Clostridioides difficile (HO-CDI) rates into value-based incentive programs in October 2016 associated with changes in HO-CDI rates in US hospitals?Was the incorporation of health care facility–onset In this interrupted time series study of more than 24 million admissions at 265 hospitals between January 2013 and March 2019, the incorporation of HO-CDI into value-based incentive programs was associated with a 6% decline in HO-CDI rates in the immediate postpolicy quarter and a 4% decline in slope per quarter.In this study, value-based incentive programs were associated with a decline in national HO-CDI rates, which may reflect improvements in infection control practices and better antibiotic and diagnostic stewardship. Clostridioides difficile infection rates.This nonrandomized clinical trial examines the association between value-based incentive program implementation and health care facility−associated  Clostridioides difficile infection (HO-CDI) rates reported to the US Centers for Disease Control and Prevention’s National Healthcare Safety Network (NHSN) became a target quality metric for 2 Centers for Medicare & Medicaid Services (CMS) value-based incentive programs (VBIPs) in October 2016. The association of VBIPs with HO-CDI rates is unknown.Health care facility–onset To examine the association between VBIP implementation and HO-CDI rates.This interrupted time series study evaluated HO-CDI rates among adults hospitalized from January 2013 to March 2019 at 265 acute-care hospitals.Implementation of VBIPs in October 2016.Quarterly rates of HO-CDI per 10 000 patient-days, as reported to NHSN by participating hospitals, were evaluated. Generalized estimating equations were used to fit negative binomial regression models to estimate immediate program effect size  and changes in the slope of HO-CDI rates, controlling for each hospital’s predominant method of CDI testing .P < .001) and other testing methods . There were no significant changes in testing methods used by hospitals immediately after VBIP implementation. Controlling for CDI testing method, VBIP implementation was associated with a 6% level decline in HO-CDI rates in the immediate postpolicy quarter  and a 4% decline in slope per quarter . Results were similar in a sensitivity analysis using a 1-year roll-in period accounting for the period after the announcement of the HO-CDI VBIP policy and prior to its implementation.The study cohort included 24 332 938 admissions, 109 371 136 patient-days, and 74 681 HO-CDI events at 265 hospitals . Compared with EIA, rates of HO-CDI were higher when detected by NAAT (adjusted incidence rate ratio [aIRR], 1.55; 95% CI, 1.40-1.70; In this study, VBIP implementation was associated with improvements in HO-CDI rates, independent of CDI testing method. Given that CMS payment policies have not previously been associated with improvements in other targeted health care–associated infection rates, future research should focus on elucidating the specific processes that contributed to improvement in HO-CDI rates to inform the design of future VBIP interventions. Clostridioides difficile (formerly Clostridium difficile) is a gram-positive, spore-forming bacillus that can cause serious infectious diarrhea. In 2017, C. difficile infections (CDI) were responsible for 223 900 cases in hospitalized patients, 12 800 associated deaths, and approximately $1 billion in attributable health care costs.1 Given its substantial health and economic burden, health care facility–onset CDI (HO-CDI) was among the health care–associated infections (HAIs) targeted by US Department of Health and Human Services 2013 Action Plan for prevention efforts.23 the Centers for Medicare & Medicaid Services (CMS) established 2 value-based incentive programs (VBIPs), the Hospital Value-Based Purchasing (HVBP) and the Hospital-Acquired Conditions Reduction Program (HACRP), that link financial incentives or penalties to hospitals’ performance on selected quality metrics, including HO-CDI rates.4 HVBP rewards or penalizes hospitals by as much as 2% of total Medicare inpatient payments based on hospital performance on selected quality measures, while the HACRP withholds as much as an additional 1% of Medicare payments from the lowest-performing hospitals.4 In October 2016, these VBIPs began including HO-CDI rates reported to the US Centers for Disease Control and Prevention’s (CDC) National Healthcare Safety Network (NHSN) as a component of targeted quality measures.5To help achieve the HAI Action Plan’s 2020 target to reduce HO-CDI by 30%,To date, national HO-CDI rates have not been evaluated in light of VBIP implementation. In this study, we used prospectively collected NHSN data from a large cohort of US hospitals to assess changes in HO-CDI rates associated with VBIP implementation.6 We obtained prospective NHSN surveillance data from a cohort of nonfederal acute-care hospitals subject to the Inpatient Prospective Payment System and enrolled in the Preventing Avoidable Infectious Complications by Adjusting Payment (PAICAP) study.7 We included CDI surveillance data from all PAICAP study hospitals conducting NHSN CDI reporting from January 1, 2013, through March 31, 2019. We analyzed data from hospitals that reported facility-wide CDI events and excluded hospitals that contributed data only from specific departments.We used an interrupted time-series design to examine the association between VBIP implementation in October 2016 and changes in trends for NHSN HO-CDI rates. The NHSN is a comprehensive national surveillance system used by more than 4000 acute-care facilities in all 50 states, Washington, DC, and Puerto Rico. Hospitals prospectively track HAIs using standardized surveillance case definitions based on laboratory and clinical data and report cases to NHSN. Hospitals started reporting CDI laboratory-identified events to the NHSN as part of CMS Hospital Inpatient Quality Reporting Program on January 1, 2013.8 The institutional review board of Harvard Pilgrim Health Care Institute approved this study with a waiver of informed consent because data were deindentified. The study followed the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) reporting guideline.We obtained hospital characteristics including hospital size, teaching status, type of ownership , location , and percentage of patient-days insured by Medicare or Medicaid from the 2015 American Hospital Association annual survey.9Per NHSN criteria, we defined HO-CDI as laboratory-identified events for stool specimens collected more than 3 calendar days after admission from any inpatient location (regardless of patient signs or symptoms). We defined community-onset CDI (CO-CDI) as laboratory-identified events for stool specimens collected from inpatient locations up to 3 days after admission or from outpatient settings for patients who did not have an inpatient discharge in the last 28 days. We calculated quarterly CDI incidence rates (cases per 10 000 patient-days) for each health care facility by dividing the overall number of CDI events by the number of total inpatient days for the facility and multiplying by 10 000. We excluded any recurrent laboratory-identified CDI and community-onset health care facility–associated events, which are laboratory-identified events collected from an inpatient or outpatient location for patients who were discharged within the prior 28 days.11 CDC classifies CDI testing methods into three groups: (1) nucleic acid amplification testing (NAAT), including NAAT alone or any testing algorithm that includes NAAT as the final step; (2) enzyme immunoassay (EIA), including EIA alone or any algorithm with EIA in the final step; and (3) other, including cell cytotoxicity assay, toxigenic culture, or another method. For multistep testing algorithms on the same unformed stool specimen, as per CDC criteria, the final test performed was used to determine whether the case definition for laboratory-identified CDI was met.Due to variations in the sensitivity of different CDI testing methods, hospitals are required to report their predominant CDI testing method on a quarterly basis, defined as the method used for more than 50% of specimens.We performed descriptive analyses to summarize continuous variables using medians and IQRs and categorical data using proportions and frequencies. We reported CDI rates using weighted mean and SD to adjust for the variation in reported patient-days between hospitals. We used generalized estimating equations (GEE) with robust sandwich variance estimators to fit negative binomial regression models to identify changes in the level and trend of HO-CDI rates associated with VBIP implementation and account for clustering at the hospital level. Terms in the models included time (in quarters), an indicator for program implementation in quarter 4 of 2016 (to assess for level change in CDI rates), the interaction between time and program implementation (to assess for change in slope after program implementation), and the predominant CDI testing method (to account for variable sensitivity of CDI testing methods). Number of patient-days was used as the model offset.In addition, we explored a 3-way interaction between time, program implementation, and predominant CDI testing method to assess whether CDI testing method modified the program implementation effect. We excluded this 3-way interaction term from the primary model because it was not significant.12 Second, we compared trends in HO-CDI to the non-VBIP targeted CO-CDI to understand the degree to which HO-CDI trends might have been associated with actions that are specific to hospitalized patients  as opposed to actions that would affect both CO-CDI and HO-CDI rates . We conducted an interrupted time series model to test the change in the ratio of absolute numbers of HO-CDI to CO-CDI cases over time, controlling for CDI testing method and VBIP implementation and its interaction with time. We considered 2-sided P < .05 to be significant, and all analyses were conducted using R version 4.02  and SAS Studio version 3.7 (SAS Institute).We performed 2 sensitivity analyses. First, we evaluated a model that considered the year prior to program implementation to be a roll-in period, as the official announcement of inclusion of HO-CDI as a VBIP target occurred with the publication of the 2016 CMS Final Rule (CMS-1632-F) in July and October 2015, approximately 1 year before program implementation.Of the 394 PAICAP study hospitals reporting to NHSN between 2013 and 2019 and subject to the Inpatient Prospective Payment System, 129 hospitals were excluded from this analysis because they contributed data only from selected departments and did not report facility-wide CDI events. The excluded hospitals were comparable with included hospitals with regard to region, bed size, teaching status, number of full-time equivalent nurses per 100 patient-days, and the percentage of patient-days covered by Medicare and Medicaid.A total of 265 hospitals from 47 states and the District of Columbia participated in the VBIPs and consistently reported facility-wide CDI events to NHSN during the study period and thus were included in this analysis. In total, these hospitals reported 24 332 938 admissions, 109 371 136 patient-days, and 74 681 HO-CDI events. Most hospitals were medium-sized , not-for-profit (205 [77%]), teaching hospitals (185 [70%]), and located in metropolitan areas (229 [86%]) . There wThe percentage of hospitals reporting NAAT as their predominant CDI testing method gradually increased from quarter 1 of 2013  to quarter 1 of 2017 (223 [84%]) and subsequently decreased to 206 hospitals (78%) in early 2019 . In geneP < .001; other CDI testing methods: aIRR, 1.47; 95% CI, 1.26-1.71; P < .001).HO-CDI incidence was highest among hospitals that predominantly used testing methods from the other  and NAAT  categories, followed by the EIA category . The GEE model confirmed that predominant use of NAAT and other CDI testing methods was associated with higher HO-CDI incidence rates compared with the EIA method  followed by a gradual slope decline after that . Results were similar in the model using a roll-in period for the year prior to VBIP implementation . Both types of CDI had commensurate trends, with a sharp decline after VBIP implementation, while the number of surveilled patient-days (denominator for HO-CDI rates) remained constant during the study period A. The raThe VBIPs are one of the broadest initiatives to incentivize prevention of HO-CDI in US hospitals. In this large cohort study of 265 US hospitals, we found that the implementation of VBIPs was associated with a consistent decline in the rates of HO-CDI infection, regardless of the predominant CDI testing method used by the hospital. Our findings were similar when including a 1-year roll-in period to account for the lag between the announcement of the inclusion of HO-CDI as a VBIP target and program implementation.13 In addition, standardized infection ratios for CDI among national acute-care hospitals declined between 2016 and 2018.14 Turner et al15 found a modest decline in HO-CDI rates in a sample of 43 community hospitals between 2013 and 2018 but only after controlling for testing method; the increasing use of NAAT as a testing method in that study might have attenuated the temporal reduction in HO-CDI rates.The rapid decline in HO-CDI rates we observed after the implementation of VBIPs is consistent with data from CDC’s Emerging Infections Program that showed a decline in both the adjusted and actual HO-CDI rates at 10 US sites from 2011 through 2017, with the greatest reduction starting in 2016.16 catheter-associated urinary tract infections,18 and mediastinitis following coronary artery bypass graft surgery.20To our knowledge, this is the first HAI for which a CMS policy has been associated with improvement. Previously implemented CMS policies and the current VBIPs showed no evidence in reducing the rates of central catheter–associated bloodstream infections, surgical site infections after colon surgical procedures and abdominal hysterectomy procedures,23 may have improved over time and are potentially modifiable with hospital-based initiatives. For example, Vaughn et al24 found an increase in reported use of infection prevention practices against CDI in Veterans Affairs hospitals. However, these are survey-reported improvements, and compliance with simple practices, such as hand hygiene, is still reported as suboptimal worldwide.25There are several possible explanations for the apparent association between VBIPs and the decline in HO-CDI rates. First, this could reflect a commitment by health care organizations in reducing the infection rates by taking increasingly aggressive measures to prevent CDI. Adherence to infection control measures, such as handwashing, contact precautions, and patient isolation, environmental screening and cleaning, and the use of sporicidal germicides,28 Two meta-analyses30 found that antibiotic stewardship, by cycling and restricting exposure to high-risk antibiotics, was associated with a significant protective effect for HO-CDI. In 2017, the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America clinical practice guidelines recommended the implementation of antibiotic stewardship practices and programs to battle CDI.31 In a cohort of US Southeastern hospitals, fluoroquinolone prescription declined between 2013 and 2017, and this reduction was even steeper after the FDA black box warning on fluoroquinolones (summer 2016),32 just before the implementation of VBIP for HO-CDI. In addition, the CDC reported a significant upward yearly trend in the percentage of national hospitals meeting all 7 core components of antibiotic stewardship since 2014.14 These antibiotic stewardship efforts also extend beyond the inpatient setting, and better outpatient antibiotic prescribing practices could partially account for the concurrent reduction in CO-CDI rates that we observed.34Second, our findings could reflect national improvements in antibiotic stewardship practices. Certain antibiotics, such as fluoroquinolones, second-generation and beyond cephalosporins, carbapenems, and clindamycin, are associated with an increased risk of immediate and prolonged CDI.35 Solanky et al36 showed that diagnostic stewardship had the most substantial association with reductions in HO-CDI rates among other interventions, including prompt isolation of patients with CDI, optimal environmental cleaning, hand hygiene, fluoroquinolone and proton-pump inhibitor stewardship, and the rejection of solid stool samples by the laboratory. Several other studies that used diagnostic stewardship interventions significantly reduced unnecessary testing using a variety of approaches, such as health care professional education, decision-making algorithms, and the deployment of what are known as hard stops requiring a specialist consultation or laboratory approval prior to test ordering.41A third potential explanation for the decline we observed in HO-CDI rates relates to implementation of better diagnostic stewardship by the health care facilities in our cohort.43 Some studies have reported that CO-CDI rates are increasing or stable over the same period as our study15; however in our analysis, we found a commensurate decline in both VBIP-targeted HO-CDI and CO-CDI events. This suggests there was likely a decline in the total number of C. difficile tests conducted , which may be due to overall better diagnostic stewardship  rather than shifting HO-CDI to CO-CDI. Regardless of the mechanism behind HO-CDI temporal decline, this change is likely to be accompanied by lower costs and less overtreatment and exposure to unnecessary antibiotics because of false-positive C. difficile test results.37Diagnostic stewardship may reduce the false-positive HO-CDI cases reported to NHSN due to laxative use, absence of significant diarrhea, and delayed testing that results in misclassification of CO-CDI as HO-CDI.Our study has several strengths, including the use of prospectively collected data from the largest national database for CDI reporting. Additionally, the hospitals in our large sample are geographically and demographically representative of the United States. Our study also has several potential limitations. First, we did not have information on the number of CDI tests ordered for each hospital, which limited our ability to study changes in diagnostic stewardship. Therefore, we used other methods  to indirectly draw conclusions on the association of diagnostic stewardship with the reduction in HO-CDI rates. Future CDI surveillance and evaluation could be enhanced by capturing data on the precise testing method used and the total number of tests performed. Second, hospital practices change over time, including the type of testing used and use of diagnostic or antimicrobial stewardship or other interventions. To address this issue, our GEE analyses were clustered at the hospital level, and we considered changes in the type of testing used over time in the model. Third, CO-CDI events (laboratory-identified events within the first 3 days of admission) used in our sensitivity analysis are captured by hospitals and may not be representative of CDI rates in the entire community. Fourth, our analysis was focused on facility-wide reported events, and we did not have data about patient characteristics that might reflect shifts in population risk of CDI over time. Fifth, the reported method of testing for each facility is classified only based on NHSN rule for the majority (>50%) testing method used; other methods that represent the principal minority could have been overlooked in our analysis. However, we did not observe significant shifts in the proportion of testing methods over time, suggesting that the impact of other testing methods was likely small. Sixth, we did not have a group of control hospitals that were not subject to VBIP, nor were we able to include patient-level data for risk adjustment. These factors limit our ability to draw conclusions on the causal association between VBIP implementation and the reduction in HO-CDI rates.The implementation of VBIPs was associated with a sustained decline in rates of HO-CDI, in contrast to previously reported VBIPs, which do not appear to have affected the rates of other targeted HAIs. The observed decline in HO-CDI rates may be due to greater opportunities for improvement in diagnostic and antimicrobial stewardship, which also align with the value these programs intend to achieve. Given that CMS payment policies have not previously been associated with improvements in other targeted HAI rates, future research should focus on elucidating the specific processes that contributed to improvement in HO-CDI rates to better inform the design of future interventions targeted by VBIPs.


Chronic graft-versus-host disease (cGVHD) is one of the major causes of late mortality after allogenic hematopoietic stem cell transplantation. Moderate-to-severe cGVHD is associated with poor health-related quality of life and substantial disease burden. While corticosteroids with or without calcineurin inhibitors comprise the first-line treatment option, the prognosis for patients with steroid-refractory cGVHD (SR-cGVHD) remains poor. The mechanisms underlying steroid resistance are unclear, and there are no standard second-line treatment guidelines for patients with SR-cGVHD. In this review, we provide an overview on current treatment options of cGVHD and use a series of theoretical case studies to elucidate the rationale of choices of second- and third-line treatment options for patients with SR-cGVHD based on individual patient profiles. The use of allogenic hematopoietic stem cell transplant  for treatment of malignant and non-malignant conditions continues to increase annually due to significant improvement in early mortality , but modThe National Institutes of Health (NIH) consensus criteria define acute GVHD (aGVHD) and cGVHD based on a combination of clinical features and time of onset . ApproxiUnlike in aGVHD, the underlying pathogenesis of cGVHD is not well understood, but is thought to be complex and multifactorial, with involvement of T and B cells as well as innate responses, including the transition from inflammation to fibrosis involving fibroblasts and macrophages –12. DecrThere is also an emerging understanding of the role of the gut microbiome on cGVHD presentation . Loss ofSigns and symptoms of cGVHD can be stratified as diagnostic, distinctive, and those in common with aGVHD , but patClinical features may affect multiple organs or body areas, with varying presentation depending on the site involved , 10. TheIn addition to organ impairment caused by cGVHD, patients often have comorbidities associated with treatment, such as osteoporosis induced by corticosteroids . OverallStandard GVHD prophylaxis for HLA-matched transplants comprises a calcineurin inhibitor plus a short course of methotrexate or mycophenolate mofetil (MMF) with or without additional antithymocyte globulin (ATG) in transplants from unrelated donors; ATG has recently been also recommended for use in HLA-identical sibling transplantation . The aimThe mechanisms of steroid resistance in cGVHD are not well described , and proThere are no standard second-line treatments for patients with SR-cGVHD. While an increasing number of treatment options are becoming available, data are limited, and no consensus has been found on an optimal approach; these circumstances lead to a wide variation in individual clinical practice , 31, 48.In the second section of this review, we discuss three case studies of patients with SR-cGVHD from our clinics and suggest potential treatment options based on their individual profiles.1) with steroid taper, FEV1 of 44%, FEV1/forced vital capacity of 0.62 (grade 2), moderate mouth symptoms with lichenoid features and ulceration (grade 2), and deep sclerotic features on lower limbs (grade 3). He has an active fungal lung infection and confirmed cytomegalovirus reactivation.Patient 1 is a 74-year-old male former smoker who received a peripheral blood HLA-mismatched graft from an unrelated female donor. He was initially treated for quiescent onset of moderate cGVHD  starting 10 months after transplantation, with 1 mg/kg/day prednisone tapered to 0.25 mg/kg/day plus tacrolimus and fluticasone, azithromycin, and montelukast therapy. He then developed a > 15% decline in forced expiratory volume in 1 second  and MMF. He developed steroid-sensitive classic grade 2 aGVHD  on day + 53 and presented 18 months after transplantation with quiescent onset of high risk cGVHD, including elevated bilirubin > 3 mg/dl (grade 3) plus fasciitis affecting wrists, elbows, and shoulders, with moderate limitation in the photographic range of motion scale (P-ROM) of 16 (grade 2), while still receiving treatment with low-dose corticosteroids and sirolimus. Both episodes (aGVHD and cGVHD), which were initially treated with prednisone 1 mg/kg/day, were complicated by latent steroid-psychosis requiring a rapid taper of steroids and combination treatment. The patient also experienced impaired renal function on CSP. At the time of cGVHD progression, immunoglobulins (Ig) were above the normal range, with concurrent elevated IgG1 and IgG2 deficiency. The patient also had an expanded CD19+ B cell count, normal CD4+ T cell counts, platelets 75/nl, and granulocytes 1.5/nl. Screening for liver-directed autoantibodies confirmed the presence of a significant titer of antinuclear and anti-smooth-muscle antibodies.In this case, as the patient is thrombocytopenic, FDA-approved ibrutinib is not the most suitable option. While ibrutinib targets both B cells and plasmablasts, it also interferes with platelet function, which may increase the risk of bleeding complications . While MPneumocystis jirovecii pneumonia, varicella-zoster virus) and continuing antibiotic prophylaxis is mandatory, and substitution of Ig in the presence of bacterial infection complications to resolve the IgG2 deficiency is indicated. Ruxolitinib also requires monitoring of blood counts and liver enzymes, as the patient already has cytopenia and impaired liver function, predisposing him to side effects.Therefore, we decided to treat the patient with a course of rituximab combined with ruxolitinib and to continue low-dose steroids because of prior intolerance. While ruxolitinib has been shown to be an effective immunosuppressive agent targeting T cells and macrophages , it also may indirectly target B cells, which are thought to be involved in this patient, by blocking follicular T helper cells inducing new B cells . The comPatient 3 is a 66-year-old female who received a matched unrelated donor peripheral blood HSCT. She has active cGVHD with fibrotic and inflammatory manifestations despite 3 months of treatment with prednisone 0.5 mg/kg/day and continued prophylactic CSP. Five months post-transplant, she presented with the following symptoms: morphea-like superficial sclerotic features in the skin plus lichen sclerosus ; moderate mouth symptoms with lichenoid features (grade 2); vulvar lichen sclerosus-like features and mild discomfort (grade 1); and moderate dry eye symptoms with corneal keratinization but no vision impairment (grade 2). Pre-existing comorbidities include type 2 diabetes, avascular necrosis, and neutropenia.Due to lack of evidence to guide which therapy is superior for this patient specifically, we would first consider treatment in a clinical trial as an option for this case. We would replace CSP with another treatment, as CSP failed to control the progression and potentially impedes the emergence of regulatory T cells, which are involved in the pathobiology of cGVHD . AnotherSeveral treatment options are available for this case. Ruxolitinib targets several signaling pathways involved in the pathobiology of cGVHD and has demonstrated superior efficacy than the best available therapy in patients with cGVHD in a recent phase 3 clinical trial . RuxolitA final important point for management of this case is to optimize supportive care , such asIn summary, these three patient cases illustrate multiple options available for patients with SR-cGVHD. While there is one FDA-approved treatment currently available, enrollment in ongoing clinical trials is also an important option for eligible patients whose treatment has failed on one or more previous therapies. In the absence of robust evidence of benefits for any one intervention, treatment choices should be based on physician experience, ease of use, need for monitoring, risk of toxicity, and potential worsening of pre-existing comorbidities.


Background: The ganglion impar  block has been used to manage coccygeal and perineal  pain due to both benign and malignant causes. However, the factors associated with successful responses to ganglion impar block are unknown. Therefore, in the present study, we aimed to identify the independent factors associated with successful responses to ganglion impar block in patients with chronic pain in coccygeal and perineal regions.Methods: From January 2008 to December 2017, we performed a retrospective review of 106 patients who underwent ganglion impar block. Patients were considered successful responders if they reported a decrease of more than 50% or 4 points on the 11-point (0 = no pain and 10 = worst possible pain) numerical rating scale 1 month after the procedure, while others were considered non-responders. Logistic regression analysis was performed to identify factors independently associated with successful responses at 1 month after the procedure.Results: Multivariable logistic regression analysis showed that cancer-related causes were significantly associated with successful responses at 1 month after ganglion impar block .Conclusion: Ganglion impar block may be more effective in cancer-related pain than pain due to benign causes. The ganglion impar  block was originally described in the treatment of sympathetically mediated cancer pain involving the perineum Previous studies have shown the effectiveness of ganglion impar block Although the effectiveness of ganglion impar block has been shown in prior studies This retrospective study was performed at the pain clinic in our institution. This study was performed in accordance with the Declaration of Helsinki and the study protocol was approved by the institutional review board of Asan Medical Center, Seoul, Korea . Informed consent was waived owing to the retrospective nature of the study. We searched our institution's Information Technology of Service Management (ITSM) system between January 2008 and December 2017 with the terms “ganglion impar block.” The inclusion criteria were as follows: 1) age 19-80 years, 2) chronic pain in coccygeal and perineal regions over 3 months, 3) received ganglion impar block. We included the patients who received ganglion impar block, not ganglion impar neurolysis. We excluded the patients who had any of the following conditions: 1) incomplete medical record, 2) loss to follow-up, 3) technical failure of block.All procedures were performed on an outpatient basis. After informed and written consent, the procedure was performed using a transsacrococcygeal approach The outcome evaluation was performed at baseline and 1 month after the procedure. For the outcome assessment, pain intensity measured using an 11-point (0 = no pain and 10 = worst possible pain) numerical rating scale (NRS-11) was reviewed from each patient's medical record P < 0.05 was considered statistically significant.Data were analyzed using R version 4.0.2 . Continuous demographic data from the non-responders and successful responders were compared using Student's t-test or the Wilcoxon rank-sum test and documented as means with standard deviations or medians with interquartile ranges, as appropriate. Categorical demographic data were compared using the chi-squared test or Fisher's exact test. By using logistic regression, the factors associated with successful responses at 1 month after ganglion impar block were analyzed. The inclusion of variables in the logistic regression analysis to identify the independent factors associated with successful responses was based on biological plausibility, clinical importance, and statistical considerations. The goodness-of-fit of the model was assessed with the Hosmer-Lemeshow test. A value of As a result of the ITSM search, we found 232 patients who received ganglion impar block. A total of 167 patients met the inclusion criteria. Sixty-one patients were excluded due to incomplete medical record, loss to follow-up, or technical failure of block. Therefore, a total of 106 patients were included in the analysis. One month after the procedure, 28 patients reported a decrease of more than 50% or 4 points on the NRS-11 and were considered successful responders in this study. The 78 remaining patients who reported a decrease of less than 50% or 4 points on the NRS-11 were considered non-responders . Pelvic or perineal organ cancer, including urogenital organ cancer, colorectal cancer, and metastasis of non-pelvic and non-perineal cancer were major causes in the successful responder group. Conversely, major causes of pain in the non-responder group were those other than cancer, including trauma or anatomical abnormality, non-cancer pelvic operation, and unknown causes. There were no significant differences between the groups in other baseline characteristics.The demographic characteristics of non-responders and successful responders at 1 month after ganglion impar block are summarized in Table P = 0.164). Post-procedural NRS-11 scores of pain intensities in non-responders and successful responders were 7.0 (5.0-8.0) and 2.0 (1.0-3.0), respectively (P < 0.001).As shown in Table P = 0.044, Fig. In addition, the proportion of successful responder in cancer-related and non-cancer-related causes were 36.7% and 17.5%, respectively (P = 0.038, Table Multivariable logistic regression analysis revealed that the cause related to pelvic or perineal organ cancer was significantly associated with successful responses at 1 month after ganglion impar block (odds ratio = 2.60, 95% confidence interval = 1.05 to 6.43, Despite the widespread use of ganglion impar block for managing coccygeal and perineal pain, the factors associated with successful responses have not been fully evaluated. The current study showed that cancer-related coccygeal and perineal pain was more responsive to ganglion impar block than pain due to benign causes.The ganglion impar block was originally described by Plancarte et al. in 1990 to treat sympathetically mediated cancer pain involving the perineum In this study, multivariable logistic regression analysis revealed that cancer-related causes were an independent factor associated with successful responses to ganglion impar block in patients with chronic pain in coccygeal and perineal regions. The ganglion impar is said to supply nociceptive and sympathetic fibers to the perineum and pelvic viscera, including the distal rectum, perianal region, distal urethra, vulva or scrotum, and the distal third of the vagina Adas et al. In our study, the proportion of successful responders in cancer-related causes was more than twice compared to that in non-cancer-related causes. However, 63.3% of patients with cancer-related pain still showed unsuccessful response to ganglion impar block. It is well-known that cancer-related pain is mediated by both somatic and visceral sensory fibers. Obviously, the present results suggested that ganglion impar block may not sufficiently interrupt somatic malignant painful stimulation, although it showed more effective response in patients with cancer-related pain than in those with non-cancer-related pain. In addition, because the superior hypogastric plexus also carries visceral nociceptive stimuli from pelvic organs There were several limitations to this study. First, the definition of successful response in the present study somewhat differed from the ones used in previous studies. This may lead to different results. We defined successful response in the present study based on IMMPACT recommendations In conclusion, ganglion impar block may be more effective in cancer-related pain than pain due to benign causes. Therefore, ganglion impar block could be a treatment option for pain due to pelvic or perineal organ cancer.


In 2011, the World Health Organization recommended injectable artesunate as the first-line therapy for severe malaria (SM) due to its superiority in reducing mortality compared to quinine. There are limited data on long-term clinical and neurobehavioral outcomes after artemisinin use for treatment of SM.From 2008 to 2013, 502 Ugandan children with two common forms of SM, cerebral malaria and severe malarial anemia, were enrolled in a prospective observational study assessing long-term neurobehavioral and cognitive outcomes following SM. Children were evaluated a week after hospital discharge, and 6, 12, and 24 months of follow-up, and returned to hospital for any illness. In this study, we evaluated the impact of artemisinin derivatives on survival, post-discharge hospital readmission or death, and neurocognitive and behavioral outcomes over 2 years of follow-up.p=0.007). Over a 2-year follow-up, artemisinin derivatives as compared to quinine were associated with better adjusted scores (negative scores better) in internalizing behavior and executive function in children irrespective of the age at severe malaria episode. After adjusting for multiple comparisons, artemisinin derivatives were associated with better adjusted scores in behavior and executive function in children <6 years of age at severe malaria exposure following adjustment for child age, sex, socioeconomic status, enrichment in the home environment, and the incidence of hospitalizations over follow-up. Children receiving artesunate had the greatest reduction in mortality and benefit in behavioral outcomes and had reduced inflammation at 1-month follow-up compared to children treated with quinine.346 children received quinine and 156 received parenteral artemisinin therapy (artemether or artesunate). After adjustment for disease severity, artemisinin derivatives were associated with a 78% reduction in in-hospital mortality . Among cerebral malaria survivors, children treated with artemisinin derivatives also had reduced neurologic deficits at discharge (quinine, 41.7%; artemisinin derivatives, 23.7%, Treatment of severe malaria with artemisinin derivatives, particularly artesunate, results in reduced in-hospital mortality and neurologic deficits in children of all ages, reduced inflammation following recovery, and better long-term behavioral outcomes. These findings suggest artesunate has long-term beneficial effects in children surviving severe malaria.The online version contains supplementary material available at 10.1186/s12916-021-02033-1. Malaria remains an important cause of morbidity and mortality in children, with an estimated 272,000 global malaria deaths in children under 5 years of age in 2018 –10. ChilIn 2011, the World Health Organization recommended intravenous artesunate as the first-line therapy for SM after clinical trials demonstrated superiority of artesunate to quinine to improve parasite clearance and reduce mortality –19. HoweThe objective of this study was to evaluate mortality and long-term outcomes following treatment with quinine or artemisinin derivatives in a prospective cohort study of children with SM that coincided with the roll-out of artesunate as the first-line therapy for SM in Uganda. This post hoc analysis evaluates the impact of artemisinin derivatives on long-term clinical, cognitive, and behavioral outcomes in children with severe malaria.The study was performed at the Mulago National Referral Hospital in Kampala, Uganda, from 2008 to 2015, enrolling children 18 months to 12 years of age . KampalaPlasmodium falciparum on blood smear. Children with cerebral malaria (CM) had a Blantyre Coma Score <3 with no other identifiable cause: ruling out meningitis, a prolonged postictal state, or hypoglycemia-associated coma reversed by a glucose infusion. Children with severe malarial anemia (SMA) had a hemoglobin level ≤5g/dL. Children with CM and SMA were classified as CM. Age-matched community children (CC) were recruited from the nuclear family, extended family, or neighborhood households of children with severe malaria. Exclusion criteria included prior coma, head trauma, hospitalization for malnutrition, cerebral palsy, or known chronic illness requiring medical care or causing developmental delay. The present study focuses on the children with CM or SMA.All children with severe malaria had Children were managed according to the Uganda Clinical Guidelines at the time of the study. In the early phase of the study, intravenous quinine hydrochloride was the first-line treatment followed by oral quinine to complete 7 days of treatment. Artemisinin derivatives (artesunate or artemether) were the second-line therapy to be used if quinine was contraindicated or not available. In November 2012, updated Ugandan Clinical Guidelines were published recommending parenteral artesunate as the first-line antimalarial for severe malaria, followed by oral artemether-lumefantrine. The change to artemisinin derivatives was implemented gradually in the health units depending on medication availability and clinician discretion.Children underwent a medical history and physical examination on enrollment. Caregivers were asked to bring their children back to study hospitals whenever the children fell sick during the follow-up period, and deaths during the study period were also recorded.In 2010, a nested randomized controlled trial recruited from within the study cohort and children were randomized to delayed or immediate iron therapy and were under active and passive surveillance for illness . Trial dP. falciparum histidine-rich protein-2 (PfHRP2) levels were measured to assess parasite biomass  [Peripheral blood smears were used to quantify parasite density using Giemsa staining with standard protocols. EDTA anticoagulated plasma was collected at admission and stored at −80°C until testing. Plasma stralia) . Plasma A neurologic deficit at discharge was defined as the presence of motor deficits, ataxia, movement disorder, or behavior, speech or visual disorders in a child with no known prior deficits. Children had neurologic, cognitive, and behavioral assessments a week after discharge and then 6, 12, and 24 months after enrollment. Neuropsychology testers were blinded to the study group. All tests have been adapted for use in Uganda and selected based on earlier studies showing an impact of cerebral malaria on cognition, attention, and memory in Ugandan children 5 to 12 years of age . For theIn children <5 years of age, the Mullen Scales of Early Learning (MSEL) , Color O2 or Fisher’s exact test. Logistic regression was used to assess the relationship between antimalarial therapy and dichotomous outcomes  and covariates were adjusted based on a known or hypothesized relationship with the outcome.Analyses were done using Stata v14.0 (StataCorp. 2015). Differences in continuous variables were assessed using Student’s t test or Wilcoxon rank sum test, as appropriate. Differences in proportions were compared using Pearson’s χPrimary study outcomes were defined a priori as risk of readmission or death within 6 months of follow-up and z scores for cognitive  and behavioral outcomes  or executive function  over the full 24-month follow-up. A 6-month follow-up was chosen for readmission or death evaluation because most readmissions or deaths occurred during this period , and because anti-malarial treatment was most likely to relate to this risk within the first 6 months after discharge. Longitudinal changes in cognition, attention, memory, or behavior by antimalarial treatment were assessed using linear mixed effects models including the age-adjusted z scores including a subject specific random intercept, time as a categorical variable to allow for non-linearity between study visits . Models included child age, sex, weight-for-age and height-for-age z scores, socioeconomic status, home environment z score, disease severity during the acute illness , child schooling, enrollment in the iron study , and the number of hospital admissions over follow-up as fixed effects. Behavioral outcomes were assessed using a caregiver questionnaire and included a random caretaker effect in behavioral analyses in children <6 years of age. To adjust for multiple comparisons, the Benjamini-Hoch correction for false discovery rate (FDR) was used at 0.05 for each age strata.The funders had no role in the study design, analysis, or decision to publish.Five hundred two children with SM were enrolled: 269 with CM and 233 with SMA. See Fig. n=74) intramuscular artemether and quinine, 6.2% (n=31) intramuscular artemether alone, and 10.2% (n=51) intravenous artesunate. Differences in clinical factors among children receiving artemether vs. artesunate are outlined in Additional file p<0.05).Baseline characteristics of study participants are shown in Table  6.2% n=3 intramusp<0.05, Table Children receiving artemisinin derivatives were more likely to have received a transfusion and less likely to receive furosemide than children treated with quinine  of 0.51 95% CI 0.22, 0.10)   compared to children treated with quinine while children treated with artesunate had a 70% reduced odds of death or readmission  following adjustment for age, sex, measures of disease severity, and enrollment in the iron study Table .Among CM survivors, 83/232 children (35.8%) had neurologic deficits at discharge. Most neurologic deficits recovered by 6-month follow-up with 12 children (4.5%) having persistent neurologic deficits at 6-month follow-up, and 7 children (2.9%) having persistent neurologic deficits at 12 and 24-month follow-up.The frequency of neurologic deficits at discharge among children receiving artemisinin derivatives was 24.0% compared to 41.9% in children receiving quinine (p=0.008). Following adjustment for age, sex, coma duration, acute kidney injury on admission, and enrollment in the iron study, children receiving artemisinin derivatives had an aOR for neurologic deficits of 0.28   Table . PreschoSchool-age children (≥6 years) treated with artemisinin derivatives had improved internalizing behavior and executive function compared to children treated with quinine, but the effects were not significant after adjustment for multiple comparisons. When looking at individual drug treatments, artesunate was associated with improved behavior and executive function in school-age children Table  and thisIn order to understand whether a more rapid reduction in systemic inflammation could be a mechanism leading to improved behavioral outcomes, we assessed CRP levels at 1-month follow-up in children enrolled in the iron study. Levels of CRP were lower in children treated with artemisinin derivatives compared to children treated with quinine and were lowest in children treated with intravenous artesunate Fig. . ArtemisIn the present study, we show that children with severe malaria treated with artemisinin derivatives have lower mortality than children treated with quinine. The unadjusted mortality benefit and confidence intervals associated with artemisinin derivative use compared to quinine in this cohort  is compatible with estimates from children in Africa treated with artesunate vs. quinine  , 31. TheWe also demonstrate the novel finding that artemisinin derivatives, compared to quinine, are associated with less acute neurologic deficits in children with cerebral malaria and better long-term behavioral and executive function outcomes in preschool children with severe malaria. Early animal studies suggested potential neurotoxicity with artemisinin derivative treatment –35. HoweIn murine studies, artesunate treatment of CM decreased pro-inflammatory cytokine production in the hippocampus , reducedOverall, there was no difference in the odds of post-discharge readmission or death compared to quinine  in the first 6 months of follow-up. In sub-group analysis, artemether was associated with an increased risk of readmission or death, and this risk was independent of study group (SMA or CM), being enrolled in the iron study, or receipt of blood transfusion. It is unclear why artemether was associated with increased risk of readmission or death, and as this was sub-group analysis with relatively small numbers, additional study will be required to confirm this association and explore potential mechanisms by which it might occur. We observed a 70% reduced odds of readmission or death in children receiving artesunate within the first 6 months of follow-up  consistent with the more rapid parasite clearance in this group. Children treated with artesunate had faster parasite clearance than children treated with quinine, consistent with rapid absorption of artesunate, which has broad activity against both ring and mature stages of the parasite life-cycle , is wateStudy strengths include the large study population; the detailed clinical characterization of study participants; the study design to assess behavioral and cognitive outcomes in children, which incorporated systematic assessment of factors related to child development such as socioeconomic status and enrichment in the home environment; and the use of previously validated instruments for assessment of cognition and behavior in this population, and the long-term follow-up of study participants. Study limitations included the observational nature of this trial, which included a change in standard medication for severe malaria over time, which could co-exist with other changes that might affect behavior. We adjusted for the most important of these, but unmeasured parameters that changed over time could also affect the outcomes in the study.In summary, the study confirms reduced mortality in children treated with artemisinin derivatives compared to quinine for the treatment of severe malaria. Further, we report better neurobehavioral and executive function in survivors treated with artesunate compared to quinine. The findings provide evidence that artesunate as compared to quinine therapy in children with severe malaria not only reduces mortality but also may provide a long-term benefit in behavioral and executive function in the survivors.Additional file 1 A .pdf file providing additional details on the Methods and Supplementary Tables and Figures. Methods: 1) Study population and clinical management of severe malaria. 2) Neurologic, cognitive and behavioral assessment. 3) Enrollment in the Iron study. Supplementary Tables and Figures: Table S1. Characteristics of severe malaria study participants by choice of in-hospital antimalarial administered. Table S2. Primary cognitive and behavioral outcomes in children over 24-month follow up, according to antimalarial treatment , and severe malaria group at presentation . Table S3. Primary cognitive and behavioral outcomes in children over 24-month follow up, according to specific antimalarial drug treatment, and severe malaria group at presentation .


Glutathione-S transferases (GSTs) are part of a ubiquitous family of dimeric proteins that participate in detoxification reactions. It has been demonstrated that various GSTs induce allergic reactions in humans: those originating from house dust mites (HDM), cockroaches, and helminths being the best characterized. Evaluation of their allergenic activity suggests that they have a clinical impact. GST allergens belong to different classes: mu , sigma (Bla g 5 and Asc s 13), or delta (Per a 5). Also, IgE-binding molecules belonging to the pi-class have been discovered in helminths, but they are not officially recognized as allergens. In this review, we describe some aspects of the biology of GST, analyze their allergenic activity, and explore the structural aspects and clinical impact of their cross-reactivity. Glutathione-S transferases (GSTs) are a part of a ubiquitous family of dimeric proteins that have triggered the interest of different biology-related disciplines due to their involvement in drug resistance, carcinogenesis, and allergy. Most of these isoenzymes participate in detoxification reactions, coupling reduced glutathione (GSH) to xenobiotics and/or endogenous substances, such as bilirubin and steroids. They have allergological importance for multiple reasons: several of them are epidemiologically relevant as environmental sensitizers and due to their sequence and structural conservation even among phylogenetically distant species, they may mediate cross-reactivity among invertebrate allergen sources, such as cockroach, house dust mites (HDM), and helminths. Also, probably because of their abundance and immunogenicity, some helminth GSTs have been evaluated in pre-clinical studies and clinical trials as vaccines to prevent helminthiasis , 2. AltoAscaridia galli with homology to a GSH-dependent prostaglandin-H D-isomerase and high activity and specificity in the GSH-dependent isomerization of prostaglandin H to prostaglandin E, a lipid mediator associated with suppression of host immunity  and were annotated as mu-like GSTs. Characterization of their biochemical features by ProtParam indicated that their pIs also ranged from five to nine as the results previously observed at the proteomic level  RNA expression in bone marrow-derived dendritic cells at even higher levels than Der f 1 or Der f 2  in UniProt, and two reported IgE-binding frequencies of 10 and 80% in Singapore and Colombia, respectively , 58. Them is low . In summm is low , 60 and,m is low , 62.Tyrophagus putrescentiae by affinity chromatography. It is a 26 kDa protein sharing 83% of amino acid sequence identity with Der p 8. IgE seroprevalence against Tyr p 8 was 45.3% (48/106) among Taiwanese allergic patients who were sensitized to the mite extract. Pre-adsorption of all sera with D. pteronyssinus extract reduced the rate of IgE recognition to 18%, which suggests cross-reactivity among GSTs from these sources. There is evidence of basophil histamine release sensitized with sera from Tyr p 8-allergic patients, confirming its allergenic activity  ethane and 4-hydroxynonenal were used as substrates, but its IgE-binding frequency was lower (17.9%) compared to the sigma class (20.5%) in cockroach-sensitized patients from Seoul, Korea. There is no evidence of its allergenic activity .B. germanica allergens are found in low-income dwellings, as detected with Bla g 2 in the United States  of IgE reactivity to this isoform. Both recombinant versions induced basophil activation as measured by the CD63-based flow cytometry assay  can induce IgE antibodies in infected individuals  purified by Acevedo et al. contained six isoforms that bind IgE  conducted in a deprived community living in Cartagena, Colombia, indicated that ~20% of children were sensitized to rAsc l 13 at a young age (6 months old), increasing to 45% at 3 years of age. A positive IgE response to Ascaris GST was associated with housing features related to poor hygienic conditions and Ascaris infection . Also, aA. lumbricoides had IgE against GSTO with a similar frequency to rAsc l 13  has only 90.3% of identity to rGSTO.To characterize other allergenic isoforms of Ascaris ssp. in our laboratory, we identified the GST genes predicted by the Davis laboratory at the University of Colorado and expressed them as recombinant proteins. We have analyzed the enzymatic activity and humoral response of an omega-class isoform. The recombinant GST omega-class (rGSTO) has dehydroascorbate reductase and thiol transferase activity reported as well for other omega-class GSTs . More thAsc l 13 . DespiteA. lumbricoides using a strain from the Republic of Ecuador. Based on this work, we identified 15 GST sequences of A. lumbricoides reported in the UniProt database. The sequence and tertiary structure were verified to confirm that these proteins belonged to this protein superfamily. Most predicted products from these sequences had features of the cytosolic subfamily, as the thioredoxin-like fold domain and the GST N-terminal and C-terminal domains. There was only one sequence identified as kappa subfamily GSTs, due to the presence of the DSBA-like thioredoxin domain, and one as microsomal subfamily GST  of A. lumbricoides did not have a similar sequence in A. suum and two sequences in A. suum (F1LBW9 and F1LCY4) were not identified in A. lumbricoides. The A. suum kappa-GST (F1LDD6) had an identity of 68.3% with an A. lumbricoides DSBA domain-containing protein with a match length of 182 of 254 amino acids.In 2018, the Parasite Genomic group at the Wellcome Trust Sanger Institute made the draft genome assembly and gene predictions of mily GST . In A. s in 2018 , we iden classes . At the  classes . It is gSeveral investigations have pointed out different parasite GSTs as immunomodulatory proteins, including molecules derived from helminths and protists . The parF. hepatica have been found over mouse BMDCs, reducing their inflammatory response to LPS and inhibiting its capacity to induce Th17 polarization , which is majorly comprised of mu-class GST isoforms (96%), in a septic shock mouse model. It was observed that nFhGST significantly suppressed the LPS-induced TNFα and IL1β in vitro production by macrophages and the pro-inflammatory cytokine/chemokine storm within C57BL/6 mice elicited by lethal doses of LPS (Immunomodulatory properties of sigma-GST (fhGST-si) from rization . Stimulas of LPS .Schistosoma haematobium has shown to induce a strong mucosal immune response, associated with IL-10 and Th2 cytokine production in animal models and humans  in experimental colitis. It was also found to induce Th2 polarization, characterized by local and systemic production of IL-13 and IL-5. An eosinophilic infiltration in colonic tissue was evidenced in GST-immunized mice, and eosinophil depletion was associated with a loss of the ameliorating effects observed for Sh28GST , whose humoral and cytokine response to Sh28GST-Alum was investigated, it was observed that immunization induced IgG1, IgG2, IgG3, and IgG4 antibodies, in contrast to IgE whose titers did not significantly raise in comparison with baseline. Production of IL-5 and IL-13 was significantly induced after two administrations of rSh28GST in six out of eight vaccinated adults  in individual sera collected from cockroach-allergic patients. Modeling and sequence analysis indicated that both molecules may share a lineal epitope in their N-terminal domain ; although with a similar global structure, determined by key conserved amino acids and positions, there is low to moderate sequence conservation among them .B. germanica, observed in nature, is needed. Defining the allergenic activity will provide better information about the clinical impact of these IgE-binding molecules. In addition, extending the studies about their mechanisms of action for inducing allergic inflammation is necessary to improve our knowledge of allergy pathophysiology and to discover other options of allergy treatment. Their biological activity may be involved in Th2 polarization, which makes it interesting to explore other non-IgE mediated mechanisms that promote allergic responses (Several IgE-binding GSTs have been evaluated for their allergenic activity, being Bla g 5 the best characterized at the recombinant level, but more information on the complete repertoire of GSTs from esponses .Schistosoma-GSTs seem to induce a protective IgE response, the Ascaris-GSTs may induce allergic reactions (Ascaris. On the contrary, it is also possible that due to the nature of the infection, Schistosoma spp. has a more immunosuppressive net effect that reduces the chance of potential allergenic molecules, such as GSTs, to elicit IgE-mediated reactions leading to a topic manifestations. Thus far, most of the studies tend to support that schistosome infection reduces skin test responses and allergic responses (Helminth-GSTs can induce different immune responses in the host; while eactions . A possieactions . There ieactions , 91. In eactions , 92. In esponses , 94.The current data suggest that cross-reactivity is not frequent among GST allergens and those detected seem to be non-clinically relevant; however, more research is needed to understand how molecules with a low degree of sequence homology exhibit cross-reactivity. It is expected that GSTs from different classes are not cross-reactive, but an important exception has been described . Since lJZ and LC: conceived this manuscript. AL and JZ: performed bioinformatic analysis and developed figures. All authors contributed to manuscript writing, reviewing, and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Following leave-one-out cross-validation, the addition of T2WI-derived radiomic features to clinical variables alone improved the area under the ROC curve for predicting progression from 0.61  to 0.75 (95% CI 0.64–0.86). These exploratory findings demonstrate the potential benefit of MRI-derived radiomics to add incremental benefit to clinical data only models in the baseline prediction of PCa progression on AS, paving the way for future multicentre studies validating the proposed model and evaluating its impact on clinical outcomes.Nearly half of patients with prostate cancer (PCa) harbour low- or intermediate-risk disease considered suitable for active surveillance (AS). However, up to 44% of patients discontinue AS within the first five years, highlighting the unmet clinical need for robust baseline risk-stratification tools that enable timely and accurate prediction of tumour progression. In this proof-of-concept study, we sought to investigate the added value of MRI-derived radiomic features to standard-of-care clinical parameters for improving baseline prediction of PCa progression in AS patients. Tumour T In the UK, 43% of men present with low- and favourable intermediate-risk localised disease, for which level 1 evidence suggests non-inferiority of active surveillance (AS) to radical treatment in terms of 10-year survival7. However, the lack of consensus on both the stringency of inclusion criteria and the definition of disease progression have led to a significant variability of how AS protocols are run both across centres8 and indeed across guidelines9. As a result, a cumulative five-year dropout rate on AS reaches 44%, of which 27% are triggered by disease progression11. This highlights the unmet clinical need for developing robust baseline risk-stratification tools enabling early detection of patients harbouring lesions with a high potential for progression12. These patients would either require stricter AS follow-up or should be considered for radical treatment.Prostate cancer (PCa) is the second commonest and the sixth deadliest male cancer worldwide, with its incidence expected to double by 2030 due to an ageing male population13 have investigated the utility of both nomograms and individual clinicopathological predictors of histopathological progression in AS cohorts. However, none of the investigated models has entered routine clinical practice due to their low predictive accuracy and poor performance with external validation. One possible explanation for this may be the intrinsic difficulty of standardising the predictors, with an obvious example being PSA density that varies considerably depending on the imaging modality used for measuring prostate volume14. Furthermore, pathology results from needle biopsy may differ from the final pathology at prostatectomy due to sampling error, inter-observer variation, borderline grades, or upgrading due to oversampling the most radiologically suspicious area10. Conversely, the ability of MRI to visualise the whole tumour volume coupled with ongoing attempts to standardise image acquisition parameters15 provide the potential to investigate the ability of quantitative image-derived features, or radiomics, to advance the development of accurate and reproducible predictors of disease progression on AS.Numerous studies recently summarised in a systematic review by Sierra et al.18 to address the moderate positive predictive value of qualitative mpMRI assessment and reduce the overdiagnosis of indolent disease20. Zhang et al.21 recently introduced a radiomic model predicting histopathological upgrading of PCa from biopsy to radical prostatectomy, which may also improve baseline lesion characterisation. Furthermore, radiomics models have been developed to preoperatively predict the probability of extracapsular extension24, which is essential for accurate local staging of the disease and subsequent clinical decision-making. However, to the best of our knowledge, no attempts have been made to utilise radiomics for predicting disease progression in patients enrolled on AS programmes, the proportion of which is growing steadily in North America, Europe, and Australia25.In PCa, a considerable body of radiomics research has focused on improving the detection of clinically significant diseaseTherefore, in this proof-of-concept study, we sought to develop a radiomics model that would predict the baseline risk of PCa progression on AS. To achieve this, we extracted MRI-derived intratumoural radiomic features from AS patients with and without disease progression over a similar follow-up period. The predictive performance of the resulting sequence-specific radiomic models was assessed both individually and in combination with a clinical predictive model consisting of standard-of-care baseline clinicopathological biomarkers, with the aim of identifying a combined model with the highest overall performance to inform the future work in the field.2-weighted Imaging (T2WI) and apparent diffusion coefficient (ADC) maps, who were enrolled on active surveillance according to local criteria26 and had a minimum follow-up of two years with at least two consecutive 3 T MRI scans performed on the same magnet. The exclusion criteria were patients on AS with no MR-visible lesion, undergoing any prior treatment for PCa or benign disease, or the presence of total hip replacement or other pelvic metalwork.This retrospective case–control study was part of a service evaluation of the prostate diagnostic pathway, with the need for informed consent for data analysis waived by the local institutional review board . All experimental protocols of this study were carried out in accordance with the Declaration of Helsinki, as well as all the relevant guidelines and regulations, and were approved by the aforementioned local institutional review board. The study included patients with biopsy-proven PCa visible on both T23 score 5). The control group included patients in whom the disease was regarded stable over the same follow-up period, with no signs of radiological progression recorded on all prospective MRI scans (PRECISE score 3) and no histopathological progression noted on all repeat targeted biopsies, with both criteria being compulsory.Patients were divided into two groups depending on disease progression status. Cases were represented by patients who demonstrated disease progression, which was defined as a switch to radical treatment triggered by either confirmed histopathological progression on repeat targeted biopsy, or definitive radiological stage progression of the target lesion , and target lesion biopsy grade group.24.Depending on clinical recommendation, biopsy was performed by either a transrectal or transperineal approach, using MRI/ultrasound fusion. All biopsy procedures were performed by experienced urologists and included 12–24 systematic cores, with 2–4 separate target cores acquired from the MRI defined lesion/s. All targets were defined by radiologists pre-procedure using T2WI as the primary and diffusion-weighted imaging as the secondary source images, using the DynaCAD system  for transrectal and Biopsee software  for transperineal approaches as previously described1 and multiplanar high-resolution T2-weighted 2D fast recovery FSE (field of view (FOV) 18 × 18 cm2; voxel size 0.35 × 0.35 mm2; slice thickness 3 mm; gap 0 mm). Diffusion-weighted imaging (DWI) was performed using a spin-echo echo-planar imaging pulse sequence  and an additional small FOV (24 cm) b-2,000 s/mm2 DWI sequence; ADC maps were calculated automatically. Dynamic contrast enhancement was performed using a standard sequence  following a bolus of Gadobutrol  at 28 s via a power injector, at a rate of 3 mL/s (dose 0.1 mmol/kg).Patients underwent prostate MRI on a 3 T MR750 scanner  using a 32-channel receiver coil. Intravenous injection of hyoscine butylbromide  was administered prior to imaging to reduce peristaltic movement, unless clinically contraindicated. Multiparametric MRI protocol included Axial T28. MRI sequences were evaluated based on the Prostate Imaging-Reporting and Data System (PI-RADS) structured scoring criteria29. An overall impression was then used to derive a Likert suspicion score, wherein Likert 1 = clinically significant prostate cancer (csPCa) highly unlikely, 2 = csPCa unlikely, 3 = indeterminate for csPCa, 4 = csPCa likely, 5 = csPCa highly likely30. The assigned Likert scores were subsequently reviewed by independent readers as part of multidisciplinary team meetings.The MR images were interpreted prospectively by one of four sub-specialist uro-radiologists with 5–16 years’ experience of reporting prostate MRI, with each having read > 2,000 cases to be considered experts25. The reliability of image segmentation was evaluated by applying ROI morphological opening and closing using the SciPy Python package.For texture analysis, tumour ROIs were drawn on anatomical T2WI  first-order intensity histogram statistics, (2) Grey Level Co-occurrence Matrix features (GLCM)34, (3) Grey Level Run Length Matrix (GLRLM)35, (4) Grey Level Size Zone Matrix (GLSZM)36, (5) Grey Level Dependence Matrix (GLDM)37, and (6) Neighbouring Gray Tone Difference Matrix (NGTDM)38. All extracted features are listed in Supplementary Table The analysed features were extracted using PyRadiomics32, the use of the number of bins is favoured over the bin width in the case of arbitrary intensity units, such as MRI. For the same motivation, no resegmentation  was applied. More details are available in the Supplementary Methods.3D feature computation without any resampling was used to avoid interpolation artifacts. According to the Initiative for Biomarker Standardization Initiative (IBSI)We aimed at reducing the initial set of extracted features by a subset of features that are both robust against ROI perturbations and independent from the MRI acquisition parameters.39. By so doing, we produced three versions for each ROI . This procedure simulates the variability of the ROIs, by considering intra- and inter-reader dependence during manual contouring40. Starting from these three sets of ROIs, the radiomic features were extracted separately for T2WI and ADC by using different quantisation configurations: the number of bins varied in {8, 16, 32, 64, 128, 256}. Thus, the two perturbations applied to the original ROIs and the different quantization settings yielded 18 configurations of radiomic features. Therefore, the ROI perturbations were aimed at assessing the most robust quantisation setting (i.e. rebinning).Firstly, with the goal of identifying the robust features, we perturbed the original prostate cancer ROIs by using morphological operators 41. ICC analysis was applied to these 18 configurations of features to establish the number of bins that achieved the largest set of robust features for T2WI and ADC separately. In particular, we considered the two-way random-effects model (or mixed-effects), consistency, single rater/measurement, ICC42:.The ICC was considered to determine the most robust features against the ROI perturbations whilst the number of bins varied too43.The chosen number of bins represents the most reliable quantisation configuration (i.e. rebinning) according to the ROI perturbations via morphological operators. A cut-off value of 0.8 was used for the ICC to identify the number of features with high robustness. The used quantisation configuration was selected accordingly, by considering the number of bins that obtained the highest number of robust features for both T2w and ADC. The highly robust features with ICC > 0.8 were then used in the downstream pre-processing phases. ICC > 0.9 is the setting used for ‘excellent robustness’, however, in our predictive radiomics analysis we chose the less aggressive cut-off ICC > 0.8 as a measure for ‘high robustness’, representing a compromise between ICC > 0.9 and ‘high or moderate robustness’ (ICC > 0.5)44. In particular, we calculated the Spearman correlation coefficient for each radiomic feature against each considered MRI acquisition parameter, namely: (i) echo time (TE); (ii) repetition time (TR); (iii) flip angle; (iv) slice thickness; (v) spacing between slices; (vi) pixel spacing. A test–retest analysis for assessing feature robustness was not performed given that clinical MRI scans were used32. Our aim was to decouple possible dependencies between each feature and the principal MRI acquisition parameters in our highly homogeneous dataset, thus, this pre-processing step was based just on a simple Spearman’s correlation.Secondly, the extracted features might be affected by the MRI acquisition characteristics, such as scanner type, scanner settings, imaging protocols and acquisition parametersIn order to accommodate the high-dimensional nature of radiomics, minimise potential model overfitting, and reduce the dimensionality, we used six feature selection approaches including Fisher Score (FSCR), T-Score (TSCR), Wilcoxon Score (WLCX), Gini index (Gini), Multivariate Mutual Information Maximization (MIM), and Minimum Redundancy Maximum Relevance (MRMR). In this proof-of-concept study, we did not intend to build a single best-performing model—instead, we aimed to investigate whether the radiomic features were complementary to clinical features. Therefore, we limited the total number of features selected by commonly applied cut-offs. Given the low number of available clinical features, we used the top 5 features from each approach, whereas for each radiological dataset, the total number of features was restricted to 10, leading us to incrementally use the top 15 features for each combination.k and λ in the KNN and GMLnet methods, respectively, which were tuned independently at each step of the LOOCV procedure. This approach enabled us to demonstrate the overall predictive ability of the analysed dataset rather than developing one best-performing model. Given the exploratory design, we did not plot the receiver operating characteristic (ROC) curves as they would be based on a LOOCV scheme that implies constructing and evaluating a number of models (as many as the number of patients included) rather than a single model.Following the identification of the optimal number of features, several machine learning techniques were developed to incorporate these features into a binary classifier for distinguishing patients with the disease progression from those who remained stable over the study period. Methods used included k-nearest neighbours (KNN), logistic regression (LG), linear discrimination analysis (LDA), general linear model (GLMnet), support vector machine (SVM) and random forest (RF), with the analysis settings set as default. Given a limited sample size of the data, a leave-one-out cross-validation (LOOCV) scheme was used in order to further minimise the risk of overfitting. In brief, to investigate the predictive ability of clinical and radiomic features, every machine learning approach was trained using data from all the patients but one, with all the hyperparameters tuned and then applied to the remaining patient. The default set of hyperparameters was used, including Along with the PyRadiomics-based feature extraction, the pre-processing and calibration steps in the radiomic pipeline were performed using the MatLab® R2019b (64-bit version) environment , whilst the feature selection and predictive modelling were performed in R 4.0.2 using the praznik, MXM, and caret packages.This case–control study included 71 patients followed-up on the AS programme in our centre between May 2013 and April 2020. 73 MR-visible lesions were included in the analysis, of which 35 showed confirmed disease progression  and 38 remained stable over the study period; sample cases representing the two groups are presented in Fig. 2-weighted imaging (T2WI) and apparent diffusion coefficient (ADC), we took into account the sum of the highly robust features for both sequences. Table Since the choice of the quantisation, or rebinning, is critical, we performed the robustness analysis based on the Intraclass Correlation Coefficient (ICC) computed on the features extracted from the original regions-of-interest (ROIs) and their perturbations using morphological operations see “”. The nu. In order to account for the different numbers of clinical and radiomic features, we used the top 5 features for analysis of the clinical data, the top 10 features for each of the radiological data and top 15 features for combinations of these. Since GLMnet used a regularisation approach, there were two instances when the model shrunk to the intercept only and therefore was not reported (Supplementary Tables The areas under the ROC curve (AUCs) for clinicopathological predictors, T2WI-derived radiomic features and ADC-derived radiomic features alone, as well as for their combinations, are presented in Fig. This proof-of-concept study investigates the added value of MRI-derived radiomics to standard-of-care clinicopathological biomarkers for baseline prediction of PCa progression on active surveillance in patients with MR-visible lesions. The combined predictive model, incorporating PSA and PSA density (PSAD) with selected T2WI-derived radiomic features, showed improved performance compared to models utilising clinical data alone. These results suggest a role for MRI-derived radiomics as an additional risk-stratification tool to triage patients suitable for AS depending on the progressive potential of the target lesions.45. Several studies have confirmed the ability of mpMRI to better identify men at risk of immediate reclassification at their initial assessment46, also highlighting the fact that the presence of an MR-visible lesion at baseline is associated with higher risk of disease progression on AS52. However, no systematic attempts other than in a diagnostic meta-analysis by Zhai et al.53 have been made to explore the ability mpMRI to further stratify MR-visible lesions based on their progressive potential in patients otherwise suitable for AS. Adding this extra risk-stratification element at baseline, which showed promise in other tumour types such as bladder54 and ovarian55 cancers, may improve clinical decision-making and help refine and personalise follow-up protocols. For these purposes, MRI-derived radiomics presents a promising approach due to its quantitative nature and the rapid development of novel machine learning algorithms for feature selection that may help overcome the known poor cross-system reproducibility of the technique57.The role of mpMRI in identifying patients suitable for AS has been expanding gradually over the recent years, primarily building on its high negative predictive value for the presence of clinically significant disease unsuitable for AS59. It should be noted that in our cohort, PSAD was largely determined by PSA rather than the gland volume, with the latter being broadly similar in both progressors and non-progressors, thereby explaining the inclusion of PSA in the best-performing model alongside PSAD. Given the relative homogeneity of the AS cohort in our centre, the inclusion of MR-visible lesions only (Likert scores 3–5), and the case–control nature of the study, other clinicopathological predictors  showed no intergroup difference, thereby providing a possible explanation for the observed moderate performance of clinicopathological predictive models.In this study, only two clinicopathological predictors (PSA and PSAD) were included in the best-performing model. These results are in line with those of previous studies, in which baseline PSAD had a significant effect on mean progression-free survival time in patients on AS programmes61. A considerable increase in the predictive performance was, however, achieved by a model combining T2WI-derived radiomic features with PSA and PSAD, highlighting a synergy between radiomic and clinicopathological features for improving baseline detection of lesions with high progressive potential. Of thirteen radiomic features included in the best-performing model, five were representative of the tumour shape, size, and volume, which aligns well with the results of previous studies suggesting a link between baseline MRI-derived lesion size and the disease progression on AS52. In terms of the model performance characteristics, the achieved specificity and sensitivity of 0.80 and 0.63 could be employed to focus its clinical use on identifying patients at low risk of progression who may benefit from less stringent AS protocols, maximising specificity whilst not being overly restrictive on patient uptake of AS. In addition to providing an evidence base for avoiding unnecessary biopsies, similar models might increase confidence of both patients and clinicians in the AS protocol chosen based on the low overall prostate cancer-specific mortality in AS cohorts even in patients with unfavourable intermediate-risk disease62.Interestingly, a similarly moderate predictive performance was demonstrated by both standalone and combined T2WI- and ADC-derived radiomic models. The moderate performance of ADC-derived radiomics may be explained by the intrinsically limited ability of ADC mapping to differentiate low- vs intermediate-risk disease using a clinical monoexponential-fit model, for which more advanced diffusion techniques such as diffusion kurtosis imaging (DKI) and Vascular, Extracellular, and Restricted Diffusion for Cytometry in Tumors (VERDICT) MRI have shown greater promise63. The choice of such a cohort was, however, deliberate given that the presence of MR-visible lesions is in itself a poor prognosticator of PCa progression on AS, thereby warranting further risk-stratification of lesions based on their progressive potential. Dynamic contrast-enhanced images, obtained as part of mpMRI protocol, were not used in this study due to the increasing body of evidence suggesting the non-inferiority of biparametric MRI for lesion characterisation65. Furthermore, in this study we used Likert scores, which is the default system used in our department being informed by the criteria defined in PI-RADS v2.1. The systems are broadly similar, but Likert will often differ in scores 4 and 5 as it lacks a size threshold for this differentiation. The non-inferiority of Likert score assessment for the detection of clinically significant disease was documented previously66.This study has several limitations. Data were collected from a single centre, and additional external validation of the proposed model is required. This was, however, mitigated by the rigorous patient selection and matching, calibration, and pre-processing stages aimed at reducing overfitting and maximising the reliability of subsequent predictive modelling and cross-validation steps. Only patients with MR-visible lesions were included in the analysis, limiting generalisability of the findings, given that only 50% of patients included on AS programmes will have an MRI lesion detected67, for explicitly dealing with the batch-effect correct in multicentric studies will be used in our future work. In such a context, automated prostate segmentation approaches69 can accelerate the outlining time in manual segmentation procedures, as well as reduce the operator dependence for repeatable radiomic feature extraction. In addition, prostate zonal segmentation71 might also be considered for extracting zone-specific radiomics biomarkers. Furthermore, as the intrinsic inconsistency of weighted images often limits the generalisability of radiomics in a multi-center context, texture analysis of both conventional and novel quantitative mapping techniques that have already been studied in PCa72 is an area of interest. Finally, whilst this study focused on baseline prediction of PCa progression on AS, there is scope for improving mpMRI performance for the follow-up monitoring of AS patients. With the recently developed Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) scoring system including only subjective criteria for the assessment of radiological progression of the disease74, the use of delta-radiomics in follow-up mpMRI scans could complement the developed baseline predictive model by acting as a quantitative tool for dynamic re-evaluation of the risk of PCa progression, further increasing confidence in mpMRI as an alternative to repeat biopsies. In this study, we already used PRECISE 5 as an alternative to histopathological progression of the disease, which aligns with the global trend towards heavier reliance on MRI in navigating follow-up in AS and makes the results more applicable to the routine clinical practice where the two surrogates are used interchangeably77.In future work, we will aim to deploy a whole-gland segmentation approach, alongside habitat radiomics, to develop similar predictive models for use in all patients eligible for AS regardless of the presence of MR-visible lesions. The increased sample size will allow us to identify the best-performing machine learning technique that uses the optimal total number of features from each relevant feature selection approach. To assess its performance, we will use conventional measures of discrimination and calibration and perform decision curve analysis. A posteriori statistical harmonisation, such as the ComBat methodIn conclusion, a combination of clinicopathological predictors and T2WI-derived radiomic features may add benefit in predicting risk of PCa progression on AS. These results pave the way for larger future studies investigating the added value of MRI-derived radiomics to standard-of-care clinical biomarkers for improving baseline risk-stratification of patients suitable for enrollment on AS programmes.Supplementary Information.