Immune checkpoint blockade has dramatically improved the outcomes of patients with melanoma. Available long-term updates of clinical studies show a sustained clinical benefit for patients treated with PD-1 inhibitors such as nivolumab or pembrolizumab or for those treated with a combination of nivolumab and ipilimumab. However, about 40–50% of patients acquire resistance to therapy within five years from the start of anti-PD-1 therapy. This review assesses available definitions of the resistance and patterns of response to PD-1 immunotherapy and summarizes the potential underlying mechanisms. The available data on resistance to PD-1 therapy, medical needs and therapeutic options for melanoma patients resistant to ICI are discussed for the metastatic setting, including brain metastases, as well as for the adjuvant and neo-adjuvant settings.Available 4- and 5-year updates for progression-free and for overall survival demonstrate a lasting clinical benefit for melanoma patients receiving anti-PD-directed immune checkpoint inhibitor therapy. However, at least one-half of the patients either do not respond to therapy or relapse early or late following the initial response to therapy. Little is known about the reasons for primary and/or secondary resistance to immunotherapy and the patterns of relapse. This review, prepared by an interdisciplinary expert panel, describes the assessment of the response and classification of resistance to PD-1 therapy, briefly summarizes the potential mechanisms of resistance, and analyzes the medical needs of and therapeutic options for melanoma patients resistant to immune checkpoint inhibitors. We appraised clinical data from trials in the metastatic, adjuvant and neo-adjuvant settings to tabulate frequencies of resistance. For these three settings, the role of predictive biomarkers for resistance is critically discussed, as well as are multimodal therapeutic options or novel immunotherapeutic approaches which may help patients overcome resistance to immune checkpoint therapy. The lack of suitable biomarkers and the currently modest outcomes of novel therapeutic regimens for overcoming resistance, most of them with a PD-1 backbone, support our recommendation to include as many patients as possible in novel or ongoing clinical trials. Melanoma is a life-threatening skin cancer arising from the oncogenic transformation of melanocytes with a tendency for widespread metastasis, causing around 57,000 deaths per year worldwide ,2. BeforThe efficacy of ICI in the unresectable metastatic setting led to its testing and approval in the adjuvant setting after the resection of metastasis in stage IV and III and after the resection of high-risk primary melanoma (Stage IIB/C) ,13,14,15Thus, depending on the stage of the disease, the majority of melanoma patients receiving ICI still experience refractoriness to or a relapse despite anti-PD-1 therapy at some point. This review summarizes the medical needs and therapeutic options for melanoma patients resistant to ICI.To review the current knowledge on ICI resistance and to develop an expert opinion on the medical needs and therapeutic options for ICI-resistant patients, experts from leading German skin cancer centers were convened. A kick-off meeting was held online in November 2020 to share insights and experiences on how to advance, diagnostically and therapeutically, melanoma patients who fail anti-PD-1 therapy.. The board included physicians from dermato-oncology, oncology, radiotherapy, and radiology. Based on this input, a present narrative review was generated; the content and recommendations were agreed upon during a virtual consensus conference held in December 2022, involving the entire author panel.The final manuscript was reviewed by the interdisciplinary panel. Standard recommendations to enhance the quality of evidence-based judgements were followed .Different types of response and resistance patterns can be distinguished, as summarized in For the classification of resistance in advanced disease, a distinction between primary resistance as non-response to therapy  or stable disease (SD) lasting less than 6 months) and secondary resistance after initial benefit  for more than six months) is commonly made in clinical practice . Due to In the neo-adjuvant setting prior to resection, a clinical response according to RECIST 1.1 can be assessed via imaging ,24. AftePrimary resistance reflects the “immunologic invisibility” of tumor cells. This can be due to the characteristics of the tumor cells as well as the immune system. Secondary resistance refers to an adaptive situation in which immunologic interaction leads to a selection of “immunologically invisible” tumor cells, which might occur due to the acquisition of new escape mechanisms of the selection of pre-existing immunologically invisible cells. Thus, secondary resistance is most likely due to tumor cell-intrinsic changes.The underlying mechanisms are diverse, and similar mechanisms have been described for primary and secondary resistance . They caMechanisms can also occur at the level of immune cells (extrinsic mechanisms). Here, T-cells play a major role, e.g., due to the blockade of T-cell activity via hypoxia or soluble factors such as TGF beta. Moreover, the induction and recruitment of immunosuppressive cell types, e.g., regulatory T-cells (Treg) or myeloid-derived suppressor cells (MDSC) ,33,34, aARr(%) = 100% − PFSr(%) − PDr(%). This parameter was newly developed in this review. As shown in While patients with PD as the best overall response (BOR) to ICI clearly belong to the group of primary resistance, it is difficult to provide exact numbers for the frequency of acquired resistance. However, rates might be indirectly estimated from long-term PFS rates . The estPredictive biomarkers would be desirable, especially to identify primary resistant tumors and to choose upfront an alternative treatment to ICI or to delineate the reason for secondary resistance allowing rational combinations. However, as mentioned in chapter 4, no tumor-derived biomarker has been established in clinical routines yet, and few blood-derived biomarkers are used. Among them, patients with increased serum lactate dehydrogenase (LDH) levels are more likely to be primarily resistant to ICI therapy ,43,44. TSeveral Phase III pivotal trials have tested various ICI combinations with varying success to decrease the number of primary resistance patients. The already approved combination of relatlimab and nivolumab within the Relativity-047 trial demonstrated an advantage of combination therapy over anti-PD-1 monotherapy, with 30% and 42% of patients revealing PD as BOR, respectively . Other cNumerous Phase I–III trials for ICI-resistant patients are ongoing, with some first results reported . The repp = 0.0009) and overall survival , interestingly, without higher toxicity  . Co. Co70]. Recently, ipilimumab monotherapy was compared with TIL therapy in an investigator-initiated trial with almost 170 patients. Here, PFS was 7.2 months for TIL therapy and 3.1 months for ipilimumab monotherapy . However, overall survival was not superior and toxicity was high with all patients in the TIL arm experiencing grade 4 adverse events . AnotherIn BRAF V600-mutated patients, there is also the option to switch between ICI and BRAF-targeted therapy. Recent prospective sequencing studies clearly showed that patients benefit from initial ICI followed (in case of progression) by BRAF-directed targeted therapy compared to the opposite sequence .Local ablative therapies such as radiotherapy may be used, either in conjunction with systemic therapy or alone, in the case of limited disease progression in the metastatic setting. Radiation therapy induces DNA damage, autophagy and necrosis in tumor cells, leading to damage-associated molecular patterns (DAMP) and the stimulation of dendritic cells, which present tumor antigens and activate cytotoxic T-cells .A recently published European consensus paper provides indication-overarching definitions for oligometastatic disease . Using aConcerning rechallenge  with anti-PD-1 therapy, only retrospective analyses and small post hoc analyses of clinical trials have been published so far . Within Primary and acquired resistance due to new or progressive brain metastases are common problems in metastatic melanoma patients. As registrational trials  usually The estimated rates of intracranial primary resistance to ICI therapy remain high in MBM; they are between 30 and 40% of asymptomatic patients, and 60–70% of symptomatic patients treated with combined nivolumab and ipilimumab progress early ,42. For In tumors harboring BRAF V600 mutations, BRAF-directed therapy is also an option. In the COMBI-MB trial, response rates of intracerebral metastases to dabrafenib + trametinib were approximately 50%, and the PFS was approximately 5 months . Studies(OXPHOS) metabolic pathway in melanoma brain metastases compared to metastases outside the brain might present a druggable resistance mechanism [New treatment options and combinations are therefore needed. Single-dose radiosurgery of melanoma brain metastases achieves 1-year local control rates of 86%  and compechanism ,103,104.echanism .For ICI therapy in the adjuvant setting, the definition of resistance differs compared to the metastatic stage , as therIn six different adjuvant Phase II–III trials in patients with stage II to IV melanoma, varying recurrence rates were reported, impacted by the recurrence risk at the melanoma stage and by different follow-up times from 1–2 years in stage II to up to 4–5 years in stage III and IV . TherapyThe most common type of recurrence in patients with stage III and IV disease was distant recurrence. Although this is not surprising for stage IV disease, this was also seen for stage III patients within the Keynote-054 trial, with 63% of all recurrences happening at distant sites  and 36% of all recurrences being loco-regional only at 3.5 years . For staConcerning predictive biomarkers, the detection of ctDNA pre-treatment  was recently shown to correlate with an increased recurrence rate within the CheckMate-915 trial  independent of the treatment arm. An improved prediction of RFS was accomplished when the ctDNA level was combined with other biomarkers from the tumor microenvironment such as CD8+ T-cells, PD-L1, interferon-gamma (IFN-g) gene expression signature and tumor mutational burden (TMB), but also Breslow level and clinical stage . In lineAccording to the definition by the SITC Immunotherapy Resistance Taskforce, primary resistance in adjuvant therapy could be roughly estimated from recurrence rates at 15 months (12 months of treatment + 12 weeks). Deduced from the Kaplan–Meier curves for RFS, under anti-PD-1 monotherapy, this would be about 14% of patients with stage II disease (Keynote-716), 30% of patients with stage III disease (Keynote-054) and about 54% of patients with stage IV disease (IMMUNED). In a retrospective multicenter evaluation, the median time to recurrence in stage III and IV disease patients under adjuvant anti-PD-1 therapy was 4.6 months (95% CI 0.3–35.7), where 76% experienced recurrence during adjuvant PD-1 after a median of 3.2 months and 24% experienced recurrence following treatment termination after a median of 12.5 months . For patProspective data on retreatment after the failure of adjuvant ICI therapy are currently limited. Within the Keynote-054 trial, patients were retreated with pembrolizumab if the recurrence occurred more than six months after the completion of adjuvant pembrolizumab therapy. Briefly, 20 of 47 patients who developed this late relapse were retreated; of these, 9 had unresectable stage IV disease and were evaluable for response. The activity was low, with only one responder  and a median PFS of 4.1 months .In a multicenter retrospective analysis of 850 patients treated with adjuvant PD-1 inhibition in stage III or IV , about 1In another retrospective analysis , out of Of note is that an increasing number of interventional trials are allowing the recruitment of patients with previous adjuvant therapy, often restricted to a minimum interval of recurrence-free survival after the completion of adjuvant therapy. Subgroup analyses of such patients will provide further insights into the resistance mechanism.With neoadjuvant treatment, the response to systemic treatment can be assessed directly, and hence, primary resistant melanoma can easily be identified. This can be carried out radiologically before surgery as in advanced disease, but also and more precisely via a pathologic review of the surgical specimen. Interestingly, radiological and pathological responses differ a lot , especiaThis means on the contrary that primary resistance rates are lower with ICI combination therapy with a pNR rate of 25% and 27% for nivolumab plus ipilimumab or relatlimab, respectively, and up to 66% for anti-PD-1 monotherapy ,118.However, in the only small trial comparing ICI combination therapy with anti-PD-1 monotherapy in the neoadjuvant setting, the difference in progression-free and overall survival was not statistically significant . ImportaThere is some evidence that melanoma resistance can be better overcome via neoadjuvant than adjuvant immunotherapy as the stimulation of the immune response seems to result in a better expansion of tumor-resident T-cell clones in the presence of macroscopic tumors . Just reImmunotherapy is today of fundamental importance in treating melanoma, in the (neo)adjuvant as well as in the advanced setting. However, for those patients who relapse or progress during or after ICI therapy, further therapeutic options are urgently needed. The different patterns of recurrence in the adjuvant setting and of resistance in the advanced setting are presumably associated with different, diverse mechanisms of resistance to therapy with high interindividual and maybe also intraindividual differences. A better understanding of cancer resistance mechanisms is needed to develop rational strategies in clinics. However, multiple Phase I and II trials on ICI-resistant advanced/metastatic melanoma show only modest outcomes . Most ofIn the meantime, clinicians have to choose among the treatment options which are available in a type of “trial and error” approach. In addition to a switch between systemic therapies, i.e., the classical sequential use of second-, third-line and subsequent salvage therapy, these options are (i) “re-treatment”—defined as “repeated treatment with the same therapeutic class following relapse after adjuvant treatment has ended” ,115;(ii)Therefore, the aim for all of us should be to include as many patients as possible in clinical and translational trials testing therapies to overcome anti-PD-1 resistance. Moreover, it is warranted that prospective clinical trials also continue data capturing after progression to provide evidence on the sequencing and efficacy of subsequent treatments.


Blinatumomab is a bispecific T cell engager that has shown efficacy in relapsed/refractory Philadelphia chromosome (Ph)-positive and Ph-negative acute lymphoblastic leukemia (ALL). Considering its favorable safety and activity in advanced ALL, blinatumomab as a targeted immunotherapy is fast gaining a frontline position in the ALL treatment paradigm. There have been multiple completed and ongoing studies showing significant promise with improved response rates and survival outcomes and decreased treatment toxicity and need for multi-agent chemotherapy regimens. The early use of blinatumomab has established success in Ph-negative and Ph-positive B-ALL, and this has extended to older adults with ALL who have historically had substantially inferior outcomes compared to their pediatric and young adult counterparts. Herein we will review the current data describing the early use of blinatumomab in newly diagnosed adults with B-cell ALL and future directions. T315I (The treatment of adult B-cell acute lymphoblastic leukemia (ALL) has witnessed substantial evolution over the recent years. With increasing understanding of the molecular and genetic blueprint of ALL, we are able to better tailor treatment regimens and thereby improve outcomes. The development of effective salvage therapies has led to improved outcomes of relapsed/refractory (r/r) B-ALL, and these novel drugs are being advanced to frontline therapies in ongoing clinical trials. Blinatumomab is a bispecific T cell engager that binds to CD19 antigen on B-lymphoblasts and CD3 on T cells, leading to the activation and proliferation of T cells that can exert cytotoxic effects against CD19-positive leukemic cells . In r/r T315I . BlinatuT315I . The optThe outcomes of younger adult patients with newly diagnosed Ph- ALL have improved with the adoption of pediatric-inspired regimens and better disease-risk stratification based on MRD response and disease genomics –11. NoneThe GIMEMA LAL2317 trial  evaluateKMT2A rearrangements, IKZF1 intragenic deletion (IKZF1del), or persistent MRD following induction  study  evaluateA single-arm, phase 2 trial conducted at MD Anderson Cancer Center (MDACC)  evaluateIn the phase 3 ECOG-1910 trial, 224 adult patients with B-ALL who achieved MRD- CR after intensification were randomized to conventional chemotherapy with or without blinatumomab . The patThese results show the promise of utilizing blinatumomab in combination with intensive chemotherapy early in the course of treatment of younger adults and may represent a new standard of care in Ph- negative adult ALL. Historically, older adults with Ph- ALL had dismal outcomes with chemotherapy treatment with a 5-year OS of 10–20% . This isIn the SWOG 1318 study conducted in patients aged ≥65 years , single-The phase II study by Kantarjian et al.  extrapolA trial by the GMALL study group evaluated blinatumomab administered sequentially with chemotherapy among patients aged 56–76 years with B-ALL . In thisIn the ALLIANCE A041703 study , patient-4 after induction cycle 1  is the most common cytogenetic abnormality among adult patients with ALL, accounting for 25% of cases, and its incidence increases in older adults . In the n = 63). The patients were induced with dasatinib and corticosteroid, followed by at least two cycles of blinatumomab with a maximum of 5 cycles. The post-consolidation treatment was left to the investigator’s choice. The molecular response rate was improved from 29% pre-blinatumomab to 60% after the first cycle of blinatumomab, and this increased further after additional cycles of blinatumomab. In an updated follow-up, the 24-month OS and DFS were 88% and 80%, respectively, and DFS was superior in patients achieving a complete molecular response (CMR) upon post-induction/consolidation compared to those who did not .In the LAL2116 (D-ALBA) trial , the GIMAdvani et al.  implemenA single-arm, phase 2 trial from MD Anderson Cancer Center was conducted in patients aged 18 years or older with newly diagnosed or r/r Ph-positive ALL or chronic myeloid leukemia in the lymphoid blast phase . This stTaken together, these chemotherapy-free strategies combining TKIs and blinatumomab in frontline treatment are highly effective and well tolerated in both young and older adults with Ph+ ALL. The frontline treatment paradigm for adult ALL is shifting rapidly. While previously limited to multiagent chemotherapy with poor tolerability and short lived remissions –33, we aIt appears that initial debulking of disease with chemotherapy or TKI-based therapy (in cases of Ph+ ALL) provided the best setting for blinatumomab use at the present time. Studies in r/r B-ALL have established a correlation between leukemia disease burden and response to blinatumomab , 37. AdmIn younger adults with Ph- ALL, consolidation with blinatumomab alternating with intensive chemotherapy is feasible and effective. Leukemia burden can be effectively cytoreduced with standard induction chemotherapy with or without InO, and blinatumomab is best to be delivered during consolidation cycles in the low- disease-burden state. The benefit of blinatumomab consolidation extends beyond patients in MRD+ CR1 and has been established even in patients in MRD-negative state. While the conversion of MRD+ to MRD- is high, the ECOG 1910 has demonstrated the survival advantage for blinatumomab when delivered to adults who achieved MRD- state with chemotherapy, and blinatumomab will likely become the new standard of care in this setting . FurtherIn older patients, blinatumomab is better positioned to be administered after cytoreduction therapy either with low-dose chemotherapy or InO. When administered in treatment-naïve patients with high disease burden in the SWOG 1813 study, CR/CRi was only 66% . In contFinally, Ph+ disease represents a significant number of adults with B-ALL, especially older patients . The higBlinatumomab has a unique toxicity profile, and cytokine release syndrome (CRS) and neurotoxicity are the most common toxicities. A high disease burden was associated with an increased risk of CRS in r/r studies. In the frontline setting, the rates of high-grade CRS and neurotoxicity have varied by study design and the timing of blinatumomab. Grade 3/4 CRS was in 0%–3% but appeared lower in studies using blinatumomab later in the treatment course , 24, 28.IKZF1 deletion that was reported in Ph+ ALL patients treated with chemotherapy and TKI was also observed in the D-ALBA study with the use of blinatumomab and dasatinib  predicted inferior outcomes in older adults with Ph- ALL treated with mini CVD + inotuzumab +/- blinatumomab , is an emerging concern with blinatumomab-based chemotherapy-free regimens . Given tFinally, the mode of administration of blinatumomab as continuous infusion can be a burden for patients and poses logistic challenges. Therefore, there has been interest in the alternate method of delivery by the subcutaneous route. The early experience with the subcutaneous (SC) formulation of blinatumomab is promising and merits further investigation. In the ongoing phase 1b dose-escalation study (NCT04521231), SC blinatumomab demonstrated an acceptable safety profile and encouraging anti-leukemia activity in heavily pretreated patients with r/r B-ALL . Data frThe frontline of ALL treatment is arguably the most paramount line of defense as it will likely ultimately determine the chance of cure. Blinatumomab offers new hope, in the way of higher risk groups by age and molecular findings, that was previously out of reach and sets the stage for a much brighter future in ALL therapy.HP and IA completed the literature review and wrote and edited the manuscript. VP and VA edited the manuscript. All authors contributed to the article and approved the submitted version.


Can longitudinal changes in systemic inflammatory response, measured by C-reactive protein and albumin within the modified Glasgow prognostic score (mGPS), predict response and outcomes in patients with metastatic renal cell carcinoma?In this prognostic study, which was a post hoc analysis of the IMmotion150 trial (915 patients) and IMmotion151 trial (305 patients), longitudinal measurement mGPS during treatment provided valuable prognostic information regardless of imaging-assessed treatment response. In the disease control subgroup, on-treatment mGPS exhibited superior and independent prognostic information compared with radiologic staging alone.These findings suggest that integrating on-treatment mGPS for more holistic and patient-centered therapy monitoring in addition to radiologic staging may improve clinical care at a low cost for patients with metastatic renal cell carcinoma. This prognostic study assesses the prognostic and predictive value of the modified Glasgow prognostic score during treatment in patients with metastatic renal cell carcinoma. In the era of immuno-oncology, imaging alone seems to be insufficient to capture treatment responses, as patients with stable disease treated with immunotherapy have a wide range of clinical outcomes. There is an unmet need for complementary  markers that enable assessment of therapy response and outcomes in conjunction with imaging.To examine whether longitudinal changes in the modified Glasgow prognostic score (mGPS), which is based on C-reactive protein and albumin, can predict responses and outcomes in patients with metastatic renal cell carcinoma (mRCC).This post hoc analysis, conducted from October 2022 to April 2023, evaluated the prognostic and predictive performance of on-treatment mGPS in patients with mRCC being treated with atezolizumab (plus bevacizumab) or sunitinib in 2 randomized clinical trials: the phase 3 IMmotion151 study (discovery cohort) and the phase 2 IMmotion150 study .Outcomes were investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and overall survival (OS) for survival analyses. To compare the prognostic value of the on-treatment mGPS with radiologic staging, we used RECIST assessed by the Independent Review Committee (IRC-RECIST) to ensure high data quality.Of the 915 patients with mRCC in the IMmotion151 discovery cohort, baseline mGPS was available for 861 patients and on-treatment mGPS for 691. The IMmotion150 validation cohort included 305 patients with mRCC, and on-treatment mGPS could be evaluated for 199. In the IMmotion150 study, on-treatment mGPS predicted outcomes as early as 6 weeks following therapy initiation, thereby opening a window for early therapy adjustments. In both clinical trials, on-treatment mGPS provided valuable prognostic information regardless of imaging-assessed treatment response at first staging. Of note, in the disease control subgroup, on-treatment mGPS exhibited superior and independent prognostic information compared with IRC-RECIST .These data support the concept of integrating on-treatment mGPS for more holistic and patient-centered therapy monitoring in addition to radiologic staging to improve clinical care at a low cost for patients with mRCC. However, in daily clinical practice, we almost exclusively rely on imaging-based staging with estimation of the tumor volume. Particularly in the era of immuno-oncology, imaging-only staging has several limitations, especially in the patient subset with stable disease (SD) while taking immune checkpoint inhibitors (ICIs), which encompasses a wide range of clinical outcomes across entities.2 The mGPS is a simple score based on only 2 markers, serum C-reactive protein (CRP) and albumin.2 Of particular note, the easy-to-implement mGPS can predict outcomes as accurately as the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score at baseline,2 which is the current clinical standard for risk stratification and influences treatment decisions.4In the phase 3 IMmotion151 trial comparing atezolizumab plus bevacizumab with sunitinib in patients with metastatic renal cell carcinoma (mRCC), the high prognostic value of the modified Glasgow prognostic score (mGPS) has been highlighted.7 International experts have recognized the challenge of defining and refining tools, such as the mGPS, that capture the impact of systemic inflammatory processes associated with advanced cancer to enable reliable prediction of disease and treatment outcomes.8The mGPS is a well-established and robust measure for cancer-related inflammation and cachexia, both of which contribute significantly to functional decline and death.11 Whether the kinetics of mGPS measured longitudinally during treatment, which provides valuable prognostic information at baseline,2 predict response to treatment and can improve imaging-only therapy monitoring has not been systematically investigated. We have thus assessed the prognostic and predictive value of on-treatment mGPS in patients with mRCC treated with atezolizumab (plus bevacizumab) or sunitinib in 2 independent clinical trials, namely the phase 3 IMmotion151 study (discovery cohort) and phase 2 IMmotion150 .13Longitudinal measurement of early on-treatment inflammatory biomarkers can provide valuable information on treatment response for patients with mRCC.NCT02420821) and phase 2 IMmotion150 (NCT01984242) trials, which were provided via vivli.org.13 The trial protocols and CONSORT flow diagrams of both trials have been previously published.13 Vivli’s independent review panel, which includes an ethics branch, approved our study. This study followed the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) reporting guideline.This prognostic study is a post hoc analysis of data from the randomized phase 3 IMmotion151 (2 Patients are then classified as low risk (0 points), intermediate risk (1 point), and high risk (2 points).The mGPS was calculated using the laboratory parameters obtained in the study. The mGPS is determined by assigning 1 point for an elevated serum CRP concentration (>10 mg/L) and, only in patients with elevated CRP levels, 1 point for a decreased serum albumin (<35 g/L).2 To determine on-treatment mGPS, CRP levels were available for 691 patients in the IMmotion151 discovery cohort at the time of first radiologic staging   were used.The IMmotion150 and IMmotion151 trials were conducted from May 2015 to February 2020, and this post hoc analysis was conducted between October 2022 and April 2023. In line with the primary efficacy objective of the phase 3 IMmotion151 trial, we used the investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and overall survival (OS) for survival analyses. To compare the prognostic value of the on-treatment mGPS with radiologic staging, we used RECIST assessed by the Independent Review Committee (IRC-RECIST) to ensure high data quality. The IRC-RECIST was available for 611 patients  in the vivli.org secure research environment, which is a remote desktop tool. According to the Vivli guidelines, only research results and not patient-level data are allowed to be exported from the environment. Therefore, we do not have copies of the patient-level data sets.Outcomes were evaluated by univariate Kaplan-Meier regression and tested with the log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were performed to compare the prognostic value of mGPS with IRC-RECIST with regard to PFS and OS. The concordance index (C-index) is calculated for Cox proportional hazards regression and reported with 95% CIs. The Pearson χP < .05 was considered statistically significant.Statistical analyses were performed using R’s survival, survminer, and rstatix packages. Figures were generated using the ggplot2 and Gmisc packages. For all statistical tests, a 2-sided 1 To explore whether reevaluation of mGPS during treatment provides additional prognostic information, we calculated on-treatment mGPS at the time of the first radiologic restaging following therapy initiation within the IMmotion151 discovery cohort.Of the 915 patients with mRCC in the IMmotion151 discovery cohort, baseline mGPS was available for 861 patients and on-treatment mGPS for 691  and 12-month OS of 96.6% (P < .001) .of 96.6% A. The smBecause only minor prognostic information is available at the initial staging in the disease control (DC) group , which comprises more than 80% of the IMmotion151 cohort, we investigated whether on-treatment mGPS can provide additive prognostic information. Therefore, the prognostic value of the on-treatment mGPS assessed at the time of first staging and beyond was analyzed. In the entire IMmotion151 cohort, on-treatment mGPS showed prognostic value with a similar C-index for OS  as IRC-RECIST at first staging . Throughout further treatment, the mGPS still provided significant prognostic information at weeks 12, 24, and 35, underscoring the robustness of this prognostic score  (P = .11 for SD vs CR/PR)  . Furthers CR/PR) .Importantly, on-treatment mGPS allowed for the identification of a high-risk group within the DC subgroup that has comparable OS to patients with PD at initial staging  . Even thTo validate the data from the IMmotion151 discovery cohort, we used the similarly designed phase 2 IMmotion150 study. In this trial, 305 patients with mRCC were treated with atezolizumab, sunitinib, or a combination of atezolizumab and bevacizumab in the first-line setting. For 199 patients, on-treatment mGPS could be evaluated. Importantly, in this study, the on-treatment mGPS could be determined at week 6  and thus approximately 6 weeks earlier than in IMmotion151 . Thus, in addition to confirming our results from the IMmotion151 cohort, we were able to demonstrate that on-treatment mGPS allowed outcome prediction as early as 6 weeks  after therapy initiation, which is a substantial time before the first radiologic staging  . BecauseIn this study, we highlight the prognostic and predictive value of on-treatment mGPS. Importantly, on-treatment mGPS provides valuable prognostic information, particularly in the large DC group (>80%), where standard imaging has only limited discriminatory power. We validate our findings in 2 independent clinical trials (IMmotion150 and 151) in patients with mRCC treated in the first-line setting. Furthermore, we demonstrate that on-treatment mGPS had a high prognostic value as early as 6 weeks after treatment initiation, thus providing valuable information well before radiologic staging, which is typically initiated after 12 weeks. Hence, assessment of early on-treatment mGPS might allow physicians to identify patients at highest risk for progression to adjust their treatment accordingly or to initiate earlier radiologic response evaluation.The mGPS is a simple score, consisting of 2 routine laboratory parameters. Hence, it can be measured cost-effectively in any clinical laboratory and can be easily implemented into everyday clinical practice, even in low-resource settings. Our results therefore provide a strong rationale to integrate on-treatment mGPS into routine clinical practice for improved patient monitoring. Furthermore, because CRP is currently not routinely determined at baseline in most large randomized trials, we propose that the measurement of CRP at baseline and early CRP during treatment should be included in future clinical trial protocols to further validate the use of on-treatment markers in different treatments and patient populations.7 Whether on-treatment mGPS also has predictive value in other cancer types remains to be elucidated. In the first-line mRCC treatment setting, baseline mGPS has been shown to predict outcomes as accurately as the IMDC score, which is the current clinical standard for risk stratification: The C-index for baseline mGPS was 0.71  compared with the IMDC score 0.63 .2 Because the IMDC score includes clinical items, such as “time from diagnosis to initiation of systemic therapy (12 months),” it cannot be determined longitudinally during therapy, unlike the mGPS, which integrates only laboratory parameters. Our data on the prognostic and predictive power of mGPS measured at baseline and during treatment strongly support the integration of mGPS for risk stratification for response and outcome prediction.Research has demonstrated a correlation of mGPS with survival across several tumor entities at baseline.14 have shown that the so-called CRP flare-response phenomenon predicts immunotherapy response in diverse entities, including mRCC. Patients with a CRP flare response, characterized by an early increase in CRP within the first month of therapy and a subsequent decrease to baseline within 3 months, demonstrated exceptional long-term survival when undergoing immunotherapy. In patients with non–small cell lung cancer, CRP flare-response kinetics already occur in a substantial proportion of patients within a period of only 4 to 6 weeks.15 In the IMmotion150 study, on-treatment mGPS provides valuable prognostic information as early as 6 weeks after therapy initiation. We hypothesize that the prognostic value of on-treatment mGPS within the first month of therapy may be perturbed by flare-like kinetics because an increasing CRP value (flare-like) would lead to an increased mGPS. Because no earlier CRP measurements are available for the IMmotion150 and 151 trials, this hypothesis remains to be confirmed.Another prominent example of an inflammatory on-treatment biomarker that can predict ICI response is early CRP kinetics. Studies3 Currently, 2 predominant drug classes are applied to treat patients with mRCC: tyrosine kinase inhibitors (TKIs) and ICIs. Currently, 4 combination therapies considered equivalent in clinical efficacy are used in the first-line treatment of intermediate and high-risk mRCC. Essentially, these therapeutic concepts can be classified as intensified ICIs (anti–PD-1 and anti–CTLA-4) vs a combination of an ICI and antiangiogenic TKI . All current therapeutic combinations in the first-line setting for mRCC induce disease control rates higher than 80%. In the large patient subgroup with DC, radiologic staging provides minimal prognostic information,8 which is also underscored by our data from IMmotion150 and 151  within 6 weeks had superior outcomes than the nonnormalized group.11 Because Tomita et al11 used the same CRP threshold that is used for mGPS assessment (low-risk mGPS vs intermediate- or high-risk mGPS), our results may also apply to ICI and TKI combination therapy. However, to definitively establish the role of on-treatment inflammatory biomarkers, such as (on-treatment) mGPS, for patients with mRCC or other cancer types, large randomized trials need to include them in their study design.Despite some strengths, such as the investigation of 2 similarly designed but independent prospective clinical trials comprising a total of 890 patients  with available on-treatment mGPS data, our study also has some limitations. First, CRP was measured at different time points, which allowed us to investigate the value of the early on-treatment mGPS at week 6 only in the IMmotion150 trial. Furthermore, CRP and albumin are both nonspecific markers of inflammation that may be altered in a variety of conditions. This fact warrants careful investigation of confounding factors, such as infection or treatment-related inflammation, that could affect mGPS dynamics in future studies. In addition, the value of on-treatment mGPS remains to be investigated in the currently used first-line therapy combinations or the combination of an ICI plus an antiangiogenic TKI. However, in the pivotal phase 3 JAVELIN-101  trial, patients with mRCC treated with avelumab plus axitinib who had an elevated baseline CRP level of 10 mg/L or higher that decreased at least once below 10 mg/L (termed This prognostic study supports the new concept of integrating on-treatment mGPS for more holistic and patient-centered therapy monitoring in addition to radiologic staging to improve clinical care at a low cost for patients with mRCC.


The objective of the present study was to examine the effect of acute neuromuscular fatigue on unilateral jump performance and inter-limb asymmetries. Thirty elite youth female team sport athletes (age: U-14 to U-18) performed the Unilateral Countermovement Jump (UCJ) and the Unilateral Drop Jump (UDJ) (18-cm box) tests before and approximately 10 minutes after the 30-15 intermittent fitness test (30-15 IFT). A paired samples t-test showed significant reductions in UCJ jump height in the right leg after the 30-15 IFT , but not in the left leg . For the UDJ, significant reductions in jump height were shown in both the right  and left  legs. In addition, for the reactive strength index (UDJ), significant reductions were seen in the left leg after the 30-15 IFT , but not in the right leg . Only UCJ inter-limb jump height asymmetries increased significantly post 30-15 IFT . In conclusion, the current study indicates that the 30-15 IFT provides a sufficient dose of activity for inducing acute fatigue in elite youth female team sport athletes. Therefore, monitoring jump height in unilateral jump testing is recommended given the tests’ sensitivity to detect significant differences in physical performance and inter-limb asymmetries under acutely fatigued conditions in healthy youth female athletes. In recent years, participation in women’s team sports has increased in popularity, and has been accompanied by increases in external loads during competition. However, such increases are likely to lead to a greater risk of lower limb non-contact injuries during training and competition if athletes are not sufficiently physically prepared . In femaWithin the context of sport, fatigue can be defined as a process in which there is a progressive decrease in objectively measured physical output . In addiTeam sports are characterized by repetitive and intermittent unilateral explosive actions, such as jumping, sprinting, throwing, etc., which often occur during crucial moments in competition . Many ofNeuromuscular fatigue has traditionally been examined with laboratory-based tasks during isometric, concentric or eccentric actions . HoweverThe present study used a prospective, experimental pretest-posttest design to compare jump performance and inter-limb asymmetries before and after an intermittent test  in a group of elite female basketball and handball players. The Unilateral Countermovement Jump (UCJ) and the Unilateral Drop Jump (UDJ) tests were performed before and approximately ten minutes after the 30-15 IFT. All tests were performed in May 2021, at the end of the sport season.Thirty elite youth female team-sport athletes from basketball (n = 22), and handball (n = 8), took part in this study . All athAthletes attended two sessions over 14 days; the first was a familiarization session, and the second one was for data collection. They performed the same neuromuscular-type warm-up before all measurements, which included mobility exercises, displacements, and jumps, which gradually progressed in intensity. After the warm-up, athletes completed two maximal effort attempts for each test. All tests were performed at random with one-minute of rest between trials. Athletes completed three trials on each limb and the greatest score was recorded for data analysis. The warm-up procedures were not repeated after the 30-15 IFT protocol.The UCJ test was registered on a contact mat  using Chronojump software to estimate the vertical jump height . PlayersThe UDJ was also performed using a contact mat . Athletes started on an 18-cm box. With hands on hips, they hopped off the box with the chosen limb and rebounded off the ground using the same limb. They were instructed to minimize ground contact time and maximize jump height . Jump heThe 30-15 IFT is a valid and reliable test created as a reference guide for interval training prescription and to measure typical physical capacities that are challenged during intermittent sports, such as handball, basketball, and soccer . In the t-tests were used to determine whether unilateral jump test heights  were significantly different between pre- and post-30-15 IFT, with statistical significance established at p < 0.05. However, asymmetry scores were not normally distributed, thus Wilcoxon Signed-Rank tests were used to identify significant differences between pre- and post-30-15 IFT. The magnitude of differences between pre- and post-tests was also computed via Cohen’s d effect sizes (ESs). To determine the magnitude of asymmetry, the asymmetry index (ASI) was calculated as described by Data are presented as mean and standard deviation (SD). Data were assessed for normality using the Shapiro-Wilk test. Within-session reliability of recorded data was analyzed using a two-way random intraclass correlation coefficient (ICC) with an absolute agreement  and the coefficient of variation (CV). ICC values were interpreted according to Koo and Li (2006). CV values were to be satisfactory if less than 10% . Paired To determine the direction of asymmetry, an “IF function” was included at the end of the formula in Microsoft Excel: *IF . In doinThe highest performing limb was determined as the leg with the greatest value in each jump. To determine the levels of agreement for how consistently an asymmetry favored the same side , the Kappa coefficient (κ) was calculated to compare pre- and post-UCJ and UDJ inter-limb asymmetries. Kappa values were interpreted according to Viera and Garret (2005).p = 0.018; d = 0.33), but not in the left leg . For the UDJ, significant reductions in jump height were observed in the right  and left  legs. In addition, for the RSI (UDJ), significant reductions were seen in the left leg after the 30-15 IFT , but not in right leg . For the UCJ, significant reductions in jump height were observed in the right leg after the 30-15 IFT . No differences were observed between pre- and post-30-15 IFT for the UDJ  and the RSI .Consistency in limb preference from pre- to post-30-15 IFT for each test was moderate or lower. For the UCJ, limb agreement was moderate (kappa: 0.53). For the UDJ, limb agreement was fair (kappa: 0.39). For the RSI, limb agreement was moderate (kappa: 0.53).The aim of this study was to examine the effect of acute neuromuscular fatigue on unilateral jump performance and inter-limb asymmetries. Results showed significant reductions in performance after the 30-15 IFT for UCJ height in the right leg, UDJ height for both legs, and the RSI in the left leg. These findings demonstrate the high sensitivity of the UDJ for detecting fatigue-related changes in performance. Regarding inter-limb jump height asymmetries (magnitude), only UCJ height increased significantly post-30-15 IFT compared to pre-30-15 IFT. This finding demonstrates the high sensitivity of the UCJ for detecting fatigue-related changes in the magnitude of asymmetry in youth athletes. Moreover, it is also important to look at the directionality, where 7 out of 30 participants showed changes in the direction of asymmetry, which represents 23% of the sample . In thisThe findings of this study show that unilateral jump performance, specifically UCJ height in the right leg (ES = 0.33), UDJ height in both legs  and the RSI in the left leg (ES = 0.31), is negatively impacted by acute fatigue. Similarly to our results, Despite these results, caution should be used in the interpretation and application of the findings. p = 0.033; d = 0.46) when comparing pre- (9.37 ± 6.08) and post-fatigue intervention (14.36 ± 15.36) values. Otherwise, no significant differences were observed in inter-limb asymmetries from pre- to post-fatigue intervention for UDJ height and the RSI. In accordance with our results, some studies showed how the UCJ inter-limb asymmetries increased significantly after a soccer competition in elite adolescent male athletes  and after repeated sprints in recreationally active male athletes , as this enables practitioners to determine what may be considered a “real change” in their data  beyond gThere were inconsistencies in the highest performing limb from pre- to post-fatigue in all tests. For the UCJ, levels of agreement were moderate (kappa: 0.53); for the UDJ height fair (kappa: 0.39); and for the RSI moderate (kappa: 0.53). These differences in directionality highlight the variable nature of inter-limb asymmetries supported by the scientific literature .Although this study offers useful findings, some limitations should be acknowledged. First, we currently know that to improve performance and reduce the risk of injury from high-load joint actions, such as jumps and changes of direction, it is not sufficient to only analyze jump height or the RSI. It is also important to assess the kinetics and kinematics of the lower extremity during high-intensity actions to evaluate the different neuromuscular control strategies applied by athletes under fatigue conditions. Second, the current findings may not be generalizable to other populations. The nature of inter-limb asymmetries is individual; thus, our findings may only apply to elite youth female team sports athletes. Third, despite the fact that the 30-15 IFT appeared to be effective at inducing acute fatigue, it does not fully mimic the reality of a practice or competition. In fact, fatigue in team sport athletes is a complex process that develops progressively and not as a point of acute muscular failure . Thus, fThough not an aim, the results of this study showed that the 30-15 IFT was an effective fatigue protocol to reduce jump performance and increase inter-limb asymmetries in a group of youth female team sport athletes. Additionally, unilateral jump testing for height and limb asymmetries can be used to monitor fatigue and performance changes in elite youth female team sport athletes, though the problem of inconsistency of highest performing limb persists. However, given the variable and individual nature of inter-limb asymmetries , practitioners can consider utilizing unilateral jumps as they are sensitive instruments for detecting fatigue. To reduce the risk of injury and performance decrements from fatigue practitioners should train sport actions under conditions of fatigue to mimic the reality of competition.


Liposomes and other types of nanoparticles are increasingly being explored for drug delivery in a variety of diseases. There is an impetus in the field to exploit different types of ligands to functionalize nanoparticles to guide them to the diseased site. Most of this work has been conducted in the cancer field, with relatively much less information from autoimmune diseases, such as rheumatoid arthritis (RA). Furthermore, in RA, many drugs are self-administered by patients subcutaneously (SC). In this context, we have examined the attributes of liposomes functionalized with a novel joint-homing peptide (denoted ART-1) for arthritis therapy using the SC route. This peptide was previously identified following phage peptide library screening in the rat adjuvant arthritis (AA) model. Our results show a distinct effect of this peptide ligand on increasing the zeta potential of liposomes. Furthermore, liposomes injected SC into arthritic rats showed preferential homing to arthritic joints, following a migration profile in vivo similar to that of intravenously injected liposomes, except for a less steep decline after the peak. Finally, liposomal dexamethasone administered SC was more effective than the unpackaged (free) drug in suppressing arthritis progression in rats. We suggest that with suitable modifications, this SC liposomal treatment modality can be adapted for human RA therapy. Nanotechnology has revolutionized the conceptual and practical framework underlying drug delivery and the pharmacological and pharmaceutical aspects of drug therapy ,2. LiposRA is a chronic inflammatory disease affecting the synovial joints , which, Using the rat adjuvant arthritis (AA) model, we describe here a peptide-targeted liposomal SC drug delivery modality that meets both these requirements. We employed a novel joint-homing peptide ART-1, which was identified earlier following phage peptide library screening in arthritic (AA) rats ,20. We sp < 0.05) increase in the size of liposomes compared to Liposome-control. We then evaluated the effect of ART-1 on zeta potential (ZP), which represents an overall charge of the liposomes. ZP induces repulsion of nanoparticles, which is necessary to prevent their aggregation and, thereby, to improve their physical stability in vivo/in vitro [We examined the characteristics of a panel of liposomes to assess the impact of entrapment of Cy7 (a near-infrared dye useful for live imaging of rats) or Dex (a mainstream anti-arthritis drug) within them as well as their surface-functionalization with ART-1 peptide (as a lipopeptide with Octadecanamine). Liposomes that both lacked any cargo as well as surface ART-1 served as the baseline (Liposome-control) . As expein vitro ,23. Intein vitro ,23. We sUsing peptide ART-1-displaying liposomes A entrappFollowing SC injection, after a period of gradual increase initially, the fluorescence intensity maintained a sustained level at 6 h and 7 h B. After To gain more insight into the biodistribution of liposomes to other organs besides hind paws, we assessed how the systemically administered liposomal Cy7 given SC or IV was distributed among different internal organs, namely the liver, brain, spleen, kidney, lung, and heart  rats. However, for the internal organs, no difference was observed in the AA rats compared to healthy rats. A positive fluorescence signal in the liver and kidney is attributable to dye (Cy7) excretion through these two organs , and it Considering that anti-arthritis drugs are frequently administered SC by RA patients at home, the SC route of Dex delivery might be more practical than the IV route; the latter requires a hospital/clinic facility ,22. In tp < 0.05) when compared with the positive control group. In contrast, although the free Dex SC group showed a trend towards arthritis reduction, the difference from the positive control group was not significant (p > 0.05). Thus, the arthritis-suppressive ability of Dex was significantly improved when it was delivered in ART-1-liposomes than that in free (unpackaged) form. The former was comparable with free Dex given IV. These results are encouraging for the translational application of the ART-1-liposomal drug delivery via the SC route to RA patients. Furthermore, this study extends and reinforces the conclusions of our previous study in which ART-1-targeted liposomes were shown to deliver an experimental biologic (not yet approved for human use), interleukin-27 (IL-27), when injected IV into arthritic rats [Our results  show thatic rats . We now Liposome preparation was performed following the procedure of the thin film hydration method previously optimized in our laboratory , but witM. tuberculosis H37Ra (Mtb) (Difco Laboratories) [Adjuvant arthritis (AA) was induced in 5–6 week old male Lewis rats by SC immunization with heat-killed atories) . Thereafatories) . Age- anAfter the onset of AA (which appears around d 10 after Mtb injection), rats were injected SC or IV with 100 uL/rat of Cy-7-loaded ART-1 liposomes. This volume was selected after pilot testing of 3 different concentrations of Cy7-liposomes. A separate group of naïve  rats treated in the same manner served as controls. All these rats were then subjected to live imaging under anesthesia using IVIS (Xenogen) equipment (Perkin Elmer) . Images After preliminary screening using different doses of Dex, a dose of 0.1 mg/Kg was selected for further testing. A cohort of Lewis rats was injected SC with Mtb for arthritis (AA) induction. At the time of onset of AA (about d 10 after Mtb injection), rats were randomized into four groups. Three of these groups were treated SC separately with ART-1-liposomal Dex, unpackaged (free) Dex, or received no Dex. Another group of rats given free Dex IV served as a reference. In each case, a total of 6 injections (0.1 mg/Kg Dex each) were given every other day, starting from the day of onset. Thereafter, rats were graded regularly for the severity of arthritis following standard grading criteria for each paw .From our results described above, we concluded that: (a) the surface-functionalization of liposomes with ART-1 peptide resulted in a marked increase in their Zeta potential, which was altered in a desired direction to facilitate dispersion of liposomes in vivo; (b) overall, the time kinetics and quantitative aspects of the in vivo biodistribution to the joints of the liposomes administered SC were comparable to that of liposomes injected IV; and (c) Liposomal Dex given SC was highly effective in controlling arthritis progression, and its effect was superior to that of free Dex SC but comparable to that of free Dex IV. When taken together, the SC route is well-suited for use in targeted drug delivery of anti-arthritis agents using peptide ligand-functionalized liposomes for RA therapy.


Widespread use of statins has improved hypercholesterolemia management, yet a significant proportion of patients remain at risk for cardiovascular (CV) events. Analyses of treatment patterns reveal inadequate intensity and duration of statin therapy among patients with hypercholesterolemia, and little is known about real-world statin use, specifically in subgroups of patients at high risk for CV events.To examine patterns of statin use and outcomes among patients with high-risk features who newly initiated statin monotherapy.Adult patients (aged > 18 years) at high CV risk who received > 1 prescription for statin monotherapy and who had not received lipid-modifying therapy during the previous 12 months were identified from the Truven MarketScan Commercial and Medicare Supplemental databases (from January 2007 to June 2013). Patients with atherosclerotic cardiovascular disease (ASCVD) or diabetes were hierarchically classified into 5 mutually exclusive CV risk categories (listed here in order from highest to lowest risk): (1) recent CV event ; (2) coronary heart disease (CHD); (3) history of ischemic stroke; (4) peripheral artery disease (PAD); and (5) diabetes. Outcomes of interest included changes in therapy, proportion of days covered (PDC), time to discontinuation, and proportion of patients with ASCVD-related inpatient visit during the follow-up period. Statin therapy was subdivided into high-intensity treatment  or moderate- to low-intensity treatment . Follow-up data were obtained from the index date (statin initiation) until the end of continuous enrollment.P< 0.001). At 1 year, Kaplan-Meier estimates of the cumulative rates for ASCVD-related hospitalizations ranged from 3.5% (diabetes) to 21.8% .A total of 541,221 patients were included in the analysis. The majority of patients were stratified in the diabetes cohort (61.1%), followed in frequency by recent ACS event (15.8%), recent non-ACS CV event (9.9%), PAD (4.7%), CHD (4.4%), and history of ischemic stroke (4.1%). Only 15.0% of the population initiated therapy with a high-intensity statin, and 22.5% of these high-intensity statin initiators switched to a moderate- to low-intensity regimen during the follow-up period. Median time to statin discontinuation was approximately 15 months. Duration of treatment was longer among those who were treated with a high-intensity versus a moderate- to low-intensity statin regimen . The PDC was highest in the recent ACS hospitalization cohort (66.4%) and lowest in the diabetes cohort (55.5%). The PDC was significantly greater among patients who initiated treatment with a high-intensity statin regimen than with a moderate- to low-intensity statin regimen (62.1% vs. 57.5%, respectively; Patients at high risk for CV events are suboptimally dosed with statins, have high rates of discontinuation, and have low rates of adherence. Despite the use of statin therapy, ASCVD-related inpatient visit rates were high, particularly among those patients at highest risk because of a recent ACS hospitalization. Future interventions are required to ensure that high-risk patients are effectively managed to reduce subsequent morbidity and mortality. What is already known about this subjectPatients with established cardiovascular (CV) disease or CV risk factors are at high risk for CV events. For these patients, optimal secondary preventive care, including lipid-modifying therapy, can improve outcomes.Available evidence suggests that patients at high CV risk because of the presence of atherosclerotic cardiovascular disease (ASCVD) are not receiving sufficient lipid-modifying therapy to mitigate disease-associated risk.The shift toward high-intensity statin therapy recommended in the 2013 American College of Cardiology/American Heart Association guidelines may be challenging, given the large proportion of moderate- to low-intensity statin use.What this study addsHigh-intensity statin therapy is infrequently prescribed to patients at high risk for CV events, regardless of the underlying risk factor(s) .Adherence to statin therapy is suboptimal, with high discontinuation rates among all high CV-risk patient subgroups.Despite the use of statin therapy, patients with recent ACS have a high 1-year risk of ASCVD-related rehospitalization.4 In 2013, the American College of Cardiology and the American Heart Association (ACC/AHA) guideline on cholesterol management shifted away from specific low-density lipoprotein cholesterol (LDL-C) levels to overall atherosclerotic CV disease (ASCVD) risk reduction.3 This guideline recommends the use of high-intensity statins in patients at highest risk  for CV events.Since their introduction in the late 1980s, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have become the cornerstone of hypercholesterolemia treatment. Although recommendations in guidelines for cholesterol management differ, major guidelines endorse statin therapy to reduce cardiovascular (CV) risk for patients with elevated cholesterol levels for whom lifestyle change alone is insufficient.5 The downstream consequences of uncontrolled hypercholesterolemia, including ASCVD events such as those related to coronary heart disease (CHD), ischemic stroke, and peripheral artery disease (PAD), are a significant burden for patients and for the health care system. CHD alone accounted for approximately 1 of every 6 deaths in the United States in 2010,6 and it is projected to result in direct and indirect costs of nearly $220 billion in 2030.7 Despite these known risks, statin therapy is widely underutilized across patient populations and clinical conditions.Approximately 35.9 million Americans, or 15% of the population aged 18 years and older, have either ASCVD or diabetes mellitus.3 This effect has been demonstrated in several randomized, placebocontrolled clinical studies.10 Furthermore, studies indicate that intensive dosing reduced CV events more than standard doses of statins.12 Nonetheless, research from real-world studies indicates that statin use is suboptimal in populations with high CV risk.17 Available evidence also suggests that clinicians frequently opt for a less aggressive statin regimen, even when treatment goals are not achieved.22 As with the primary prevention population, adherence to therapy is a significant challenge to maintaining adequate risk reduction in patients with established CV disease (CVD).24Patients at high risk for CV events, especially those with ASCVD, stand to gain the most from statins.To further understand statin use among subgroups of patients with ASCVD, we conducted a large-scale, comprehensive evaluation of statin intensity, modification, adherence, and associated outcomes in a treatment-naive cohort of patients at high risk for CV events.This retrospective study identified patients from the Truven MarketScan Commercial and Medicare Supplemental databases from January 2007 through June 2013. These databases contain medical, pharmacy, and enrollment data from large self-insured employers representing approximately 30 million lives. Major data contributors include employers and health plans that cover employees and their dependents through a variety of offerings, including fee-for-service, fully capitated, and partially capitated health plans. The Truven MarketScan Medicare Supplemental database encompasses 2.9 million covered lives of individuals aged ≥ 65 years who had Medicare coverage plus employer-paid commercial plans. The datasets fully integrate pharmacy and medical claims and provide longitudinal information on patient treatment history.Adult patients (≥ 18 years) who newly initiated statin mono-therapy (index date) and had ≥ 1 medical claim for 1 of the following ASCVD conditions or diabetes during the pre-index period were included in the analysis: acute coronary syndrome (ACS), history of myocardial infarction (MI), stable or unstable angina, coronary or other arterial revascularization, ischemic stroke, PAD, or diabetes. Patients were required to have continuous enrollment for 12 months pre-index.25 Stratification was performed such that a patient was assigned a CV risk category based on the presence or absence of the foremost risk factor using the following organizational scheme: (a) recent CV event ; (b) CHD; (c) history of ischemic stroke; (d) PAD; and (e) diabetes. CVD/CV risk factors were identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes26 and procedure codes in the Current Procedural Terminology, 4th edition (CPT-4), Healthcare Common Procedure Coding System Level II (HCPCSII), or revenue code format. A complete list of included ICD-9-CM diagnostic codes and CPT and HCPCSII procedure codes is provided in the Appendix (available in online article).Patients were hierarchically classified into the highest mutually exclusive CV risk category.The following definitions were applied to patient classification:Recent CV eventRecent ACS hospitalization: ≥ 1 inpatient stay for acute MI or unstable angina within 90 days pre-indexRecent non-ACS CV event: ≥ 1 inpatient stay for revascu-larization or ischemic stroke within 90 days pre-indexCHD: > 1 inpatient or ≥ 2 outpatient visits for stable angina or a prior MI (≥ 90 days) during the 12 months pre-indexHistory of ischemic stroke: ischemic stroke that occurred between 90 days and 12 months pre-indexPAD: ≥ 1 inpatient or ≥ 2 outpatient visits for PAD or carotid artery disease during the 12 months pre-indexDiabetes: ≥ 1 inpatient or ≥ 2 outpatient visits for diabetes management during the 12 months pre-indexAccording to this stratification algorithm, a patient with diabetes and CHD would be classified within the CHD CV risk category. The existence of CV risk factors was determined by their presence in medical claims records within 12 months before statin initiation, with the exception of recent CV events, which were evaluated 90 days pre-index.Statin monotherapy was defined as a prescription for a drug within the HMG-CoA reductase inhibitor drug class  without any concomitant lipid-modifying therapies at baseline. Statin therapy was subdivided into high-intensity  or moderate- to low-intensity  treatment.A variable follow-up period was used, with patients tracked from the index date until the end of continuous enrollment. Follow-up measures included statin discontinuation, changes to the statin therapy regimen, proportion of days covered (PDC) by a statin, and the occurrence of ASCVD-related hospitalization. A patient was considered to have discontinued statin therapy if he or she failed to receive any statin treatment for 90 consecutive days. Modifications of the statin monotherapy regimen included switching to another statin class member, adding concomitant lipid-modifying therapy or prescription of a fixed-dose combination , and upward or downward adjustments to the intensity of statin therapy. PDC for statin therapy was calculated as the total number of covered days with statin supply divided by the total number of days from index until the end of continuous enrollment. The proportion of patients experiencing an ASCVD-related hospitalization was determined based on the presence of an ICD-9-CM code indicative of ≥ 1 ASCVD condition of interest .Descriptive statistics were calculated for baseline patient demographic and clinical characteristics and for statin treatment utilization patterns. Analyses of postbaseline treatment patterns  included all patients with > 120 days of continuous enrollment post-index. The requirement of > 120 days of continuous enrollment was selected to allow patients sufficient time on the index statin before discontinuing their statin. A minimum of >30 days supplied was assumed, and discontinuation was defined as the absence of any statin use for > 90 days.All baseline and outcome measures were stratified by CV risk category . Kaplan-Meier survival analyses were conducted for time to statin discontinuation and ASCVDrelated hospitalizations during the follow-up period, which was defined as index to the end of continuous enrollment. Two-sided log-rank tests comparing across all cohorts were used to determine statistical significance. A Cox proportional hazards regression model was used to estimate the hazard ratio for the relationship between high-risk cohort and discontinuation while adjusting for age, gender, and comorbidity index. The regression analysis on discontinuation was run on a subset of patients with > 120 days of continuous enrollment post-index. Kaplan-Meier survival analysis and Cox regression models were conducted with Statistical Analysis System (SAS) software package, version 9.3 . All other analyses of descriptive statistics were conducted using R, version 3.1.2 .A total of 541,221 patients met the eligibility criteria and were included in the baseline assessments . The proAt the time of index, 15.0% of the overall population was started on high-intensity statin therapy . High-inMore than 20% of patients initially treated with a high-intensity regimen switched to moderate- to low-intensity therapy B. ReductP < 0.001 comparing across all cohorts). Patients receiving a high-intensity statin regimen had a significantly longer median time to discontinuation . Variables significantly associated with statin discontinuation on regression analysis included younger age (18-44 years), female sex, and a Charlson comor-bidity score > 2 . Recent ACS event and history of stroke risk categories were associated with lower hazard ratio for discontinuation (P < 0.001).During the course of follow-up, 53.0% of patients discontinued statin therapy. Kaplan-Meier curves showed a median time to statin discontinuation of approximately 15 months A. Time tinuation B and hadP < 0.001).The PDC on statin therapy was 58.2% for all cohorts, ranging from 55.5% (diabetes) to 66.4% .Hospitalizations related to ASCVD occurred in 12.0% of patients during the follow-up period . These hospitalizations were significantly higher among patients with a recent ACS hospitalization or PAD and lowest for the diabetes cohort , and approximately half discontinued treatment within 20 months. Previously published data from a large cohort of patients  with ASCVD or diabetes who had not reached the LDL-C goal of < 70 mg/dL showed that most patients (76%) were initially treated with moderate-intensity statin therapy, and < 2% of patients received a high-intensity statin regimen.20 After reevaluation of LDL-C levels posttreatment, only 13% of patients were prescribed a higher-intensity regimen either through switching or uptitrating statin therapy or via the addition of another lipid-lowering agent. Notably, 47% of patients not at the LDL-C goal discontinued therapy within 12 months of beginning treatment without first attempting a change in their lipid-lowering regimens. A modestly higher rate of statin intensification (25.3%) was reported in a recent retrospective observational study that evaluated patients with CHD or CHD risk equivalents , yet the majority of patients (70.2%) continued with their initial regimen or downtitrated statin therapy during the follow-up period.18 Interestingly, as we had observed in our high-risk patient cohort, add-on therapy was infrequently used as an adjunct to lipid-lowering with a statin.Widespread use of suboptimal-intensity therapy has been routinely reported in high-risk populations.21 At hospital discharge, one third of patients were prescribed statin therapy at the goal level. Intensification of treatment after hospital discharge was rare, with fewer patients (26%) receiving their target statin doses at the 12-month follow-up time point than at the time of hospital discharge.Analysis of data from the Prospective Registry Evaluating Myocardial Infarction: Events and Recovery (PREMIER) and Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients' Health status (TRIUMPH) registries reinforces the suboptimal utilization of target statin intensity in high-risk patients, specifically those who had experienced an acute MI .24 Nonadherence to therapy is an ongoing issue in the management of hypercholesterolemia.28 The underlying reasons for statin nonadherence range from concerns about adverse effects to perceived lack of therapeutic benefit.30 Several treatment-related factors that decrease the likelihood of statin adherence, including higher copays and higher drug doses, have also been identified.34 Higher rates of statin discontinuation have also been reported among younger patients and women—findings that are consistent with our observations.35 Routine monitoring is suggested as a means to promote adherence. Although treating to goal is no longer the emphasis in U.S. lipid management guidelines, it is recommended that practitioners monitor lipid levels within 4 to 12 weeks of initiating treatment to evaluate therapeutic response and patient adherence.3 It is also advised that adherence to therapy be reinforced at routine follow-up visits every 3 to 12 months.The generally low rate of adherence observed in our high-risk cohort is compatible with previous observations for statins.3 High-intensity therapy would be appropriate for those patients who also have a 7.5% or greater estimated risk for ASCVD. Whether more patients in the diabetes CV risk category should have received high-intensity therapy is not possible to ascertain from our analysis because of the lack of CV risk scoring. The observed differences in adherence based on cohort designation align with previous data demonstrating that patients at very high CV risk  are more likely to be adherent to statin therapy.17 In our assessment, patients with a recent hospitalization for ACS had the greatest statin therapy PDC (66.4%) and the longest duration of statin treatment (median = 27 months).Statin treatment patterns and adherence to therapy in our study differed among cohorts. Patients with diabetes and no other ASCVD diagnosis were among the least aggressively managed groups in terms of intensity of statin therapy and PDC. Less intensive therapy for this patient subgroup is consistent with the ACC/AHA guideline, which gives a Level I recommendation for moderate-intensity statin therapy in adults aged 40-75 years who have diabetes.P < 0.001). Data from previous evaluations of prescription/administrative data have reported that higher statin dose/intensity was associated with lower adherence rates.32 However, previous studies have not specifically assessed patients who were newly initiating statin therapy and who had high CV risk conditions. In the recent study by Virani et al. (2014),32 the difference in PDC between high-intensity and moderate- to low-intensity statin regimens in patients with established CVD  who were receiving ongoing statin therapy was statistically significant  but not considered to be clinically relevant. Importantly, patients with diabetes and no other ASCVD diagnosis—a group that made up a substantial proportion of our study population and had both the lowest PDC rates and the lowest high-intensity therapy rates—were not included in the analysis.Patients with a recent hospitalization for ACS were also more likely than patients in other CV risk categories to initiate treatment with a high-intensity statin regimen. We observed a significant difference in PDC between statin intensity groups, with a greater PDC (62.1%) for high-intensity treatment compared with patients who received a moderate- to low-intensity regimen  survey, side effects, particularly muscle-related side effects, were the predominant reason cited by former statin users for discontinuing therapy.41 Emerging concerns regarding an increased risk for new-onset diabetes44 or acute kidney injury46 with high-intensity statin therapy may also have factored into the decision to limit treatment to a moderate- to low-intensity regimen.Several limitations inherent to the nature of the data source affect the conclusions that can be drawn from this assessment. The claims databases did not capture information on the reasons for initial therapy choice or for modifying or discontinuing therapy. Clinical considerations such as contraindications or conditions that increase the risk for treatment-related adverse effects may have led to the selection of less intensive therapy. For patients on statin treatment, discontinuation or switching to a nonstatin lipid-modifying therapy, the latter of which occurred in 2%-3% of patients per cohort in our study, could have been the result of apparent statin intolerance. Clinicians may have chosen not to intensify statin therapy during the follow-up period for patients who were tolerating and adhering to therapy because of the minimal additional reduction in LDL-C that is observed with statin dose escalation and/or the increased likelihood for side effects and intolerance at higher doses.An additional consideration regarding study interpretation is the method by which statin discontinuation was detected. Discontinuation was identified based on a 90-day gap in statin treatment; use of any other statins was not assessed after this 90-day gap. Therefore, we were unable to distinguish between “temporary” and “permanent” treatment discontinuation, potentially overestimating our discontinuation rates. The metric used to gauge adherence is also subject to limitations that may underestimate  or overestimate  adherence, and it does not distinguish physician-mandated changes from patient choice.47 The proportion of patients switching from high-intensity therapy was potentially affected by this guidance.Finally, a number of factors could influence the decision to switch between statins, including the availability of generics, regulatory approval of new agents, or changes in recommended use for a particular agent. For example, in June 2011 (during the data collection window), the U.S. Food and Drug Administration advised physicians to limit the use of simv-astatin 80 mg (a high-intensity regimen) because of the risk of muscle injury.3 Similarly, the National Lipid Association advocates the use of moderate- to high-intensity statins for the first-line treatment of hyperlip-idemia and consideration of moderate- to high-intensity statin therapy for patients with ASCVD or type 2 diabetes, regardless of baseline atherogenic cholesterol levels.48 Given the results of this study, health care system-based interventions and new therapeutic paradigms are necessary to optimize patient care, manage risk, and enhance outcomes.These data indicate a lack of intensive statin-based therapy among patients at high risk for CV events. The continued use of moderate- to low-intensity therapy, failure to intensify treatment, poor adherence, and high rates of discontinuation result in a large number of patients who are inadequately protected from recurrent CV events. The current ACC/AHA lipid management guidelines recommend high-intensity statin treatment for men and women who are aged 75 years or younger and who have clinical ASCVD .


Migrants and ethnic minorities are disproportionately affected by the Coronavirus Disease 2019 (COVID-19) pandemic compared to the majority population. Therefore, we studied mortality and use of mechanical ventilation (MV) by country of birth and migrant status in a nationwide cohort in Denmark. Nationwide register data on all cases hospitalized for > 24-hours with COVID-19 between February 2020 and March 2021. Main outcome measures were mortality and MV within 30 days of hospitalization for COVID-19. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by region of origin and migrant status using logistic regression analyses, adjusting for age, sex, comorbidity and sociodemographic factors. Of 6,406 patients, 977 (15%) died and 342 (5%) were treated with mechanical ventilation. Immigrants  and individuals of non-Western origin had a lower odds  of death upon admission with COVID-19 compared to Danish born individuals. Immigrants and descendants  as well as individuals of non-Western origin  had a significantly higher odds of MV compared to Danish born individuals. Outcomes of individuals with Western origin did not differ. Immigrants and individuals of non-Western origin had a significantly lower COVID-19 associated mortality compared to individuals of Danish origin after adjustment for sociodemographic factors and comorbidity. In contrast, the odds of MV was higher for immigrants and individuals of non-Western origin compared to individuals of Danish origin. Coronavirus Disease 2019 (COVID-19) has shown disturbing health inequalities worldwide asmigrants and ethnic minorities have been affected to a higher degree than the majority population. Across Europe and the United States, remarkably higher positive rates of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and subsequent hospitalization with COVID-19 occur among migrant and ethnic minorities compared to majority populations . In EuroIn 2021, 10% and 4%, respectively, of the Danish population were either immigrants and descendants, of which 58% and 83% were of non-Western origin . FurtherStudies on disease severity and mortality from COVID-19 among migrants and ethnic minorities from the UK, Norway and United States have shown an alarming tendency to poorer outcomes compared to the majority population –12. NatiThis nationwide register study was based on data of all individuals residing in Denmark aged 18 years or older on January 1st 2020. We included all patients admitted between February 1st 2020 and March 15th 2021 with a primary COVID-19 diagnosis according to ICD-10  as used previously . NationaDanish born , (ii) Western ; and ii) non-Western 19. We further divided into three geographical regions origin: (i) Asia; (ii) Africa and (iii) Europe, as these were the main world regional origins represented in our data. This was done according to World Bank regional definitions [The exposure variables were ‘regional origin’ and immigrants or descendants (using mother’s country of birth) versus Danish origin. Information on country of birth was obtained from Statistics Denmark and categorization into non-Western versus Western was preformed according to their definitions . We diviOutcome variables were mortality and need of MV among COVID-19 hospitalised patients during follow-up from 1th of Februar 2020 until 1th of July 2021. Thirty-day mortality was calculated from the day of admission. Data on MV while receiving intensive care treatment was retrieved from the Danish Intensive Care Database.2.Covariates included the following seven socioeconomic and demographic variables obtained from Statistics Denmark: (i) length of residence; (ii) marital status; (iii) highest-attained educational level (ISCED) ; (iv) pe21 Comorbidities were weighted by the Charlson Comorbidity Index (CCI) to create a continuous weighted comorbidity score [Further comorbidity was included as a covariate based on information on all ICD-10 diagnoses from The National Patient Register registered between 1st January 1980 and 31st December2020.In descriptive analyses, the distribution of comorbidity, socioeconomic and demographic factors was investigated among individuals of Danish, Western and non-Western origin, who were hospitalised with COVID-19, died with COVID-19, and had been treated with MV. Logistic regression models were used for the main analyses. First, the odds ratios (OR) of death with 95% confidence intervals (95% CI) was calculated among immigrants and descendants, individuals of Western origin and non-Western origin, and individuals originated from Africa, Asia, or Europe. Second, the risk of mechanical ventilation was investigated for immigrants/descendants, individuals of Western and non-Western origin, and individuals from Africa, Asia, or Europe. Third, the risk of death was also examined among patients receiving mechanical ventilation. Individuals of Danish origin were used as the reference group for all analyses. Six step-wise models were applied to adjust for sex, age, CCI, household size, education and income.For all analyses, SAS Enterprise Guide version 7.1 was used with a statistical significance level of 0.05. The study is approved by the University of Copenhagen Ethics Board, reference number 514 − 0231/18-3000. Individual consent is not required by Danish legislation for register-based studies.Of 17,073 individuals admitted with a diagnosis of COVID-19, 9,395 had been admitted for less than 24 h, 935 individuals had COVID-19 as a secondary diagnosis for hospital contact, 323 had no information on comorbidity and 14 had missing information or negative income (see Fig. Table Table Table Table In this unique nationwide register-based study of ethnic disparities in 30-day mortality and use of MV during the first year of the pandemic, we highlight several findings. First, immigrants and individuals of non-Western origin had a significantly lower mortality compared to individuals of Danish origin. Second, immigrants, descendants, individuals of non-Western origin and individuals originating from Asia had a significantly higher risk of receiving MV compared to individuals of Danish origin. No significant intergroup differences were found in mortality among those who had received with mechanical ventilation.First, our results showed that albeit immigrants of non-western origin had a higher rate of admission from COVID-19 in Denmark , 10, 12.Second, we found that immigrants of non-Western origin were more likely to receive MV than individuals of Danish origin. Here we were not able to divide immigrants and descendants. The higher use of MV among immigrants is in line with previous findings , 22. AgaOur study has several methodological strengths. First, it is based on unique nationwide data representing all hospitalised COVID-19 cases in Denmark from March 2020 to February 2021. Use of national data made it possible to include the entire population and link with different national registers including a number of relevant confounders on an individual level. Second, the validity of COVID-19 diagnoses is increased by only including cases where COVID-19 was the primary reason for hospital contact. Third, we were able to divide migrants into several subcategories based on country of origin. The study also has several limitations. First, on a positive note Denmark’s management of the pandemic through restrictive policies resulted in a comparatively limited number of hospitalisations restricting the sample size of specific country groups and reducing statistical power in some analyses. Second, the study population only included the most severe COVID-19 cases hospitalized for ≥ 24 h and is not representative of COVID-19 cases in the general population. Therefore, our results are not generalizable to mortality from COVID-19 in the general population.Our study showed that among individuals, who had been admitted for COVID-19, immigrants as well as individuals of non-Western origin had a significantly lower mortality compared to individuals of Danish origin, however, they had a significantly higher risk of MV. No significant differences between any of the groups were found in mortality among those with MV. To disentangle these complex relationships, future research on mortality and MV should ideally include clinical and biomarker data as well as qualitative data related to interpreter use and patients’ experiences of cultural competency among health care professionals.


Globally, emergency nutrition program adaptations were implemented as part of COVID-19 mitigation strategies, but the implications of the adoption of all protocol changes at scale in the context of deteriorating food security are not yet well characterized. With ongoing conflict, widespread floods, and declining food security, the secondary impacts of COVID-19 on child survival in South Sudan is of great concern. In light of this, the present study aimed to characterize the impact of COVID-19 on nutrition programming in South Sudan.A mixed methods approach including a desk review and secondary analysis of facility-level program data was used to analyze trends in program indicators over time and compare two 15-month periods prior to the onset of COVID-19  and after the start of the pandemic  in South Sudan.The median number of reporting Community Management of Acute Malnutrition sites increased from 1167 pre-COVID to 1189 during COVID. Admission trends followed historic seasonal patterns in South Sudan; however, compared to pre-COVID, declines were seen during COVID in total admissions (− 8.2%) and median monthly admissions (− 21.8%) for severe acute malnutrition. For moderate acute malnutrition, total admissions increased slightly during COVID (1.1%) while median monthly admissions declined (− 6.7%). Median monthly recovery rates improved for severe (92.0% pre-COVID to 95.7% during COVID) and moderate acute malnutrition (91.5 to 94.3%) with improvements also seen in all states. At the national level, rates also decreased for default  and non-recovery , with mortality rates remaining constant at 0.05–0.15%.Within the context of the ongoing COVID-19 pandemic in South Sudan, improved recovery, default, and non-responder rates were observed following adoption of changes to nutrition protocols. Policymakers in South Sudan and other resource-constrained settings should consider if simplified nutrition treatment protocols adopted during COVID-19 improved performance and should be maintained in lieu of reverting to standard treatment protocols.The online version contains supplementary material available at 10.1186/s40795-023-00696-y. At the onset of the COVID-19 pandemic, more than half of the population of South Sudan (SSD) faced crisis or worse levels of food insecurity, and several areas were at risk of famine . The fooCommunity Management of Acute Malnutrition (CMAM) programs are designed to help children recover from acute malnutrition. The vast majority of children with acute malnutrition are managed on an outpatient basis and recover within a several month period . In SoutTo avoid health facilities becoming epicenters of transmission, UNICEF, the Global Nutrition Cluster (GNC), and the Global Technical Alliance Mechanism for Nutrition (GTAM) released interim guidance for Management of Child Wasting in the Context of COVID-19 on March 27, 2020 . In addiThe South Sudan Ministry of Health released ‘Guidelines for Nutrition Service Delivery in the Context of COVID-19’ on March 31, 2020, adopting all adaptations recommended in global guidance . The guiThe implication of changing context on CMAM admissions has large operational implications for the management of CMAM programs. If rising food insecurity is associated with an increase in acute malnutrition prevalence, this would drive an increase in CMAM admissions; however, protocol changes may have the opposite effect. Suspension of WHZ as an admission criterion excludes a subset of children otherwise eligible for treatment of acute malnutrition and suspension of mass screening activities could decrease program coverage. Following admission, protocol simplifications such as reduced visit frequency and simplified dosing could impact both recovery rates and length of stay, though this is not yet well characterized. Some studies have identified non-inferior outcomes when select simplifications were implemented , 11. HowA mixed methods approach consisting of a desk review and secondary analysis of facility-level program data was used. The analysis focused on trends over time and descriptive comparison of two 15-month periods: 1) January 2019 – March 2020 (“pre-COVID period”), and 2) April 2020 – June 2021 (“COVID” period).A review of contextual factors  that may have impacted nutrition program performance concurrent to the impacts of the pandemic was conducted with a focus on information available from government, humanitarian NGOs, and United Nations sources. Searches were performed across relevant public databases and websites . Several publicly available reports were identified prior to web searches and were incorporated into the review . Situational timelines of key factors impacting nutrition programming, including conflict, natural disasters, and climate were developed at national and state levels, with state-level timelines incorporating county-level detail when available.Partners operating CMAM sites for treatment of SAM and MAM in South Sudan are requested to report monthly aggregate performance indicators by facility to the South Sudan Nutrition Cluster. For children 6–59 months of age, reported performance indicators include monthly number of children enrolled and exiting from each site, as well as exit outcomes  by sex and type of program of enrollment  for SAM and targeted supplementary feeding programs (TSFP) for MAM). These site-level data shared by the Nutrition Cluster, consisting of routine reporting from all CMAM sites in South Sudan  from January 2019 through June 2021, were analyzed to evaluate changes in nutrition programming within the context of the COVID-19 pandemic , 12.Indicators were analyzed separately for SAM and MAM and included: 1) SAM/MAM admissions: Number of children 6–59 months of age admitted to OTP and TSFP programs, respectively; and 2) SAM/MAM program exit outcomes: Number of children exiting from OTP/TSFP by outcome type  as a proportion of all children existing in each program. These proportions  are standard indicators of program performance. All indicators are presented both monthly and as monthly medians for each 15-month period (pre-COVID and COVID). Secondary analysis was conducted at national and state levels with a focus on overall trends between January 2019 and June 2021, as well as descriptive comparison of change between the pre-COVID and COVID periods across states; no statistical testing was performed. Data are exhaustive, reported from all facilities operating CMAM activities during the review period, not a sample; thus, all analysis was unweighted. No adjustments were made for sites with missing data for select months.The study was reviewed and approved by the South Sudan Ministry of Health Ethics Committee and Institutional Review Board at Johns Hopkins Bloomberg School of Public Health. This activity was reviewed by the US Centers for Disease Control and Prevention (CDC) and was conducted consistent with applicable federal law and CDC policy.The national analysis of CMAM program data included sites operated by 58 partners, including both national and international NGOs. A total of 1852 unique CMAM sites provided data for at least 1 month during the review period, including 120 operating only OTPs, 75 operating only TSFPs, and 1657 operating both. Of all sites, 257 (14%) reported data for all 30 months under review. The number of CMAM sites reporting ranged from 1082 to 1197 in the pre-COVID period and 1164–1223 during COVID with the median number of CMAM sites increasing from 1167 pre-COVID to 1189 during COVID. The monthly median number of CMAM sites reporting data increased in seven of the ten states, with only Upper Nile (− 24), Northern Bahr el Gazal (− 11), and Lakes (− 9) states reporting decreases  and spring (April to June), and a decrease through the second half of the year. Prior to the onset of the pandemic, seasonal declines in SAM and MAM admissions were observed from May to December 2019, which were followed by enrollment increases in the first quarter of 2020. Following the onset of COVID-19, trends for both SAM and MAM admissions were similar, though there was less month-to-month variation in SAM admissions compared to the previous year.Aggregated by period, the total number of SAM admissions declined by 8.2% during COVID-19  despite the increase in the number of reporting sites. The total number of MAM admissions increased slightly by 1.1%  , CMAM programs report the proportion of children that exit as non-recovered, defaulters, and deceased. The recovery, default, and non-recovered rates improved for both OTP and TSFP at the national level, with mortality rates remaining constant at 0.05–0.15%. The default rate declined from the pre-COVID to COVID period by 2.4% (4.8% pre-COVID vs. 2.4% during COVID) for SAM and 1.7% for MAM (4.3% pre-COVID vs. 2.6% during COVID). The non-recovered rate declined by 0.9% (2.6% pre-COVID vs. 1.7% during COVID) for SAM and 1.1% for MAM (4.1% pre-COVID vs. 3.0% during COVID)  can impact outcomes that are designed to allow for individual-level adjustment for child characteristics is important.The presented analysis is novel in that it presents trends over 30 months, a long enough period to capture pre-COVID seasonal trends, and includes data from all health facilities reporting they were operating CMAM programs in South Sudan during the review period. In contrast to previous analyses based on samples or sub-national datasets, this allows for a more comprehensive picture of trends in admissions and program outcomes following the onset of the pandemic.. Finally, while the COVID period in our analysis begins in April 2020, there were numerous protocol revisions implemented at different times in different locations beyond this time.The present analysis is nevertheless subject to several limitations. First, the data provided are aggregated facility-level counts; without individual level data, it was not possible to adjust for child-level demographic characteristics or nutritional status. Second, many sites reported no admissions for many months during the review period, but there is no documentation of whether this reflects site closures or gaps in reporting. Third, the analysis is observational in nature and not designed to understand the cause of the changes in admissions or program outcomes described. Evidence to support nutrition treatment protocol simplifications, many of which were implemented at scale as COVID-19 mitigation strategies, is strong and suggests numerous benefits alongside similar treatment outcomes compared to standard protocols. Within the context of the ongoing COVID-19 pandemic in South Sudan, improved recovery, default, and non-responder rates were observed following adoption of changes to nutrition protocols. Policymakers in South Sudan and other resource-constrained settings should consider if simplified treatment protocols adopted during COVID-19 improved performance and should be maintained in lieu of reverting to standard treatment protocols.This analysis leveraged national program data to investigate changes in nutrition programming in South Sudan during the onset of the COVID-19 pandemic. The study builds on existing evidence, largely from pilots and research studies with smaller sample sizes, by analyzing national-level outcome data when protocol modifications were implemented at scale. Comparison of pre-pandemic and pandemic periods found a modest reduction in admissions during COVID that coincided with worsening food insecurity, conflict, displacement, and several significant floods. States with the largest admission declines also saw reductions in the number of treatment facilities during COVID, suggesting that coverage was a key issue. Given the situational complexity and large annual variations in admissions, it is unclear what changes in admissions, if any, are due to treatment protocol adaptationsAdditional file 1. Number of CMAM Sites by State during the Pre-COVID and COVID Periods.Additional file 2. Timeline of Shocks and Drivers.