Safety-net hospitals (SNHs) and facilities are the cornerstone of healthcare services for the medically underserved. The burden of chronic liver disease—including end-stage manifestations of cirrhosis and liver cancer—is high and rising among populations living in poverty who primarily seek and receive care in safety-net settings. For many reasons related to social determinants of health, these individuals often present with delayed diagnoses and disease presentations, resulting in higher liver-related mortality. With recent state-based policy changes such as Medicaid expansion that impact access to insurance and critical health services, an overview of the body of literature on SNH care for chronic liver disease is timely and informative for the liver disease community. In this narrative review, we discuss controversies in the definition of a SNH and summarize the known disparities in the cascade of the care and management of common liver-related conditions: (1) steatotic liver disease, (2) liver cancer, (3) chronic viral hepatitis, and (4) cirrhosis and liver transplantation. In addition, we review the specific impact of Medicaid expansion on safety-net systems and liver disease outcomes and highlight effective provider- and system-level interventions. Lastly, we address remaining gaps and challenges to optimizing care for vulnerable populations with chronic liver disease in safety-net settings. The mission of safety-net hospitals (SNH) and facilities in the United States (US) is to provide comprehensive and critical healthcare services to individuals regardless of their ability to pay. For those with chronic liver disease, there is a greater reliance than ever on these institutions, as the burden of cirrhosis and its complications has increased over the past two decades, particularly among populations living in poverty who are under- or un-insured. This was the case when hepatitis C (HCV) was the dominant liver disease etiology in the US and remains the case as alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD) come to the forefront. These safety-net populations with liver disease—comprising low-income racial/ethnic minorities and immigrants in both urban and rural regions—face substantial obstacles in accessing high-quality healthcare and in turn experience many disparities across disease conditions, which is increasingly recognized to be the consequences of negative structural and social determinants of health.In this narrative review, we describe the increasing burden of chronic liver disease and cirrhosis-related complications in the low-income populations served by SNHs, highlight barriers to care and disparities in liver-related outcomes, and provide an overview of patient-, provider-, and system-level interventions in the delivery of SNH liver disease care. A focused perspective on the impact of Medicaid expansion and policies on both liver disease outcomes and safety-net systems is also presented. We conclude with an overview of knowledge gaps and future directions for research and policy.The Institute of Medicine defines the safety net in healthcare as “those providers that organize and deliver a significant level of health care and other needed services to uninsured, Medicaid and other vulnerable patients” . This deRegardless of the definition used, there are general characteristics of the population served—and barriers to care—that are consistent across safety-net systems. First, a higher proportion of safety-net populations are racial and ethnic minorities, more so in urban areas  . These ip = 0.0005) [Chronic liver disease and cirrhosis are common in the US, accounting for 400,567 emergency department visits and 280,645 hospital admissions in 2018, according to the Healthcare Cost and Utilization Project (HCUP) . The bur 0.0005) . Inpatie 0.0005) . Indeed,The liver disease etiologic profile of safety-net patient populations may depend on the clinical context, though ALD and HCV are leading conditions. Among the hospitalizations in five different safety-net hospitals across the country, ALD alone was most common at 28–49% ,22. ThisThe following sections highlight presentation and outcome disparities experienced within safety-net systems and among safety-net populations for common liver disease conditions  associated with elevated transaminases. Interestingly, the correlation between BMI and transaminase elevation was stronger in safety-net patients without diabetes compared to those with diabetes, supporting the need to expand MASLD screening beyond traditional high-risk groups . A proviFrom 2011 to 2017, the percentage of alcohol-induced hepatitis hospitalizations with Medicaid as the primary payer increased from 21.5% to 32.5% , with inThere are suboptimal rates of guideline-concordant screening and surveillance for HCC  in the US for all cirrhotics, but they are lowest in those of a lower socioeconomic status . Only onAmong safety-net patients, a lack of surveillance has been associated with more advanced HCC at diagnosis and worse overall survival, particularly among the uninsured ,36,37. HSafety-net patients also experience disadvantages at multiple stages of the viral hepatitis care continuum, starting with screening. At one large SNH in California, the risk-based screening rates for hepatitis B (HBV) and HCV were only 25.1% and 30.9%, respectively , with loDownstream from screening, follow-up testing and linkage to care for viral hepatitis has been relatively poor amongst safety-net populations. In a retrospective analysis of 600 safety-net patients with chronic HCV between 2002 and 2018, only 57.7% were seen by HCV specialists within a year of diagnosis, though the vast majority (91.6%) were followed-up after the initial visit . In termFortunately, treatment for viral hepatitis is highly effective. Across multiple US SNHs, real-world studies report high sustained virologic response (SVR) rates for direct-acting anti-HCV (DAA) treatment in underserved populations with significant barriers to healthcare ,50,51,52The safety-net setting presents unique challenges for patients with cirrhosis. According to a study of cirrhosis patients admitted for liver-related decompensations in four SNHs across the country, inpatient mortality ranged from 4 to 13%, and up to a quarter were readmitted within 30 days . CompariLiver transplantation (LT) is lifesaving for patients with complications of cirrhosis but is a difficult and complex process for safety-net populations to navigate. Sociodemographic disparities in access to LT are frequently reported, including lower referral and higher MELD upon listing among racial/ethnic minorities and the underinsured ,63. In ap < 0.0001) and an independent association between HCV education and SVR  [p < 0.0001) [To address some of the disparities highlighted above, many studies have focused on interventions to improve care delivery to vulnerable populations with liver disease within safety-net systems see . The str = 0.03) . When co 0.0001) . Similar 0.0001) .Among safety-net populations, patient navigators have the potential to improve the completion of screening, linkage to care, and retention within healthcare systems . For exap < 0.001 for both comparisons) [p < 0.001) at 6 months post-randomization [Mailed outreach programs within safety-net healthcare systems have increased success in recommended screening uptake. For HCC surveillance, Singal et al. demonstrated that mailed invitations for HCC screening US plus patient navigation (47.2%) or mailed invitations alone (44.5%) yielded higher screening rates compared with the rates for those who received usual care (24.3%) (arisons) . An extearisons) . Notablyarisons) , suggestmization .p  =  0.03) and median overall survival  [p = 0.005) [Additional innovations within safety-net systems are worth mentioning. In a SNH in Atlanta, establishing a HCC multi-disciplinary management team increased HCC treatment rates  . The use= 0.005) . Lastly,= 0.005) .On 1 January 2014, a Medicaid expansion (ME) policy was enacted under the Affordable Care Act (ACA) in which states had the option to extend Medicaid coverage to most non-elderly adults with an income of up to 133% of the federal poverty line. Under this policy, 30 states expanded Medicaid in 2014. In fact, ME led to one of the largest gains in in health insurance for non-elderly adults in the United States and extended health insurance to >20 million previously uninsured patients . This poVarious aspects of liver-related care have improved since ME. With regards to liver disease-related mortality, 8.3  fewer liver-related deaths per 1,000,000 adult residents per year occurred in ME states compared with what would have been expected to occur if those states followed the same trajectory as non-ME states . CirrhosThere is some data to suggest that minority groups have not benefitted equally from the ME policy with respect to LT, though this remains to be characterized further . In addiHow has ME specifically impacted SNHs? One study examined the percentages of Medicaid inpatient days, percentage of Medicaid revenues, and uncompensated care costs as a percentage of total operating costs in the pre- and post-ME eras and found that ME had a significant favorable financial impact on SNH; ME states had larger Medicaid revenues and reduced uncompensated care costs, and these changes improved operating margins . AnotherOne of the first steps to improving the delivery of care to SNH patients is to standardize the definition of a “safety-net” across research and policymaking in a manner that accurately captures the underlying population and resource constraints, such that funding can be appropriately allocated. Toward this end, there has been a call to action for a “sliding-scale” or continuous measure of disadvantage. Upstream policy changes that match SNH compensation to this sliding scale would be of great benefit. Next, addressing the well-documented disparities in SNH populations with liver disease requires sophisticated, comprehensive, and prospective assessments of social needs to facilitate a more targeted and effective implementation of social interventions. With respect to research, investigators should collect multilevel data  to investigate direct and indirect pathways and the interactions between such factors on liver disease care and outcomes. Lastly, we need to learn how best to implement strategies demonstrated to be effective in improving liver care delivery across different SNHs, including structured and integrated multi-disciplinary models, patient navigation services, and educational efforts. There is a gap in studies demonstrating the cost effectiveness and even potential cost savings incurred with these interventions; these studies would be helpful in promoting administrative buy-ins. Low-cost interventions that utilize existing healthcare visits or harness technology  may also be paths forward.Challenges that remain to be addressed in SNHs include the following: (1) accessing the most vulnerable underserved populations  who have multi-level barriers that impede healthcare delivery; (2) establishing programs  that are logistically and financially sustainable in the long term, to continue to address these care gaps; and (3) continually investing in and building the infrastructure needed to provide high-quality, cost-effective, and evidence-based care in safety-net systems. Achieving these goals will require a coordinated response from all safety-net stakeholders including but not limited to providers, hospital administrators, policymakers, researchers, and community advocates. Additionally, despite the many challenges ahead, the high prevalence of liver disease and its significant morbidity and mortality mean efforts to shore up the “safety-net” for our nation’s most vulnerable patients with chronic liver disease is a critical and worthwhile venture.


Resting state functional MRI data and serum blood samples were collected and compared before and after the intervention. We could not identify differences between the groups in resting state functional connectivity. However, the functional organization of attention-, salience- and executive functioning-related neural networks differed between both intervention groups and the waitlist control group. Additionally, physical training could alter therapy-induced immune deregulation. In conclusion, physical training had the most pronounced effects on functional network organization and biomarkers of inflammation, two mechanisms that might be involved in CRCI.Cognitive impairment is a common side effect of cancer treatment and impacts the quality of life of cancer survivors. As there is currently no golden standard for the treatment of cancer-related cognitive impairment (CRCI), we investigated the potential of a mindfulness-based intervention to impact the underlying mechanisms of CRCI. Breast cancer survivors with cognitive complaints (n = 117) were randomly assigned to a mindfulness-based intervention (n = 43), physical training (n = 36), or waitlist control condition (n = 38). Region-of-interest (ROI) and graph theory analyses of resting state functional MRI data were performed to study longitudinal group differences in functional connectivity and organization in the default mode, dorsal attention, salience, and frontoparietal network. Additionally, bead-based immunoassays were used to investigate the differences in inflammatory profiles on serum samples. Measures were collected before, immediately after and three months post-intervention. Results: No ROI-to-ROI functional connectivity changes were identified. Compared to no intervention, graph analysis showed a larger decrease in clustering coefficient after mindfulness and physical training. Additionally, a larger increase in global efficiency after physical training was identified. Furthermore, the physical training group showed a larger decrease in an inflammatory profile compared to no intervention . Conclusion: Both mindfulness and physical training induced changes in the functional organization of networks related to attention, emotion processing, and executive functioning. While both interventions reduced functional segregation, only physical training increased functional integration of the neural network. In conclusion, physical training had the most pronounced effects on functional network organization and biomarkers of inflammation, two mechanisms that might be involved in CRCI.Background: Cancer-related cognitive impairment (CRCI) has been linked to functional brain changes and inflammatory processes. Hence, interventions targeting these underlying mechanisms are needed. In this study, we investigated the effects of a mindfulness-based intervention on brain function and inflammatory profiles in breast cancer survivors with CRCI. Methods: Female breast cancer survivors reporting cognitive complaints ( Breast cancer is the most diagnosed cancer among women worldwide . EarlierChanges in cognition after cancer treatment have been linked to widespread changes in both the structure and function of the brain . For exaAdditionally, increased levels of pro-inflammatory markers have been associated with neural changes and decreased objective cognitive performance  and self-reported cognitive function after cancer treatment, although the latter evidence is still preliminary . More spAlthough more research is currently focusing on potential interventions for CRCI, there is still no golden standard for the treatment of CRCI ,30. In tWe hypothesized that MBIs might alleviate CRCI indirectly via several pathways. First, MBIs might alter functional connectivity between networks associated with CRCI in healthy and clinical populations, i.e., DMN, FPN, DAN, and SN . In breaIn this multimodal study, we investigated the impact of MBI on CRCI and related mechanisms compared to a physical training and a waitlist control group in breast cancer survivors reporting cognitive complaints. Physical training was used as an active control condition to control for non-specific intervention effects like being part of a group, interaction with the trainer, and expectations for improvement . The phyThe first results of our study showed a decrease in subjective cognitive impairment in the three groups over time, without group differences. Additionally, no differences between the groups in objective cognitive impairment could be identified . In thisThe study was registered at ClinicalTrials.gov (NCT03736460). Detailed information about the study protocol has been published elsewhere .Patients were recruited from the Multidisciplinary Breast Cancer Center, University Hospitals Leuven, after identification through the patient database and via flyers on social media between October 2018 and October 2021. Participants were eligible if they were 18–65 years old, diagnosed with breast cancer with or without solitary metastases (except solitary brain metastases), received chemotherapy and ended this treatment 6–60 months before enrolment in the study and were native Dutch speakers. Participants were excluded in case of MRI contraindications, previous experience with meditation training, or when diagnosed with intellectual disability, neurologic or psychiatric disorders. After screening the medical records, candidates received information via e-mail about the general outline of the study. Interested candidates received the informed consent form and the Cognitive Failure Questionnaire (CFQ) to assess subjective cognitive impairment. For more information about the CFQ, refer to the http://minimpy.sourceforge.net/, accessed on 2 February 2022) by an independent researcher. Group stratification was based on time since chemotherapy completion, age, and endocrine therapy. Participants in the waitlist control group received no intervention and continued to receive their usual care. No specific instructions were given to this group. Researchers collecting the data were blinded to participants’ group allocation.Participants were randomly assigned to an MBI, a physical training (PT) active control group or a waitlist control (WL) group using an online random number generator MinimPy , immediately after the intervention (t2), and three months post-intervention (t3). The 3-month follow-up period was chosen based on previous research from our group that showed that this period was sufficient to study the potential long-term effects of MBIs ,54. At eThis intervention was based on Mindfulness-Based Stress Reduction  and MindThis intervention was based on the recommended levels of physical activity for adults  and the 3, TR/TE = 5.8/2.6ms, and FOV = 256 × 240 × 166 mm3) and rsfMRI with a whole-brain T2*-weighted echo-planar imaging (EPI) sequence . During rsfMRI, the lights were turned off and participants were asked to close their eyes, lay still, relax but stay awake. To check whether participants stayed awake, they had to report their level of wakefulness before and after the scan on a scale from 0–10.MRI of the brain was acquired on a 3T Philips Achieva scanner with a 32-channel phased-array head coil. The scanning protocol included 3D-TFE T1-weighted images (voxel size = 0.80 × 0.80 × 0.80 mmVenous blood was collected in tubes (two 5 mL BCA) and centrifuged at 1200 g for 10 min. Serum (supernatant) was divided into aliquots and stored at −80 °C until analysis. Inflammatory markers  were determined via bead-based multiplex immunoassay , with concentration determination via fluorescence-encoded beads on a flow cytometer. Groups were equally distributed across plates, and the mean values across duplicates (separate plate assays) were used for analysis. The coefficient of variation (standard deviation/mean) was calculated to express the extent of variability relative to the mean. The mean intraplate variability was 19% and the mean interplate variability was 33%, suggesting low dispersion of the data relative to the mean.p-values were false-discovery-rate (FDR) corrected on ROI level at p < 0.05, with an uncorrected connection-level threshold of p < 0.01.Prior to processing, all images were converted to the Brain Imaging Data Structure (BIDS)  and visuGraph theory analysis was performed using in-house developed MATLAB (r2022a) scripts and the Brain Connectivity toolbox (v2019-03-03). Weighted connectomes were derived from the absolute correlation values from the ROI-to-ROI analysis with self-connections removed. Weighted graph measures of characteristic path length, global and local efficiency and clustering coefficient were calculated for connections between the nodes described above see . Charactp-values . Age and time since chemotherapy were tested as covariates, but the covariates were not included in the final models based on backwards selection. All values were scaled so that the standardized coefficients provide information about the effect size [Intervention effects were assessed using two-level linear mixed models with a random intercept (participant) and group, time-point, and their interaction as fixed effects in RStudio  . To accoect size . No corrn = 3). Longitudinal group differences in biomarkers of inflammation were estimated using linear mixed models with a random intercept (participant) and with group, time-point, and their interaction as fixed effects. Based on previous research, participant age [A principal component analysis  on the correlation matrix of the 13 human inflammatory cytokines/chemokines data was performed to (1) account for the network structure of these markers, especially when involved in neural functioning ,69, and pant age  were incpant age . All valpant age . No corrp < 0.05. Due to the exploratory nature of this analysis, we did not correct for multiple comparisons.First, based on the identified significant group-by-time interaction effects, we investigated the correlation between significant changes in graph metrics and changes in the inflammatory profiles. Second, as our primary outcome was the change in cognitive complaints over time , we inven = 43), physical training (n = 36), or waitlist control condition (n = 38). In total, 95 participants completed the assessments at the three time-points. For the rsfMRI data, we performed a complete case analysis and data of 21 additional participants had to be excluded: 15 participants with signal-to-noise-ratio < mean −1.5 SD on at least one time-point, 4 with failed denoising, and 2 with unspecific neuroanatomical abnormalities. This resulted in the data analysis of 74 participants (30/21/23 MBI/PT/WL). For the blood serum analysis, all available data have been analyzed.n = 117), 69% of the MBI participants practiced at least several times a week at t2, and 51% at t3. Of the physical training participants, 55% practiced at least several times a week at t2, and 35% at t3.p = 0.01). Additionally, the physical training group had significantly lower values of global efficiency at baseline compared to the waitlist control group (mean (SD): PT = 0.87 (0.03); WL = 0.90 (0.02); p = 0.01). No other baseline differences between the groups were identified.All participants indicated that they stayed awake during the resting state scans. No significant differences in ROI-to-ROI functional connectivity between the treatment groups were observed at baseline, nor between or within groups from pre-to-post intervention (t2–t1 and t3–t1). In terms of functional network organization, at baseline, significant differences in characteristic path length existed, with the MBI and physical training group having higher baseline values than the waitlist control group (mean (SD): MBI = 1.25 (0.07); PT = 1.27 (0.07); WL = 1.21 (0.06); p = 0.01) and three-month follow-up  in the physical training compared to the waitlist control group, with within-group effects showing a significant decrease in characteristic path length in the physical training group  and no significant changes in the waitlist group over time. These findings reflect increased functional network integration in the physical training group compared to no intervention.p = 0.03) and physical training group  compared to the waitlist group. Within-group effects showed a significant decrease in the MBI  and physical training group  at three-month follow-up, and no significant changes in the waitlist group. These findings reflect decreased functional network segregation in both the MBI and physical training group compared to no intervention.For the clustering coefficient, a larger decrease from baseline to three-month follow-up was found in the MBI  and MBI . Within-group effects showed a significant increase in the physical training group from baseline to post-intervention and at three-month follow-up . These findings reflect increased functional network integration in the physical training group compared to MBI and no intervention. Finally, no significant differences in local efficiency were identified.For global efficiency, a larger increase from baseline to post-intervention and three month-follow up was found in the physical training group compared to the waitlist group , the effects of an 8-week MBI on resting state functional connectivity have been studied using seed-to-whole-brain connectivity analysis with a seed in the DMN . The authors reported increased functional connectivity between the posterior cingulate cortex seed and the medial prefrontal cortex after MBI compared to no intervention, which correlated with a reduction in the experience of pain [n = 33) [Contrary to our hypothesis, we could not identify differences between the groups in resting state functional connectivity patterns. Other studies investigating the impact of standardized 6- to 8-week MBIs on functional connectivity did find changes in attention-, emotion-, and executive function-related networks. However, these studies used a variety of seed regions and ROIs depending on the pathology under investigation which makes it difficult to compare the results . In brea of pain . In the [n = 33) . Hence, Alternatively, the lack of significant findings could in general be linked to (1) insufficient power to detect differences, (2) lack of sensitivity due to data quality, and (3) the absence of a true effect. First, studies have detected changes in resting state functional connectivity after MBI compared to a control group in samples with only 10 participants per group . Hence, In terms of functional organization of the network encompassing regions related to attention, emotion, and executive functioning, we found reduced segregation as characterized by a lower clustering coefficient after receiving either MBI or physical training compared to no intervention at three-month follow-up. Although this might reflect less cohesion of the neighboring nodes in the network , the balIn a previous study, we did not identify differences between the groups in terms of subjective and objective cognitive impairment after the interventions . TherefoFinally, although it has been summarized in a systematic review that MBIs might aid in the recovery of the immune system in cancer patients by altering cytokine levels, the evidence remains contradictory . Additio2-max) at baseline and throughout the study, as physical fitness levels might have confounded our effects. Moreover, different types of physical activity can have differential effects on biological outcomes. For example, aerobic exercise might have the largest effect on brain-derived neurotropic factor (BDNF) and anti-inflammatory cytokines, resistance training might have a larger effect on insulin-like growth factor-1, and yoga might have the largest effect on oxidative stress [To better understand the (lack of) treatment effects, future research could assess potential adverse effects using standardized questionnaires, therapist fidelity using the Mindfulness-based Intervention–Teaching Assessment Criteria (MBI-TAC), and homework practice using smartphone monitoring. Additionally, although participants were excluded if they had previous meditation experience and participants in the control groups were expected not to engage in meditation-related practices during the study, the amount of physical exercise and meditation practice could be more specifically assessed in both groups in future research. Furthermore, this study showed that physical training can impact inflammatory profiles compared to no intervention. However, within-group effects were non-significant, suggesting that the group-by-time interaction effect was driven by subtle changes in inflammatory profiles over time. As this study was not designed to test the effects of physical training on CRCI, but merely to use physical training to control for non-specific intervention effects, future studies could adapt the physical training to potentially increase the treatment effect. For example, the physical training could be adapted to individual needs by letting participants select the exercise modality, intensity, and context . This wae stress . TailoriIn this study, we found no evidence for an effect of MBI on resting state functional connectivity in brain networks that have previously been linked to CRCI. However, both MBI and physical training could induce changes in the functional organization of the neural networks related to attention, emotion, and executive functioning. After receiving either MBI or physical training, reduced functional segregation was found, whereas only physical training increased functional integration of the neural network. Hence, physical training might have the most pronounced effect on the efficiency of neural information processing in areas related to attention, emotion and executive functioning. Additionally, physical training might reduce therapy-induced immune deregulation by reducing levels of pro-inflammatory cytokines. This research suggests that both MBI and physical training might impact biomarkers of CRCI in women with cognitive complaints after breast cancer treatment, although the effects were more pronounced after physical training.


Healthcare workers (HCWs) are at risk of SARS-CoV-2 infections due to occupational exposure. The use of airborne personal protective equipment (PPE) significantly reduces this risk. In June 2021, an epidemic of the Delta variant began in New South Wales (NSW), Australia. Concurrent PPE guidelines, set by the Clinical Excellence Commission (CEC), restricted the use of respirators.  To understand the relationship of PPE guidelines with workplace-acquired HCW SARS-CoV-2 infections in different clinical settings and to examine the relationship between rates of community transmission and workplace-acquired HCW infections during the Delta outbreak in NSW.  Total SARS-CoV-2 HCW infections between 13 June and 30 October 2021 (first four months of the Delta wave) were estimated from the government COVID-19 surveillance reports and compared with the surveillance reports of community transmission. In the absence of a detailed reporting of HCW infections, open-source data including news articles, media releases, and epidemiological surveillance reports were also collected. Data were extracted on HCW cases of SARS-CoV-2 from four hospitals, including the number of HCW cases , clinical setting, PPE guidelines, and evidence of increasing local transmission. n = 177) and those without a known transmission source (n = 532) increased during the period of increasing community transmission  in NSW. Four hospital COVID-19 clusters affecting 20 HCWs were identified between June and October 2021. HCW clusters occurred in general wards where staff were recommended to wear surgical masks. No workplace-acquired HCW infections were reported in these hospitals from critical care wards, where respirators were recommended during the same outbreak weeks.  SARS-CoV-2 infections in HCW identified as workplace-acquired infections ( Differences in PPE policy across different wards may leave healthcare staff at risk of SARS-CoV-2 infection. During periods of high community transmission, respirators should be provided to protect hospital staff. Formal reporting of HCW infections should occur. Since the emergence of COVID-19, the disease caused by the SARS-CoV-2 virus, in December 2019, more than 495 million cases have been confirmed globally .The World Health Organization (WHO) has identified HCWs as a group at increased risk of becoming infected with SARS-CoV-2 due to the increased likelihood of exposure through contact with people infected with the virus . This riTransmission of SARS-CoV-2 is airborne . In perfThe NSW Department of Health policy regarding the use of PPE is informed by the guidelines set by the Clinical Excellence Commission (CEC) . During The objective of this study is twofold: first, to investigate the relationship between PPE guidelines and workplace-acquired HCW SARS-CoV-2 infections at different clinical settings within hospitals, in the absence of a formal reporting of HCW infections; and second, to examine the correlation between rates of community transmission and HCW infections.In the absence of formal, public reporting of workplace-acquired HCW infections in NSW, open-source data can provide valuable information on workplace outbreaks, although it may be limited with regard to completeness of case information .We searched for open-source reports of HCW clusters of SARS-CoV-2 infections in hospitals in NSW, Australia, between 13 June 2021  and 30 We conducted a study with a retrospective comparative analysis using open-source data to identify HCW clusters in the Delta variant epidemic in NSW in 2021. In addition, we compared the PPE policy implementation across the affected and nonaffected wards in the same hospitals.Total SARS-CoV-2 HCW infections between 13 June 2021 and 30 October 2021 were collated using information from the State COVID-19 surveillance reports  8, 12–1–112–14. Open-source data were collected for NSW, Australia, including media articles, hospital and state government media releases, and state government epidemiological surveillance reports, and were reviewed to identify workplace-acquired HCW infections between 13 June and 30 October 2021. The cohort study data collection began on 15 August 2021 and continued through 30 October 2021. A line list of reported positive cases was created with information including infection source, date of reported case, location including specific wards, policies relating to PPE, and vaccination coverage  guidelines for epidemiological studies . Data coA descriptive analysis was conducted, and case counts were compared between noncritical care wards and critical care wards within the same hospital over the same period.Total SARS-CoV-2 community and HCWs confirmed infections between 13 June 2021 and 30 October 2021 were collated using information from the state and commonwealth COVID-19 surveillance reports.n = 532) were classified as “unknown source,” followed by community-acquired cases (n = 181) and workplace-acquired cases (n = 177) [Total SARS-CoV-2 HCW infections between 13 June 2021 and 30 October 2021 are shown in ses n = 11 and worn = 177) –14.n = 375) were vaccinated with two doses of COVID-19 vaccine, 11.3% (n = 101) had received one dose, and 46.5% (n = 414) were unvaccinated [During epidemic periods, HCWs in NSW have had an increase in workplace-acquired infections . There hccinated . The oveccinated .We identified six HCW outbreaks involving 25 infected HCWs, of which four met the inclusion criteria –27.  TabThe hospital A cluster was reported on 24 July with the index case of a partially vaccinated nurse who worked across two wards whilst infectious, neurology and geriatrics . During The hospital B cluster was reported on 14 August, with the index case of an oncology patient who tested positive on 13 August . SubsequThe hospital C cluster was reported on 14 August, with an unknown index case. The first four cases of staff members in this cluster who tested positive for workplace-acquired COVID-19 were reported on 14 August . During The hospital D cluster was reported on 9 September, when two patients and three nurses tested positive in the geriatric ward . FollowiThere is variable public reporting of HCW infections due to workplace exposure to SARS-CoV-2. Due to this, we utilized open-source data to extract more detailed information on workplace outbreaks . There wWe have shown that differences in PPE policy across different wards may contribute to healthcare staff risk of SARS-CoV-2 infection. The guidelines in operation during the study period recommended airborne precautions in critical care wards and no workplace-acquired infections in these settings were reported in open-source media or publicly available reports. In contrast, reported outbreaks occurred in general wards  where surgical masks were recommended during the same periods of high community transmission. Exposure of HCWs in emergency departments, intensive care units, and COVID-19 wards was likely, due to the high levels of community transmission; however, there were no HCW clusters reported in open-source media or publicly available reports in these clinical areas during that time. The guidelines used in NSW assumed that airborne transmission only occurs in selected situations such as aerosol-generating procedures; however, SARS-CoV-2 is airborne . ApproxiAustralian HCWs are up to three times more likely to have SARS-CoV-2 infection than the general population , 6. The There were high rates of HCW vaccination in NSW, in part due to eligibility, and also as a public health order mandating COVID-19 vaccination at least one dose of a COVID-19 vaccine by 30 September 2021 and both doses by 30 November 2021, as a condition of employment . At the The WHO formally acknowledged that SARS-CoV-2 was spread through airborne transmission in May 2021 . During The Clinical Excellence Commission in NSW updated the infection control and PPE guidelines on several occasions in 2021; however, the recommendations regarding the use of N95/P2 respirators did not change . TherefoThese guidelines may not have been sufficient to protect HCWs in noncritical care wards during the pandemic . FollowiThe lack of formal reporting on health worker infections necessitated the use of open-source data for this study. Although the number of HCW cases was provided in Health bulletins, other information was not available, and the attribution of the source of infection was not described, with the majority of cases classed as “unknown.” Compliance with the outbreak measures by HCWs was also assumed and it is unknown what strategies were employed to measure it. The quantitative measure of compliance rates and qualitative data on the reasons for compliance with infection control measures could provide more depth to our understanding of the transmission of the SARS-CoV-2 virus among HCWs in a tertiary hospital setting. Further limitations to the study include the use of open-source data, including media articles, government reports, and documents, which may vary in completeness of case information and impact validity. The quality of the data used may be further improved by verification of the open-source data by hospital authorities or formal reports being issued, similar to the state of Victoria. This study conducted a descriptive analysis by comparing case counts of workplace-acquired HCW SARS-CoV-2 infections in noncritical care wards and critical care wards within the same hospital over the same period, as well as investigating HCW infections at times of increasing community transmission. While the variables under study (lack of policy requirement to use respirators in the work environment and workplace-acquired infection and community transmission and HCW infections) appear to have a relationship, no statistical analysis was performed, and therefore, a positive correlation between the variables cannot be concluded.In this descriptive study, we analysed four hospital outbreaks affecting 20 HCWs during the Delta wave of SARS-CoV-2 in Sydney, Australia. All the identified HCW clusters were in general wards who utilized surgical masks as PPE. Differences in PPE policy across different wards may leave healthcare staff at a disproportionate risk of SARS-CoV-2 infection. All hospital HCWs should be provided with respirators during periods of increasing community transmission of SARS-CoV-2. To meet work health and safety obligations toward HCW, healthcare-acquired infections should be reported.


Self-medication is a treatment based on symptoms without prescription and medical consultation. Despite being one of the critical practices that impose a harmful effect on the fetus and the woman herself, evidence on its practice and associated factors are not well-documented. This study, therefore, assessed the self-medication practice and associated factors among pregnant women in Wolaita Zone, Southern Ethiopia.An institutionally based cross-sectional study was conducted at public health institutions in Wolaita Zone, Southern Ethiopia by recruiting a total of 408 pregnant women using a systematic random sampling technique between March 2019 and April 2019. We used the Antenatal care (ANC) registry as a sampling frame. A pre-tested, structured, interviewer-administered questionnaire used to depict Self-medication practice and associated factors. Data entered using Epi-data and analyzed by SPSS 23.0.The overall prevalence of self-medication was 14.9% (95% CI:11–18). The odds of using self-medication may decreased by 75% for women who were in their third trimester . However, the odds of practicing increased by 13-folds among pregnant women reported earlier (previous) self-medication experience .The prevalence of self-medication was high in the current study setting. Women's gestational period (third trimester) and earlier self-medication experience were associated with their current self-medication practice. Self-meSelf-medication is a common practice worldwide with the prevalence varying from country to country for several reasons, but the tendency of self-medication practice has been increasing both in developed and developing countries . LiteratRampant irrational use of medicines with no adequate guidance from medical professionals may result in a high probability of inappropriate, incorrect therapy, missed diagnosis, delays in appropriate treatment, microbial resistance, and higher morbidity and death imposing a major global health challenge with significant implications for patients, healthcare systems and communities as a whole ,10.Such practice is also common among pregnant women and has gotten serious attention for its erroneous consequences on the health of both mother and the fetus . One in For reasons of either not being well-known or given less priority among policymakers and program designers, self-medication practice during pregnancy, and possible interventions are not articulated in the current strategies on maternal and reproductive health including antenatal care programs . Therefo22.1https://en.wikipedia.org/wiki/SodoSodo. Currently, there is one teaching referral hospital ), 4 Primary Hospitals(PH), and 69 Health Centers(HCs) in Wolaita Zone. The target populations of the study were all pregnant women who visited the antenatal care unit at public health facilities in Wolaita zone during the study period. The following public health institutions were selected for this study: Areka Health Center, Bale Primary Hospital, Bittena PH, Boditi HC, Sodo HC, and WUSTRH. Women were included in the study irrespective of their gestational age and the pregnant women who were seriously ill and who lived for less than 6 months in the study area at the time of the study period were excluded from the study.We conducted an institution-based cross-sectional study from March 11 to Apr. 26, 2019, at public health facilities in Wolaita zone. Wolaita Zone is one of the thirteen zonal administrations of Southern Nations, Nationalities, and People's Region (SNNPR) of Ethiopia, found three hundred kilometers south of the capital city, Addis Ababa. The administrative center of Wolaita Zone is Wolaita 2.2The largest sample size for this study was obtained by using single population proportion formula by the consideration of the prevalence of 20.1% prevalence of self-medication practice among pregnant women attending antenatal care in Jima University Specialized Hospital, South West Ethiopia , 95% con2.3Self-medication – is a situation in which no health professionals take part in any stage of the therapeutic decision [decision . In thisPrescription Only Medicines (POMs) - restricted medicinal agents, obtained on prescription, from a designated practitioner; not available for over-the-counter purchase [purchase .Over-The-Counter drugs (OTCDs) - non-prescription medicines that you can buy without a prescription [cription .Allopathic medicine - A system in which medical doctors and other healthcare professionals  treat symptoms and diseases using drugs, radiation, or surgery. Also called conventional medicine, biomedicine, mainstream medicine, orthodox medicine, and Western medicine [medicine .2.4Data was collected via face-to-face interviews. The questionnaire was developed by reviewing different literature on similar or related topics. The validity of the questionnaire is established by the subject experts which comprised of a pharmacist who had prior research experience, a gynecologist and obstetrician, and an experienced midwife in ANC services. After reviewing all the contents of the questionnaire, they concluded it measures the outcome of interest (self-medication). The questionnaire was translated into Amharic and ‘Wolaittaato doona’ and then back into the English language by language experts to check for its original meaning. Six clinical nurses who had earlier experience in data collection were selected and assigned as data collectors while two clinical pharmacists were assigned as supervisors. A pre-test was conducted on 5% of the actual sample size in Bedessa health center a week before the actual data collection. Based on the findings of the pre-test, proper amendments were made to the questionnaire. Thorough training was given to data collectors and supervisors by the principal investigator. The collected data was sent on a regular basis to supervisors and was checked for completeness, consistency on daily basis, and possible corrections were made by tracing respondents by their address.2.5Data was checked for completeness and consistency before data entry. Then, data were coded and entered into EpiData 4.4 and exported to SPSS version 23 for analysis. Descriptive statistics such as frequencies, percentages, summary measures, tables, and graphs were used to describe respondents' results. Bivariable logistic regression analysis was done to assess the relationship between each independent variable with self-medication practice and those variables with p-value <0.25 were selected as candidates for multivariate logistic regression analysis. In a multivariate analysis using a backward logistic regression model, an adjusted odds ratio (AOR) with 95% CI was estimated and an independent variable with a p-value <0.05 is considered statistically significant and an independent predictor of self-medication practice.2.6 Ethical approval and consent to participateEthical approval was obtained from the Institutional Review Board of Arba Minch University, College of Medicine and Health Sciences. An official support letter was also obtained from Arba Minch University and Wolaita Zone health bureau for undertaking the study. The purpose of the study was explained to all study participants and they were informed that they have full right not to participate and written informed consent was obtained from each study participants. Confidentiality was kept at all levels of the study.33.1Among the 408 samples of pregnant women, 396 pregnant women took part in the study making the response rate 97.1%. The mean (±SD) age of respondents was 24.9(±4.7) years .Table 1S3.2Among 396 respondents in the current study, 123(31.1%) have had previous self-medication experience. Concerning self-medication practice during the current pregnancy, the overall prevalence was found to be 14.9% . The major reason reported to practice self-medication were emergency use 28(44.4%), time-saving 10(15.9%), perceiving illness as minor (not serious) 9(14.3%), and previous self-medication experience 6(9.5%). Women who do not practice self-medication mentioned fear of adverse drug reactions 200(59.3%) and not using the wrong drug 120(35.6%) as their major reasons for not practicing self-medication. The major illnesses/symptoms initiated for self-medication reported were headache 28(43.8%), gastrointestinal disorder (14.1%), and common cold and cough (12.5%). The major source of information was health care professionals . The mosThe results of bivariable analyses revealed that place of residence, gestational period (stage of pregnancy), membership of health development army, membership of community-based health insurance, and previous self-medication experience were found to be a candidate for multivariable analysis having p-value <0.25 ., only women's gestational period and their previous experience of self-medication showed a statistically significant association among the candidate variables selected and fit to the model. Thus, pregnant women in their third trimester were found to be 75% less likely to practice self-medication during the current pregnancy as compared to those pregnant women in their first trimester , and pregnant women who had previous self-medication experience were found to be 13 times more likely to practice self-medication during the current pregnancy as compared to pregnant women who had no previous self-medication experience   .Table 2S4This study found a high magnitude of irrational self-medication practice among pregnant women in Wolaita Zone, Southern Ethiopia. Women's gestational period (third trimester) and previous self-medication experience were factors associated with self-medication practice in the current study setting. Given the dearth of evidence in the Southern region of the country, the findings will contribute to the literature so that interventions can be sought for this dangerous practice particularly early during pregnancy. The findings may also have an input to program planners in the local area and policymakers at large to intervene in the sustained practice of self-medication among the target women in the study area and by extension to the country.The overall prevalence of self-medication practice was found to be 14.9%. A similar finding was reported from previous studies in Goba-Ethiopia, Congo, Gujarat-India, Mexico, and the Netherlands where self-medication practice was 15.5%, 14%, 8.5%, 21.9%, and 12.5% respectively . HoweverIn the current study, the classes of drugs most utilized were analgesics, antibiotics, and gastrointestinal drugs of which around 50% were gotten from retail drug outlets. This finding revealed a need for adequate regulatory enforcement by the Ethiopian Food and Drug Authority (EFDA) in retail drug outlets where a significant proportion of drugs for self-medication by pregnant women are obtained. Nowadays self-medication practice is one of the leading contributors to global antimicrobial resistance , thus irAmong pregnant women who have self-medication practice in the current study, 47 out of 59(80%) had previous self-medication experience which is in line with a finding from Addis Ababa in which 121 out of 164(74%) had previous self-medication experience . This reIn conclusion, healthcare providers should focus on counseling pregnant women visiting for ANC on self-medication experience prior to the current pregnancy and deliver adequate counseling on self-medication to those who had experience. The government's regulatory agency, the Ethiopian Food and Drug Authority (EFDA), should control sell of both prescription-only medications and over-the-counter medications to society.4.1This study has a few limitations to consider. It assessed the magnitude of self-medication with modern  medicines; women's herbal medication use was not assessed. In addition to this, self-medication was assessed using a structured questionnaire for self-report which might be affected by social desirability bias that would underestimate the result.Temesgen Leka Lerango; Amsalu Alagaw; Abayneh Tunje: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.Eshetu Andarge; Bereket Duko; Asres Bedaso Tilahune; Semalgn Leka Lerango: Conceived and designed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Data will be made available on request.Questionnaire (English Version)Part-01 Socio-demographic information.Part-2. Factors related with self-medication.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


RAS/BRAF wild-type metastatic colorectal cancer (mCRC). The maximal benefit is observed in patients without resistance mutation at the baseline plasma circulating tumor DNA (ctDNA) evaluation. In the CAVE and VELO clinical trials, 1 out of 4 patients had ctDNA RAS/BRAF mutant disease at pretreatment liquid biopsy assessment. There was no direct association between the length of anti-EGFR drug-free interval and the presence of plasma ctDNA RAS/BRAF mutations at pretreatment liquid biopsy analysis. Interestingly, even the disappearance of mutant clones was time-dependent, and resistance mutations were found at liquid biopsy analysis in approximately 15% of patients after 18 or more months of anti-EGFR drug-free window. These results support the use of liquid biopsy to appropriately select amenable patients to EGFR inhibitor rechallenge.Rechallenge with epidermal growth factor (EGFR) inhibitors represents a promising therapeutic strategy in patients with refractory RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC). We performed the pooled analysis of the CAVE and VELO studies to evaluate the percentage of patients with WT circulating tumor DNA (ctDNA) tumors and the association of mutational status with time from the last anti-EGFR drug administration. At baseline, 97/129 patients had RAS/BRAF WT plasma ctDNA, while 32/129 had RAS/BRAF mutated plasma ctDNA. Median anti-EGFR drug-free interval was 10.6  months in the plasma RAS/BRAF mutant group as compared to 13.0  months in RAS/BRAF WT group (p = 0.169). To investigate the time window of the RAS/BRAF mutant cancer cell clone disappearance, descriptive analysis using different time points was performed. No difference in the proportion of patients whose baseline plasma ctDNA was RAS/BRAF WT or mutated was found between 4 and 18 months since the last administration of anti-EGFR drugs. In contrast, 38/44 of patients with anti-EGFR drug-free interval of 18 months or more displayed a ctDNA RAS/BRAF WT status. Taken together, these results shows that the length of anti-EGFR free interval is not a sufficient criterion for patient selection, supporting the role of liquid biopsies for improving treatment efficacy.Rechallenge with anti-EGFR drugs represents a promising strategy in refractory  RAS and BRAF wild-type (WT) tumors [RAS mutations that occur in 30–40% of cases [RAS and EGFR mutant allele frequency decays exponentially after stopping anti-EGFR therapy with an estimated half-life of approximately 4 months [Better knowledge of the molecular biology of colorectal cancer (CRC) has radically changed the therapeutic scenario, allowing for the development of more effective therapies . Treatme) tumors . In this) tumors ,3,4. Fur) tumors . Howeverof cases ,3,4,5,6.of cases ,7,8,9,10of cases ,12. ParsRAS/BRAF wild-type (WT) tumors [RAS/BRAF WT tumors received the highest benefit. Despite the reduced number of included patients, the CRICKET study provided the first piece of evidence of a rechallenge with anti-EGFR in a molecularly selected population.Thus, after anti-EGFR drug-free intervals that allow for the clearance of resistant cancer cell clones, a rechallenge with EGFR inhibitors might represent an appealing therapeutic option in patients that benefit from prior anti-EGFR therapy ,2,11. On) tumors ,16,17,18) tumors . In the RAS WT mCRC received cetuximab and avelumab as rechallenge therapy. The study was positive, with a median overall survival (mOS) of 11.6 months  and a median PFS (mPFS) of 3.6 months  in the intention to treat the population. Interestingly, mOS exceeded 17 months in the pretreatment plasma ctDNA RAS/BRAF WT population [In the CAVE Phase II clinical trial, patients with pretreated pulation ,16. The pulation . The pripulation .RAS/BRAF WT tumors for anti-EGFR rechallenge therapy. However, there are several unsolved issues, including which the optimal anti-EGFR drug-free interval is before rechallenge, and if there is a correlation between the time of the last anti-EGFR drug administration and the persistence of RAS/BRAF mutations, in order to better identify patients without resistance mutations that are suitable for anti-EGFR rechallenge strategies.In the CHRONOS Phase II study, 27 molecularly selected patients received panitumumab as a later line of treatment . RemarkaTherefore, we performed the pooled analysis of the CAVE and VELO clinical trials, which have been the largest published anti-EGFR rechallenge therapy clinical trials.RAS WT mCRC [2 loading dose and subsequently 250 mg/m2 weekly) until disease progression or unacceptable side effects. The major inclusion criteria were that all patients must have had RAS WT mCRC, have obtained complete (CR) or partial response (PR) during first-line chemotherapy and an anti-EGFR drug, and have progressed and received at least second-line therapy after the failure of the first-line treatment. Moreover, an anti-EGFR drug-free interval of at least 4 months was required. The primary end point was OS, and the secondary end points were PFS, overall response rate (ORR), and safety. The study aimed to demonstrate an mOS of 11 months for the experimental arm as compared with the historical mOS of 8.0 months with trifluridine/tipiracil or regorafenib, which corresponds to an improvement of 37.5% in mOS. VELO (NCT05468892) was a multicenter, randomized, Phase II study investigating the role of combining panitumumab with trifluridine/tipiracil compared to trifluridine/tipiracil as a rechallenge in patients with RAS WT mCRC [2 dose of trifluridine/tipiracil was orally administered twice daily, 5 days a week with 2 days of rest for 2 weeks, followed by a 14-day rest period. Treatment was administered in 28-day cycles until disease progression, unacceptable toxicity, the withdrawal of consent, or death due to any cause. The primary endpoint was PFS, and secondary endpoints were OS, ORR, and safety. The study was designed to have 80% power to detect a hazard ratio for PFS of 0.56 (44% reduction in risk) in the panitumumab and trifluridine/tipiracil arm as compared to the standard-of-care trifluridine/tipiracil arm, with a two-sided Type I error rate of 0.1.CAVE (NCT04561336) was a single-arm, multicenter, Phase II trial evaluating the combination of cetuximab and anti-PD-L1 monoclonal antibody avelumab as rechallenge therapy in 77 patients with refractory  WT mCRC ,16. In p WT mCRC . In totaThe inclusion criteria were almost the same between the two studies, with the main difference being that, in the VELO trial, treatment was administered as third-line therapy in all patients, while a subgroup of patients enrolled in the CAVE study received rechallenge with cetuximab and avelumab as a later line of treatment.TM Biocartis platform) at the baseline before trial treatment, and with complete clinical and pathologic data. The analysis was performed in the laboratory of the coordinating center . At least 6 mL of whole blood was collected with the standard procedures with peripheral vein blood draw using Vacutainer® with EDTA as the anticoagulant. Plasma was separated through two different centrifugation steps . Plasma was stored at −80 °C until analysis in the IdyllaTM Biocartis platform. The complete process of the sample collection and processing, and the result analysis has been previously reported [KRAS exons 2 and 3 or BRAFV600E mutations was >1%; for KRAS exon 4 and NRAS exons 2–4, it was >5%. The anti-EGFR free interval was defined as the time in months from the last EGFR inhibitor administration and enrollment in the CAVE and VELO studies, and ctDNA analysis. Correlation between anti-EGFR drug-free interval and mutational status was calculated with Mood’s median test. Moreover, patients were divided into different subgroups depending on the length of the anti-EGFR free interval . A descriptive evaluation of the frequency of plasma RAS/BRAF WT and mutant ctDNA in the different subgroups was performed. Statistical analyses were performed using the SPSS package .For the present study, we selected patients enrolled in the two trials with available plasma samples for ctDNA analysis with a RT-PCR-based test  via liquid biopsy analysis with the IdyllaTM Biocartis platform. KRAS mutations  were the most common gene alterations, BRAF mutations were observed in 2 patients, while an NRAS mutation was reported only in 1 case  in patients with plasma RAS/BRAF mutant ctDNA, and 13.0 months  in patient with plasma RAS/BRAF WT ctDNA (RAS/BRAF mutations was observed in the subgroup of patients (44/129) with very long anti-EGFR drug-free intervals, longer than 18 months. Of the patients, 38/44 (86.4%) in this subgroup displayed plasma RAS/BRAF WT ctDNA tumors; there was still a small subset of cases with ctDNA RAS/BRAF mutant tumors . These results indicate that the time from the last anti-EGFR drug treatment should not be considered the only parameter to select patients for anti-EGFR rechallenge strategies. Thus, a liquid biopsy should be performed before considering rechallenge with anti-EGFR-based therapies.The main patient characteristics are summarized in n 1 case . In thisWT ctDNA . To furtWT ctDNA . A reducThe insurgence of mechanisms of secondary resistance is a limitation to the efficacy of anti-EGFR-based therapies ,25,26,27In this scenario, there could be room for an anti-EGFR drug rechallenge after a treatment holiday that allows for the clearance of resistant clones ,12.TM Biocartis platform) we observed that 3 out of 4 patients  did not show RAS/BRAF mutation at the liquid biopsy analysis of plasma ctDNA before treatment. Thus, there is a significant number of patients that might benefit from a rechallenge with anti-EGFR drugs. These data are also potentially relevant since the IdyllaTM Biocartis could be used in clinical practice and allows for the detection of the main resistance mechanisms in a few hours [RAS MAF < 5% on anti-EGFR drug response are still matters of debate [KRAS/NRAS/BRAF/PIK3CA mutation from 5% to 1% by NGS was not correlated with improved outcomes. Therefore, the definition of the optimal limit detection for liquid biopsy analysis should be further investigated in larger prospective studies.The present pooled analysis of the CAVE and VELO clinical trials represents, to our knowledge, the largest currently available dataset from prospective clinical studies. By using a RT-PCR-based  study is a prospective, multicenter, randomized Phase II trial investigating a rechallenge with panitumumab compared with regorafenib and the inverse sequence in 214 patients with chemorefractory mCRC with baseline ctDNA RAS/BRAF WT tumors. A preliminary analysis of the PARERE study was presented at the ESMO World Congress on Gastrointestinal Cancer 2022 [KRAS/NRAS or BRAFV600E mutations were detected. Our group is currently conducting a large and randomized Phase II study  investigating the combination of cetuximab and avelumab compared with cetuximab as a rechallenge strategy in 173 patients with refractory mCRC [Another intrinsic limitation of this RT-PCR-based test is the possibility of detecting only hot-spot mutations and thereby missing other potential mechanisms of resistance. Despite these limitations, the reported results here are in line with findings from other groups ,30. In tory mCRC . During RAS/BRAF WT ctDNA as compared with patients with RAS/BRAF-mutated ctDNA. In the subgroups of patients with an anti-EGFR free interval of. less than 18 months, no major differences in the proportion of RAS/BRAF ctDNA mutant vs. wild-type tumors were reported. However, a relatively long anti-EGFR drug-free period of more than 18 months was associated with the reduced probability of having mutant tumors (38/44 patients displayed RAS/BRAF WT tumors). Nevertheless, approximately 14% of these patients still had RAS/BRAF mutant tumors, suggesting that the temporal criteria are not sufficient by themselves for patient selection.By increasing the time from the last administration of anti-EGFR drugs, a progressive reduction in resistant cancer cell clones was proposed ,12. In tRAS/BRAF wt mCRC. Robust translational studies have proven that the half-life of resistant clones is approximately 4 months after the cessation of anti-EGFR administration. The results of the pooled analysis of the CAVE and VELO clinical trials support the use of defined clinical criteria and pretreatment evaluation of RAS/BRAF ctDNA mutational status with liquid biopsies for the appropriate selection of patients that could effectively benefit from anti-EGFR rechallenge therapy in the continuum of care of mCRC. Nevertheless, there are some open questions. One of the main issues is the identification of better assays for liquid biopsy NGS vs. PCR tests. Furthermore, the availability of a liquid-biopsy test could be a major problem outside referral centers. Lastly, the optimal cut-off for RAS/BRAF mutations in the liquid biopsy has not yet been defined and is debated. Studies are ongoing to clarify the role of anti-EGFR rechallenge in the continuum of care of mCRC [Rechallenge with anti-EGFR drugs for patients with refractory mCRC is a promising option for chemo-refractory  of mCRC ,11,30,31


Tacrolimus is a first-line immunosuppressive therapy to prevent rejection and graft failure in kidney transplant recipients. Once-daily extended-release tacrolimus tablets (LCPT) have been shown to be efficacious, particularly for Hispanic and Black patient subpopulations who are rapid metabolizers, but is more costly than twice-daily immediate-release tacrolimus (IR-Tac).To evaluate the cost-effectiveness of LCPT during the first year of treatment vs IR-Tac in kidney transplant recipients who are Hispanic or Black.A decision analytic model from a US payer perspective was developed using (1) subgroup outcomes data pooled from two phase 3 clinical trials that compared LCPT and IR-Tac, and (2) direct costs from real-world data sources . The primary outcome was cost per successfully treated patient, defined as having a functioning graft after 1 year and without treatment-related SAEs. Probabilistic sensitivity analyses established distributions for cost and outcomes estimates, and a series of one-way sensitivity analyses identified parameters that had the most effect on results.Total overall cost for the Hispanic group was $14,765 for LCPT and $12,416 for IR-Tac, and total cost in the Black group was $16,626 for LCPT and $9,871 for IR-Tac. Total overall effectiveness of LCPT and IR-Tac was 88.32% and 84.75% in the Hispanic group and 93.24% and 85.78% in the Black group, respectively. The incremental cost-effectiveness ratio (ICER) for using LCPT over IR-Tac during the first year of treatment in the Hispanic group was $65,643 per additional successfully treated patient. The ICER for the Black group was $90,458. The single parameter having the most impact on results in both groups was the probability of a treatment-related SAE in IR-Tac, which accounted for 49% of variation in results in the Hispanic group and 46% in the Black group.Overall results for both groups show that LCPT is incrementally more costly and more effective compared with IR-Tac, indicating a trade-off scenario. LCPT is a cost-effective strategy if a decision makers’ willingness to pay for 1 additional successfully treated patient exceeds the ICER and must be weighed against the costs of graft loss, continuing dialysis, and potential retransplant. This study provides a foundation for further research to update and expand inputs as more data become available to improve real-world relevance and decision making. What is already known about this subjectTacrolimus is a first-line immunosuppressive therapy to prevent rejection and graft failure in kidney transplant recipients, but some patient subpopulations are rapid metabolizers and require higher doses to achieve target trough levels.Once-daily extended-release tacrolimus tablets (LCPT) have a unique pharmacokinetic profile, which results in a lower peak and less peak-to-trough fluctuation compared with immediate-release tacrolimus taken twice daily (IR-Tac).What this study addsUse of LCPT in Hispanic and Black kidney transplant recipients during the first year of treatment is more effective and costs more than IR-Tac, indicating a trade-off scenario.The incremental cost-effectiveness ratio (ICER) for using LCPT during the first year of treatment over IR-Tac in the Hispanic group was $65,643 per additional successfully treated patient who avoids treatment-related serious adverse events and graft loss with consequent dialysis; the ICER in the Black group was $90,458.1 However, tacrolimus has a narrow therapeutic index, and it is important to achieve therapeutic concentrations soon after transplant to avoid potentially toxic effects that result from higher concentrations or graft loss from underdosing.2The primary goal of immunosuppressive therapy after kidney transplantation is to prevent rejection and graft failure. Although acute rejection is treatable, allowing the graft to continue functioning, graft failure is an irreversible loss that requires patients to return to dialysis and await another transplant. Tacrolimus, a calcineurin inhibitor, is currently approved for the prophylaxis of organ rejection in patients receiving allogeneic liver, kidney, or heart transplants. Tacrolimus is one of the most widely used immunosuppression drugs, and clinical guidelines recommend it as a first-line immunosuppressive therapy following kidney transplantation.2 Black patients are much more likely than Caucasian patients to express the CYP3A5*1 wild-type allele associated with increased tacrolimus clearance and variability ,6 and they may also experience low drug levels immediately following transplantation, delaying therapeutic tacrolimus levels.7 Because of this enzyme, Black patients often need higher doses to reach therapeutic levels, which leads to higher peak concentrations of tacrolimus.8 Some toxicities are associated with peak concentrations of tacrolimus.9 Similarly, compared with Caucasian patients, Hispanic patients may also be more likely to express the CYP3A5*1 wild-type allele and less likely to express the CYP3A5*3 allele associated with slower tacrolimus clearance.12 Prevalence of the CYP3A5*1 expression is also higher in East Asian populations—specifically Chinese, Japanese, and Korean—than in European populations.5Since release of the current clinical guidelines by the Kidney Disease Improving Global Outcomes in 2009, advances in sequencing technologies and a growing body of genome-wide association studies have identified genotypes affecting CYP3A enzymes associated with pharmacokinetic differences in tacrolimus-centered immunosuppression that should be considered when prescribing.16 Due to these characteristics, LCPT requires on average a 20% lower dose than IR-Tac.18 In addition, reduced dosing from twice to once daily can also improve adherence, a major risk factor for graft failure.21Orally administered tacrolimus is available as an immediate-release capsule taken twice daily ; an extended-release capsule taken once daily ; and an extended-release tablet taken once daily . LCPT employs a MeltDose drug delivery technology that uses small particle size to alter pharmacokinetic properties, resulting in increased bioavailability and broader absorption in the gastrointestinal tract with a lower peak and less peak-to-trough fluctuation compared with IR-Tac.18 The first study was an open label trial of stable adult patients who received a kidney transplant 3 months to 5 years before enrollment and randomized to either continue with IR-Tac or convert to a reduced dose of LCPT.18 The second study was a double-blind, double-dummy trial of adult de novo patients randomized to receive LCPT or IR-Tac.17 These 2 studies together evaluated 861 patients  over a 1-year period, followed by further post hoc pooled and subgroup analyses.25Two phase 3 clinical trials demonstrated noninferior efficacy and similar safety between LCPT and IR-Tac overall.24 Subgroup analyses, however, showed that Black patients in the LCPT group experienced numerically fewer treatment failures and adverse events (AEs) than Black patients in the IR-Tac group ,24 whereas Hispanic de novo patients in the LCPT group experienced significantly less treatment failures .23At 12 months, the overall incidence of treatment failure was statistically similar for LCPT and IR-Tac groups, defined as a composite endpoint including biopsy-proven acute rejection (BPAR), graft loss, death, or lost to follow-up.Despite the perceived advantages of LCPT compared with IR-Tac, especially among rapid metabolizers, no studies have examined its cost-effectiveness. Recent data available from the clinical trials provide an opportunity to pursue this topic. Specifically, the purpose of this study was to evaluate the cost-effectiveness of LCPT vs IR-Tac in Hispanic and Black kidney transplant recipient subpopulations.24 Although the clinical trials were conducted in the United States and abroad, the treatment patterns in this model reflected current US practices, and the analysis perspective of this study was that of a US health care payer, such as a managed care organization. Similar outcomes data for Hispanic and Black patients from the other once-daily tacrolimus formulation were not publicly available at the time of this study to include in an indirect comparison.Following approval by the University of Arizona Institutional Review Board, we developed a decision analytical model to evaluate the cost-effectiveness for the first year of LCPT vs IR-Tac therapy based on outcomes data for Hispanic and Black subgroups from the pooled clinical trials.The decision tree model simulated the following possible outcomes, comprising 20 total pathways : (1) funTreatment-related SAEs may occur with any of the first 5 outcomes, resulting in 10 pathways each for LCPT and IR-Tac. Severe BPAR events, treatment-related deaths, and kidney retransplants did not occur in the selected patient populations during the 1-year clinical trial period and thus were excluded from the model. The model structure for the Hispanic and Black groups was identical and was analyzed separately using Microsoft Excel (2015) and decision tree modeling software .24 Although BPAR was an unwanted complication, it was a treatable condition that resulted in a functioning kidney, which was the desired model outcome.The primary outcome in this model was a successfully treated patient, defined as having a functioning graft without treatment-related SAEs, regardless of BPAR . In other words, treatment failure involved treatment-related SAEs or graft loss . This definition more closely reflects safety and efficacy endpoints in clinical practice, differing from the original clinical trials, which included BPAR as a treatment failure.The primary result of this analysis was to calculate and interpret the incremental cost-effectiveness ratio (ICER), which indicated the cost per additional successfully treated patient using LCPT vs IR-Tac. The ICER value equaled the difference in total costs between LCPT and IR-Tac divided by the difference in probabilities of treatment success.To capture variations in dosing regimens , average doses were used from 4 dosing periods  for each patient group and treatment arm . All model pathways included 1 year of immunosuppressant therapy (LCPT or IR-Tac) except for the graft loss pathway, which included only a partial year of immunosuppressant therapy based on the average time to graft loss .34The clinical trials did not collect information about treating borderline, mild, and moderate BPAR. Resource use associated with these outcomes therefore relied on the literature and author experience.borderline BPAR, the model assumed a 1-day hospitalization that included a percutaneous renal biopsy and augmented dose of immunosuppressant. In addition, 50% of cases received intravenous methylprednisolone (500 mg daily for 3 days) through an outpatient infusion clinic, while also taking oral prednisone (40 mg taper over 5 days).To treat Mild and moderate BPAR treatments involved 3- and 5-day hospitalizations, respectively; percutaneous renal biopsy; augmented dose of immunosuppressant; intravenous methylprednisolone; and thymoglobulin. In addition, all mild BPAR cases received a 40 mg oral prednisone taper over 5 days, whereas half the cases also resumed opportunistic infection prophylaxis comprising valganciclovir (450 mg daily for 90 days), sulfamethoxazole-trimethoprim (1 single-strength tablet daily for 90 days), and nystatin (20 mL daily for 30 days). In contrast, all moderate BPAR cases resumed the same opportunistic infection prophylaxis and received a more intensive prednisone regimen (60 mg taper over 40 days).graft loss and dialysis pathway accounted for a partial year of immunosuppressant medication and hospitalization  followed by dialysis for the remainder of the year.35Using the average number of days to graft loss by patient group and treatment arm , the 36This analysis included AEs that resulted in hospitalizations, classified as “serious” by the US Food and Drug Administration, and reported by the clinical trial investigators as related to the study drugs .24; 2 research abstracts focused on Hispanics from the pooled data23; and additional data for each patient group . The pooled clinical studies included specific information on the number and types of treatment-related SAEs, number and severity of BPAR events, and other information needed to estimate costs of resource use described elsewhere in this article .Movement through the decision tree was based on data extracted from the pooled analysis for Black patientsMany patients experienced multiple types of events during the 1-year study period. The number of patients who experienced 1 or more treatment-related SAEs determines the probability of occurrence, whereas the total numbers and types of SAEs determine the costs. Similarly, some subjects experienced multiple BPAR events with different severity levels during the study period. The probability of BPAR occurrence included anyone with 1 or more BPAR events categorized by their highest level of severity. For example, a patient who experienced 2 borderline and 1 mild BPAR events would appear in “mild BPAR.” However, the per person cost incorporated the multiple BPARs experienced by a single person, calculated as the sum of costs associated with all events divided by the number of patients who experienced the events. Those who experienced BPAR and graft loss appear separately in the BPAR probability and costs, as well as in the graft loss probability and costs.37 The WAC was $5.31 per mg for LCPT, $6.03 per mg for branded IR-Tac, and on average $1.54  for generic IR-Tac. Generics included any active status drugs with tacrolimus active ingredient administered orally as capsules, excluding repackagers. Further, IR-Tac costs reflected the proportion of generic and branded 2019 US prescription claims by patient subgroup, with generic comprising 94.42% and 92.06% of the claims among Hispanic and Black patients nationwide.38 Thus, the final IR-Tac costs used in this study were $1.79 per mg and $1.90 per mg in the Hispanic and Black groups.The model included the following direct medical costs: LCPT and IR-Tac treatments; borderline, mild, and moderate BPAR; graft failure and resulting dialysis; and treatment-related SAEs. The costs for all outpatient medications in this analysis were based on current wholesale acquisition costs (WAC) retrieved on January 6, 2020.35 HCUPnet is a database of acute care encounters across the United States and is broadly representative of inpatient services and costs. Hospitalization costs were assumed to include a percutaneous biopsy, augmented dose of immunosuppressant, and, for mild and moderate BPAR, intravenous methylprednisolone and thymoglobulin. If augmented dosing of LCPT or IR-Tac continued after discharge, then it was assumed already captured within the average daily dosage . Costs of oral medications taken as an outpatient were based on WAC pricing.37 For borderline BPAR, the cost of administering intravenous methylprednisolone at an outpatient infusion clinic was based on current Medicare Physician Fee Schedule for CPT #96365 “Intravenous infusion, hydration; initial, 31 minutes to 1 hour.”40Costs to treat BPAR derived from multiple sources. The hospitalization costs associated with all 3 levels of BPAR were based on 2016 national weighted estimates from HCUPnet National Inpatient Sample using the ICD-10-CM diagnostic code (T86.11 Kidney transplant rejection) and adjusted for a daily average .35 In addition, this pathway included the costs of a partial year of medication (LCPT or IR-Tac) until the average time to graft loss (for a given treatment arm), followed by dialysis costs for the remainder of the year. The average number of days on dialysis for Hispanic patients was 237.75  in LCPT and 241.75  in IR-Tac . No Black patients experienced graft loss in the LCPT arm, while only 1 patient experienced it in the IR-Tac arm (176.25 days).24 Dialysis costs were from the recent US Renal Data System 2019 Annual Report.41 The clinical trials did not collect information on the type of dialysis patients received, so the model assumed the proportions of hemodialysis and peritoneal dialysis recipients in the United States by patient subgroups.41Hospitalization costs related to graft loss also derived from HCUPnet using ICD-10-CM diagnostic code T86.12 Kidney transplant failure.Supplementary Table 1, available in online article) to identify hospitalization cost estimates.35 To calculate per-person costs, we summed the hospitalization costs for all treatment-related SAEs and divided by the number of patients who experienced at least 1 event.We linked the list of treatment-related SAEs  with ICD-10-CM codes  were uncorrelated. Concomitant immunosuppressant use was also assumed to be equivalent between treatment groups.The model components, structure, and interpretation of results rested on several assumptions. First, the model assumed that all patients start with a functioning graft. Hence, the model did not include delayed graft function, where newly transplanted kidneys require temporary dialysis until the kidney “wakes up” nor any pretransplant tacrolimus costs or resources used. The model also assumed that generic and branded twice-daily immediate-release tacrolimus are clinically equivalent and have the same dosing and that all patients self-administered LCPT tablets and IR-Tac capsules. Although BPAR may be associated with increased risk of graft loss,18 whereas all patients in the second clinical trial received corticosteroids per local use (requiring at least 5 mg of prednisone for 12 months), mycophenolate mofetil (2 g/day), and an IL-2 receptor anatagonist induction with basiliximab .17Subgroup level data were unavailable, but the most frequently used concomitant immunosuppressants overall in the first clinical trial by treatment group (LCPT [n = 162]/IR-Tac [n = 162]) included mycophenolate mofetil (60%/66%), mycophenolic acid (34%/31%), and corticosteroids (66%/74%) ,The analysis included 3 subjects lost to follow-up in the IR-Tac arm for 52 days on average (SD = 26) after starting treatment. During this time, 1 subject experienced a graft loss and was included in the “graft loss/dialysis” branch of the model, so the subsequent loss to follow-up was nonconsequential. However, the other 2 subjects experienced neither graft loss nor BPAR during their study participation and so appear in the “functioning graft” branch. This favors IR-Tac because the potential for BPAR or graft loss events for these subjects would otherwise continue in that arm for the remaining approximately 10 months.The model used a probabilistic sensitivity analysis, based on 5,000 Monte Carlo simulations, to account for uncertainty or variability in all inputs. Cost ranges were based on variability estimates previously mentioned using a gamma distribution, while uncertainty in effects were based on proportions observed in the clinical trial using a beta distribution.24 Upper values for high frequency events, such as 84.09% (37/44) of this group that experienced functioning graft without BPAR, capped at 100% . A separate series of deterministic and one-way sensitivity analyses were also used for periodic diagnostic and validity checks during model construction.A follow-up series of one-way analyses used the lower and upper ranges of all parameters to examine the independent impact of each parameter on overall results. These deterministic analyses used the same cost ranges previously noted but vary estimates ± 20% for each probability instead of using a beta distribution. For example, 13.64% of the 44 Black patients in the LCPT arm experienced borderline BPAR, with a ± 20% range of 10.91%-16.37% . For events with no patients, such as graft loss/dialysis in this same group, 1 was added and the upper value became 2.27% (1/44), while the lower value remained at 0% (0/44).Supplementary Table 2 (available in online article).Internal clinical trial analyses showed no statistically significant differences in sample characteristics between treatment arms within the Hispanic and Black patient groups . These cost values represent the “fully-loaded” cost estimates over 1 year, accounting for complications  and graft-loss/dialysis. Total effectiveness represents the probability of a successfully treated patient without treatment-related SAEs and graft loss/dialysis. The total effectiveness in the Hispanic group was 88.32% in the LCPT arm and 84.75% in the IR-Tac arm, while the total effectiveness in the Black group was 93.24% for LCPT and 85.78% in IR-Tac.Total overall average costs for the Hispanic group were $14,765 in the LCPT arm and $12,416 in the IR-Tac arm, whereas total costs for the Black group were $16,626 for LCPT and $9,871 for IR-Tac . Six parameters common to driving the results in the Hispanic and Black groups were the medication costs for LCPT and IR-Tac, the probabilities of graft loss for both medications, and the probabilities of treatment-related SAEs for both medications.A series of one-way sensitivity analyses identified parameters that independently had the greatest influence on the ICERs within each group. Of the 66 model parameters included, 11 in the Hispanic group and 7 in the Black group accounted for over 99% of significant changes in ICER values for each group, while the remainder of the 66 parameters in each group had little to no impact  favored IR-Tac and would have increased the original ICERs from $65,643 to $243,106 in the Hispanic group and from $90,458 to $145,963 in the Black group. Conversely, using a high range value favored LCPT and would have decreased the original ICERs to a lesser extent from $65,643 to $31,286 in the Hispanic group and from $90,458 to $67,096 in the Black group. For other parameters, such as the cost of LCPT or the probability of treatment-related SAE in LCPT, high values favored IR-Tac and would have increased ICERs, whereas low values favored LCPT and would have decreased ICERs.12In the Hispanic and Black subpopulations, LCPT was incrementally more costly and more effective compared with IR-Tac. The ICERs for the Black  and Hispanic  groups represent the cost of using LCPT during the first year of treatment over IR-Tac to achieve 1 additional successfully treated patient who avoided treatment-related SAEs and graft loss with consequent dialysis. For these subpopulations, LCPT may be useful because of its specific pharmacogenomic characteristics affecting pharmacokinetics of tacrolimus.41 while the median cost for a deceased donor transplant is $125,033, including the cost of organ acquisition and hospital care.44 Patient quality of life and the potential for additional complications must also be considered. Even 1 year of dialysis followed by retransplant exceeds the additional cost of using LCPT.LCPT appears to be a cost-effective strategy, given the relatively low ICER values. In general, when a decision maker’s WTP for 1 additional successfully treated patient exceeds the ICER, the technology should be reimbursed and made available. While no known accepted WTP thresholds exist for these outcomes, one may weigh these ICERs against the costs of treating graft loss, resuming dialysis for an indefinite period of months or years, and potential retransplant. Adjusted for inflation to 2019 US dollars, Medicare spent $96,253 per patient per year for hemodialysis and $81,954 for peritoneal dialysis,46 During the time that we incorporated these inputs, the average cost per milligram of branded IR-Tac remained the same, while generic IR-Tac, the largest proportion of the overall IR-Tac cost, increased by 10.4% and LCPT increased by 2.5%.37 The effect on results of an additional WAC increase of IR-Tac over LCPT would only favor LCPT further. If we updated our model using these current costs, the ICERs for LCPT would be even more favorable.Costs of LCPT and IR-Tac medications were among the several parameters that most influenced results in the Hispanic and Black analyses. These were based on WAC, but payers may substitute with their actual costs. Current tacrolimus costs are especially difficult to estimate, given the price fluctuations due to continued global shortages reported since May 2019.Similar outcomes data for Hispanic and Black patients are not publicly available elsewhere to include as indirect comparisons at this time. As more data become available, researchers can update and expand inputs from this model to improve real-world decision making. Additional research is needed, for example, to compare the long-term costs and effectiveness beyond the first year of treatment, incorporate other outcomes such as the quality-of-life impacts of preventing graft loss and dialysis, and evaluate additional comparators such as another once-daily tacrolimus formulation currently available.A unique feature of this study is the direct comparison between LCPT and IR-Tac based on actual, rather than simulated, event probabilities from clinical trial data for the 2 groups. However, presence of so few or zero events  lacks variation for probabilistic sensitivity analyses. Given such small numbers, a single extra graft loss in either arm can dramatically affect results. These results are based on randomized clinical trial data and may not be generalizable to real-world settings where patient outcomes may be less favorable.Some data that may improve parameter estimates, such as the actual health care resource utilization of the clinical trial patients following BPAR and treatment-related SAEs, were also unavailable. Although generalizability to real-world settings is an inherent limitation of randomized clinical trials, all costs included in this model were based on real-world sources.The one-way sensitivity analyses explored a series of “what if” scenarios associated with the extreme ranges of values of all parameters, which may be realistic but rare occurrences. Given the single source of outcomes data, this analysis assigned ± 20% to all probability values to gauge potential effects on ICER results. However, future research can assign different ± percentage ranges or update these ranges as more data sources become available.Overall results for both groups show that LCPT is incrementally more costly and more effective compared with IR-Tac, indicating a trade-off scenario. The ICERs for Hispanic  and Black  groups represent the cost of using LCPT over IR-Tac to achieve 1 additional successfully treated patient who avoids treatment-related SAEs and graft loss with consequent dialysis. LCPT is a cost-effective strategy because of the relatively low ICER value, especially if weighed against the costs of graft loss, continuing dialysis, and potential retransplant. As more data become available and tacrolimus prices stabilize following the shortage, researchers can build on this model to update and expand inputs to improve real-world relevance and decision making.