Background: Hepatocellular carcinoma (HCC) is the most common liver malignancy and the leading cause of death in patients with cirrhosis. Various treatments for HCC are available, including transarterial chemoembolization (TACE), which is the commonest intervention performed in HCC. Radiologic tumor response following TACE is an important prognostic factor for patients with HCC. We hypothesized that, for large HCC tumors, assessment of treatment response made with automated volumetric response evaluation criteria in solid tumors (RECIST) might correlate with the assessment made with the more time- and labor-intensive unidimensional modified RECIST (mRECIST) and manual volumetric RECIST (M-vRECIST) criteria. Accordingly, we undertook this retrospective study to compare automated volumetric RECIST (A-vRECIST) with M-vRECIST and mRESIST for the assessment of large HCC tumors' responses to TACE.Methods:We selected 42 pairs of contrast-enhanced computed tomography (CT) images of large HCCs. Images were taken before and after TACE, and in each of the images, the HCC was segmented using both a manual contouring tool and a convolutional neural network. Three experienced radiologists assessed tumor response to TACE using mRECIST criteria. The intra-class correlation coefficient was used to assess inter-reader reliability in the mRECIST measurements, while the Pearson correlation coefficient was used to assess correlation between the volumetric and mRECIST measurements.Results:Volumetric tumor assessment using automated and manual segmentation tools showed good correlation with mRECIST measurements. For A-vRECIST and M-vRECIST, respectively, r = 0.597 vs. 0.622 in the baseline studies; 0.648 vs. 0.748 in the follow-up studies; and 0.774 vs. 0.766 in the response assessment . The A-vRECIST evaluation showed high correlation with the M-vRECIST evaluation .Conclusion:Volumetric RECIST measurements are likely to provide an early marker for TACE monitoring, and automated measurements made with a convolutional neural network may be good substitutes for manual volumetric measurements. Hepatocellular carcinoma (HCC) is the most common liver malignancy and the leading cause of death in patients with cirrhosis. Despite advances in various treatment modalities over the past several years, the prognosis for HCC remains poor, with 5-year overall survival ranging from 24 to 41% . These pIn the United States, transarterial chemoembolization (TACE) is the most common intervention for HCC . It is tThe recent attempts to improve the accuracy of radiologic response criteria to predict overall survival and Progression-free survival have focused on using quantitative volumetric analysis. This has resulted in the development of the volumetric RECIST (vRECIST) and quantitative EASL (qEASL) methods with better results in predicting patient's outcome than the currently used mRECIST –15.The volumetric assessment of tumor response depends on manual segmentation of tumor and needs contouring of the lesion in every single slice of the study. This process is time consuming and tedious. The manual volumetric assessment show high inter- and intra-observer variability which make it impractical in daily practice –18. On tConvolutional neural network (CNN) shows promise to achieve automated segmentation of liver and liver masses. These are, however, computationally demanding , 13. CNNThe purpose of this study is to assess the feasibility of volumetric assessment of pre- and post-TACE HCC using fully automated segmentation and to evaluate the correlation of automated volumetric assessment with both manual volumetric assessment and mRECIST measurements.This is a retrospective, single-institution, IRB approved study. This study included patients with large HCC tumors (≥5 cm) diagnosed and treated at our institution between November 2002 and June 2012. Patients were included in the study if (1) they had undergone TACE as their sole first-line or initial bridging therapy; (2) their medical records included multiphasic, contrast-enhanced CT images that were obtained at baseline and that included no image artifacts ; and (3) their tumor was diagnosed as tumor-node-metastasis (TNM) stage III or IV HCC based on the American Joint Committee on Cancer (AJCC). Although there are numerous HCC scoring systems that incorporate liver functional reserve, patient performance, and gross tumor characteristics , we chose the TNM staging system because it is the only HCC staging system that considers tumor characteristics (including size) without taking any other factor into consideration .Briefly, TACE is delivery method of chemotherapy delivery to the tumor through its feeding arteries using trans-arterial approach. The hepatic artery was selected and injected with chemotherapy by super selection of the feeding vasculature using advanced micro-catheters. There are two main chemotherapeutic regimens that may be delivered. In conventional TACE, a mixture of radio-opaque ethiodized emulsion oil  and doxorubicin or cisplatin was injected followed by embolization of the feeding vessels. While in TACE with drug eluting beads (DEB-TACE), a mixture of micro-sphere particles, doxorubicin and soluble non-ionic contrast was injected .Our patients received one of the following chemotherapeutic regimens (Drug regimen details are missed from 2 cases): (1) embolic microsphere beads  loaded with doxorubicin  (15 lesions), (2) cisplatin, doxorubicin, and mitomycin C (22 lesions), or (3) cisplatin and mitomycin C only (3 lesions) (such information is missed from 2 cases).All patients underwent dynamic, contrast-enhanced CT scans of the abdomen on 4-, 16-, or 64-slice multidetector CT LightSpeed scanners  pre-TACE and post-TACE. Liver protocol was used in all studies . Injection was done with an automated contrast injector using a bolus tracking technique and an injection rate of about 3–5 mL/s. The image reconstruction thicknesses were 2.5 mm and 5 mm.Tumor TACE response was assessed using mRECIST, M-vRECIST, and A-vRECIST . Three dThe porto-venous phase of CT (both baseline and follow-up) were used to simplify lesion assessment, they were exported in DICOM format from our institution's picture archiving and communication system to a separate research server. Subsequently, the images were converted into the format recommended by the Neuroimaging Informatics Technology Initiative (Nifti) to preserve the orientation information for further data processing. Then the files were compressed and the images were reoriented into right-anterior-inferior orientation with Convert3D.n = 42 pairs) used to develop a neural network classifier for segmentation of tumors from the background liver tissue. Automated segmentation, performed using a CNN approach (U-Net), was used to segment the liver and tumor in two steps  was used to delineate the tumors, including the (i) enhancing portions, (ii) non-enhancing portions, and Lipiodol containing portions of the tumors. Enhancing tumor tissue was defined as a “region with uptake of contrast agent in the arterial phase of dynamic contrast CT” while non-enhancing tumor tissue was defined as a “region of no enhancement within HCC on the arterial phase images,” while Lipidol was defined as a “portions of high attenuation in pre-contrast images.” Manual segmentation of the whole tumor in the baseline study was done by one author (AM) to ensure the consistency of the segmentation throughout the dataset. The segmentation was done for all axial CT images. These manual segmentations provided the training data . Inter-reader reliability for mRECIST measurement was assessed using the intraclass correlation coefficient (ICC). The Pearson correlation coefficient (r) was used to measure the correlation between the diameter change (the average reading from mRECIST) and (i) the automated and (ii) manual volume changes after TACE. A There were 320 patients  found in our institutional database with HCC patients underwent TACE, we excluded 8 patients due to difference in their treatment plan (either TACE was used as second line or combined with other form of therapy). After thorough review of patients imaging studies, another 209 patients were excluded for different reasons . The finThe mRECIST response comparing the pre- and post-TACE images is listed in P < 0.001).The manual vRECIST and automated vRECIST response comparing the pre- and post TACE are presented in r = 0.622 and 0.748, respectively). The correlation between tumor diameter measurement changes was higher (r = 0.766). The differences between these measurements were statistically significant . The correlation between mRECIST and A-vRECIST was similar: r = 0.597 for the baseline and r = 0.648 for the follow-up studies . For the correlation between the baseline and follow-up tumor measurements, r = 0.774.To determine the correlation between mRECIST and vRECIST , we compared the average unidimensional mRECIST measurements to the M-vRECIST and A-vRECIST volumetric assessments  and compr = 0.967 for the baseline studies, r = 0.937 for the follow-up studies, and r = 0.826 for the tumor volume change after TACE [P < 0.001 for all])  , 4.In this study, we hypothesized that, for large HCC tumors, assessment of volume changes before and after TACE using A-vRECIST would correlate with the measurement changes using uni-dimentional mRECIST and that, accordingly, A-vRECIST can be used to assess tumor response to TACE therapy.Volumetric assessment of HCC have been emerged as recent tool for assessing of HCC response to treatment. Although assessment of treatment response of is some patterns of HCC is challenging  due to its indistinct borders. Previous studies showed that both uni-dimensional and volumetric measurement highly correlated with the actual pathological tumor volume, with volumetric assessment was similar to pathological volume while uni-dimensional measurement overestimate the volume by 28% , 26. SucAnother study showed that HCC response to Sorafenib using volumetric assessment can be used an alternative tool for monitoring therapy better than mRECIST measurement . AnotherThere are challenges to the automated segmentation of the liver on CT. Among these is that the attenuation of adjacent organs and tissues that may be very similar to the liver tissue itself. In addition, model-based approaches to segmentation are challenging due to the liver's widely varying shape . Also, aIn our study, we found that A-vRECIST measurements highly correlated with both M-vRECIST and unidimensional mRECIST measurements in large HCCs from patients who had undergone TACE.r = 0.766 for M-vRECIST and r = 0.774 for A-vRECIST.Because mRECIST is currently the preferred method of monitoring TACE therapy, we used it as the standard to which vRECIST was compared. Our results showed that, between our experienced radiologists, there was moderate to high inter-reader agreement for monitoring therapy using mRECIST measurements (ICC = 0.824). Our study also showed that correlation between unidimensional mRECIST and the vRECIST measurements was good r = 0.967, 0.937, and 0.826, respectively).Results of our vRECIST measurements are likely to provide an early marker for TACE monitoring , 28, 32.r = 0.648 vs. 0.748, respectively) may have been due to differences in TACE techniques, as the Lipiodol used in conventional TACE can distort CNNs, leading to differences in automated tumor segmentation.Our study had some limitations. First, the small cohort (42 patients) may have masked variability in the automated segmentation results. However, this study was a pilot, and we were aware from the outset that its findings would need to be confirmed prospectively in a larger population with more variable tumor sizes and stages. Second, we did not examine correlation between A-vRECIST and patient's outcome. However, this study serves as a step for further evaluation of clinical importance of A-vRECIST and its relation to patient's survival endpoints. The small differences observed between A-vRECIST and M-vRECIST in the follow-up images . Also, we will thoroughly study the confounding factors, such as chronic parenchymal liver disease, that may affect the performance of neural networks.The datasets generated for this study are available on request to the corresponding author.The study was approved by the Institutional Review Board (IRB) at MD Anderson Cancer Center, office of protocol research. The informed consent was waived and approved by our institutional IRB.AM contributed to the planning of the project, data collection, curation, data analysis, preparing figures, and write the first draft of the manuscript. KB helped in data curation, planning of the project, and reviewed the final draft of manuscript. AK contributed to the planning of the project, data collection, and shared in writing the first draft of the manuscript. DF and JH technical leaders of the project, construction of the neural network we used, planning of the project, and reviewing the first draft of the project. JS, AQ, and KE three radiologists who read the RECIST of the tumors, helped in planning the project, and also reviewed the final draft of the manuscript. KE provided supervision, support, conceptualization, and guidance throughout the project.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.


Babesia rossi, results in a marked systemic inflammatory host response in dogs. Neutrophils form part of the innate immune response and contains myeloperoxidase (MPO) as the predominant component of the neutrophil lysosomal protein in azurophilic granules. The neutrophil myeloperoxidase index (MPXI), determined on the ADVIA hematology analyzer, is a quantitative estimate of intracellular MPO content. Objectives of this study were to: (a) compare MPXI in dogs with babesiosis with healthy control dogs; (b) compare MPXI in dogs that died from babesiosis with dogs that survived and controls; and (c) correlate the MPXI with the previously determined segmented and band neutrophil count and cytokine concentrations in dogs with babesiosis. Data for 140 dogs naturally infected with B. rossi and 20 healthy control dogs were retrospectively evaluated. Neutrophil counts and MPXI were determined on an ADVIA 2120 analyzer. Cytokine concentrations  were determined using a canine-specific multiplex immunoassay. The mortality rate of the Babesia-infected dogs was 11% (15/140). MPXI was significantly higher in Babesia-infected dogs (P = 0.033), and in Babesia-infected non-survivors (P = 0.011), compared with healthy control dogs. In Babesia-infected dogs a significant positive correlation was found between MPXI and IL-10  and a significant negative correlation was found between MPXI and IL-8 . In Babesia-infected non-survivors, significant positive correlations were found between MPXI and IL-2 , IL-6 , IL-18 , GM-CSF , and MCP-1 . In Babesia-infected survivors, a significant negative correlation was found between MPXI and IL-8 . MPXI was correlated with pro-inflammatory cytokines in Babesia-infected dogs that died. The potential of MPXI as a novel marker of inflammation and prognosis in dogs infected with B. rossi, thus warrants further investigation.Babesiosis caused by the virulent tick-borne hemoprotozoan,  Babesia rossi is a hemoprotozoan parasite, transmitted by Haemophysalis elliptica ticks, and is considered the most pathogenic of the large canine babesias  and serum amyloid A were significantly increased in the Babesia-infected group  and light scatter , that determine the location of cells on the generated peroxidase scattergram  content and cell volume to determine the automated differential leukocyte count , 10. Quattergram , 10. Cluttergram . In humattergram . The MPXttergram , 14. In ttergram , 15. Onettergram , 16, 17.ttergram .There is a dearth of research on MPXI in domestic animals. A study in horses with systemic inflammation correlated low MPXI values with an increased risk of mortality, especially when it remains unchanged 24 h after therapeutic intervention . NeutropB. rossi to that in healthy control dogs and to establish the correlation of MPXI with the severity of the host inflammatory response, using cytokine concentrations and neutrophil counts. We hypothesize that MPXI will be decreased in Babesia-infected dogs compared to healthy controls and that MPXI will be correlated with pro-inflammatory and immune-modulating cytokines.The objectives of this study were to retrospectively compare MPXI in dogs infected with B. rossi and healthy control dogs, generated on an automated hematology analyzer , using multispecies software and the canine species setting at the Clinical Pathology laboratory, Onderstepoort Veterinary Academic Hospital. The study was approved by the Faculty Research Ethics committee (REC041-18).This was a retrospective observational study that evaluated the admissions records of MPXI in dogs with babesiosis caused by Babesia-infected dogs and 15 healthy control dogs, collected between October 2011 to April 2013 as part of the first study cohort  and reverse line blot (RLB). Criteria for exclusion for the first study cohort were RLB-PCR confirmation of co-infection with B. vogeli, the only other large Babesia spp. found in the area, or Ehrlichia canis; euthanasia for reasons other than a poor prognosis; evident comorbidities such as existing inflammatory or infectious, cardiac, neoplastic or traumatic conditions; or treatment with anti-inflammatory therapy at, or within 4 weeks prior to presentation. Criteria for exclusion for the second study cohort were RLB-PCR confirmation of co-infection with B. vogeli or E. canis; concurrent infections, wounds or indications of trauma; vaccination, glucocorticoid therapy or any unrelated metabolic disease within 4 weeks prior to presentation.For both studies, inclusion criteria included: dogs of either breed or gender; older than 12 weeks of age; weighing more than 5 kg (first cohort) or more than 3 kg (second cohort); and with a demonstrable parasitemia on blood smear, that was confirmed as Patients in either study cohort received the standard therapy for canine babesiosis, which involved treatment with diminazene aceturate  at 3.5 mg/kg and transfusion with packed red blood cells and/or intravenous fluids therapy as indicated. Any complications were treated as deemed appropriate by the attending clinician. Outcome was noted as short-term survival , or death/euthanasia due to poor prognosis during hospitalization.Babesia-infected study population was further divided based on outcome (survivors and non-survivors).The controls included 20 healthy, client-owned dogs admitted for blood donation or routine ovariohysterectomy or castration. The control dogs were regarded to be healthy based on history, a complete physical examination, peripheral blood smear evaluation, complete blood count (CBC), complete serum biochemistry profile as well as RLB-PCR assay to exclude infection with any hemoparasites. The Blood was collected from the jugular vein in EDTA and serum Vacutainer  tubes at presentation, prior to any treatment, for a CBC on the ADVIA 2120 and a complete serum biochemical profile . Blood smear evaluation was performed on all dogs by experienced hematology technologists and a 100-cell manual differential leukocyte count was performed. The generated peroxidase scattergrams were evaluated for each sample by an experienced clinical pathologist (AG), to confirm correct separation of the neutrophil population. In the first study cohort, blood was also collected in serum Vacutainer tubes for determination of cytokine concentrations  . The cytU was used to determine significance across groups; including Babesia-infected vs. healthy controls and non-survivors vs. survivors vs. healthy controls. Sex proportions between groups were assessed using the Chi square test. Correlations between MPXI and cytokine concentrations, as well as MPXI, and selected leukocyte counts  were determined using the Spearman's rank correlation coefficient. The level of significance was set at P < 0.05. Data is represented as median and interquartile range (IQR).Statistical analysis was performed using a commercial software package . The Shapiro Wilk test was used to assess data for normality. The data was found to be not normally distributed and therefore non-parametric statistical analysis, such as Kruskal Wallis and Mann-Whitney B. rossi and 20 healthy control dogs from both study cohorts were included. Of the 140 Babesia-infected dogs included, 15 died (11%). There was a significant age difference between the groups. The median age of the Babesia-infected dogs  and the survivors  was significantly lower (P = 0.005 for both), than the healthy control dogs . There was no significant age difference between the non-survivors vs. the survivors or healthy control dogs. The ratio of male to female for each group was as follows: healthy control dogs (7:13), survivors (82:43) and non-survivors (10:5), with a significant difference found between groups (P = 0.028).A total of 140 client-owned dogs naturally infected with Babesia-infected dogs (survivors and non-survivors)  compared to the healthy control dogs  (P = 0.033) (P = 0.011)  and the healthy control dogs, as well as between the survivors and non-survivors. The segmented neutrophil count  was significantly lower (P = 0.006) in the Babesia-infected dogs compared to the controls  and the band neutrophil count  significantly higher (P < 0.001) compared to the controls . For the Babesia-infected dogs that survived, the segmented neutrophil count  was significantly lower (P = 0.002) and the band neutrophil count  significantly higher (P < 0.001), compared to the controls. For the non-survivors only the band neutrophil count  was significantly higher (P < 0.001) compared to the controls. Both the segmented- and band neutrophil counts were significantly higher in the non-survivors compared to the survivors . Results for the serum biochemistry and cytokine concentrations were previously reported for the two study cohorts and are included in the MPXI was significantly higher in the whole group of = 0.033) . MPXI wa= 0.011) . There wBabesia-infected group (survivors and non-survivors) a significant positive correlation was found between MPXI and IL-10 , and a significant negative correlation between MPXI and IL-8 . For the non-survivors, significant positive correlations were found between MPXI and IL-2 , IL-6 , IL-18 , GM-CSF  and MCP-1 . For the survivors, a significant negative correlation was found between MPXI and IL-8 .No significant correlations were found in any group between MPXI and segmented- or band neutrophil counts. Cytokine concentrations were only measured in the first study cohort and included 96 infected dogs . For theB. rossi infection. The findings suggest that a higher MPXI is associated with a more severe inflammatory response, as determined by the concentration of pro-inflammatory cytokines, and a poorer outcome.This is the first report on MPXI, as determined by the ADVIA 2120, as a marker of disease severity in dogs with B. rossi-infected dogs, specifically the non-survivors, compared to healthy control dogs. Considering that the marked pro-inflammatory host response reported in B. rossi infection has been correlated with mortality  University of Pretoria, Faculty of Veterinary Science. Written informed consent was obtained from the owners for the participation of their animals in this study.AC: study design, data and result analysis, and primary author of the manuscript. YR: data collection for the second study cohort and manuscript editing. EH and MC: manuscript editing. AG: study design, data analysis, data collection for the first study cohort, and manuscript editing. The retrospective data was derived from studies done by AG and YR.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.


Systematic review.Preoperative neuromuscular function is predictive for knee function and return to sports (RTS) after reconstruction of the anterior cruciate ligament (ACL). The aim of this review was to examine the potential benefits of prehabilitation on pre-/postoperative objective, self-reported and RTS-specific outcomes.A systematic search was conducted within three databases. From the 1.071 studies screened, two randomized control trials (RCTs), two control trials (CTs) and two cohort studies (CS) met the inclusion criteria. Methodological quality rating adopted the PEDro-  or Newcastle-Ottawa-Scale (CS).Methodological quality of the included studies was moderate . Two studies reported higher increases of the maximal quadriceps torque from baseline to pre-reconstruction: one study in the limb symmetry index (LSI), and one in both legs of the prehabilitation group compared to the controls. At 12-weeks post-reconstruction, one study (from two) indicated that the prehabilitation group had a lesser post-operative decline in the single-leg-hop for distance LSI . Similar findings were found in terms of quadriceps strength LSI (one study). At both pre-reconstruction (three studies) and two-year post-surgery (two studies), the prehabilitation groups reached significantly higher self-reported knee function  than the controls. RTS tended to be faster (one study). At two years post-surgery, RTS rates (one study) were higher in the prehabilitation groups. The results provide evidence for the relevance of prehabilitation prior to ACL-reconstruction to improve neuromuscular and self-reported knee function as well as RTS. More high quality confirmatory RCTs are warranted.PROSPERO 2017: CRD42017065491. Anterior cruciate ligament (ACL) reconstruction is the usual treatment for athletes after ACL tears, followed by evidence-based physical rehabilitation therapy to restore function , 2. The The RTS-decision should be based on the systematic and stepwise assessment of potential risk factors , 6. PartOne of these strategies is pre-operative rehabilitation (prehabilitation). Numerous studies indicate the relevance of preoperative neuromuscular performance factors, such as knee extension and flexion strength as well as single-leg-hop performance in ACL-injured individuals for postoperative knee function –19. AccoLow-level evidence supports the relevance of prehabilitation to improve return to sports (RTS)-rates and two years self-reported knee function . Prehabihttps://www.crd.york.ac.uk/PROSPERO/ (registration number: blinded for review). As studies on prehabilitation before ACLR often include participants below 18 years of age, the inclusion criteria on age was changed accordingly after the PROSPERO registration. This review is reported in accordance to the PRISMA statement.The protocol for this systematic review was registered in the PROSPERO international prospective register of systematic reviews We included randomized controlled trials, controlled trials  and prospective cohort studies published in English and German. We considered only studies including participants with primarily unilateral ACL rupture scheduled for reconstruction regardless of the surgical technique (i.e. single or double bundle technique), graft type (i.e. patellar or semitendinosus tendon) and concomitant injuries. Included studies had to assess, at least, one objective or subjective functional outcome measure and, at least, two of the following measuring points: Baseline (pre-prehabilitation), post-intervention (post-prehabilitation/ pre-surgery), post-surgery/after rehabilitation or follow-up.Non-controlled studies  case reports, protocols, oral presentations and studies not based on original data were not included. Furthermore, trials including patients who were not scheduled for reconstructive surgery (non-operative rehabilitation), undergoing other orthopaedic operations than the reconstruction of the isolated, unilateral injured ACL, and scheduled for secondary ACLR were not included.Intervention groups consisted of patients who received a preoperative exercise programme prior to ACLR and standard care following surgery (i.e. rehabilitation). Patients scheduled for ACLR who received standard treatment  before and standard care following reconstruction (i.e. rehabilitation) were considered controls.The databases PubMed/MEDLINE, Web of Knowledge and the Cochrane Library were searched using the following search terms:PubMed/Medline: (("acl"[All Fields]) OR "anterior cruciate ligament"[All Fields]) AND (Prehabilitation [All Fields] OR prehab [All Fields] OR pre-rehabilitation [All Fields] OR preoperative [All Fields] OR pre-operative [All Fields]) AND (exercise OR physiotherapy OR training OR intervention OR rehabilitation)Web of Knowledge and the Cochrane Library: TOPIC: ((("acl" OR "anterior cruciate ligament") AND (Prehabilitation OR prehab OR pre-rehabilitation OR preoperative OR pre-operative)) AND (exercise OR physiotherapy OR training OR intervention OR rehabilitation))The initial search was performed for studies published until October 31th, 2017; an update search was performed on June 12th, 2019.Reference lists of the studies of interest were screened to identify extra articles. Two authors  independently selected trials for inclusion based on titles, keywords, and abstracts to determine eligibility. Any disagreements in terms of the study selection were discussed. If a conclusion could not be reached after discussion, a third reviewer (LV) was asked to resolve any conflicts. Full-texts of all trials considered eligible were retrieved. Then, one author (FG) performed first data extraction. Another author (DN) reviewed all data blindly. Again, any disagreements were discussed bilaterally. If a conclusion could not be reached, the third reviewer delivered the decisive vote. The following data from included papers were extracted: sample size, participant characteristics , study methods (statistics), study specifics . Outcomes of interest were quadriceps strength and single-leg hop test (limb symmetry indices) as well as self-reported knee function. If not retrievable from the original publications, the authors were asked to send us the required data by e-mail.The methodological quality of (randomized) controlled trials was assessed using the PEDro scale (11 criteria). The PEDro scale is a valid and reliable tool to assess the methodological quality of clinical studies , 24. TheAccording to the PEDro-Rating (11 points maximum), the controlled and randomized controlled trials were rated from four (one study ) over seRisk of bias assessed for the controlled and randomized controlled trials was rated low for one study’s  five ou. Risk ofA total of 5.131 participants (thereof n = 4.961 from cohort studies) were included. Two studies recruited men only , 36. TheFive studies , 42, 51 Participants with any injury induced associated fractures, injuries to other ligaments in the same knee, collateral ligament injuries requiring repair/reconstruction and contralateral injuries , 35, 36,Bone-patellar tendon-bone (BPTB) grafts, Hamstring autografts and soft tissue allografts , 32 or BIn one study, the time from injury to surgery was 6.3 ± 4.1 months in the prehabilitation, and 6.8 ± 4.2 months in the rehabilitation cohort (control group) . In anotAll six studies compared preoperative exercise interventions with no treatment or usual care in participants scheduled for unilateral ACLR , 36, 51.Postoperatively, all participants received a standardised, criterion-based rehabilitation programme aiming to increase knee RoM and weight bearing to restore gait pattern and limb symmetry of neuromuscular performance factors. In two studies, only preoperative measuring points were considered , 34.Both prospective cohort studies , 32 did Type/content. The preoperative interventions included strengthening exercises mainly of the lower limb in open and closed chain, [d chain, , 41, 50 d chain, , 32–36 md chain, , 34, 36,d chain, , 34 and d chain, , 32.Intensity. The same two studies used progressively increased strength training, with maximal effort for 3 or 4 sets of 6 to 8 repetitions. Progress was made, as the patients were told to perform as many repetitions as they could manage in the last three or four sets. If they were able to add two additional repetitions, weight was increased in the next session. Shaarani et al. [i et al.  also usei et al. , respecti et al. . In one i et al. , 30 secsi et al.  Seperatei et al.  performei et al. , 32 conti et al. .Duration/frequency. The preoperative intervention lasted 4.8 weeks on average  through prehabilitation beyond the postoperative rehabilitation period may explain both the continuously higher symmetry indices of the prehabilitation compared to the control group indicated by Kim et al.  and the Kim et al.  found anSingle-legged hop tests are highly reliable in ACL-injured and -reconstructed participants , 38. TheBeneficial effects of prehabilitation on both preoperative , 34 and These positive implications may be a consequence of the prehabilitation-related improved pre- and postoperative neuromuscular performance as indicated above. The assumed association between objective and self-reported outcomes are supported by Logerstedt et al.  providinThe higher RTS rates or shorter time until RTS success found by two studies , 35 may The prehabilitation programmes of the included studies differed in terms of frequency, intensity, time, supervision and setting. Nevertheless, the preoperative training protocols varied less in terms of content: The studies included in the review primarily adopted stretching and balance exercises as well as strengthening and control and co-contraction training with particular focus on the quadriceps. The prehabilitation protocols also included hamstrings strengthening. The hamstring muscles represent a major synergist of the ACL as its contraction reduces anterior tibia translation . In the Based on two of the included studies training compliance appears to be high and dropout rates appear to be low , 35. TheThe average time from injury to surgery 6.5 months , 8.2 monDue to the relatively long preoperative period, some participants may have been engaged in physical training and exercise before or beyond prehabilitation. Except both of the cohort studies in which exercises were already performed early after injury to restore basic knee function, no of the other studies reported if and which exercises/treatment preceded prehabilitation. Therefore, we cannot estimate the effects of these preoperative actions on the results of this review.A common limitation in exercise trials is the limited possibility to blind participants . This liHowever, the included studies have certain limitations:Time between diagnosis of ACL tear and surgical reconstruction was not consistently reported across the included studies.No consistent definition of standard care treatment (control condition) was provided. Physical activities and therapies potentially performed early after ACL injury have not been reported neither for interventions nor for control groups.The heterogeneity across studies in terms of the characteristics of participants was high. For instance, the age of the participants included in one study was quite high (about 40 years) relative to the age groups (18 to 25 years), which are mainly affected by ACL-injuries . The kinMethodological quality of the included studies was moderate and risk of bias ranged from low to high.This systematic review has also certain limitations:We included only studies written in English and German. Therefore, relevant literature published in other languages may not have been included.The number of the studies included into this systematic review was quite low (n = 6).The evaluation of the effects of prehabilitation on long-term self-reported function is based on two prospective cohort studies implying low levels of evidence. Furthermore, both studies referred to the same prehabilitation cohort. The partial overlap of participants may have resulted in a substantial bias. Furthermore, the prehabilitation group exhibited higher self-reported knee function at baseline. Although considered as a covariate in statistical analyses, this may have limited the comparability between both groups.Due to the small number of studies available investigating the same outcome at comparable measuring points, the overlap in participants in two studies, the diverse and partly unknown content of the interventions, as well as the variations in study populations, we did not performed qualitative data syntheses .We only screened the databases PubMed (Medline), Web of Knowledge and the Cochrane Library. Considering the topic of our review, almost all manuscripts of interest should be found therein. However, expanding the search to even more databases, like EMBASE, PEDro, CINAHL, AMED, SportDiscus and CENTRAL may would have led to slightly more hits.Our findings apply to physically active adults with primary, unilateral ACL rupture without additional severe injuries to other intraarticular structures who had delayed ACLR. Besides improved preoperative functions, this review provides first evidence that prehabilitation may reduce the decline of postoperative neuromuscular performance of the lower limb and improve self-reported knee function and RTS success. Although more high quality confirmatory RCTs are needed to finally evaluate the clinical importance of prehabilitation, the outcomes found to be impacted by prehabilitation in this review are mostly the same as those found to be predictive for a second ACL injury . DespiteDelayed compared to early ACLR is unlikely to result in postoperative differences in secondary knee pathologies  and functional outcomes  as well Furthermore, the pre-ACLR contact time associated with a delayed surgery can help to identify ACL-deficient individuals without knee instability who may be able to RTS without surgery (copers ). This iBased on the studies included in this review, the preoperative or post-injury training protocols  should contain muscle control and co-contraction exercises of the knee muscles with particular attention of the quadriceps as well as strengthening (open and closed chain) and stretching exercises of the lower limb. Moreover, advanced neuromuscular  as well as plyometric exercises (e.g. single leg hops with soft landings) need to be considered. Such more intensive preoperative interventions should be not started before initial impairment resolution (about 2–3 months) in dependence on the functional and tissue repair status as well as concomitant injuries. Although, there are no specific evidence-based guidelines for strength and neuromuscular training in the early stage after ACL injury available yet, we recommend in exemplary the exercise protocols published by Eitzen et al.  and WilkLow to moderate quality evidence indicates that exercises have a positive impact on pre-operative and postoperative functional performance. Low-level quality evidence supports the superiority of prehabilitation in terms of self-reported knee function at both pre-reconstruction and three months as well as two years after ACLR. Due to the low number of studies included into this systematic review, divergent methodologic quality and high heterogeneity across the studies, high quality RCTs are warranted to finally evaluate the clinical importance of prehabilitation. Specifically, future trials need to investigate, if prehabilitation before delayed compared to early ACLR lead to a faster or improved restoration of postoperative RTS-specific neuromuscular or self-reported function and sport participation. Furthermore, the potential effects of prehabilitation on re-injury incidences need to be assessed.S1 Checklist(DOC)Click here for additional data file.


Heart failure (HF) is a complex disease in which cardiomyocyte injury leads to a cascade of inflammatory and fibrosis pathway activation, thereby causing decrease in cardiac function. As a result, several biomolecules are released which can be identified easily in circulating body fluids. The complex biological processes involved in the development and worsening of HF require an early treatment strategy to stop deterioration of cardiac function. Circulating biomarkers provide not only an ideal platform to detect subclinical changes, their clinical application also offers the opportunity to monitor disease treatment. Many of these biomarkers can be quantified with high sensitivity; allowing their clinical application to be evaluated beyond diagnostic purposes as potential tools for HF prognosis. Though the field of biomarkers is dominated by protein molecules, non-coding RNAs  are novel and promising biomarker candidates that encompass several ideal characteristics required in the biomarker field. The application of genetic biomarkers as genetic risk scores in disease prognosis, albeit in its infancy, holds promise to improve disease risk estimation. Despite the multitude of biomarkers that have been available and identified, the majority of novel biomarker candidates are not cardiac-specific, and instead may simply be a readout of systemic inflammation or other pathological processes. Thus, the true value of novel biomarker candidates in HF prognostication remains unclear. In this article, we discuss the current state of application of protein, genetic as well as non-coding RNA biomarkers in HF risk prognosis. Heart failure (HF) is a complex cardiovascular disease (CVD) in which the heart's functional capacity is reduced, leading to failure in meeting the body's blood and oxygen demand . The mosHF is a multi-system disorder which is characterized by a decrease in functional capacity of the heart. Reduced cardiac output due to impairment in left ventricular function leads to an activation of the neuro-hormonal system. This, in turn, stimulates the renin-angiotensin-aldosterone system leading to increased concentrations of renin, angiotensin II and aldosterone, each of which causes salt and water retention, vasoconstriction, and enhanced sympathetic activity. Prolonged exposure to neuro-hormonal activation leads to dilation and structural changes in the myocardium and fibrosis, thereby further worsening cardiac output . The sevA biomarker is defined as a biological compound that is easily accessible and measurable in the body. The biomarker can be classified as molecular, cellular, or imaging as long as they help in identifying the disease or provide therapeutic guidance. Diagnosis of HF through different diagnostic tools such as chest X-ray , 9, echoIn this review article, we elucidate the role of the most prominent circulating protein biomarkers which show promising results in HF prognosis. In addition, we provide details on genetic biomarkers and polygenic risk scores that are currently being developed along with details about emerging evidence on circulating non-coding RNA biomarkers.Protein biomarkers are released into the circulation and can be detected using various assays. Protein biomarkers that have entered the prognostic field for HF are either released from the heart exhibiting its value of tissue-specific damage, or are released from other cells as a systemic response to HF . In addiNatriuretic peptides (NPs) are hormones that play an important role in regulating volume and pressure overload, thereby maintaining homeostasis within the cardiovascular system . NPs areNPPB gene, is secreted in response to increased ventricular stretching . In another prospective multi-center study of 171 patients with acute decompensated HF, BNP, and NT-proBNP measurements were taken at the time of hospital presentation, after 24 h, after 48 h and at the time of discharge. The primary end point  was reliably predicted by BNP and NT-proBNP, with the prognostic accuracy of both biomarkers increasing over the course of hospitalization. The area under the receiver operating curves (ROC) curve (AUC) increased during the course of hospitalization for BNP  and NT-proBNP   . This obn = 405 acute decompensated HF patients was guided by NT-proBNP, 6-month outcome was not improved in the PRIMA II trial (2018)  investigated whether lowering of NT-proBNP concentration (NT-proBNP guided therapy) led to an improvement in echocardiographic parameters when compared to standard of care management in 151 chronic HF patients with LV systolic dysfunction. The authors reported that guiding therapy through NT-proBNP levels demonstrated prognostically meaningful improvement in echocardiographic parameters such as LV volumes and function . By contl (2018) .BNP and especially NT-proBNP are reliable gold standard diagnostic biomarkers in heart failure, likely driven by their well-understood and cardiac-specific biological function. Their prognostic potential seems promising, while at the same time, when used as single markers, their accuracy doesn't yet allow for clinical applicability and their use in HF treatment guidance still needs to be further evaluated.NPPA gene, is secreted in response to atrial volume stretch receptors , p = 0.004]  prognostic value  . A secon= 0.004] . In the = 0.004] . Similar= 0.004] , 49. ThuNPs function as cardiac-specific hormones, released in pathologic states of increased cardiac strain. Therefore, their biomarker function is directly derived from a cardiac-specific pathology and comprises a strong link to a natural therapeutic attempt. This may well be an important reason why NPs remain unparalleled in the field of biomarkers for heart failure diagnosis, prognosis, and now also in guided therapy .TNNI3 gene) and troponin T (Tn-T encoded by TNNT2 gene), known as the troponin complex. Cardiac isoforms of Tn-I (cTn-I) and Tn-T (cTn-T) are exclusively expressed in cardiac muscle, whereas Tn-C is expressed as one isoform in both cardiac (encoded by TNNC1 gene) and skeletal muscle (encoded by TNNC2 gene). The troponin complex plays a key role in cardiac and skeletal muscular contraction , troponin I  with systolic HF of ischemic origin. The authors reported that elevated hs-cTn-T levels (above 99% upper reference limit) provided a strong and independent prognosis of CV death, non-fatal MI, non-fatal stroke and HF hospitalization in older patients with chronic ischemic HF (p = 0.0004) (The ASCEND-HF study examined the prognostic importance of cardiac troponin I (cTn-I) in patients with acute decompensated HF. Elevated levels of cTn-I (above 99% upper reference limit) was observed in 50% of acute decompensated HF patients and helped in predicting in-hospital outcome (p=0.01), but was not an independent predictor of post discharge outcomes . The CORhemic HF . The REL 0.0004) .When measured with other biomarkers, Tn-T retained its prognostic value. The RED-HF trial tested the prognostic values of various cardiac inflammatory and renal biomarkers in HFrEF patients. The authors concluded that NT-proBNP and hs-Tn improved risk stratification in HFrEF subjects, outperforming other emerging biomarkers tested by the group . A biomaThe above-mentioned studies show a combined prognostic value of using cTn with BNP or NT-proBNP for predicting HF morbidity and mortality, as is also mentioned in the ESC and the AHA guidelines , 17. ComMYBPC3 gene, is a component of the sarcomere thick filament complex along with titin and myosin. cMyBP-C plays an important role in sarcomere structure and maintenance, and regulation of muscle contraction through modulation of actin-myosin cross-bridges (Cardiac myosin-binding protein C (cMyBP-C), encoded by the -bridges , 59. cMy-bridges , 61. cMy-bridges , 62–64. -bridges –67. This-bridges , 68. Pho-bridges –73.As a circulating biomarker, cMyBP-C has first been assessed as a highly sensitive marker for myocardial injury and recent studies provide evidence that cMyBP-C could outperform cTn in the early detection of MI –77. ReascMyBP-C is an important regulatory protein of the cardiac contractile complex. As a biomarker, there is convincing data on its promising potential to be clinically used to improve early rule-in and rule-out of MI. With respect to HF prognostication further trials are warranted to validate the prognostic and diagnostic ability of cMyBP-C.FABP3) gene, is a member of cytoplasmic protein group and is classified as a cardiac cell death marker (Heart type fatty acid binding protein (hFABP), encoded by the fatty acid-binding proteins 3  by Hoffmann et al. investigated the prognostic ability of hFABP when compared to Tn-I in patients suspected of acute HF with a 5-year follow-up period. Higher hFABP levels were associated with all-cause mortality and acute HF related hospitalization at 5-years, and hFABP levels could predict the acute HF related hospitalization better than Tn-I , encoded by l domain . Gal-3 il domain . Hence, l domain . Within l domain –97. Thisl domain –100.p < 0.0001], however this association did not withstand multiple testing or adjustment for NT-proBNP    . Convers = 0.27) . In two = 0.046) .The above information suggests that Gal-3 may well be a biomarker in the setting of HF. Its expression is upregulated in fibrosis, a common phenomenon associated with HF. The tissue of origin remains a matter of debate and thus its lack of cardiac specificity seems to be reflected by a limited prognostic value when compared with more established biomarkers such as NT-proBNP.Growth Differentiation Factor 15 (GDF15), also known as macrophage inhibitory cytokine-1 is a distant member of the transforming growth factor-β cytokine superfamily –107. Then = 1,734) and 12-months follow-up  in HF patients. GDF15 levels were independently associated with risk of death, even after adjustment for BNP, hs-Tn-T, and hs-C reactive protein. Serially increasing GDF15 levels at follow-up were associated with worsening renal function and increase in cardiac strain biomarkers  , the investigators evaluated serial measurements of GDF15 at baseline  . In anotP, Tn-T) .HF causes release of GDF15, whereas the specific tissue of origin is not completely determined. Instead, the utility of GDF15 must be taken as marker for systemic causes or effects of HF. Whether GDF15 allows for specific HF-related prognostication remains matter of debate. We can speculate that in patients with other causes of systemic inflammatory processes, GDF15 may lose its HF-specific prognostic value. Nevertheless, results from clinical trials suggest a promising role of GDF15 as a biomarker in HF prognostication. In this respect, further investigations and validations remain to be undertaken.Soluble suppression of tumorigenicity 2 (sST2), is a member of interleukin (IL)-1 receptor family and is a ligand for IL-33 . IL-33 ip < 0.001); at follow-up: 2.64; (p < 0.001)]. However, the prognostic value of sST2 decreased after adjustment with NT-proBNP  and has been associated with advanced HF  gene might act as biomarkers to identify individuals more susceptible to HF , a disease of the sarcomere, is identified by mutations in MYBPC3 gene encoding cMyBP-C. More than 350 mutations have been identified in the MYBPC3 gene, representing 40–50% of all HCM mutations, making it the most frequently mutated gene in HCM disease  allow functional interpretations of gene network modules . In a res for HF . These hs for HF . For ins protein . Amongsthy to HF . Even throlaemia . Screenirolaemia . Althougrolaemia , 155.The identification of CVD loci has not revolutionized diagnostics or treatment of CVD yet because CVD is a complex multi-genic disease and SNP variants have mainly small effect sizes. As strong genetic biomarkers have not been established for HF, genetic risk scores were a new approach to consolidate the small effect sizes of SNP variants. Initial studies creating genetic risk scores had only limited success due to small size of the initial GWAS, limited computational methods and lack of large datasets for validation and testing . PresentPresently, few gene panel assays are commercially available but have not been applied in clinical settings , 161. EvThough many genetic loci for increased CVD risk have been identified, the heritability of CVD is still largely unknown. One reason is that the functions of the identified loci remain largely elusive. Only 30% of the SNPs were found to modify classic risk factors for CVD and very few affect the protein structure . Most vaPresently, the laboratory methodology for genetic biomarkers is time-consuming, complex, and expensive for clinical routine compared to protein-based biomarkers and currently these genetic biomarkers do not add significant additive value to classic cardiovascular risk factors. However, in a mid- to long-term perspective, genetic biomarkers may provide a unique opportunity for treatment and early risk prediction through lifestyle changes or medication. If genetic biomarkers are combined with classic and clinical risk factors, they can add significant value by helping clinicians to practice personalized medicine at an early point of the disease process .Transcripts of non-coding regions in the genome have been widely implicated in biology. Several subcategories of non-coding RNAs have been described . Of thesmiRNAs are an abundant class of non-coding RNAs of 19–25 nucleotides in length, recognized as evolutionarily conserved RNA molecules that fine-tune protein synthesis by regulating gene expression at the post-transcriptional level . By bindIn vivo findings suggest that specific subsets of miRNAs are dysregulated with different features of CVD  Onlon in EF , 195.Detailed reviews of specific cardiac-enriched  and otheFurther to miRNAs, long non-coding RNAs (lncRNAs) were recently investigated as regulators of protein function . lncRNAsp < 0.001) indicating an association of these SNPs with chronic HF risk and prognosis  that was shown to have a circular shape was described by Chandler et al. in 1964 , whereasomic DNA”. These “omic DNA”. Only duomic DNA”. circRNAomic DNA”, 215. Thomic DNA” and are omic DNA” (Figure omic DNA”. circRNAomic DNA”, 218. InFunctionally, circRNAs appear to influence gene expression in different ways. They act as potent miRNA sponges—decreasing the inhibitory effect of miRNAs on protein synthesis . More reBearing in mind the vast opportunities for disease detection and possibly treatment offered by miRNAs, efforts have been undertaken to evaluate circRNAs for their applicability as biomarkers and disease modifiers. A growing number of studies have reported the involvement of circRNAs across features of CVD, indicating diagnostic potential as well as potential relevance as regulators of biology . SequencThe identification and further exploration of biomolecules suitable as biomarkers for specific disease is a complex process, which requires numerous prerequisites to be met such as detectability in the circulation, reliable quantification methods, pathophysiologic relation to the suspected disease, and many more . ProteinWith respect to HF prognostication, currently the best data is available for NT-proBNP, which has been used in the diagnosis of HF for decades. Its value in HF prognostication has recently been recognized and validation of currently available results seems to be only a matter of time. NT-proBNP has been included into the ESC and AHA guidelines not only because it provides insights into the severity of cardiac damage, but also because current assays allow its detection even at small amounts. But importantly, there is still need for validation of sensitivity and specificity. Large-scale population-based cohort studies applying state-of-the-art laboratory methodology will give the opportunity to identify additional prognostic biomarkers such as genetic biomarkers and validate existing biomarkers for the prognosis of HF. Tissue-specificity seems to play a major role in the application of biomolecules as biomarkers when assessing single markers and it is not surprising that NT-proBNP, as one of only few heart-specific markers, ranks high in the list of biomarker candidates for HF prognostication. On the other hand, given the complex etiology of HF, up until now trials failed to identify single biomarkers in the prognostic assessment of patients with HF. This stretches the importance of the idea to identify complementary biomarkers in order to define biomarker panels as a promising way of improving prognostication of multifactorial disease entities such as HF and argues to include non-organ-specific molecules, which may provide a readout of systemic disease, such as i.e., inflammation, in the seek for biomarkers in HF.AS, TH, and CS wrote the manuscript. TZ and CS edited the manuscript, figures and tables. All authors were responsible for overall editing of the manuscript. All authors contributed to the article and approved the submitted version.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.


Moderately-late preterm (MLP) children  are followed-up within community services, which often use developmental milestones as indicators of delay. We aimed to examine associations of parental report of smiling-age and walking-age with developmental delay upon school entry for MLP and full-term children.n = 514) and walking-age (n = 1210) were recorded in preventive child healthcare. To determine developmental delay at school entry (at age 4) we used the Ages and Stages Questionnaire (ASQ) total and domain scores. We assessed the association of smiling-age and walking-age with dichotomized ASQ-scores, using logistic regression analyses.This study regards a community-based cohort study, including 1241 children. Parent-reported smiling-age (For MLP children, each week later corrected smiling-age was associated with a relative increased likelihood of delays of 31, 43, 36 and 35% in the personal-social, problem-solving, gross motor and general developmental functioning, respectively. Each month later corrected walking-age was associated with a relative increased likelihood of delays of 10, 15 and 13% in the personal-social, gross motor and general developmental functioning, respectively. All corrected smiling-ages and walking-ages were within normal full-term ranges. For full-term children, we only found that later walking-age was associated with delays in the personal-social and gross motor domains.Smiling-age and walking-age are associated with developmental delay in several domains for MLP and full-term children. Professionals could use these milestones to identify children that may benefit from closer monitoring of their development.Clinical Trial Registry name and registration number: controlled-trials.com, ISRCTN80622320. Approximately 10% of all children are born preterm, of which a large majority 80–85%) are moderately-late preterm  . Close m% are modFor full-term children, attainment ages of various developmental milestones have been firmly established,  and studTo the best of our knowledge, for MLP children, attainment of these two important milestones and their value as indicators of developmental delay upon school entry is unknown. Nonetheless, particularly for MLP children, understanding the associations between early developmental milestones and later developmental delay may lead to closer monitoring, enabling earlier identification of developmental delays and offering timely targeted preventive interventions . In the For our study we used data from the Longitudinal Preterm Outcome Project (LOLLIPOP). LOLLIPOP is a community-based cohort including MLP children, as well as early preterm and full-term children. Children were enrolled in this study at age 4. Thirteen PCHCs participated in the study, from which 45,446 children  were screened for eligibility. All children with a GA < 36 weeks were included. After every second preterm child, the next full-term child from the same birth year was selected as a control. The children were included via 13 PCHCs covering 25% of the Dutch population with some overrepresentation of the Eastern half of the Netherlands. All five NICUs operating in this catchment area were included as well. One of the initial aims of the LOLLIPOP study was to construct growth charts for every gestational age week, with a particular focus on MLP children. Therefore, MLP and full-term controls were sampled in a 2:1 ratio.N = 1241). All parents provided written informed consent. The study was approved by the Ethics Review Board of the University Medical Center Groningen (METc 2005/130). All procedures performed in the context of this study were in accordance with ethical standards of our institution and with the 1964 Helsinki Declaration.Upon inclusion, children with major congenital malformations and syndromes were considered ineligible. Of the 2517 eligible children, 1983 participated in LOLLIPOP (response 79%), of which 927 were MLP, 544 were full-term children, and the remaining 512 were early preterm. For the present study, we included all full-term and MLP children within this cohort whose smiling- and/or walking-age had been recorded by PCH professionals  based upon parental report. Parents are not asked beforehand to determine attainment of these two milestones. Around the approximate attainment age, PCH physicians ask whether the milestone is attained and at what age. In general, for full-term children, for smiling this approximate attainment age is 6 weeks and for walking 18 months. We calculated the corrected smiling-age and walking-age by subtracting the number of weeks a child was born too early from the chronological age. We did so for all MLP children.Development at age 4  was assessed by parents using the Dutch version of the Ages and Stages Questionnaire (ASQ) 48 months’ form. The ASQ was completed after informed consent was provided, as part of the LOLLIPOP study; the ASQ is not part of routine care in PCHCs in the Netherlands. The Dutch ASQ is recognized as a valid, reliable, cost-effective, fast and easy way to screen children for developmental delay, with high sensitivity (89%) and acceptable specificity (80%) for the detection of school problems . The ASQGA was extracted from medical files and verified by early ultrasound measurements during pregnancy in over 95% of all cases. Children whose GA could not be reliably established were excluded. Other covariates were gender, ethnicity (defined as Dutch versus non-Dutch), being born small-for-gestational age ,  and mateP-values below 0.05 were considered statistically significant. Analyses were conducted with SPSS version 26.0 .First, we compared background characteristics of MLP and full-term children, using chi- square tests for binary variables and Mann-Whitney-U tests for continuous variables. Next, we compared the median attainment ages of smiling and walking between the two GA categories using Mann-Whitney-U tests. Third, we performed univariable logistic regression analyses, with corrected smiling-age and walking-age as determinants and the dichotomized score on ASQ domains as outcomes. The children who reached the milestones first (after correction for GA in the MLP group) were defined as the reference, to identify the added risk that each week later attainment age would give. We stratified these analyses by GA category. In the final step we performed multivariable logistic regression analyses and included gender, ethnicity, SGA and maternal educational level for found statistically significant associations in the univariable regression analyses. p < 0.001). Children without a recorded walking-age more often had a lower educated mother .Participant characteristics are presented in Table p < 0.001). For walking age, median (range) for full-term children was 14.0  months and for MLP children 13.4  months (p = 0.59). Using corrected ages for MLP children thus resulted in ages that were within the normal ranges for full-term children. In Table In Fig. 14.0 7.5;4.0 monthRegarding walking-age of MLP children, each month later walking-age was associated with a 10, 15 and 13% relative increased likelihood of personal-social and gross motor problems, as well as a general developmental delay, respectively. For full-term children, we also identified increased likelihoods of delays in these domains. Combining the two GA categories in one model resulted in additional increased likelihoods in the communication and fine motor domains. All results remained similar after adjustment for gender, SGA status, maternal educational level and ethnicity, except for the association between walking-age and general developmental delay in full-term children.This study demonstrated that in MLP children each week later corrected smiling-age increased the likelihood of personal social, problem solving, gross motor problems, and general developmental delay at school entry. Similarly, each month later corrected walking age increased the likelihood of personal-social and gross motor problems, and general developmental delay at school entry. Corrected smiling-ages and walking-ages were within the normal ranges of full-term children. For full-term children, we found no associations of smiling-age with developmental delay at school entry, but we did identify increased likelihoods of later walking-age with later personal-social and gross motor domains, and general developmental delay. In our multivariable models most increased likelihoods of developmental delay remained significant after adjustment for other covariates.We found different associations for smiling-age and walking-age with distinct developmental domains at school entry. For a later attainment of smiling we found an increased likelihood of developmental delay for MLP children only. The only further available study by Flensborg-Madsen et al. on smiling reports that for full-term children smiling-age is predictive of IQ at 34 years of age . This coFor a later attainment of walking we found increased likelihoods of general developmental delay, and of delays in gross motor and personal-social functioning, for both full-term and MLP children. Other studies, regarding full-term children, also reported associations of walking-age with IQ and educational level in adolescence and adulthood , 24. ForWe identified several associations between smiling-age, walking-age and several ASQ domains at school entry in MLP children, which may also relate to school readiness of these children. Internationally, the concept of school readiness is often defined as cognitive and behavioral outcomes at school entry  and encoWe found strong associations of outcomes for two milestones with developmental delay at school entry, especially for MLP children, which may indicate the need for more extensive early life monitoring of development. There are several other early life assessments of neurodevelopmental risk in preterm infants, for example the General Movements Assessment and developmental tests such as the Bayley Scales of Infant and Toddler Development. However, in clinical practice, in many countries including the Netherlands, it is not feasible to monitor every (preterm-born) child with such assessments, because of time constraints or requirements of specific expertise. For early preterm children many follow-up programs exist, including extensive neurodevelopmental testing, but for MLP children, such programs are often not cost-effective. Routine PCH assessments based on developmental milestones such as smiling-age and walking-age, take less time and are more feasible in a population-based setting. Potentially, these two milestones could be used as a first step in developmental assessment, with unfavorable outcomes serving as red flags for MLP children requiring a more intense developmental monitoring. This evidently requires further study.Major strengths of our study were that we examined the role of developmental milestones early in life as potential red flags of an increased risk of developmental delay and potential identification of targets for preventive intervention, thereby enhancing chances for closer monitoring, earlier identification and early interventions. Second, we used data from a large community-based cohort, in which PCH data on development were included that had been recorded prospectively from birth onward at regularly scheduled consultations in PCHCs. Because of the community-based character of the LOLLIPOP study, we did not only include the MLP children admitted to a neonatal intensive care unit, but also the relatively “healthy” MLP children. This study creates awareness for developmental risks in MLP children, who do not routinely participate in follow-up programs. We add to the existing evidence by focusing on two important and easily obtainable developmental milestones based on parental report of attainment ages. This differs from using only physician observed attainment, which focuses on whether a milestone has been obtained or not, rather than on the timing of it. Our study shows that parental report of these milestones is associated with developmental delay at school entry. In addition, this is one of the first studies to do so for MLP children, which concerns a rather large group of children. We believe that our findings confirm the feasibility of follow-up with risk assessment using developmental milestones based on parental report in community-based settings.p-values were mostly very small and were also significant with Bonferroni correction.We also recognize the limitations of our study. First, we used parent-reported information both for our determinants and our outcome measure, which may be suboptimal. However, it has been shown that parents know their own children very well and are known to accurately report on developmental milestone attainment . In addiA potential next step for research could include studying whether MLP children with delays on these two developmental milestones  actually experience a developmental delay at school-age. Moreover, studies should focus on associations between developmental milestones and in-depth developmental testing, to identify which domains are most affected. In addition, a more sophisticated prediction model could be developed, for example a dynamic prediction model including these and other milestones, and other relevant characteristics (such as socio-economic status or Apgar score) that are collected at birth and during the life course. Such a model could preferably be used at various ages to estimate risks of developmental delay, repeatedly, enhancing to adjust medical decision making during the life course of these high-risk children.For clinical practice, MLP children with delays on these two developmental milestones may benefit from more extensive follow-up and early interventions. Studies have reported that early intervention indeed improves neurodevelopmental outcomes . Thus, wIn conclusion, corrected smiling-age and walking-age of MLP children are mostly within normal ranges. However, within this MLP group later attainment of these two milestones still is associated with developmental delay on several domains upon school entry. Pediatricians and PCH physicians could use these two developmental milestones as red flags, indicating a need to monitor the children with late attainment ages more closely or offer them more thorough assessments or interventions.


Membrane rafts are dynamic, small (10–200 nm) domains enriched with cholesterol and sphingolipids that compartmentalize cellular processes. Rafts participate in roles essential to the lifecycle of different viral families including virus entry, assembly and/or budding events. Rafts seem to participate in virus attachment and recruitment to the cell surface, as well as the endocytic and non-endocytic mechanisms some viruses use to enter host cells. In this review, we will introduce the specific role of rafts in viral entry and define cellular factors implied in the choice of one entry pathway over the others. Finally, we will summarize the most relevant information about raft participation in the entry process of enveloped and non-enveloped viruses. Membrane rafts have the ability to concentrate or segregate specific elements in order to regulate their interactions with other components. Rafts may induce conformational changes in resident proteins, affecting their activity . BecauseRegarding host–pathogen interactions, membrane rafts have been shown to play a role in viral life cycles, especially in processes like virus entry, assembly and/or budding , 2011. VMembrane rafts are small (10–200 nm), heterogenous, highly dynamic, sterol- and sphingolipid-enriched domains that compartmentalize cellular processes. Small rafts can sometimes be stabilized to form larger platforms through protein-protein and protein-lipid interactions” (o) phase’ (d) phase,” in which lipid molecules are mostly immobile (A consensus definition for a membrane raft  was estaactions” . For mem) phase’ . In thisimmobile . Two typimmobile . The rafimmobile   or “detergent-insoluble glycolipid-enriched membranes” (DIGs). The tight packing of the domains enriched in sphingolipids and cholesterol confers resistance to solubilization with non-ionic detergents  at low temperatures . Due to tergents .The involvement of membrane rafts in viral entry is usually evaluated by the effects of raft-disrupting treatments, which mainly remove cholesterol from the plasma membrane or inhibit its synthesis. Inhibition of virus infection by cholesterol depletion is generally recoverable by the addition of exogenous cholesterol. The most commonly used raft-disrupting compound is methyl-β-cyclodextrin (MβCD), which extracts cholesterol from cells and rafts, abolishing association of raft proteins with DRMs and disrupting raft-regulated cell signaling pathways. However, MβCD not only extracts cholesterol from the plasma membrane, but also from intracellular compartments, thereby disrupting organelle function and structure as well as vesicular transport . Also, eo structure, but rather forms its own lipid microdomain structure  has a high affinity for cholesterol- and sphingolipid-enriched microdomains . SMases catalyze the hydrolysis of SM into ceramide, converting rafts into ceramide-rich platforms (CRPs). Although CRPs can be found in DRMs, ceramide no longer forms part of a raft with Ltructure . Depletitructure , rubellatructure , Influentructure , and heptructure  , receptor for severe acute respiratory syndrome coronavirus (SARS-CoV)  and SARSThe presence of viral particles and/or viral glycoproteins in membrane rafts during virus attachment is another way to demonstrate the involvement of rafts in entry process. For instance, a fraction of the glycoprotein gB of HSV-1 is associated with cell rafts from the moment of attachment and during entry  Table 1Table 1. However, although location of viral particles and/or cell receptors on membrane rafts gives us a lot of information about the entry pathway, it is important to consider that viruses may enter through a region different from the initial attachment site. Virus particles can bind to non-raft membranes, but then shift to raft domains. Vaccinia virus particles bind initially to glycosaminoglycans and laminin in non-raft domains, inducing further interactions with integrin β1 within rafts. The subsequent recruitment of the receptor CD98 into rafts and activation of downstream kinases lead to endocytosis of the virus . In otheEndocytosis is a cellular mechanism by which cells internalize substances from the external environment and can be classified into phagocytosis or pinocytosis. Phagocytosis is generally restricted to specialized cells, such as macrophages, and is typically employed to digest bacteria and/or large particles. Pinocytosis is a non-specific, non-saturable, and non-carrier-mediated form of membrane transport via vesicular uptake of fluids, macromolecules and small pathogens . This laClathrin-mediated endocytosis (CME)  is, to dClathrin-independent endocytosis (CIE) pathways  are cholIn 2001, it was suggested that caveolar vesicles fuse with a newly discovered organelle called a “caveosome” , charactMore recently, an alternative classification system has been established, taking into consideration the role of lipid rafts in endocytosis. Depending on membrane rafts, endocytic pathways may be classified into (i) pathways in which lipid rafts are not present in the endocytic vesicle -CME-; (ii) pathways for which endocytic vesicle can contain rafts and non-raft domains -phagocytosis and macropinocytosis-; and (iii) pathways that take place in membrane rafts – the majority of CIE-. The endocytic vesicles that are formed in lipid rafts can be stabilized by the enrichment of certain proteins, such as caveolin (caveolae-mediated endocytosis) or flotillin (flotillin-dependent endocytosis). Alternatively, endocytic vesicles can be formed into lipid rafts by the action of small guanosine triphosphatases (GTPasas), such as Cdc42 and Arf1 (GRAF1-dependent endocytosis), Arf6 (Arf6-dependent endocytosis) or RhoA (RhoA-dependent endocytosis) .Cell endocytic mechanisms can be exploited by viruses to enter host cells . ReceptoViral entry via endocytic vesicles can occur in raft domains of the plasma membrane. These raft-dependent pathways can be caveolae-mediated or clathrin- and caveolae- independent. Whereas caveolae-mediated endocytosis has been highly studied and reviewed in both enveloped and non-enveloped viruses , non-claMore recently, viral entry mediated by non-clathrin non-caveolae endocytosis in lipid rafts has been especially characterized in adeno-associated virus 2 (AAV2)  infectioIn viruses such as human adenovirus species C (HAdv-C) , rhesus Another example of raft-independent entry is the non-clathrin non-caveolae endocytosis of HIV-1 in polarized trophoblastic cells. Treatment with the cholesterol-sequestering drug filipin severely impaired virus internalization, whereas treatment with MβCD had no impact on this pathway. Part of the reduction in HIV-1 infectivity in the presence of filipin may be related to an indirect effect of the drug on HIV-1 gene expression. Collectively, authors concluded that the pathway requires free membrane cholesterol, and that membrane rafts appear to be involved at later points of virus entry process .Macropinocytosis is a specialized form of CIE that is dependent upon cortical actin ruffling and results in the internalization of large amounts of fluid by enlarged vesicles, denominated macropinosomes . Regulatper se has been demonstrated. For example, in Ebola virus (EBOV) infection  , type C The implication of intact membrane rafts in CME actually occurs at the virus attachment step. For example, cell surface attachment in hepatitis C virus (HCV) -via tetraspanin CD81 and scavenger receptor B type I (SR-BI)  - and thOn the other hand, there is emerging evidence that some viruses take advantage of cross-talk between clathrin- and caveolae-mediated pathways. Specifically, there are studies that propose that JC virus (JCV) , bovine Fusion process is a crucial entry mechanism for certain enveloped viruses. Viral fusion proteins are stimulated by a signal during the attachment at the target cell -such as receptor or co-receptor binding or proton binding in an endosome- promoting a series of conformational changes. The hydrophobic segment known as “fusion peptide” triggers the viral-cell membrane fusion, process which requires cooperation between lipids and proteins . Viral pSeveral studies have shown the importance of cholesterol for viral fusion processes, not only in the cell plasma membrane , but also within the viral envelope. This is the case of HIV-1 , ecotropOrthomyxoviridae, Paramyxoviridae, Filoviridae, and Retroviridae  infections, cholesterol is necessary for fusion, even being proposed as an essential fusion membrane cofactor , and theSince viruses can exploit more than one entry mechanism, even a combination of raft-dependent and -independent processes is possible. One such example is influenza A virus (IAV) , whose mGenerally, a specific viral entry pathway prevails over the others. The choice of primary entry mechanism can sometimes be virus strain-specific. For instance, in keratinocytes, human papillomavirus (HPV) type 31  enters vIn general, the cellular determinants of the route of viral entry are unknown. However, there are studies that have proposed certain cellular factors that determine this choice. For instance, αVβ3-integrin on the cell surface determines which entry pathway is used by HSV-1 ; in its The role of membrane rafts in viral entry is not easy to elucidate. Viral entry is a complex process composed of different steps, and raft domains may not be implicated in all of them. In some cases, raft participation has only been demonstrated during the attachment event, without insight about an involvement in endocytosis or fusion. In other cases, there is a clear dependence between rafts and viral endocytosis, but initial virus binding occurs in non-raft domains. These studies become more complicated due to the fact that one virus can hijack multiple entry mechanisms in the same cell. Moreover, entry pathways can change according to viral strain and cell line, and the reasons for the predominance of one entry pathway over the others are not clear most of the time. Finally, it is important to consider that although many studies analyze the effects of cholesterol depletion in viral entry, cholesterol dependence may not necessarily imply the participation of membrane rafts, but rather need more research to draw conclusions. The same precaution should be taken when extrapolating data obtained from DRMs, as well as when using certain entry controls, such as SV40 or cholera toxin B, which have been shown to exploit different endocytic pathways.Although many questions remain to be answered, current studies have already shown the relevance of membrane rafts as portals for viral entry. Several viruses that hijack membrane rafts to enter the cells are pathogens of public health importance. Knowledge about the entry mechanisms mediated by rafts can help us to understand their life cycles and, as a consequence, may drive forward future discoveries of novel antiviral therapies.IR and RB-M: conceptualization. IR: writing—original draft preparation. IR, RB-M, SA, and JL-G: writing—review and editing. JL-G: project administration. RB-M and JL-G: funding acquisition. All authors have read and agreed to the published version of the manuscript.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.


Whole-body magnetic resonance imaging (WB-MRI) is an imaging method without ionising radiation that can provide WB coverage with a core protocol of essential imaging contrasts in less than 40 minutes, and it can be complemented with sequences to evaluate specific body regions as needed. In many cases, WB-MRI surpasses bone scintigraphy and computed tomography in detecting and characterising lesions, evaluating their response to therapy and in screening of high-risk patients. Consequently, international guidelines now recommend the use of WB-MRI in the management of patients with multiple myeloma, prostate cancer, melanoma and individuals with certain cancer predisposition syndromes. The use of WB-MRI is also growing for metastatic breast cancer, ovarian cancer and lymphoma as well as for cancer screening amongst the general population. In light of the increasing interest from clinicians and patients in WB-MRI as a radiation-free technique for guiding the management of cancer and for cancer screening, we review its technical basis, current international guidelines for its use and key applications. Progreset al . Evidencet al , has ledet al –9. In thet al –15. In lWB-MRI imaging protocols generally include morphological T1- and T2-weighted sequences along with DWI . T1-weigT2-weighted images, acquired using single-shot or half-acquisition turbo spin echo (HASTE) sequences without fat suppression, can be used for the evaluation of disease in organs other than bone  with a gSagittal T1-weighted TSE and fat-saturated (short tau inversion recovery—STIR) T2-weighted TSE images of the whole spine are used for the detection of vertebral metastases, fractures and spinal cord compression , 13.b-values are needed in order to calculate the corresponding apparent diffusion coefficient (ADC) map for image interpretation and disease response assessment [b-value should be at least 50 s/mm2 in order to reduce perfusion-related signals, while a high b-value in the range between 800 and 1,000 s/mm2 is recommended [b-value images, that have intrinsically higher SNR, is one measure for minimising acquisition times.The final essential component of a WB-MRI protocol is a single-shot diffusion-weighted echo-planar imaging sequence. DWI has become central to WB-MRI due to its ability to detect malignant lesions characterised by high cellularity. Acquiring multiple averages of the DWI data during free-breathing is recommended in order to reduce motion artefacts and increase SNR . At leassessment . The lowommended , 21, 22.ommended . The valommended , 25. ObtCoverage of the lung and brain can be incorporated with less than 2 minutes of scanning by using a single breath-hold, short echo-time GRE sequence for evaluation of lung parenchyma , and a fFollowing well-established practices for WB positron emission tomography (PET) and computed tomography (CT), WB-MRI acquisitions span from the vertex to mid-thigh. A distinction is that with the patient lying supine, the arms remain adducted. The acquisition should be extended to the feet when performed for diseases that frequently involve the extremities, such as neurofibromatosis , or as pBoth coronal and axial acquisitions have been used in WB-MRI , 17, 18.WB-MRI can be performed on both 1.5 T and 3 T scanners, but 1.5 T may be preferred when patients have non-removable metallic prostheses. An advantage of 3 T scanners is seen in higher SNR, but the lower homogeneity of the static field can reduce the effectiveness of fat saturation leading to a variable SNR in DWI, and increases the risk of ‘phase-wrapping’ in DIXON scans .The impact of magnetic field inhomogeneity is particularly evident where the superior and inferior limits of successive stations are seen adjacent to each other as happens when viewing the images in anatomic order or in maximum intensity projection (MIP). Attempting to deal with this problem by not shimming the different stations, by applying the same centre frequency to all stations or by limiting the superior-inferior coverage of each station  have larAchieving WB coverage while optimising SNR requires the use of a large number of receiver coils. Given that most modern systems provide a fixed head-coil position, the patient is generally positioned headfirst in the head and neck array coil. In addition, a spine array coil and anterior body coil array(s) are necessary to cover the chest, abdomen and pelvis. If the examination is to be extended to the feet, a lower limb coil should be added in order to maintain a high SNR on the entire body . To avoiImage quality of the Dixon T1- and HASTE T2-weighted images may be improved if the chest and abdomen stations are obtained in breath-hold. The patient should be informed before the examination of the instructions and breath-hold duration. During the examination, they must be able to hear the instructions clearly and communications should be maintained between scans to ensure they are awake when the instructions are given.b-value DW images, rotating around the cranio-caudal axis, allow an ‘at-a-glance’ overview for disease assessment and lesion detection. Typically, these are displayed in inverse grey scale, thus providing an appearance similar to that of PET.Where possible, ‘set-up and go’ acquisition and post-processing should be used to simplify and accelerate the operational workflow for WB-MRI and reduce the scope for operator errors. To facilitate image reading and reporting, we can unify (compose) the different stations of each sequence into single-stack of images with WB coverage. A series of MIPs of the high Relative fat fraction (rF%) maps have emerged as an objective image-based biomarker of disease . Obtaineb-value DWI images:ADC maps are useful for classifying findings and response to therapy , 13. ADChighS and lowS are the signal intensities in the high and low b-value images (highb and lowb), respectively [where ectively .The large number of images produced in each WB-MRI examination complicates extracting the quantitative information provided via rF% and ADC maps. This necessitates considerable time for reading and reporting, and can increase the risk of misinterpretations. Several semi-automatic segmentation techniques have been developed to assist in distinguishing malignant lesions from healthy tissue and benign findings , 39. A rDespite considerable progress, WB-MRI still faces a number of technical and practical challenges. Several of these are tied to the quality of the static and radiofrequency magnetic field homogeneities that are available . When atWB-MRI has entered a clinical domain dominated by bone scan (BS), (CT), PET and the combination—PET/CT. In WB-MRI, morphological images are produced with a choice of contrasts being available, including DWI associated with changes in the cell density, and T1- and T2-weightings that largely reflect fat and water and fat content, while PET contrast derives from metabolic activity of the administered radioactive tracer. Consequently, differences in sensitivity between WB-MRI and PET are typically attributed to mismatches between hypercellularity or chemical content, and altered metabolism in the chemical pathway targeted by the specific PET tracer. WB-MRI examination times tend to be longer than those of PET, but the examination does not necessitate injection of a radioactive tracer, nor the wait for the tracer to achieve adequate biodistribution for imaging.Britain’s National Institute for Health and Care Excellence guidance recommends WB-MRI as first-line imaging for suspected myeloma and include it along with fluorodeoxyglucose (FDG)-PET/CT and spine MRI for monitoring in case of serological relapse or disease progression . The OxfAt initial staging for unfavourable intermediate risk (Gleason Score 4+3) and high-risk PC patients, European Association of Urology (EAU) guidelines recommend at least cross-sectional abdominopelvic imaging and a BS . SimilarFor APC, the ASCO guidelines consider WB-MRI, PET/CT and PET/MRI as alternatives . As pros18F)fluoro-D-glucose, sodium (18F)fluoride, (11C)choline and (18F)choline have been found to perform comparably or worse than MRI and CT for nodal disease, but recent preliminary reports suggest that PET/CT with some (PSMA)-based tracers may permit greater sensitivity without sacrificing specificity [Lymph nodes are another common site of PC metastasis and are thus a concern both in staging and in oligoprogression. In a 2016 study by Larbi et al , only oncificity , 63. Noncificity .Standards for image acquisition, interpretation and reporting for clinical care and clinical trials involving APC patients have recently been defined in the Metastasis Reporting and Data System for Prostate Cancer (MET-RADS-P) guidelines . For repThe German Dermatological Society and the Dermatologic Cooperative Oncology Group , 15 sugg19F-NaF PET-CT (93%) consistent with previous bimodality comparisons [Currently, international guidelines are mixed as to the which WB imaging techniques to apply and under what conditions  in the evaluation of breast cancer (BC) patients  study  monitoreAs BC is the second most common cause of brain metastases , contrasA subgroup of BC patients for whom WB-MRI is seeing increasing use, is that of young BC patients for whom serial treatment monitoring is necessary. This use of WB-MRI is driven by growing awareness of radiation induced risks, especially for those under 35 years of age .WB-MRI is also establishing an important role in the care of pregnant women with BC , 80 wherFor staging and follow-up of ovarian cancer patients, the European Society of Urogenital Radiology guidelines recommend contrast-enhanced chest-abdomen-pelvis CT . EvidencOwing to its high accuracy, FDG-PET/CT is the recommended imaging technique for the staging and follow-up of most common lymphomas (e.g. follicular lymphoma and Hodgkin’s lymphoma) . It has NCCN guidelines recommend the staging of lung cancer with PET/CT and/or total body CT, with the addition of an MRI examination of the brain when needed . The StrESMO and NCCN guidelines both recommend an abdomen-pelvis CT for colon cancer staging, and a chest-abdomen-pelvis CT together with a rectal MRI for rectal cancer staging , 92. TheDue to its spatial resolution and high sensitivity, along with its non-invasive nature and the absence of ionising radiation , WB-MRI According to the American Association for Cancer Research (AACR), as well as a multicentre cohort review involving 13 cohorts and 578 participants, an annual WB-MRI is recommended for patients with LFS as a screening examination , 31. TheFor constitutional mismatch repair deficiency (CMMR-D) syndrome, an annual WB-MRI examination from the age of 6 years has been recommended in a consensus statement by the Care for CMMRD Consortium and the International Biallelic Mismatch Repair Deficiency Consortium . For herThe application of WB-MRI to oncological screening in the general population is still a matter of debate. Several reports have demonstrated the use of WB-MRI in asymptomatic individuals , 98–106,Thanks to a series of improvements in scanner hardware and imaging technique, it is possible to achieve in clinical routine what 20 years ago seemed impossible: a WB-MRI examination that provides a core clinical protocol for WB imaging in little more than half an hour. Continuing developments in imaging strategy and artificial intelligence hold the promise of further improvements and are likely to expand the use cases of WB-MRI in oncology. Existing guidelines demonstrate the central role of WB-MRI examinations with DWI in some oncology applications, but further efforts to standardise acquisition and reporting are warranted to reduce the variation in diagnostic performance.Not applicable.Dr Summers is co-owner of QMRI Tech, a company that provides support for medical physics activities and MRI research.The other authors declare that they have no conflicts of interest.This work was funded by FIEO-CCM, and partially supported by the Italian Ministry of Health with ‘Ricerca Corrente’ and 5x1000 funds. The funding bodies did not participate in the planning, design or execution of the study.