument for using risk models instead of NLST or USPSTF criteria to determine screening eligibility, while maintaining equivalent target numbers of screening-eligible individuals , 25, 26.The possible downside of using minimal model risk as inclusion criterion is that higher-risk groups thus identified tend to include older subjects compared to NLST, USPSTF or NELSON criteria and, depending on the model used, higher numbers of patients with chronic pulmonary disease, which may limit efficiency gains of screening in terms of life years to be gained and result in more over-diagnosis. Recent quantitative modeling of US data showed that, due to these shifts in risk profiles, risk-based screening strategies requiring similar screens among individuals ages 55–80 years as the USPSTF criteria would avert considerably more lung cancer deaths, but result in only modestly higher life-years gained, while leading to significantly more overdiagnosed cases. Further sensitivity analyses, however, suggested that excluding individuals with limited life expectancies (< 5 years) from screening retains the life-years gained by risk-based screening, while reducing overdiagnosis by about two thirds .M2012 or another well-calibrated risk model. Based on federal-wide survey data for the years 2008–2013, we find that this target population would encompass about 3.0 million men and women, and that about 40% of all incident lung cancer cases in Germany will occur within this risk set . In view of ongoing and projected changes in the population structure and smoking habits, future screening programs should be implemented with a surveillance system closely monitoring efficiency in strata of age, sex and eligible risk groups, and with continuous monitoring of benefits and harms in terms of reduced mortality and false positive findings. While at first introduction it will be prudent to stop screening at age 75, in view of rapidly growing risks of being over-diagnosed at higher ages, future work may focus on replacing maximum-age limits by using more differentiated models or decision algorithms for predicting individuals’ residual life expectancy, and their potential of gaining a meaningful number of life years in case of early lung cancer detection, e.g. combining basic questionnaire data and clinical fitness indicators.Taken together, the results from our and other studies suggest that using a minimal risk estimate, determined by a well-calibrated prediction model, as inclusion criterion may improve the overall efficiency of lung cancer screening, and improve the balance of screening benefits over possible harms caused by radiation or false-positive screen tests, provided that concurrent measures are taken exclude individuals with low (e.g. less than 5-years) residual life expectancy. For Germany, and possibly other European countries, a possible start for introducing CT screening could be to target the ever smokers age 50 to 75 who have a 5-year lung cancer risk above the threshold of about 1.6%, e.g. according to PLCOFinally, we recommend that simulation modeling should be performed specifically for the German population context to estimate expected benefits and harms of screening scenarios with eligibility based on absolute model risk thresholds, as compared to more concise eligibility criteria, and to examine the possible consequences of electing more individuals of older age and with more frequent history of COPD and other comorbidities. Furthermore, as recent studies suggest that CT screening may lead to greater relative mortality reduction among women than among men, due to more frequent occurrence of non-small cell and non-squamous tumors among women , 44, 45 Supplementary material 1 (DOCX 1435 kb)Below is the link to the electronic supplementary material.


The present study aimed to examine the association between the presence/absence of help-seeking behavior  and psychological distress among private and public employees by age group using a nationally representative sample of the Japanese population.The present study analyzed data obtained from the 2016 Comprehensive Survey of Living Conditions, a nationwide cross-sectional survey. Of 568,426 participants, 78,284 private and public employees aged 20 to 59 years, who were receiving no mental health services at the time of the survey and reported at least one stressor in daily life, were eligible. The primary outcome measure was self-rated psychological distress as measured by the Kessler Psychological Distress Scale. Multiple logistic regression analyses were carried out separately by age group, adjusting for sociodemographic and job/life-related factors.P < 0.001). Participants without help-seeking behavior had significantly higher odds ratios (ORs) for psychological distress, regardless of age group , 1.6–2.0] and OR = 1.6  for the age 20–39 years and 40–59 years groups, respectively), compared to those showing help-seeking behavior.The proportion of participants not showing help-seeking behavior was significantly higher among those aged 40–59 years compared to those aged 20–39 (30.5% and 22.7%, respectively; Participants not showing help-seeking behavior were more likely to have severe psychological distress, and this trend appeared to be slightly stronger among those aged 20–39 years. These findings suggest that promoting help-seeking behavior is important for improving mental health among workers. Previous systematic reviews have suggested that several factors, such as low mental health literacy, financial issues, and stigma and negative attitudes towards people with mental health problems, influence help-seeking behavior  for psychological distress or mental health-related problems.3 medical professionals,4 ambulance personnel,5 railway workers,6 police workers,7 and firefighters,8 and all have used unrepresentative data. To our knowledge, no previous study has examined associations between help-seeking behavior and mental health issues among workers in various industries/occupations using nationally representative data.Promoting help-seeking behavior for mental health problems among workers has also been an important occupational health issue worldwide. Previous studies regarding help-seeking behavior for mental health issues among workers have focused on specific industries or occupations, such as military personnel,9,10 Thus, it is necessary to examine age-specific associations between help-seeking behavior and mental health issues among workers.Previous research has shown that the types of or resources for help-seeking behavior for mental health problems vary across age groups. Compared to older persons, young individuals tend to avoid seeking professional help for mental health issues and use more informal sources of help, such as family members, parents, and friends.11 The CSLC is a cross-sectional nationwide survey using a representative sample of the Japanese population. It is one of Japan’s designated Fundamental Statistics.Since 1986, the Japanese Ministry of Health, Labour and Welfare (MHLW) has conducted the Comprehensive Survey of Living Conditions (CSLC), which provides a large database of information on Japanese residents’ basic living conditions, including working conditions, occupation/job-type, mental health status, and help-seeking behavior.Thus, the present study examined the association between the presence/absence of help-seeking behavior and psychological distress among private and public employees by age group, using a nationally representative sample of the Japanese population from the CSLC. A better understanding of the age-specific associations between help-seeking behavior and psychological distress using nationally representative data may contribute to promoting help-seeking behavior for mental health issues among workers with different ages and demographic/job-related backgrounds.11 The large-scale CSLC has been conducted by the MHLW every 3 years to investigate basic living conditions in order to develop and implement a national policy regarding health, labor, and welfare. The CSLC comprises various questionnaires and is addressed to all members of households selected randomly from national census districts in Japan.The present study analyzed data obtained from the CSLC.11In the present study, we analyzed data from the Household Questionnaire and the Health Questionnaire of the 2016 CSLC, which included 224,208 households with 568,426 individuals .The eligibility criteria for the study participants were as follows: 1) Japanese residents aged 20 to 59 years, (2) private or public employees , (3) having reported at least one stressor in daily life, and (4) having received no mental health services for depression or other mental disorders at the time of the survey. In the CSLC Health Questionnaire, a single question asked participants whether they were private or public employees, regardless of contract type. In addition, only participants who reported at least one stressor answered questions concerning help-seeking behavior; thus, participants who did not report any stressor in daily life were excluded. Furthermore, to examine the association between help-seeking behavior and mental distress, we removed the participants who were receiving psychiatric treatment and medication. With regard to the presence/absence of mental health service use, participants were asked the question “Are you attending a hospital due to illnesses/injuries at present?” Those who answered “yes” were subsequently asked to select all illnesses/injuries from a list of 42 categories, including depression and/or other mental disorders. Of 568,426 participants, 78,284 were eligible for the present study  regarding their present problems/stressors. Participants who reported not seeking any help were asked to select their reasons from the following three options: (1) “I want to consult, but I have not done so yet,” (2) “I want to consult, but I do not know where to consult,” and (3) “I do not need to consult anyone.” Participants were asked to select all that applied from among the 11 categories.14 job type was categorized into the following seven subtypes: managerial, professional/technical, clerical, sales/service, manufacturing, transport/construction, and other workers.As potential confounders, other demographic , job-related  or non-standard (including part-time)], and presence/absence of job-related stress), and life-related variables  were also measured. Based on the Japan Standard Occupational Classification established by the Japanese Ministry of Internal Affairs and Communications,15 The K6 consists of six items that assess psychological distress over the previous 30 days . Respondents rate each item on a five-point scale . Total scores thus range from 0 to 24, with higher scores indicating higher psychological distress. Following previous studies, we defined a K6 score of ≥13 as indicating severe psychological distress. In the present study, we used the Japanese version of the K6, which has high internal consistency and reliability.16The primary outcome measure for the present study was self-rated psychological distress. Non-specific psychological distress during the last 30 days was measured with the Kessler Psychological Distress Scale (K6).First, for each variable, cross-tabulation was conducted by age group. To examine whether the frequency distribution of the variables, including help-seeking, differed by age group, we performed chi-square and Fisher’s exact tests. To examine whether the frequency distribution of the type of help-seeking differed by the presence/absence of psychological distress and age group, we performed Fisher’s exact tests.To examine the association between the presence/absence of help-seeking behavior and psychological distress, logistic regression analyses were carried out with the presence/absence of severe psychological distress as the dependent variable. In the logistic regression models, we adjusted for demographic factors , job-related factors , and life-related factors . The presence/absence of job/non-job-related stress was assessed using a list of 21 categories of stressors, and stressors other than those related to a job were recategorized as “non-job-related stress.” To examine whether the association between the presence/absence of help-seeking behavior and psychological distress differed by age group, logistic regression analyses were carried out by age group.P < 0.05 was considered statistically significant. All analyses were conducted using SPSS version 25 .Of the 78,284 eligible participants, 7,357 had missing data on demographic and job/life-related variables. These participants’ data were removed from the study. Thus, data from 70,927 participants  were included in the analysis .Table P < 0.001). Regardless of age group, the proportion of participants without help-seeking behavior was significantly higher among those with severe psychological distress than those without . In both age groups, family members, friends, and supervisors in the workplace were the most frequently reported sources of help sought by respondents.Table Table In the present study, we examined the association between the presence/absence of help-seeking behavior and psychological distress by age group in a nationally representative sample of Japanese workers. The proportion of participants without help-seeking behavior was significantly higher among older participants compared to younger participants. Participants without help-seeking behavior tended to have severe psychological distress regardless of age group, and this trend appeared to be slightly stronger among those aged 20–39 years.17 These differences in the proportions of those with severe psychological distress might be partially due to the fact that the sample in the present study consisted only of private/public employees with problems in their daily lives who did not use mental health services.Among the 2016 CSLC participants not using any mental health services for depression or other mental disorders, 9% and 6% of those aged 20–39 and 40–59 years, respectively, reported severe psychological distress. Previous studies in Japan reported that approximately 4% of the general public aged 18 or older had severe psychological distress defined by a K6 score of ≥13 in 2007, 2010, 2013, and 2016.17,18 Furthermore, the results of the present study might be consistent with the suicide statistics from the National Police Agency of Japan showing that the proportion of suicides due to work-related issues appeared to be higher among those aged 20–29 years than among older people.19The proportion of participants with severe psychological distress was significantly higher among younger participants compared to older participants. These findings are consistent with previous studies showing that the proportion of individuals with severe psychological distress was higher among young people. These trends have gained strength in recent years in economically developed countries, including Japan.20,21 The findings of the current study are consistent with previous studies suggesting that younger individuals have better mental health literacy than older persons. Moreover, poor mental health literacy may delay help-seeking.22The proportion of participants without help-seeking behavior was significantly higher among older participants compared to younger participants. Mental health literacy, defined as knowledge and understanding regarding symptoms and treatment of mental health issues, was found to be one of the key factors for help-seeking behavior related to mental health issues such as depression.After adjusting for sociodemographic and job/life-related variables, participants without help-seeking behavior were more likely to have severe psychological distress regardless of age group. Help-seeking behavior has been suggested to have a buffer effect against psychological distress. Our findings suggest that removing barriers to help-seeking behavior, especially among those who did not have help resources  is crucial for improving mental health among workers.23 Third, there was no information concerning the industries  of the CSLC participants. However, the CSLC included questions regarding participants’ occupation/job-type, and this factor was adjusted for as a potential confounder in the analyses in the present study. Finally, caution should be exercised when generalizing the present findings to populations with different backgrounds, as the sample in the present study was restricted to private and public employees in Japan in 2016.The present study analyzed the association between the presence/absence of help-seeking behavior and psychological distress among workers adjusting for relevant job/life-related factors, using a large representative data in Japan with a moderate response rate. However, this study has several limitations. First, although the CSLC is a large nationwide survey using a representative sample, due to its cross-sectional nature it was not possible to determine causality between help-seeking behavior and psychological distress. For instance, intention to seek help may be partially affected by the mental health status of participants, and vice versa. Second, psychological distress, the dependent variable, was assessed by self-ratings rather than using structured interviews with mental health professionals. However, the K6 has been validated in studies using a diagnostic structured interview method.The proportion of participants without help-seeking behavior was significantly higher among older participants compared to younger participants. After adjusting for sociodemographic and job/life-related variables, participants without help-seeking behavior were more likely to have severe psychological distress regardless of age group. This trend appeared to be slightly stronger among those aged 20–39 years. The findings of this study using a nationally representative sample of the Japanese population suggest that, regardless of age, promoting help-seeking behavior is important for improving mental health among workers.