Background: In patients after experiencing stroke, the cognitive-behavioral deficits and disorders of verbal communication limit the effectiveness of rehabilitation. The key is to diagnose them at an early stage of rehabilitation and to implement appropriate psychological and speech therapy. Objective: Identify differences in the frequency and effectiveness of cognitive-behavioral disorder therapy depending on the clinical type of stroke, assessed before and after rehabilitation treatment, and their presentation using the ICF  classification. Materials and Methods: The study was prospective and included the analysis of cognitive-behavioral and verbal communication disorders. The study consisted of 47 patients after intracerebral hemorrhage (ICH) and 47 patients after an ischemic stroke (IS) before the implementation of rehabilitation and after completing a 4-week rehabilitation. Results: In the group after ICH, psychological therapy significantly reduced the disturbances of consciousness and orientation (p < 0.001) and improved the speed of performing tasks in tests (p < 0.001). In patients after IS and ICH, memory and attention function improved significantly (p < 0.001). Moreover, in patients after ICH, language function deficits decreased significantly (p = 0.018). Mood disturbances were maintained in 17% of patients after ICH and 40% of patients after IS (p = 0.007). Speech therapy reduced speech articulation disorders and aphasia in 85% of patients after ICH (p = 0.001) and in 68% of patients after IS (p = 0.033). Conclusions: The frequency and type of cognitive-behavioral and verbal communication disorders vary depending on the history of ICH or IS. The ICF classification may be useful in assessing and analyzing cognitive-behavioral and verbal communication disorders, which may lead to the implementation of appropriate psychological and speech therapy at an early stage of rehabilitation and increase the effectiveness of the therapy. The clinical consequences of stroke constitute the third leading cause of mortality and the second leading cause of long-term disability in Poland ,2. StrokThe ICD-10  includes causes of stroke. According to the ICD-10 classification, the diagnosis does not provide sufficient information on the functional status and impairment of fitness and independence. Due to pathophysiological differences, IS and ICH have different long-term cerebral and functional consequences . The attIn the available literature, the ICF classification was used to recode data contained in the medical records of patients after stroke ,14, and The study was prospective. The principles of ethical biomedical research set out in the Declaration of Helsinki were respected. The condition for qualifying for the study was a stable clinical condition and consent to participate. The study included an analysis of cognitive-behavioral and verbal communication disorders based on a clinical examination performed by a psychologist and speech therapist on admission to the Neurological Rehabilitation Department of the Rehabilitation Clinic at the Orthopedic and Rehabilitation Clinical Hospital Wiktor Dega in Poznań before the implementation of rehabilitation treatment and again after its completion on the day of discharge from the Department in the period from December 2017 to September 2020. Patients were divided into two groups depending on the IS or ICH history. As part of the rehabilitation program, each patient underwent psychological therapy for cognitive-behavioral disorders and speech therapy for language deficits. The therapy was conducted daily and included one hours of personal psychological therapy, one hours of individual speech therapy and one hours of group therapy focused on interpersonal communication.Restoring executive functions .Training of memory processes .Attention processes training .Personal psychological therapy was individualized in terms of the patient’s needs and was based on:For this purpose, sets of paper-pencil exercises (worksheets for exercises in cognitive and executive functions) were used. Additionally, Poppelreuter Tables (Poppelreuter Tables) and open source PEBL (Psychology Experiment Building Language) software. Mackworth Clock Test, Time Wall and Connections. Despite the experimental and, above all, diagnostic nature of the tools, in practice, it has training possibilities. Additionally, elements of Solution Focused Brief Therapy and mindfulness training were used as supportive.Personal speech therapy was based on exercises covering the essential linguistic functions: creating and understanding linguistic statements, reading, and writing. Additionally, the therapy was conducted using the AfaSystem computer program, extended package version 2.1.1.1 dated 16 July 2017, Harpo . The AfaSystem program consists of a management system  and thirty-two therapeutic programs (modules). Speech therapies are organized according to the disorders of the linguistic function, based on which tasks of understanding linguistic messages are created. The program includes duties based on illustrations and audio presentations sorted by difficulty levels, among others, according to frequency and word complexity. During therapy, a speech therapist has many modifications that allow individual adjustment of tasks to the current needs and capabilities of a particular patient.The language message comprehension therapy included the differentiation of the wording , the interpretation of the meaning of the messages (understanding linguistic content of varying complexity), and the use of verbs (understanding the audio content related to an activity).Linguistic expression therapy included forming statements based on the development of nouns, adjectives, phraseological compounds, and the updating of names in sentences.Reading therapy included: reading nouns, verbs, adjectives, synonyms, reading sentences (developing nouns in context), arranging sentences (building complex statements), developing comparisons in context (reading sentences) and out of context (matching words to a pair), abstract thinking by developing nouns based on phraseological compounds.Writing therapy included: writing nouns, verbs, adjectives, antonyms, and writing phraseological relationships with clarification of meaning, writing compound sentences.The study inclusion criteria were as follows: (1) patients after the first episode of IS or ICH (2) confirmed stroke by medical imaging (3) hospitalized patients in the early period after stroke (3) up to 14 days from the diagnosis of stroke, in the neurological rehabilitation department, (4) complete medical records regarding the assessment of cognitive disorders and verbal communication made by a psychologist and speech therapist on admission and discharge from the Department (5) assessment of the patient’s condition in the NIHSS  below 12 points (6) completion of 4-week psychological therapy and speech therapy in the early period after stroke.The study exclusion criteria were as follows: (1) patients with multiple histories of strokes (2) lack of imaging studies in the medical records confirming the occurrence of a stroke (3) patients hospitalized as part of late neurological rehabilitation, more than 14 days after the diagnosis of stroke, in the neurological rehabilitation department (4) patients with whom it was impossible to establish contact and obtain consent to participate in study (5) patients who did not undergo a full assessment of cognitive disorders and verbal communication by a psychologist and speech therapist (6) an NIHSS stroke score above 13 points (7) discontinuation of psychological therapy and/or speech therapy during rehabilitation. After applying the inclusion and exclusion criteria, 47 patients with a history of ICH and 47 with a history of IS were finally qualified for the study. All patients underwent a 4-week early neurological rehabilitation focused on psychological and speech therapy for cognitive-behavioral disorders and verbal communication. The results were recoded into ICF classification categories and presented in a graphical form.The Bioethics Committee approved the study of the Karol Marcinkowski University of Medical Sciences in Poznań No. 810/2017 of 22 June 2017.The assessment was made on the basis of a standardized hospital psychological examination protocol. Before the implementation of rehabilitation, each patient had an examination qualifying for psychological therapy. The examination was also repeated after completed the rehabilitation. The disorders of consciousness and allopsychic orientation, autopsychic orientation, attention and memory functions, emotional-personality system, executive functions, agnosia and apraxia were analyzed. Qualitative and quantitative research was carried out based on the observations and interview of a clinical psychologist experienced in working with stroke patients. The qualitatively assessed types of dysfunction and the depth of disturbances in the discussed areas were described in intervals on a scale from 0 to 4, where 0—means no disturbances, 1—slight functional disturbance but not significantly influencing the functioning in daily living, 2—small disturbances of functions affecting functioning in daily living, 3—moderate function disturbances that interfere with daily living, 4—severe disturbances that prevent independent functioning in daily living.Before the implementation and after the completion of rehabilitation, each patient underwent an examination qualifying them for speech therapy. The same neurologist carried out the research. The assessment was made based on a standardized hospital protocol of speech therapy examination, which included an analysis of the depth of speech, language, and interpersonal communication disorders. To describe the depth of these deficits, a scale from 0 to 4 was used, where 0—no disturbances, 1—slight functional disturbances but not significantly affecting functioning in daily living, 2—slight functional disturbances affecting functioning daily living, moderate dependence by supervision or belaying, 3—disturbance of functions of moderate intensity, clearly disrupting daily living, assistance required 4—disturbance of functions to a severe degree, preventing independent functioning in daily living, complete dependence.To better emphasize the differences in the type and frequency of cognitive-behavioral and speech therapy disorders in the analyzed clinical types of stroke, the graph presents the percentage distribution of the category qualifiers according to the ICF classification markings: qualifier 0—no disorder present if the percentage distribution was from 0% to 4%, taken as dark green; 1—insignificant occurrence of a disturbance if the value of the percentage distribution was from 5% to 24%, the light green color was used; qualifier 2—moderate occurrence of the disorder if the value of the percentage distribution was from 25% to 49%, the yellow color was used; qualifier 3—significant occurrence of the disorder if the value of the percentage distribution was from 50% to 95%, the orange color was used; qualifier 4—extremely high occurrence of disturbance—if the value of the percentage distribution was from 96% to 100%, the red color was used.According to the ICF classification, the following codes and qualifiers have been assigned to the individual categories of psychological disorders:Disturbances of consciousness were coded in category b110 consciousness functions and the following qualifiers were assigned: qualifier 0—full consciousness, qualifier 1—sleepy, qualifier 2—not fully conscious, qualifier 3—unconsciousDisorientation was coded in category b114 orientation functions and the following qualifiers were assigned: qualifier 0—full orientation as to time and place preserved, qualifier 1—orientation to place and time preserved, qualifier 2—lack of full orientation as to the place or time, qualifier 3—complete disorientation as to place and timeMood disorders were coded in category b130 energy and drive functions, and the following qualifiers were assigned: qualifier 0—no mood disorders, qualifier 1—depressed mood.Attention system disorders were coded in category b140 attention functions and the following qualifiers were assigned: qualifier 0—no disturbances in attention systems, qualifier 1—slight attention disorders, qualifier 2—moderate attention disorders, qualifier 3—severe attention disorders.Memory disorders were coded in category b144 memory functions and the following qualifiers were assigned: qualifier 0—no memory impairment, qualifier 1—mild memory impairment, qualifier 2—moderate memory impairment, qualifier 3—severe memory impairment.Psychomotor slowing down was coded in category b147 psychomotor functions and the following qualifiers were assigned: qualifier 0—no psychomotor slowing down, qualifier 1—psychomotor slowing down.Emotional disorders were coded in category b152 emotional functions and the following qualifiers were assigned: qualifier 0—no emotional disturbances, qualifier 1—slight emotional disturbances, qualifier 2—moderate emotional disturbances, qualifier 3—severe emotional disturbances.Agnosia was coded in category b156 perceptual functions and the following qualifiers were assigned: qualifier 0—no agnosia 1—light agnosia, qualifier 2—moderate agnosia, 3—severe agnosia.Executive system disorders were coded in category b164 higher cognitive functions and the following qualifiers were assigned: qualifier 0—no disorders of the executive systems, qualifier 1—slight disorders of the executive systems, qualifier 2—moderate disorders of the executive systems, qualifier 3—severe disorders of the executive systems.Apraxia was coded in category b176 mental functions of complex movements and the following qualifiers were assigned: qualifier 0—no apraxia, qualifier 1—slight apraxia, qualifier 2—moderate apraxia, qualifier 3—severe apraxia.According to the ICF classification, the following codes and qualifiers have been assigned to individual categories of speech therapy disorders:Language disorders were coded in category b167 mental functions of language and the following qualifiers were assigned: qualifier 0—linguistic functions preserved, qualifier 1—partially impaired language functions, qualifier 2—completely impaired linguistic functions.Speech fluency was coded in category b1671 expression of language and the following qualifiers were assigned: qualifier 0—no speech disorders, qualifier 1—blurred speech, qualifier 2—dysarthric speech.Aphasia was coded in category b1672 integrative language functions and the following qualifiers were assigned: qualifier 0—no aphasia, qualifier 1—sensory or motor aphasia, qualifier 2—sensory and motor aphasiaDysphagia was coded in category b5108 ingestion functions and the following qualifiers were assigned: qualifier 0—no dysphagia qualifier 1—dysphagia.Speech disturbances were coded in the category speaking d330 and the following qualifiers were assigned: qualifier 0—no word choice disorders, qualifier 1—inadequate, limited word choice, qualifier 2—no sentence formulation, qualifier 3—no speech, making sounds.Social communication disorders were coded in category d710 basic interpersonal interactions and the following qualifiers were assigned: qualifier 0—preserved, qualifier 1—moderately disturbed, qualifier 2—completely disturbed.t-test for independent samples or the non-parametric Mann–Whitney U test was used to check whether there were significant differences between the results obtained by people after ischemic and hemorrhagic stroke. Paired student’s t-test or non-parametric Wilcoxon pairwise test were used to compare pre-treatment and post-treatment results within each group. The results expressed in the nominal scale were dependent on the Pearson chi² test or the Fisher test, while changes in the values of these parameters occurring after treatment were assessed using the McNemara test. p values < 0.05 were considered statistically significant.Statistica version 13.1 TIBICO Software Int. , and MS Excel from Microsoft Office 2019 MSO, version 2208,  were used to elaborate the results. Descriptive statistics were presented using: mean, standard deviation (SD), median, minimum and maximum. In the case of qualitative variables, the number of people in each category was described and the percentages were calculated. The normality of the distribution was checked with the Shapiro–Wilk test, and the homogeneity of variance with the Levene’s test. Depending on the nature of the variables and the fulfilled assumptions, parametric or non-parametric tests were used, respectively. The student’s p = 0.038) and sex distribution (p = 0.039). The mean age of patients after ICH was 67.3 years, while after IS it was 71.7 years. The group of patients after ICH was dominated by men—57.4%, while the group after IS was dominated by women—63.8%. The time of rehabilitation after stroke differed significantly between the groups (p < 0.001). Patients after ICH were rehabilitated approximately 29 days after the stroke incident, while patients after IS after 16 days after the stroke incident. After rehabilitation, patients after ICH achieved greater efficiency by 3 points on the NIHSS scale than after IS (p = 0.001). A detailed list of the study groups is presented in The study groups differed significantly in age (p = 0.007). Emotional, attention, and memory deficits dominated in both groups of the examined patients. Psychological therapy significantly reduced these deficits. The implemented therapy significantly reduced consciousness and orientation disorders in the group after ICH (p < 0.001). Moreover, in the group after ICH after rehabilitation, the speed of task performance in psychological tests significantly improved (p < 0.001). No significant improvement was noted in the remaining areas of cognitive-behavioral disorders. A detailed list is presented in In both groups of patients, there were significant mood disorders. After rehabilitation in 17% of patients after ICH and in as many as 40% of patients after IS, the depressed mood was observed (p = 0.055) and after rehabilitation (p = 0.763). The use of speech therapy in both groups of patients significantly reduced disorders of speech articulation and aphasia. Moreover, in patients after ICH, rehabilitation significantly reduced language function deficits (p = 0.018). Before rehabilitation, over 59% of patients in both groups had proper interpersonal communication in terms of speech. In patients after ICH, the most common deficit was associated with the inadequate choice of words, while in patients after IS, the greatest problem was the formulation of sentences. The implemented therapy reduced disorders in 85% of patients after ICH (p = 0.001) and in 68% of patients after IS (p = 0.033). A detailed summary of the data is presented in There was no significant correlation between verbal communication disorders and the type of stroke before rehabilitation  or its change to a significant and moderate extent.Before rehabilitation in the group after ICH, compared to the group after IS, a significantly higher percentage of impairment was observed at an extremely high level in regarding memory function disorders, attention systems, and expression of language. At the level of significant functional impairment, disturbances in memory functions and attention functions were observed more often. At the level of moderate functional impairment, psychomotor disturbances and fluency in speaking were observed more often. After rehabilitation treatment, a more significant reduction in functional impairment was observed in the group after ICH, from the extreme, severe and moderate degrees compared to the group after IS.Stroke is a significant social problem because it remains one of the main causes of morbidity and long-term disability and the second most frequent cause of death ,11. TherResearch by Hurfold et al.  shows thhttps://www.icf-research-branch.org/ (accessed on 1 January 2020) WHO publishes examples of shortened functional assessment kits for stroke patients (Stroke Brief), for patients undergoing rehabilitation (Rehabilitation Set) and for neurological patients  [For practical reasons, the ICF classification includes as few categories as possible and at the same time, takes into account all categories needed to describe various aspects of the functioning of a patient with a specific disease in a comprehensive and cross-sectional assessment . On the e Brief) ,35,36,37e Brief) ,38 It ise Brief)  prove th(1).The type of stroke suffered determines the frequency and type of cognitive-behavioral and verbal communication disorders.(2).The ICF classification can be used to assess the occurrence of psychological and speech therapy disorders depending on the clinical type of stroke.(3).Using one tool during rehabilitation containing a description of cognitive-behavioral disorders as well as verbal communication in the form of an ICF sheet may improve communication between a speech therapist and a psychologist, which in turn may lead to an increase in the effectiveness of the therapy.


FHR2) gene, and western blot analysis revealed a significant reduction in the level of FHR2 protein in the patient’s serum. Although FHR2 involvement in complement 3 glomerulopathy has been reported previously, a role for FRH2 as a complement modulator has not yet been definitively shown. In addition, no cases of aHUS in individuals with FHR2 variants have been reported. Given the role of FHRs in the complement system and the fact that this patient was a candidate for a kidney transplant, we studied the relevance of low FHR2 plasma levels through a set of functional in vitro assays. The aim of our work was to determine if low FHR2 plasma levels could influence complement control at the endothelial surface with a view to identifying a therapeutic approach tailored to this specific patient. Interestingly, we observed that low FHR2 levels in the patient’s serum could induce complement activation, as well as C5b–9 deposition on human endothelial cells, and affected cell morphology. As C5b–9 deposition is a prerequisite for endothelial cell damage, these results suggest that extremely low FHR2 plasma levels increase the risk of aHUS. Given their ability to reduce C5b–9 deposition, recombinant FHR2 and eculizumab were tested in vitro and found to inhibit hemolysis and endothelial cell surface damage. Both molecules showed effective and comparable profiles. Based on these results, the patient underwent a kidney transplant, and received eculizumab as induction and maintenance therapy. Five years after transplantation, the patient remains in good general health, with stable graft function and no evidence of disease recurrence. To our knowledge, this is first reported case of an aHUS patient carrying FHR2 mutations and provides an example of a translational therapeutic approach in kidney transplantation.Atypical hemolytic–uremic syndrome (aHUS) is a severe thrombotic microangiopathy in which kidney involvement is common. aHUS can be due to either genetic or acquired abnormalities, with most abnormalities affecting the alternative complement pathway. Several genetic factors/alterations can drive the clinical presentation, therapeutic response, and risk of recurrence, especially recurrence following kidney transplantation. We report here the case of a 22-year-old man who developed a severe form of aHUS. Renal biopsy revealed thrombotic microangiopathy and features of chronic renal damage. Despite two eculizumab infusions, the patient remained dialysis dependent. Two novel rare variants, c.109G>A (p.E37K) and c.159 C>A (p.Y53*), were identified in the factor H-related 2 ( Atypical hemolytic–uremic syndrome (aHUS) is a systemic endotheliosis that is characterized by severe microangiopathy and renal failure, leading to uncontrolled activation of the alternative complement pathway , 2. The The specific or individual genetic background of patients with aHUS influences the subtle effects of complement action, thus affecting therapeutic responses, recurrence rates, and prognosis throughout the entire process of renal transplantation , 5. In tThe risk of aHUS recurrence on the allograft ranges from less than 20% to more than 90% depending on the patient’s genetic background and the therapeutic strategy. Recipients with mutations in the genes encoding circulating complement factors  have a higher risk of recurrence than patients with genetic variants encoding membrane and local modulators of the complement system, such as cluster of differentiation 46 (CD46) .FHR) genes, gain of function mutations in C3 and complement factor B, and a previous history of aHUS recurrence were found to be associated with a high recurrence risk, and this was confirmed Kidney Disease Improving Global Outcomes (KDIGO) working group, which recommends the prophylactic use of eculizumab on the day of transplantation to prevent overactivation of the complement system , severe kidney failure (creatinine 16.85 mg/dl), and low C3 plasma levels  , with a normal cortical thickness. Of note was that the patient had no family history of thrombotic microangiopathy (TMA) or other kidney diseases, and reported good health. Laboratory analyses carried out before the onset of aHUS, when the patient was aged 6 years, showed normal kidney function and no urinary abnormalities.A 24-year‐old Caucasian man was referred to the nephrology unit for a pre-transplantation kidney evaluation. At the age of 22 years, the patient had been admitted to hospital following the sudden development of swelling of the face and legs, epistaxis, postural instability, chest pain, purpuric rush on both arms, and high blood pressure (180/90 mmHg). The patient reported flu-like symptoms without fever during the previous 2 weeks. Laboratory analysis revealed hemolytic anemia , thrombocytopenia , tubular atrophy, and the vascular lesions typically associated with TMA. aHUS was diagnosed. Despite blood transfusions, hemodialysis, steroid treatment, and the administration of two doses of eculizumab (900 mg/week × 2 weeks) starting 1 month after hospitalization, the patient rapidly progressed to end-stage renal disease. Given the findings of kidney biopsy, eculizumab administration was discontinued and the patient remained dialysis dependent.FHR2 gene: 1) a novel missense variant, c.109G>A, resulting in the exchange of E37 to K37; and, 2) a nonsense variant, c.159 C>A, which introduces a premature stop codon at position 53 (FHR genes or genomic deletions were detected by multiplex ligation-dependent probe amplification (MLPA) The screening of complement genes associated with aHUS was performed with next-generation sequencing using an in-house genetic panel, and confirmed by Sanger sequencing (see FHR2) and that the p.E37K exchange was a de novo variant  modulation and to define the specific therapeutic approach for our patient.Considering the possibility of a kidney transplant, we then performed a set of functional assays in vitro . The negative control was 5% NHS. When recombinant FHR2 was added to the HS#2337, erythrocytes lysis was reduced from 34% to 12%, suggesting a role for FHR2 as a surface regulator of the alternative pathway (As shown in p ≤ 0.05). As low FHR2 levels reduce complement regulation, causing more C5b–9 deposition, we carried out an assay to determine whether or not recombinant FHR2 was able to reverse the strong C5b–9 deposition induced by HS#2337. To this end, HUVECs were incubated with 30% patient serum to which increasing amounts of recombinant FHR2 (from 0 to 280 ng) were added, and C5b–9 signaling was evaluated by flow cytometry. In vitro addition of FHR2 to HS#2337 reduced HUVECs C5b-9 deposition in a dose-dependent manner. When FHR2 was used at a concentration of 280ng, C5b-9 signaling on HUVECs was completely lost   express in percentage: HS#2337, 554; NHS, 208]  was added Finally, we compared FHR2 and eculizumab efficacy in regulating HS#2337-induced C5b–9 deposition. HUVECs were incubated with HS#2337, with HS#2337 plus FHR2 (280 ng), and with HS#2337 plus eculizumab (35 ng). C5b–9 signaling was then evaluated by confocal microscopy , receiving a cadaveric graft from a standard criteria donor. Two  of six antigens were mismatched, four  of six human leucocyte antigens were matched, no donor-specific antibodies were detected, and the panel-reactive antibody positivity was 0%  to confer a high level of graft protection. During the post-transplant phase, steroids were gradually reduced, and plasma exchange was replaced by plasma infusion, which was administered as thymoglobulin for 6 days. This therapeutic scheme allowed the introduction of calcineurin inhibitors  4 days after the transplant, attenuating the endothelial damage, coupled with mycophenolate  and the introduction of a premature stop codon  in SCR1. These variants are located within the N-terminal domain, which mediates FHR2 dimerization and inhibition of C5b–9 assembly, suggesting an important impact on protein function  on endothelial cells cause cell death and unmask prothrombotic agents, favoring TMA development . In our in vitro assays, we demonstrated that eculizumab was effective in reducing C5b–9 signaling in this specific patient with FHR2 deficiency, as demonstrated through ELISAs and observation of HUVECs incubated with the patient’s serum. Interestingly, eculizumab and the recombinant FHR2 showed a comparable effect on controlling the complement system, indicating their potential benefits for the treatment of these patients.When it became apparent that our patient would need to undergo kidney transplantation, we evaluated the opportunity to administer a C5b-blocking complement inhibitor. Thus, we investigated the effect of eculizumab on C5b–9 serum levels and deposition of C5b–9 on cells. Through a series of different Based on the results of these biological tests, we decided to prophylactically administer eculizumab plus plasma therapy before the transplant surgery . The proPlasma therapy was administered for 6 days after transplantation, whereas eculizumab was used for 2 months to confer a higher protection from complement activation. The discontinuation of eculizumab is debated, and depends on genetic variants, clinical history, and laboratory tests . AlthougIn summary, we reported the first case of aHUS in a patient with a genetic defect within FHR2 that seems associated with very low plasma level of this protein. We successfully transplanted the patient using personalized induction and maintenance therapy. Moreover, the analyses carried out in this index clinical case allowed us to investigate in depth the role of the FHR2 surface complement regulator, and to demonstrate that loss of/reduction in this factor may contribute to the pathogenesis of aHUS. This unique patient provides an example of the application of a translational medicine framework that could be useful in managing patients with aHUS carrying novel genetic variants of unknown significance, with the aim of defining the best therapeutic strategy in those undergoing kidney transplantation.The original contributions presented in the study are included in the article/Ethics review and approval were not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.ES collected the data, created the figures, and drafted the manuscript with PFZ and CS. ES carried out the experiments with support from AH. MA, PP, FC and GC supported the genetic analysis and the collection of clinical and biological materials. FC provided linguistic and scientific support during revision. TW provided the kidney biopsy and supported the experimental project design. FP revised all statistical analyses and helped draft the manuscript. PFZ and LG supervised the project. All authors discussed the results and contributed to the final manuscript. LG, GC, and ES defined the therapeutic strategy for patient #2337 during the kidney transplantation. All authors contributed to the article and approved the submitted version.PFZ and TW received funding by the Collaborative Reserch Center CRC 1192, by the Deutsche Forschungsgemeinschaft. PFZ received support from KIDNEEDS Iowa, USA. ES was supported by a scholarship from the Società Italiana di Nefrologia .We thank the patient and his family for participating in the study and for contributing valuable specimens. We thank Monika von der Heide, Hans-Martin Dahse, and Ina Löschmann  for excellent technical support.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


TNF-alpha inhibitors have revolutionized the therapeutic care in chronic inflammatory diseases. Several biosimilar products were commercialized at their patent expiry, substantially decreasing the cost of treatment. This longitudinal descriptive study aimed at assessing infliximab, etanercept and adalimumab biosimilar penetration rates using data of the French National Health Data System. A total of 207,118 new or prevalent users from the date of first biosimilar commercialization in France  were included in the study and followed until September 30, 2021. Biosimilars represented respectively 78%, 46% and 53% of the overall initiations, and 94%, 66% and 60% last year’s initiations. A total of 46%, 19% and 17% of originator product prevalent users switched for a biosimilar during the follow-up. Biosimilar penetration rate was much higher for infliximab than for its counterparts, due to its hospital delivery modality. Biosimilar initiation and originator-to-biosimilar switch tended to be observed more in rheumatology than in the other specialties. Biosimilar use was mostly consistent across patient socio-demographic characteristics. Biosimilar initiation rate increased rapidly from their market arrival and originator-to-biosimilar switch rate remained moderate, highlighting the need and usefulness of political action and biosimilar use tracking. Infliximab, etanercept and adalimumab were marketed respectively in 2000, 2003 and 2005 at expensive costs, leading to an issue of either access for patients or healthcare system sustainability due to the large number of patients treated. TNF-alpha inhibitors patent expiry and biosimilars progressive market approvals partly answered these issues by lowering the cost of treatment2. Biosimilars are highly similar formulations of the originator product (same dosage forms and volumes), approved through a rigorous regulatory process including head-to-head clinical trials to demonstrate their bioequivalence, i.e. efficacy and safety5.Tumor necrosis factor alpha  inhibitors are a class of biotherapies that has revolutionized the therapeutic care in chronic inflammatory diseases, such as psoriasis, rheumatoid arthritis and Crohn’s disease6 or Japan7, thanks to accelerated market approvals and country level policies: fast reimbursement, financial incentives to push biosimilar prescription, authorization of switching or substitution of the originator product by the biosimilar at pharmacy level9. Despite some utilization studies11, data on the level of use of biosimilars in Europe, in particular TNF-alpha inhibitors, remain scarce.Biosimilar use is highly dependent of the internal policy in each country. Biosimilars have been more implanted in Europe than in the United States12. It is worth noting that TNF-alpha inhibitors initial prescription and annual renewal are done at the hospital level, along with delivery for infliximab but etanercept and adalimumab delivery is carried out by retail pharmacists. A recent study13 based on French data, but limited to hospital dispensations, showed that TNF-alpha inhibitor biosimilar penetration rate was close to 80%.In France, as TNF-alpha inhibitors are fully reimbursed and widely used, biosimilar utilization has been a particularly important challenge for the healthcare system sustainability: to date, three TNF-alpha inhibitors have been biosimilarized, infliximab in 2015, etanercept in 2016 and adalimumab in 2018The aim of the present descriptive study was to assess the level of biosimilar use in France of these three TNF-alpha inhibitors with a marketed biosimilar, in order to understand the key drivers for biosimilar prescription and be able to improve their penetration, with a national payer perspective. For each molecule, we estimated penetration rate globally, and penetration rate depending on the pathology treated, the specialty or patient characteristics. We focused our study on two populations: initiators within the period of biosimilar commercialization, to compare biosimilar versus originator initiators, and prevalent users at the date of first biosimilar commercialization, to study their switches along time. We used the French National Health Data System , the French comprehensive health claims database, including inpatient and outpatient reimbursements, to address this issue.During the study period, 115,656 unique patients initiated a TNF-alpha inhibitor treatment, for a total of 217,756 unique prevalent users. Adalimumab utilization increased while it remained stable for infliximab and etanercept. Adalimumab initiations increased from 14,711 in year − 1 to 20,198 in year 2, totalizing 85,082 users in year 2, whereas etanercept initiations went from 6639 in year − 1 down to 5341 initiators in year 4, with 36,306 users in year 4, and infliximab from 5460 in year − 1 to 5041 in year 5, with 32,577 users in year 5.  versus etanercept (11% at peak in year 3) or adalimumab (8% at peak in year 0). As a matter of fact, in the last year of follow-up, originator product infliximab represented only 19% of the total infliximab use; it was still much higher for etanercept (61%) and adalimumab (63%).  reached the highest penetration rate versus its competitors  , we included 25,950 infliximab patients (78% of biosimilar initiators), 27,727 etanercept patients (46% of biosimilar initiators) and 48,768 adalimumab patients (53% of biosimilar initiators), for a total of 102,445 initiators. Patient characteristics were mostly similar between originator and biosimilar initiators Table .Table 1IInfliximab new users were mostly women (52%), aged 44 years on average and with a uniform repartition of quintiles of deprivation index. Infliximab new patients were mostly treated for inflammatory bowel diseases (40% in Crohn’s disease and 21% in ulcerative colitis), then for rheumatology pathologies  and then for psoriasis (4%).Etanercept new users were mostly women (63%), aged 51 years on average. Etanercept new patients were mostly treated for rheumatology pathologies  and then for psoriasis (7%).Adalimumab new users were mostly women (55%), aged 44 years on average. Adalimumab new patients were mostly treated for inflammatory bowel diseases (26% in Crohn’s disease and 14% in ulcerative colitis), and for rheumatology pathologies  and then for dermatology (8% for psoriasis and 1% for hidradenitis suppurativa) and uveitis (2%).Corticosteroid use before initiation was consistent within molecules, with 69% of patients having used at least once corticosteroids. Respectively 37%, 69% and 50% of infliximab, etanercept and adalimumab new users had at least one delivery of a NSAID before initiation. Non-biological systemic drugs and biological and targeted drugs had been used respectively by 52–54% and 11–17% of TNF-alpha inhibitor initiators. Comorbidities were evenly distributed between biosimilar and originator products and across molecules.The pathology treated and thus the specialty of interest (after grouping pathologies) had an important impact on biosimilar versus originator initiation. Except infliximab, for which biosimilar initiation rates were almost uniform whatever the specialty, we observed a gradient of biosimilar use according to the pathology: biosimilars were mostly used in rheumatology, then in dermatology, then in gastro-enterology and finally ophthalmology. Fig. .Figure 4The prevalent population of TNF-alpha inhibitors users at study start date (ii) was constituted of 20,254 infliximab patients, 31,038 etanercept patients and 53,381 adalimumab patients, for a total of 104,673 prevalent users. Table .Table 2P51%, 56% and 50% of infliximab, etanercept and adalimumab prevalent users were women. Mean age was 45, 53 and 47 years in the respective groups. Pathology repartition was similar to the initiator group.Follow-up characteristics and median times are presented in Table During the follow-up period, 35% (n = 2031) of infliximab originator initiators switched to an infliximab biosimilar within 1.6 years after initiation and among them a fifth (n = 439) retransitioned to the originator product less than 6 months later. On the other hand, 6% (n = 1226) of infliximab biosimilar initiators retransitioned 6 months after initiation, and 11% (n = 2277) of biosimilar initiators biotransitioned at least once 1.2 years after initiation.There were less switches in etanercept and adalimumab initiating patients: transitions occurred respectively in 10% (n = 1575) and 6% (n = 1396) of patients 1.6 and 0.6 years after initiation, with almost a third (n = 528 and n = 417) of them switching back to the originator product less than 6 months later; 6% (n = 712 and n = 1634) of biosimilar initiators retransitioned 0.4 and 0.3 years after initiation and 2% (n = 291 and n = 644) biotransitioned 0.5 and 0.4 years after initiation respectively.There were more switches in the group of TNF-alpha inhibitors prevalent users. A total of 46% of infliximab prevalent patients (n = 9417) transitioned to a biosimilar 3.1 years after index date, and 22% of them (n = 2054) went back to the originator less than 6 months after, whereas 19% (n = 1895) biotransitioned around 2 years after the transition. Among etanercept prevalent users, 19% of patients (n = 5907) transitioned to a biosimilar 3 years after index date, and 2183 switched back to the originator 0.6 years after, whereas only 161 biotransitioned. Among adalimumab prevalent users, 17% of patients (n = 9285) transitioned to a biosimilar a year after index date, and a third (n = 3055) switched back to the originator less than 6 months after, and 541 biotransitioned.Biosimilar transition rate in prevalent users followed the same scheme in terms of specialty as for biosimilar initiators: low impact of specialty in infliximab prevalent users, and a trend for higher transition rates in rheumatology for etanercept and adalimumab Fig. .Figure 5Cumulated major switches  are represented in the interactive Sankey diagrams in Supplementary Materials, showing for each group of patients included  and for each molecule the switch pathways from inclusion to end of study. Patients’ characteristics according to the switch pattern are presented in Supplementary Tables In this large descriptive study, including 102,445 initiating patients from biosimilar market entry and 104,673 prevalent patients at biosimilar market entry, we show that the level of penetration of TNF-alpha inhibitors’ biosimilars varies greatly according to the molecule and the pathology treated. Intrinsic characteristics of patients such as sex, age, deprivation, previous treatments, do not seem to influence biosimilar use.One could have hypothesized that later biosimilar market entries would benefit from gained experience from the previous entries, with faster biosimilar penetration rates for adalimumab than for etanercept and infliximab. In fact, infliximab biosimilar initiation  and transition  rates were high, and increased faster than the others. As a matter of fact, as infliximab is a perfusion medicine and thus exclusively delivered at the hospital level, hospital tendering processes favor biosimilar procurement, leading to a high biosimilar penetration for this specific molecule. On the other hand, etanercept biosimilar penetration rate  and adalimumab biosimilar penetration rate  are lower. Retail delivery modality indeed allows more originator use. Lower biosimilar use in dermatology and gastro-enterology could also explain this lower penetration rate. Nevertheless, adalimumab biosimilar market entry seems to have benefited from etanercept experience, with a faster biosimilar adhesion. Adalimumab faster biosimilar penetration rate might as well be explained by a more important number of biosimilar marketed products than etanercept. Meanwhile, several measures were taken to improve biosimilar penetration rate in France: the French agency for medicine safety (ANSM) has recommended biosimilar prescription and originator switching since 2016 and hospital-targeting experimentations of financial incentives promoting etanercept and adalimumab biosimilar prescription have been conducted from 2018. Finally, as a result, originator product still represents 61% of etanercept users and 63% of adalimumab users while it represents only 19% of infliximab users.14 that calculated lower retransition rates, with an average of 8% of retransitions among patients having previously transitioned from originator to biosimilar product a year after the first transition. Nocebo effect has already been suggested to explain biosimilar discontinuation16, while previous studies did not show any adverse events profiles in transitioning patients compared to non-transitioning patients19. Additionally, biotherapies (biosimilars and originators) might be subject to manufacturing drift over time21, ending up with a substantial biological difference between the approved form and the current form and effectiveness differences between products. In our study, the longitudinal visualization of the switch patterns shows a significant number of patients alternating between originator and biosimilar products, suggesting potential switches due to product availability, and thus non-medical isolated switches, or perceived total exchangeability between products.We report in this study that retransition is not an isolated fact, with respectively 22%, 37% and 32% of infliximab, etanercept and adalimumab prevalent users retransitioning during the study follow-up. This is not consistent with a systematic reviewThe main strength of this descriptive study is the large and comprehensive (at the French level) sample provided by the SNDS claims database: we were able to include every initiating and prevalent TNF-alpha inhibitor user within the period of biosimilar products reimbursement, and describe the population.This study has nevertheless some limitations. Due to the medico-administrative nature of the SNDS, we had to use algorithms and proxies in particular to assess the patient pathologies. However, apart from the choice between multiple pathologies, the medical background codes used in this study relied on ICD-10 and were described and used in previous studies. Besides, we could not have access to clinical or behavioral data that could explain the reasons of use of the originator product rather than the biosimilar. Moreover, these results are specific to the case of France and, considering the fact that internal country policies on biosimilars are a major driver of their penetration, these findings cannot be extrapolated to other countries.In conclusion, there is still some way to go to implement biosimilar use in the treatment by TNF-alpha inhibitors. Biosimilar prescription should be particularly encouraged at the retail level, especially for dermatologists and gastro-enterologists. The number of patients under the originator product is still very important and is unlikely to decrease rapidly as we observed a relatively low transition rate in etanercept and adalimumab users. Biosimilar initiation rate needs to be tracked further, with specific methods for estimating the impact of public policies, in order to assess the efficacy of country-level policies such as financial incentives for biosimilar prescription or the potential opportunity for pharmacists to substitute the originator product with a biosimilar.The SNDS covers almost the totality (> 99%) of the French population—68 million residents. Each person is identified by a unique and anonymous number. The SNDS records comprehensive outpatient (reimbursed drugs and procedures) and inpatient  reimbursement information since 2006. The SNDS also contains sociodemographic information on sex, age, place of residence, vital status, and complementary universal health insurance  and quintiles of deprivation index . Patients’ status for 100% reimbursement of care related to a severe and costly long-term disease (LTD) is recorded and LTD diagnosis coded according to ICD-10. Due to the medico-administrative nature of this database, clinical information such as treatment indication is not systematically recorded.25.The SNDS has been extensively used to conduct pharmacoepidemiological studies, especially on the use, safety, and effectiveness of health productsOriginator and biosimilar products names, dates of reimbursement and formulations are presented in Supplementary Table Study start date was defined by biosimilar entry date in France which differed for each of the three studied TNF-alpha inhibitors , infliximab (ATC L04AB02), etanercept (ATC L04AB01), adalimumab (ATC L04AB04). The time 0 of the study was thus fixed to January 27, 2015 for infliximab users, May 10, 2016 for etanercept users and October 9, 2018 for adalimumab users. Study end date was fixed to September 30, 2021.Patients initiating or using a TNF-alpha inhibitor from year -1 of the study to the study end date were included for a global analysis of biosimilar penetration rate, whatever the age and pathology of the patients. Then, analysis was restricted to adult patients to establish underlying pathologies with more accuracy, and the study focused on two groups of patients for individual analysis: (i) adult (≥ 18 years old) patients initiating a TNF-alpha inhibitor treatment from study start date to study end date (initiators), initiation was defined as a first dispensing of a TNF-alpha inhibitor after at least one year without any other dispensing of a TNF-alpha inhibitor; (ii) adult patients under a TNF-alpha inhibitor treatment at study start date , defined as having had at least one delivery of TNF-alpha inhibitor within the theoretical treatment covering period  supplemented with a buffer period of 90 days before study start date.Index date was defined as the date of the first TNF-alpha inhibitor delivery for initiating patients (i), and as the last delivery before stud start date for prevalent users (ii).Several patient characteristics were analyzed. Sociodemographic characteristics  were measured at the index date.26. History of dispensing of corticosteroids, non-steroidal anti-inflammatory drugs (NSAID), non-biological systemic drugs on the one side and biological and targeted drugs on the other side was assessed within the year before index date. ATC codes for these drugs are presented in Supplementary Table Comorbidities were assessed within five years before the index date, using ATC and ICD-10 codes shown in Supplementary Table S7The study focused on the eight pathologies the TNF-alpha inhibitors were indicated for and reimbursed in France: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and non-infectious uveitis  recorded in the database before index date. In case of equalities, hospitalizations with a PD or RD for this pathology (criterion (a)) and LTD (criterion (c)) were preferred indicators to establish the pathology; if still equal, the predominant number of hospitalizations (PD-RD) the year before index date was used. Other cases of equalities were left in a category “Multiple pathologies”.Patients with no identified pathology were categorized as “Undetermined” pathology. Patients treated with a molecule not reimbursed for the identified pathology , Dermatology (psoriasis and hidradenitis suppurativa), Gastroenterology (Crohn’s disease and ulcerative colitis) and Ophthalmology (non-infectious uveitis); the patient was considered to be treated by a Rheumatologist, Dermatologist, Gastroenterologist or Ophthalmologist according the corresponding specialty group of his/her pathology.Patients were followed from index date to study end date, molecule switch  supplemented with a 90 days buffer period. Discontinuation date was set to the end date of the buffer period.Based on the initial global population, biosimilar initiation rate, originator product prevalence rate and transition rate were computed annually and per molecule. The biosimilar initiation rate was defined as the number of biosimilar initiations divided by the total number of initiations of the molecule. Originator product prevalence rate was estimated by dividing the number of patients having at least one delivery of the originator product by the total number of patients having at least one delivery of the considered molecule. Transition rate was defined as the number of transitions divided by the number of patients eligible to the transition, i.e. the number of patients having at least one delivery of the originator product.Patient characteristics for populations (i) and (ii) were analyzed descriptively. Qualitative variables were summarized using effectives and percentages in each category and quantitative variables by mean and standard deviation (SD) and median and interquartile range (IQR).dplyr, ggplot2, plotly.All extractions from the SNDS were carried out with SAS Enterprise Guide software version 9.4; analyses were done with R version 3.5.2, using multiple packages including https://www.snds.gouv.fr/SNDS/Processus-d-acces-aux-donnees and https://www.indsante.fr/). EPI-PHARE has permanent regulatory access to the data from the French National Health Data System (SNDS) via its constitutive bodies ANSM and CNAM. This permanent access is given in accordance with the French Decree No. 2016–1871 of December 26, 2016 relating to the processing of personal data called the “National Health Data System”, and French law articles Art. R. 1461–13 and 14. All requests in the database were made by duly authorized people, all methods were carried out in accordance with relevant guidelines and regulations and the study was conducted in accordance with the Declaration of Helsinki. In accordance with the permanent regulatory access granted to EPI-PHARE via ANSM and CNAM, this present work did not require the approval from the French Data Protection Authority (CNIL). The study was registered on the study register of EPI-PHARE concerning studies from SNDS data. Given that data are anonymous, no informed consent to participate was required.In accordance with data protection legislation and the French regulation, the authors cannot publicly release the data from the French National Health Data System . However, any person or structure, public or private, for-profit or non-profit, is able to access SNDS data upon authorization from the French Data Protection Office (CNIL), in order to carry out a study, research or an evaluation in the public interest (Supplementary Information 1.Supplementary Information 2.


Thoracic trauma is the second leading cause of death after traumatic brain injury in children presenting with blunt chest trauma, which represents 80% of thoracic trauma in children. We hypothesized that older children undergo more clinical and surgical changes in management than younger children screened for intrathoracic injury at a single, urban, pediatric Level I trauma center.In this retrospective observational study, we determined the frequencies and types of lesions diagnosed only by chest computed tomography (CCT) and resulting changes of clinical and surgical management among different age groups in a pediatric cohort examined for blunt trauma with chest radiograph and CCT. We used logistic regression to quantify variations in CCT diagnoses and changes in clinical and surgical management across age groups. For each age category, we determined the odds ratio for diagnosis made only on CCT and subsequent changes in all clinical management and, specifically, surgical management. We performed the test of trend to determine the relationship across age with changes in management resulting from additional diagnoses made by CCT.We analyzed data on 1,235 patients screened for intrathoracic injury. We found the following overall clinical management and surgical management changes, respectively, per age group: 0–2 years, 5/128 (3.9) and 0/128 (0.0); 3–6 years, 11/212 (5.2) and 1/212 (0.5); 7–10 years, 16/175 (9.1) and 2/175 (1.1); 11–13 years, 17/188 (9.0) and 3/188 (1.6); 14–17 years, 58/532 (10.9) and 25/532 (4.7). There were no observed surgical management changes in the 0–2 age group and, thus, no estimated odds ratio could be calculated. The adjusted odds ratios for the occurrence of surgical change in management (14–17 age group as reference) was 0.1 (0.0–0.9) for 3–6 years, 0.3 (0.1–1.3) for 7–10 years, and 0.3 (0.1–1.1) for 11–13 years. The trend of odds ratios across ages showed that with every subsequent year of life there was a 10% increase in management change and a 30% increase in surgical management change.Chest computed tomography plays a limited role in younger children and seldom significantly changes management albeit making additional diagnoses. Trauma is the leading cause of morbidity and mortality in children. While thoracic trauma occurs in about 5–12% of children admitted to the hospital with trauma, it has a high morbidity and mortality.6A decision instrument has been derived and validated for when to obtain a CCT in trauma patients ≥15 years.We hypothesized that older children would undergo more clinical and surgical changes in management than younger children screened for intrathoracic injury at a single, urban, pediatric Level I trauma center when CCT identified an injury not demonstrated on CXR.and pediatric trauma center in Houston. Annually, the center sees about 6000 trauma patients ≥16 years and about 1200 trauma patients 15 years and younger.We analyzed data from a retrospective observational study of pediatric trauma. Our local institutional review board (IRB) approved the study. We performed a retrospective analysis of children treated at Children’s Memorial Hermann Hospital in Houston, TX, from 2009–2015. Memorial Hermann Hospital Medical Center is the only American College of Surgeons-verified Level I adult International Classification of Diseases, revisions 9 and 10 (ICD9/ICD10) codable injury presenting within 14 days of the injury . In addition, patients must meet one of the following criteria: admitted patients (observation or inpatient); dead on arrival/died in the ED; transfer out of the ED for higher level of care; or transfer in from an acute care ED/hospital regardless of whether they were discharged from the ED or admitted to the hospital.We included patients <18 years evaluated with CXR followed by CCT within 24 hours of blunt trauma. Therefore, all patients had a gold standard comparison to the CXR and represented all patients screened for thoracic trauma at our institution. Patient data elements were queried from the institutional trauma registry. The trauma registry uses as its inclusion criteria the National Trauma Data Standard Data Dictionary, which includes the presence of What do we already know about this issue?Thoracic injury is the 2nd leading cause of death in blunt trauma. Computed tomography chest (CCT) is more sensitive than radiograph but doesn’t always spur change in management.What was the research question?Do older children undergo more changes in management than younger children screened for thoracic injury with CCT?What was the major finding of the study?Diagnoses on CCT prompted surgical management in 0.9% of patients 13 years and under, in contrast to 4.7% of patients 14–17 years.How does this improve population health?Assessing the impact of diagnoses made by CCT on clinical and surgical management by pediatric age groups will help clinicians tailor their use of CCT.The registry identifies trauma patients presenting to the ED and assigns them a registry number. Registrars abstract patient medical records for 65 data points containing such elements as vitals, dates and times, prehospital data, procedures, comorbidities, outcomes, and financial data. The validation process is rigorous and includes audits of up to 10% of each trauma registrar by the trauma registry manager, physician investigator, nurses, and trauma program managers. In addition, data abstraction forms, software-related validation, feedback to the trauma registrars, and educational courses, including workshops on Abbreviated Injury Scale-ISS coding and scoring, ensure reliable data collection.We did not analyze patients who only had CCT performed without a CXR or those who had CXR occurring after the CCT, as the latter may have influenced the reading on the CXR. While some children had a pan CT scan (a wide field-of-view CT imaging protocol from the head to the pubic symphysis) during this time period, some received the CCT only after a screening CXR. This was clinician dependent. We excluded patients with penetrating injury or injuries occurring greater than 24 hours prior to admission. As age of the injury could alter the appearance on the imaging study introducing bias, we focused on acute injuries. While it is difficult to isolate patients who specifically experienced blunt chest trauma, we obtained the total number of blunt trauma patients. We focused our analysis on patients definitively evaluated for chest trauma with CXR and CCT from all blunt trauma patients. We further subdivided the patients into five age groups: 0–2 years; 3–6 years; 7–10 years; 11–13 years; and 14–17 years to discern differences in diagnoses made on imaging and management changes based on differences in diagnoses by modality.Four physician chart extractors queried the electronic health record (EHR) to determine specific diagnoses made on CXR and CCT and confirm the timing of any resulting procedures. Another physician reviewed 20% of these, and any discrepancy was settled by all parties. Images were read by radiologists from Memorial Herman Hospital. Change in management is the occurrence of a procedure resulting from a new diagnosis by CCT, not observed by the CXR. Outcome variables were diagnoses made by CCT as well as ensuing changes in clinical management attributable to the diagnoses reported by the CCT. The intrathoracic diagnoses categories were as follows: 1) contusion/atelectasis; 2) pneumothorax; 3) hemothorax/effusion; 4) rib fractures; 5) other fracture; 6) vascular injury; 7) mediastinal abnormality; 8) diaphragm rupture; 9) foreign body; and 10) incidental findings. The presence of each was determined on both CXR and CCT.We also determined the types of clinical management changes, including surgical and medical changes, attributable to the CCT. These included the following: 1) chest tube; 2) surgical repair of fractures; 3) utilization of a brace, sling or non-weight-bearing (NWB), corset; 4) additional imaging such as magnetic resonance imaging (MRI) of specific body parts, esophograms, aortic angiograms, and skeletal radiographs; (5) surgical vascular repair; 6) medical vascular repair (therapeutic anticoagulation); 7) removal of a foreign body; 8) follow-up/referral to a specialist for incidental finding on CCT ; and 9) surgical repair of the diaphragm. When any of these situations were present along with a discrepancy between diagnoses found on CXR and CCT, we considered it a change in management.The independent variables were patients’ demographic and clinical characteristics. We collected information on age, gender, race/ethnicity, ISS, systolic blood pressure (SBP), heart rate, and GCS measured at arrival to the ED, as well as information on the mechanism of injury, and disposition from the ED. We further classified SPB and heart rate as hypotension and tachycardia, respectively for age, using Pediatric Advanced Life Support guidelines. We classified the mechanism of injury as MVC, including motorcycle and all-terrain vehicles, pedestrian or cyclist struck by a vehicle (auto-ped), falling, sports, machinery , and assault as well as non-accidental trauma. Emergency department disposition included admission to the hospital, admission to the intensive care unit, disposition to the operating room for surgery, discharge to home, or death in the ED.We conformed to the methods of proper medical review studies.We determined the characteristics of patients in each age group including demographics, injury mechanism, and hospital disposition. We determined the rates and types of clinical and surgical management changes across different age groups. To quantify the variations in CT diagnosis, change in clinical management and change in surgical management across age groups, we used logistic regression. We fit separate models for the dependent variables: CT diagnosis; change in clinical management; and change in surgical management. The independent variable was patient age, which we classified into five pediatric age groups: 0–2 years; 3–6 years; 7–10 years; 11–13 years; and 14–17 years. For each age category, we determined the odds ratio for CT diagnosis, change in clinical management, and change in surgical management. We repeated the analysis adjusting the model for injury mechanism , ISS, and GCS.There were 1,235 patients with blunt trauma evaluated by both CCT and CXR meeting inclusion criteria from 8,283 similarly aged patients presenting with blunt trauma over the study time period. P = <0.01.) The MVC/motorcycle injuries were most common in the two oldest age groups. A GCS ≤ 12 and hypotension for age were present in the highest percentages in the youngest age groups, but only GCS ≤ 12 was statistically significant (P = < 0.01). Tachycardia was most common in the two oldest age groups (P = < 0.01).When the five age groups were compared, the unadjusted and adjusted ORs of undergoing any clinical management changes were lower across younger age groups but only statistically significant for the 3–6 year group ; adjusted OR 0.5; CI: 0.2–1.0.) See P-value < 0.01) and 1.1 , respectively. There was 10% increased odds of undergoing a change in management with each subsequent year of life. Similarly, the trend test across consecutive ages demonstrated an unadjusted and adjusted OR of undergoing a surgical management change of 1.3  and 1.2 , respectively. There was 20% increased odds of undergoing a surgical change in management with each subsequent year of life. The trend test did not show a difference in the odds of CCT finding specific lesions not captured on CXR across consecutive age groups  if the child is less than age five years and over 8 mSV when the child is over 10 years of age.5Ultimately, readers will differ in opinion as to what delineates significant thoracic trauma as there are no widely accepted delineations or gauges of magnitude. Inter-specialty differences of opinion about the clinical implication of specific injuries exist.The American College of Surgeons has historically used age 15 as the cutoff between adult and pediatric trauma designation based upon physiological and anatomic estimates. The age cutoff may vary depending on local resources within a hospital system. This is important as imaging protocols are often developed separately for pediatric and adult patients. Information about the outcomes associated with CCT is pivotal in judicious imaging practices and limiting radiation exposure to more vulnerable populations.First, because our study was retrospective some information from the EHR and trauma registry may have been more susceptible to misclassification and bias compared to prospective studies. Our study represents pediatric patients treated at our mixed trauma facility in Houston, Texas, which sees both adults and children. Our results may not be generalizable to other institutions locally or nationally with differing proportions of age groups in their centers. However, we do have the influence of both general trauma surgeons as well as pediatric surgeons, as experienced at different centers. Studies have shown higher rates of CT usage at adult and mixed trauma centers vs pediatric trauma centers.30Our categories of changes in management secondary to CCT may not encompass factors that other clinicians may deem important. Some would add to our list and include admission to hospital for observation, as a significant change in management. Furthermore, we defined a change in management resulting from a procedure performed after the CCT in the setting of a discordance of diagnoses between the two imaging modalities. This has the inherent risk of overselling the impact of CCT. It is also possible there was a bias toward change in management given the overdependence on CCT. None of the 128 patients in the 0–2 years age group who received a CCT had a surgical change in management. However, there were far fewer patients in this category than in the older age groups, limiting the power of the observation. These limitations naturally occur with retrospective studies.We demonstrate that young children seldom undergo management changes when additional diagnoses occur on chest computed tomography in pediatric trauma. Practitioners should be thoughtful about automatically obtaining a CCT on the young, multi-trauma patient.


Introduction: Single intrauterine fetal death (sIUFD) in monochorionic diamniotic (MCDA) twin pregnancy may be associated with adverse clinical outcomes and possible metabolic changes in the surviving co-twin. Metabolomic profiling has not been undertaken before in these complex twin pregnancies.Methods: In this prospectively collected case-control study, three cross-cohort comparisons were made between sIUFD MCDA (n = 16), uncomplicated MCDA , and uncomplicated singleton pregnancies (n = 8). To identify major sources of variation within the sIUFD MCDA cohort, a secondary comparison was conducted between spontaneous sIUFD (n = 8) and sIUFD in MCDA twins due to selective termination of a single abnormal fetus by radiofrequency ablation (RFA) (n = 8). Metabolomics analysis of placental tissue and umbilical cord plasma was performed using LC-MS profiling. The underlying metabolic networks and pathways were analyzed by web-based platforms. Associations and statistical correlations of all identified differential metabolites with neonatal birthweight and birth length were assessed by multivariable linear regression, adjusted for maternal age and gestation.Results: Across four comparisons, 131 and 111 differential metabolites were identified in placental tissue and cord plasma, respectively, with the highest variation seen between the spontaneous vs. single-induced IUFD in MCDA twins by RFA in the cord plasma. Conversely, the number of viable fetuses and the presence of sIUFD in MCDA twins had the highest impact on metabolite variation in placental tissue. Compounds correlated with fetal growth including placental acylcarnitines and gangliosides, along with specific amino acids , xenobiotics and biliverdin in cord plasma.Conclusion: sIUFD in MCDA twin pregnancy correlates with distinctive metabolic signatures, mostly in fatty acyls and complex lipids, in placental tissue and cord plasma of the surviving cotwin. Some metabolites are also associated with fetal growth. The prevalence of multiple pregnancies is rising internationally due to the increasing use of assisted reproductive technology (ART) and the trend toward advanced maternal age in pregnancy . The majSingle intrauterine fetal death (sIUFD) complicates up to 6.8% of all twin pregnancies but is more common in MC twin pregnancies (7.5%) . sIUFD mversus induced (by selective termination of pregnancy) sIUFD in MCDA twins on the metabolic profile of the surviving twin has yet to be assessed.As with other prenatal complications , sIUFD mIn this prospective case-cohort control study, we performed a metabolomics analysis of placental tissue and cord plasma from surviving cotwins in monochorionic diamniotic (MCDA) pregnancies complicated by spontaneous or induced sIUFD in MCDA twins relative to uncomplicated MCDA twins and singleton pregnancies. The underlying associations between the identified differential metabolites and neonatal birthweight and birth length were also investigated.From the beginning of 2016 to the end of 2018, participants were prospectively recruited in the Department of Obstetrics and Gynecology at The First Affiliated Hospital of Chongqing Medical University.Participants included: 1) sixteen cases of MCDA twin pregnancies complicated by sIUFD, among which eight were spontaneous sIUFDs and the other eight were patients who had undergone radiofrequency ablation ; 2) eighMCDA twin pregnancies, were diagnosed as monochorionic and diamniotic, using ultrasound with the follow features: 1) a single gestational sac and placenta by 10 weeks of gestation and 2) T-sign of the intertwin membrane and absent twin peak (lambda) sign, with a single placenta between 11 and 14 gestational weeks. The placental features of MCDA twin pregnancy were further confirmed by postpartum clinical examination .Spontaneous sIUFD in MCDA twin pregnancy was diagnosed by ultrasound after clinical presentation. MCDA twin pregnancy with sIUFD following RFA  was also confirmed by ultrasonography postoperatively.A conservative strategy was followed after sIUFD in MCDA twins diagnosis unless the pregnancy was >34 weeks and then delivery was considered with care being individualized . ThroughThe clinical characteristics of these participants were recorded within 24 h after delivery, which included: 1) maternal age, body mass index [BMI ], lifestyle behavior , parity, and mode of conception (ART or spontaneous); 2) obstetric complications; 3) method of and gestational age (GA) at delivery; and 4) neonatal sex, birthweight, birth length, Apgar scores , and NICU admission. For patients in the sIUFD group, information regarding the etiology and GA of sIUFD was added. The interval between sIUFD occurrence and pregnancy termination was calculated as well. The study was approved by the Ethics Committee of Chongqing Medical University (No. 201530). Written informed consent was obtained from all participants.3, and then blotted dry. The dry tissue was rapidly frozen in liquid nitrogen and stored at −80°C. A total of 4 ml cord blood was collected from the umbilical vein of the living fetuses into an EDTA-coated blood collection tube, which was then centrifuged at 3,000 rpm for 15 min at 4°C. The supernatant plasma was aliquoted into new sterile tubes and stored at −80°C.As previously described , placent® concentrator  at 30°C, and cryopreserved at −80°C. Before further determination, the dried extract was reconstituted in 100 μl 50% acetonitrile and centrifuged at 14,000 rpm for 5 min at 4°C. Finally, 80 μl of the supernatant was transferred to a fresh vial specialized for LC-MS profiling. The quality control (QC) sample was prepared, separately for placenta tissue and cord plasma, by combining 5 μl aliquots from each reconstituted sample of corresponding specimen type.This is the standard protocol used in our laboratory . The pla5 μl of each extract was injected into the ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) system for metabolomic fingerprinting . The injSD) and were analyzed with unpaired Student’s t-test; nonnormally distributed data are presented as median  and were analyzed with Mann-Whitney test; categorical data are described as numbers (%) and were analyzed with Fisher’s exact test. PRISM version 8.0  was used, and a significance level of p-value < 0.05 was applied.For clinical data, normally distributed variables are presented as mean  max fold change (FC) > 2.0.Metabolic raw data were imported into Progenesis QI™ , a software that enabled peak alignment, peak selection, deconvolution, and the annotation of metabolites against the HMDB, ChemSpider, LipidBlast, METLIN, and CCS library databases. Mass error, fragmentation and isotope similarity were scored: maximum score for each criterion was 20; hence, the overall score was 60. Only ions with a mass threshold within ±5 ppm and an overall score ≥36 were considered to be highly confident and retained for further investigation. For ions with more than one possible annotation, the most likely one was manually annotated based on the overall score (higher score preferred) and the origin (endogenous compound preferred). The ions and corresponding peaks were then exported into EZinfo™  for a combinational analysis using ANOVA, principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA). The scattering plot of PCA was used to evaluate the data quality by checking the clustering pattern of QC samples. The variable importance for projection (VIP) from OPLS-DA was used to gauge the statistical significance of the metabolite features that contributed to the difference between the two groups in each comparison. The criteria for differential metabolites were: 1) VIP >1.0; 2) ANOVA p-value < 0.05.These metabolites were classified by 1) their presence in different comparisons (different regions in Venn diagrams) and 2) corresponding categories in the Human Metabolome Database (HMDB) (in pie charts). The metabolic differences between placental tissue and cord plasma were analyzed by Fisher’s exact test using PRISM version 8.0  with the significance level set at a p-value < 0.05, and false discovery rate (FDR) < 0.05 were recognized as potential pathways of interest.The networks of metabolites, based on their chemical and biochemical relationships, were reconstructed using MetaMapp  and plotp-value < 0.05 was applied as the significance level. The statistically significant estimate (β) with its 95% confidence interval (CI) was plotted in forest plots using PRISM version 8.0 .Multivariable linear regression was performed within each cohort to investigate the correlation between metabolites and fetal growth, adjusted for maternal age and GA. Birthweight and birth length were set as dependent variables separately; the test was repeated for each differential metabolite, which was set as an independent variable, while maternal age and GA were considered confounding factors. Statistics Analysis Software version 9.4  was used, and a n = 16) were compared to twins from uncomplicated MCDA twin pregnancies (8 pregnancies and 16 neonates); 2) In comparison 2 (C2), the surviving cotwins after sIUFD in MCDA twin pregnancies (n = 16) were compared to singletons from uncomplicated singleton pregnancies (n = 8); 3) In comparison 3 (C3), comparisons were conducted within the sIUFD group, wherein “spontaneous” sIUFD (n = 8) was compared to iatrogenic sIUFD due to single termination a fetus by RFA (n = 8); and 4) In comparison 4 (C4), a general comparison of uncomplicated MCDA twin pregnancies (8 pregnancies and 16 neonates) and singleton pregnancies (n = 8) was performed.This study was designed to evaluate metabolic differences associated with sIUFD in MCDA twin pregnancy by examining placental tissue and cord blood plasma. We considered placental tissue and cord plasma as specimens for the “environment” on the maternal and fetal sides of the interface, respectively. Additionally, to assess the relative impacts of the mode of sIUFD and overall fetal number on the metabolome, we performed four comparisons : 1) In cp < 0.05), and the sIUFD MCDA cohort had a lower maternal BMI, both during the pre-pregnancy stage and at delivery, than the uncomplicated singleton pregnancy cohort . Compared to those of the uncomplicated singleton pregnancies, the rates of PTB in the MCDA cohorts with and without sIUFD were higher (p < 0.01), and the gestational ages (GAs) at delivery were lower (p < 0.0001) (C1 and C4).The demographic and clinical information of the mothers is displayed in The clinical characteristics of the neonates are shown in p = 0.3105), sIUFD occurred at an earlier GA after RFA (p = 0.0120), which consequently prolonged the corresponding GA interval (p = 0.0042). A description of the underlying etiologies for sIUFD in MCDA twin pregnancies is provided in As presented in The stability and repeatability of the system are shown in A summary of all metabolites showing differential levels for each of the comparisons undertaken is detailed in vs. RFA), p < 0.0001), and the majority of these metabolites were downregulated on both sides of the interface if sIUFD occurred spontaneously (35/43 and 3/3). In addition, these mode-related metabolites were specific to the plasma network (For the comparison between two modes of sIUFD [C3 (spontaneous p < 0.01) and VII . Additionally, at the maternal side, twin pregnancies had higher metabolite levels during the earlier period (20/32) but lower levels later in pregnancy (6/6), which was opposite to the dynamic for fetal circulation (14/14 and 6/7). In the placental network, where more fetal number-related compounds were identified, fatty acyls , glycerophospholipids or glycerolipids /18:1 (11Z))), and sphingolipids  were noted (As shown in p < 0.05), especially for complex lipids .Regardless of whether the offspring was full term, the levels of metabolite variations in placental tissue and cord plasma were similar between sIUFD MCDA and uncomplicated MCDA pregnancies  and between sIUFD MCDA and singleton pregnancies   and fetal  sides of the interface. Some differential metabolites, including acylcarnitines and gangliosides in the placenta, and histidinyl-hydroxyproline, biliverdin and some xenobiotics in cord blood, were correlated with intrauterine fetal growth (biometry).Across the four specific comparisons, similar numbers of differential metabolites were identified in placental tissue and cord plasma, but the compositions of these metabolites in the comparisons were distinct according to specimens being tested. The goal of RFA is to stop acute twin-to-twin transfusion when iatrogenic termination of a single fetus occurs in monochorionic twins  in this Lipids are essential for fetal growth . In thisAmino acids (AAs) are key building constituents for fetal and placental development . We deteBilirubin in fetal circulation was found to decrease with the time spent carrying two fetuses in the following order: singleton pregnancy > sIUFD in MCDA > uncomplicated MCDA . We alsoSome xenobiotics, such as 3-hydroxylidocaine, fulvestrant, and dipyridamole, were also identified in cord plasma, which indicates that xenobiotics taken up by the mother could readily transfer into the fetal circulation, despite the placental barrier . DipyridFrom endogenous metabolic aspects, we found nearly opposite trends in metabolic changes on the two sides of the interface. Specifically, lipids  and AAs are elevated in the placenta but lower in the cord blood of MCDA and sIUFD pregnancies. Considering the positive effects of these compounds on fetal growth , the impIntrauterine development is critical for the lifelong health of an individual . DiffereIn this study, the relative impact of fetal number and mode of sIUFD was considered to further discriminate sIUFD. Additionally, comparisons between the two sides of the maternal-fetal interface were conducted. However, this preliminary comparison may be accurate only when the efficiencies for metabolite extraction and LC-MS profiling are constant in different sample types, which can be further validated by targeted methods.The chromatographic column is relatively stable in batches and among cohorts (because of the randomized sequence), which is supported by the system pressure . HoweverOur study has some other limitations, including the small sample size and strict criteria used to define differential levels of metabolites, that potentially limit the sensitivity of the study, despite increasing specificity. Furthermore, our study did not consider dichorionic or dizygous twin pregnancies or fetal order, limiting the interpretation of the findings . FinallyThis work provides the first evidence that metabolomes in placental tissue and umbilical cord plasma are associated with sIUFD, with each tissue demonstrating specific variations. Although the mechanisms of differential metabolite levels on fetal growth require further clarification, placental transport of lipids and AAs may be involved. Thus, this study presents certain targets that may be suitable for rescuing fetal development.


Strategy to mitigate various Ebola virus disease (EVD) outbreaks are focusing on Infection Prevention and Control (IPC) capacity building, supportive supervision and IPC supply donation. This study was conducted to assess the impact of a Pay for Performance Strategy (PPS) in improving IPC performance in healthcare facilities (HF) in context of the 2018–2019 Nord Kivu/ Democratic Republic of the Congo EVD outbreak.A quasi-experimental study was conducted analysing the impact of a PPS on the IPC performance. HF were selected following the inclusion criteria upon informed consent from the facility manager and the National Department of Health. Initial and process assessment of IPC performance was conducted by integrating response teams using a validated IPC assessment tool for HF. A bundle of interventions was then implemented in the different HF including training of health workers, donation of IPC kits, supportive supervision during the implementation of IPC activities, and monetary reward. IPC practices in HF were assessment every two weeks during the intervention period to measure the impact. The IPC assessment tool had 34 questions aggregated in 8 different thematic areas: triage and isolation capacity, IPC committee in HF, hand hygiene, PPE, decontamination and sterilization, linen management, hospital environment and Waste management. Data were analysed using descriptive statistics and analytical approaches according to assumptions. R software (version 4.0.3) was used for all the analyses and a p-value of 0.05 was considered as the threshold for statistically significant results.Among 69 HF involved in this study, 48 were private facilities and 21 state facilities. The median baseline IPC score was 44% (IQR: 21–65%); this IPC median score reached respectively after 2, 4, 6 and 8 weeks 68% (IQR: 59–76%), 79% (71–84%), 76% (68–85%) and 79% (74–85%). The improvement of IPC score was statistically significative. Spearman’s rank-order correlation revealed the associated between proportion of trained HW and IPC score performance after 8 weeks of interventions .Pay for Performance Strategy was proved effective in improving healthcare facilities capacity in infection prevention and control practice in context of 2018 EVD outbreak in Nord Kivu. However, the strategy for long-term sustainability of IPC needs further provision. More studies are warranted on the HW and patients’ perceptions toward IPC program implementation in context of Nord Kivu Province. Lessons learned from previous Ebola outbreaks showed that health workers (HW) are at highest risk of exposure to Ebola virus disease (EVD) –6. DurinTo strengthen the DRC’s health system in IPC, a comprehensive ring approach was advocated by several IPC experts based on other EVD outbreak’s lessons learned –6, 8. BaPPS provides financial incentives to HW or HF based on the achievement of pre-specified performance targets. It has been widely conducted in health systems across low and middle-income countries (LMICs) where their impact was evaluated to improve hospital service delivery . AlthougThis study assesses the impact of PPS in improving HF capacity in IPC practices in the context of 20,218–2020 DRC EVD outbreak.We have conducted a prospective analytical quasi-experimental study in Beni City , one of the EVD outbreak epicentre, to assess the impact of a pay for performance strategy on the improvement of IPC performances in HF during the Ebola outbreak from December 2018 to February 2019.We included HF that have admitted at least 1 EVD case, HF with admission services, HF in districts with at least 3 EVD confirmed cases. We numbered and recorded the HW and beds of each HF. HF were categorized according to the number of beds they had: HF category 1 had more than 39 beds, HF category 2 had 20–39 beds, HF category 3 had 5–19 beds, and HF category 4 had 4 beds maximum.Interventions included training of HW, donation of IPC/WASH kits, supportive supervision during the implementation of IPC activities, and monetary reward.A piloting committee oversaw the overall implementation of the PPS. It comprised seven IPC experts and one program manager. We established a health area prevention committee in each health area comprising selected HF. Each prevention committee was formed by the registered nurse, the representative private HF, the representative of the healers, and the neighbourhood chief. Prevention committee’s members provided technical support to focal points in HF and IPC mentors in the rollout of activities and the piloting committee in the implementation of the project. They weekly organized, activities’ meeting.The heads of each HF selected signed a contract of performance in which they acknowledged supporting IPC activities versus a financial incentive allocated to the facility as a reward of the IPC performance. We recruited 24 IPC mentors (one IPC mentor for three HF) to play following roles: assessment of IPC performance in HF, identification of IPC gaps, suggestion of key actions for improvement, provide assistance to HF in the planning of IPC activities and training of HW.To reinforce IPC measures in HF, the following items constituting IPC/WASH kits were donated: examination gloves, thermoflash, N95 masks, surgical masks, rubbish bins, alcohol-based hand rub gel, paper towels, sharp containers, dishwashing gloves, stickers with Ebola toll-free number, soap, raincoats, face shields, chlorine, laboratory coat, aprons, goggles, different posters , gumboots, plastic chair, plastic table, hand washing tap buckets and small waste disposal incinerators. An IPC focal point was appointed among HW in the concerned facility.A three-day training session was conducted as per WHO and DRC’s Ministry of Health modules. The first day of the training focused on basic principles of EVD and IPC standard precautions, triage and patients’ isolation, and hospital-based surveillance. Day 2 training addressed injection safety, cleaning and decontamination of the environment, waste management, safe and dignified burial, and psychological aspects of EVD. Day 3 training supported IPC ring strategy, IPC kit constitution, assessment of IPC in HF and stock management.IPC practices in HF were assessment every two weeks. The IPC assessment tool comprised 34 questions aggregated in 8 sections: triage and isolation capacity, IPC committee in HF, hand hygiene, PPE, decontamination and sterilization, linen management, hospital environment and Waste management.Depending on the category of the HF and the IPC score generated, an amount of money was allocated to that facility. HF with IPC scores > 80% would get 100% of the total amount, HF with an IPC scores between 60 and 80% perceived 80%, HF with 50–59% scores received 60%, and HF with scores < 50% were not rewarded.® to manage IPC indicators. Data were summarized in descriptive analysis. Category variables were presented as frequencies and percentages; median and interquartile range (IQR) were used to summarize numerical data as they presented an asymmetric distribution using the Shapiro Wilk test. To compare IPC scores before and after the implementation of the intervention, we use the Friedman test (nonparametric test that compares medians of two paired groups). We performed the Man-Whitney U and Kruskal–Wallis H tests to compare variable with asymmetric distribution for 2 and more than 2 unpaired groups, respectively. Spearman’s rank-order correlation was run to determine the relationship between the proportion of HWs trained and the IPC score after 8 weeks of intervention. P-value of 0.05 was considered statistically significant for all analyses. The R software (version 4.0.3) was used for these statistics analyses.We used an IPC assessment tool in Microsoft ExcelWe included 69 HF coming from 15 health areas in the district of Beni among which 48 were private and 21 public. Eleven (15.9%) HF were listed in the category 1, 21 (30.4%) HF in the category 2, 32 (46.3%) in the categories 3 and 5 (7.2%) in the category 4. The median number of beds in HF was 18 (IQR: 8–27). We recorded 1,121 HW from 69 HF with a median number of 12 HW per HF (IQR: 6–18 HW). Five hundred sixty-four HW were trained in IPC practices  and 874 HW (77.9%) were immunized with rVSV-ZEBOV-GP vaccine   Table .Table 3CThe median baseline IPC score was 44% IQR: 21–65%) and it has progressively improved to 68% (IQR: 59–76%), 79% (71–84%), 76% (68–85%) and 79% (74–85%)  after 2, 4, 6, and 8 weeks, respectively  . However, there was no improvement in practice for sterilization of medical equipment and decontamination of surfaces score IPC (p3) Table .Table 5CThis study, conducted in North Kivu during the 2018 EVD outbreak, was the first of its kind in DRC assessing the impact of PPS in improving IPC practices. Results showed that there was a statistically significant change between mean IPC performance score at baseline and after 2, 4, 6 and 8 weeks.There was a moderate positive correlation between the proportion of HWs trained in HF and the IPC scores after week 8 of implementation of the PPS strategy. A number of key IPC performance indicators were improved from the baseline to week 8 of intervention. These included triage functionality, implementation of IPC committee and program at facility level, multimodal strategy for hand hygiene, PPE use, waste management, hospital sanitation and linen management. The implementation of improvement plan for each IPC component consisted not only in providing monetary incentive but as well by training HW, supplying equipment and materials needed for IPC practices and supportive supervision at the point of care. Multimodal strategies have shown its efficiency in improving IPC practices , 20. A sIn our study, however, there was no improvement in IPC performance for sterilization of medical equipment and decontamination of surfaces. This can be explained by the fact that sterilization involves the use of specialized materials that most of the HF did not have before the outbreak and during the response phase, these materials were distributed in a very low quantity.This study also displayed that smaller HF were less compliant to IPC measures compared to bigger HF. In the Beni District, many of these small private HF did not have required infrastructure and materials, and HW did not, in most of the cases, required qualification for medical practice. Moreover, due to a high number of HW, bigger facilities were able to identify an IPC focal point fully dedicated to IPC work; but in small facilities, the person identified for IPC activities was mostly multitasking.Our findings support many studies evaluating the impact of PPS to improve IPC practice without negative effects on the health system if the resilience strategies are implemented , 22–24. During the 2014–2016 EVD outbreak, affected countries shared similar health system weaknesses as highlighted during the 2018–2020 EVD outbreak in DRC. These may include insufficient surveillance systems and lack of standardized IPC programs implemented in local HF. This resulted in an increase in the incidence of nosocomial EVD infection as documented during outbreaks in Sierra Leone, Guinea and DRC –24. DespLack of control group is likely associated with limited external validity of the study results. HF included in this study may not be representative of all HF of the province of North-Kivu. This was due to funding limitation and inaccessibility of some areas where army groups are established. The IPC assessment tool did not include quality assurance on hospital management from different departments of HF . As resuPay for Performance Strategy was proved effective in improving health facilities capacity in IPC practices in context of 2018 EVD outbreak in Nord Kivu associated with the IPC multimodal strategies which include continuing HW training, supportive supervision, donation of IPC/WASH kits, facility quality improvement plans, and allocated the national budget to strengthen IPC programs. Additional studies are warranted on HW and patients’ perceptions toward IPC program implementation considering limited accessibility and security context of the region.