Pathologies of the male urethra are mostly obstructive in nature and require imaging to delineate the lesion type, site, extent and associated abnormality of the urinary bladder. Contrast urethrography (CU) is the gold standard investigation for urethral assessment but has many limitations. Cross-sectional imaging is infrequently used for the evaluation of the urethra but has been gaining importance recently. Multidetector computed tomographic urethrography (MDCTU) has the capability of evaluating the entire length of a male urethra in a single setting and overcomes many technical and patient limitations of CU. Being a novel technique, most radiologists are not familiar with MDCTU and the imaging spectrum of various urethral and bladder pathologies. This pictorial review attempts to present the imaging appearance of the normal male urethra and spectrum of pathological findings, with highlights on its advantages over the CU technique. Sonourethrography has a small field of view, assesses only the anterior urethra and is operator dependent.2 Transrectal voiding sonourethrography3 evaluates the posterior urethra with much patient discomfort. Magnetic resonance imaging is not frequently used because of its cost and complexity.Contrast urethrography (CU) – retrograde urethrography and micturating cystourethrography – evaluates the anterior and posterior male urethra, respectively, and is the gold standard for urethral assessment.4 a contrast-filled urinary bladder. Better sensitivity to the contrast and post-processing of iso-volumetric axial images to obtain reformatted two-dimensional (2D) and 3D images explicitly demonstrate a plethora of urethral pathologies. Comprehensive evaluation of the entire length of the urethral lumen, periurethral, pelvic soft tissues and bones is possible with MDCTU.4Multidetector computed tomographic urethrography (MDCTU) is obtained using a multidetector computed tomographic scanner to acquire fast, thin slices of a distended urethra as the patient voidsThe possibility of post-processing in MDCTU allows the patient to micturate in a comfortable position with representation of non-distorted urethral anatomy, leading to better patient compliance. Therefore, MDCTU proves useful in uncooperative patients or in the following clinical situations:when procedural failure is expected because of technical difficulties: unsuccessful catheterisation, inadequate bladder filling and inability to assume an oblique position during micturition because of a pelvic fracturefollowing suboptimal examination on CU resulting in inadequate urethral evaluation: failure to delineate the pathology, especially of the posterior urethra because of obscuration from the pelvic bones; faint contrast density in the urethra and contrast extravasation into periurethral tissues, hindering urethral visualisationif surgical intervention is planned: improved surgical planning can be done in cases such as pelvic trauma with suspected posterior urethral distraction defects; accurate measurement of the stricture length ensures optimal treatment decisions, especially when associated periurethral diseases such as fistula and false passages are present.Initially, bladder filling is achieved either directly by instillation of contrast (250 millilitres [mL] – 400 mL of 10% diluted ionic or non-ionic contrast media) through a supra-pubic catheter or a Foley’s catheter or indirectly by intravenous contrast administration. Thin axial computed tomography (CT) sections (e.g. 64 × 0.6 with a 64-slice CT) are obtained as the patient voids into a condom catheter in a comfortable position .Multiplanar reformatting (MPR), maximum intensity projection (MIP) and volume rendering technique (VRT) images are used for vivid representation of the urethra and its pathology. Multiplanar reformatting images depict the urethra and periurethral soft tissues, enabling visualisation of normal anatomy and pathology simultaneously. Curved MPR images show the entire length of the curved urethra and thus delineates a stricture, if present. Thick MIP reconstructions clearly depict the capacity, outline of the contrast-filled bladder, vesico-ureteric reflux into the lower ureters as well as the urethral outline and calibre. The volume rendering technique is used to provide a 3D external view of the bladder and urethra. Bone removal algorithms help in the optimal visualisation of the posterior urethra.A 64-slice multidetector computed tomography scanner, Somatom Definition AS , was used to acquire all the scans presented in this review. The various types of images present exquisite details of the common urethral pathologies encountered in a male patient.The urethra can be visualised on VRT , MIP Fi and curvThe VRT and MIP images can be represented with bone subtraction for depicting a clear 3D volumetric view (VRT) of the urethra, whilst the MIP image shows the contrast-filled urethra and bladder as a composite CU image without the overlapping pelvic bones. This provides a clear understanding of any abnormal morphology of the urethra.1  is the result of pelvic fractures or penetrating trauma. Multidetector computed tomographic urethrography reveals a variable path of extravasated contrast material.Intra-peritoneal (10% – 20%) typically results from a direct blow to a distended bladder and demonstrates intra-peritoneal contrast material around the bowel loops, between mesenteric folds and in the paracolic gutters .A fistulous communication between the bladder and an adjacent structure, such as the rectum , colon  or small bowel , is better seen on MDCTU as an irregular contrast-filled tract from the bladder to the adjacent organ. Sometimes, only a nipple-like projection outside the bladder lumen may suggest the presence of a fistulous tract .Additional findings in the periurethral, vesical and pelvic soft tissues and bones may also be observed on MDCTU, including vesico-ureteric reflux , prostat14 whereas in CU, it is less than 1 mSv. Radiation exposure can be further reduced on MDCTU by using a low-dose protocol, single acquisition, mA tube modulation and iterative reconstruction techniques. Although the radiation dose is higher with MDCTU, radiation exposure to the operator can be avoided, unlike in CU.The effective radiation dose on MDCTU varies between 5 millisievert (mSv) and 6 mSv,This pictorial assay apprises radiologists and clinicians about the novel technique of MDCTU, its advantages over CU and appropriate patient selection to justify the increased radiation exposure, a shortcoming associated with it.Multidetector computed tomographic urethrography is capable of comprehensive evaluation of both the anterior and posterior male urethra, periurethral tissues, urinary bladder, pelvic soft tissues and bones in a single scan, thus rendering it an effective diagnostic tool.


Bacterial effector proteins, delivered into host cells by specialized multiprotein secretion systems, are a key mediator of bacterial pathogenesis. Following delivery, they modulate a range of host cellular processes and functions. Strong selective pressures have resulted in bacterial effectors evolving unique structures that can mimic host protein biochemical activity or enable novel and distinct biochemistries. Despite the protein structure-function paradigm, effectors from different bacterial species that share biochemical activities, such as the conjugation of ubiquitin to a substrate, do not necessarily share structural or sequence homology to each other or the eukaryotic proteins that carry out the same function. Furthermore, some bacterial effectors have evolved structural variations to known protein folds which enable different or additional biochemical and physiological functions. Despite the overall low occurrence of intrinsically disordered proteins or regions in prokaryotic proteomes compared to eukaryotes proteomes, bacterial effectors appear to have adopted intrinsically disordered regions that mimic the disordered regions of eukaryotic signaling proteins. In this review, we explore examples of the diverse biochemical properties found in bacterial effectors that enable effector-mediated interference of eukaryotic signaling pathways and ultimately support pathogenesis. Despite challenges in the structural and functional characterisation of effectors, recent progress has been made in understanding the often unusual and fascinating ways in which these virulence factors promote pathogenesis. Nevertheless, continued work is essential to reveal the array of remarkable activities displayed by effectors. The pathogenesis of many Gram-negative bacteria is highly dependent on specialized multiprotein machines that deliver a repertoire of bacterial effectors in a spatiotemporally coordinated manner into the host cell, where they modulate a range of eukaryotic cellular processes. These specialized multiprotein machines are known as secretion systems. Of the seven known secretion systems found in Gram-negative bacteria, the direct delivery of effectors across a host cell membrane can only be achieved by the type III, type IV, and type VI secretion systems  . The typN-acetylglucosamine transferase, NleB, from pathogenic Escherichia coli, modifies bacterial glutathione synthetase (GshB) to promote GshB activity and bacterial survival to oxidative stress  to the Golgi Network  and modulate host cell signaling . Like euIn this review, we will examine common themes of effectors from diverse bacterial species in terms of structure and biochemical activity. We will take examples from several pathogens that utilize type III and type IV secretion systems yet acknowledge that we are unable to review the vast array of effector-mediated functions and biochemical activities. The first group of effectors we will consider are those that have adopted structural similarities to eukaryotic proteins that enable them to mimic the biochemical activities of host proteins. For example, effectors that act as proteases, phosphatases, kinases, glycosylases, and more, have been described. Other bacterial effectors have unique structures that lack homology to our current knowledge of eukaryotic proteins and have interesting biochemical activities that perform unique and alternative PTMs and functions in comparison to those exhibited by normal eukaryotic processes. The final structural property of bacterial effectors we will consider is the occurrence of intrinsically disordered regions (IDRs). In general, prokaryotic proteomes show a low degree of IDRs when compared to eukaryotes . HoweverWe will end our review by highlighting some of the current challenges in characterising the structure and function of effectors in different bacterial species as well as the advances in experimental techniques that may be used to improve our knowledge and characterization of bacterial effectors. Understanding the structures and functions of diverse effectors improves our understanding of the mechanisms that drive bacterial pathogenesis. Furthermore, uncovering unique biochemical mechanisms, which appear to be absent from normal host cell biology, provides potentially new targets for the development of antimicrobials that will not interfere with host biochemistry.Legionella meta-effector and E3 ubiquitin ligase, LubX, acts to spatiotemporally regulate the activity of the effector SidH  effector NleL represent homologous proteins that both exhibit ubiquitin ligase activity. SopA and NleL, which do not share any sequence homology, contain some structural similarities to each other and the host cell protein domain, eukaryotic E3 ubiquitin ligase homologous to E6-AP carboxy terminus (HECT), which mediates the addition of ubiquitin on to target proteins -xxx-glutamine (E) motif, which is found among effectors from diverse species and among TIR (Toll/Interleukin-1 receptor)-domain containing eukaryotic proteins . The Wxxand SifB , and EPEand SifB , EspM  domain that is similar to YopE of Yersinia and ExoS of Pseudomonas aeruginosa, whereas the C-terminal domain shows sequence similarity to the protein tyrosine phosphatase YopH of Yersinia  cellular processes. Interestingly however, bacteria have evolved different types of effector biochemistry that uniquely mediate, target and modify eukaryotic protein ubiquitination. The first example we will consider is the evolution of a family of “novel E3 ligases” (NELs) found among effectors that are structurally unique from mammalian E3 ligases . The NELors SIrP , SspH1 aors SIrP , YopM ofYersinia , and theShigella . AlthougShigella , which eShigella . This hiShigella . WhetherLegionella effector MavC uses a remarkable E1-independent ubiquitin ligation method to block eukaryotic ubiquitination mediated via a specific E2 protein, Ube2N. Although MavC has some structural and functional similarities to the bacterial deamidases Cif from EPEC and CHBP from Burkholderia pseudomallei, MavC also contains a unique “insertion” domain which recognizes and interacts with the Ube2N-ubiquitin conjugate (Ub-Lys92Ube2N) isopeptide crosslink. Functionally, this inactivates the E2-ubiquitin conjugate in the Uev1a:Ube2N-Ub complex, where Uev1a is a non-catalytic partner protein, preventing Lys63-linked poly-ubiquitin chains, and ultimately NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) activation  ubiquitination. SdeA catalyzes the conjugation of ubiquitin to a target protein on serine residues in an E1 and E2 independent manner (R42) with cofactor NAD+. Subsequently, the PDE domain cleaves the phosphodiester bond of ADP-ribosylated ubiquitin, resulting in phosphoribosyl ubiquitin (PR-Ub), which can be linked to the hydroxyl group of serine residues in target substrate proteins  (The t manner . Structuproteins . Interesnd DupB) . Meta-efnd DupB) .Shigella T3SS effector OspG, and its homologous effectors NleH1 and NleH2 from EPEC, are atypical serine/threonine kinases that share sequence homology to eukaryotic kinase subdomains I-VII , inhibiting G protein-coupled receptor signaling in the host cell  that are found in eukaryotic cells and can therefore be reversed by host cell enzymes. In contrast, other effectors have evolved biochemical activities that appear to mediate irreversible PTMs. For example, the  targets . OspF shreaction . Phosphareaction . This lereaction . This isSalmonella, catalyze the transfer of N-acetylglucosamine (GlcNAc)  Rossman like fold, where substrates are retained until the transfer reaction is complete  . In the (GlcNAc) . The con(GlcNAc) . Mechanicomplete . Functiocomplete . In addicomplete . Intrigucomplete . Differecomplete . TherefoVibrio, Legionella, and Bartonella and are also conserved from bacteria to humans  has the ability to remove the phosphocholine group from Rab1, restoring the GTPase to its unmodified state  domains, which typically bind ATP and transfer adenosine monophosphate (AMPylation) onto target proteins , are fouo humans . Howeverost cell . Similarost cell . Unexpeced state . Presumapeptides .via non-canonical mechanisms that have not previously been described, such as PR-ubiquitination and transglutamination. Whereas other effectors mediate variations of known chemistry, for example the GlcNAcylation of non-canonical residues and the NEL effectors functioning like eukaryotic E3 ligases. There are also effectors that mediate unconventional PTMs that have not been seen before or are rare in eukaryotes, such as phosphocholination and irreversible phosphate elimination. Together, these studies provide intriguing perspectives and comparisons to traditional eukaryotic-like PTMs. The analysis of novel effector biochemistry also provides fresh and exciting research potential for the development of anti-microbial therapies that target bacteria-specific mechanisms within the host cell.This section has described examples of bacterial effectors that mediate covalent modifications with interesting biochemistry. We described effectors that carry out PTMs commonly found in both eukaryotes and bacteria, such as phosphorylation as well as PTMs that, despite only occurring in eukaryotes, have been adopted by bacterial effectors in order to manipulate eukaryotic intracellular signaling, such as ubiquitination. Some of these effectors mediate eukaryotic PTMs Although the function of a protein is generally related to its three-dimensional structure, the classical structure-function paradigm is not applicable to all proteins. A lack of globular structure is found in many proteins, including bacterial effectors. Proteins that are unstructured and flexible with little or no secondary and/or tertiary structure under physiological conditions are referred to as intrinsically disordered proteins (IDPs). IDPs range from fully unstructured to partially unstructured proteins, which contain intrinsically disordered regions (IDRs) . In contIn a study consisting of a large group of structures  from 5,434 different proteins and from 910 different organisms, only ~7% contained no disorder and only ~25% of structures had >95% of their sequence resolved . A lack Salmonella enterica effectors, 52% of Pseudomonas syringae effectors and 71% in Xanthomonas subspecies  motif and the CagA multimerization (CM) motif, are essential for the biological activity of CagA as an oncogenic virulence factor that promotes the transformation of gastric epithelial cells into gastric cancer cells  forms a high affinity tri-molecular complex with host proteins N-WASP and insulin receptor tyrosine kinase substrate (IRTKS)  that interacts with N-WASP and the XPxXP motifs that promote interaction with the Src homology 3 (SH3) domain of IRTKS , can be used to determine biomolecular structures at near-atomic resolution. Cryo-EM is mainly limited to larger biomolecules and complexes and has been instrumental in solving the structures of many bacterial secretion systems . HoweverAs the overall number of characterized effectors remains relatively low, it is likely that new effector-mediated biochemistries await discovery. Therefore, these challenges should not deter from continued attempts to structurally and functionally determine effectors from diverse pathogens. This is essential for the continued understanding of how bacterial virulence factors manipulate the host system to promote pathogenesis.Conceptualization: HM and TT. Investigation: HM. Writing—original draft: HM. Reviewing and editing: HM and TT. Supervision: TT. All authors contributed to the article and approved the submitted version.The work of the authors is funded by a BBSRC David Phillips Fellowship (BB/R011834/1) to TLMT.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.


With progressive advancements in cancer detection and treatment, cancer-specific survival has improved dramatically over the past decades. Consequently, long-term health outcomes are increasingly defined by comorbidities such as cardiovascular disease. Importantly, a number of well-established and emerging cancer treatments have been associated with varying degrees of cardiovascular injury that may not emerge until years following the completion of cancer treatment. Of particular concern is the development of cancer treatment related cardiac dysfunction (CTRCD) which is associated with an increased risk of heart failure and high risk of morbidity and mortality. Early detection of CTRCD appears critical for preventing long-term cardiovascular morbidity in cancer survivors. However, current clinical standards for the identification of CTRCD rely on assessments of cardiac function in the resting state. This provides incomplete information about the heart's reserve capacity and may reduce the sensitivity for detecting sub-clinical myocardial injury. Advances in non-invasive imaging techniques have enabled cardiac function to be quantified during exercise thereby providing a novel means of identifying early cardiac dysfunction that has proved useful in several cardiovascular pathologies. The purpose of this narrative review is (1) to discuss the different non-invasive imaging techniques that can be used for quantifying different aspects of cardiac reserve; (2) discuss the findings from studies of cancer patients that have measured cardiac reserve as a marker of CTRCD; and (3) highlight the future directions important knowledge gaps that need to be addressed for cardiac reserve to be effectively integrated into routine monitoring for cancer patients exposed to cardiotoxic therapies. Cancer-related survival has improved substantially over the past few decades due to advances in early detection and improved treatment regimens . This isCancer treatment related cardiac dysfunction can be broadly considered as abnormalities that develop in systolic or diastolic function as a result of exposure to cardiotoxic cancer treatments , 13. It Currently, the cornerstone for detecting CTRCD is the quantification of left-ventricular (LV) systolic function using non-invasive cardiac imaging , 21, 22.cardiac reserve (defined as the increase in cardiac function from rest to peak exercise), which implies that the heart's functional capacity may be more completely determined by assessing its output under the hemodynamic and metabolic demands of exercise. Cardiac reserve assessment does not specifically relate to one parameter of cardiac function , but the premise that measuring the response of these parameters to increased demand overcomes the limitations of the standard approach of measuring cardiac ejection and filling at rest, and trying to extrapolate what this performance will be like under increased demand when patients typically develop symptoms. Indeed, individuals with heart failure demonstrate a reduced augmentation of cardiac function during exercise, even in those who show relatively normal measures of resting cardiac function  measured in middle-aged and older adults without cardiovascular disease show strong, linear associations with risk of incident heart failure (well before resting measures of cardiac function are impaired)  , 50, andmpaired) –53. Whilmpaired) –59. As smpaired) . Intrigue values –65. Furtulations , but no function . This hifunction . In thisAt present there are a number of approaches for the assessment of cardiac reserve. The challenge has been to develop tools with sufficient accuracy to measure cardiac function when challenged by the greater respiratory drive and rapid heart rates encountered during exercise. The first descriptions of cardiac reserve were performed using invasive catheterization and direct ventriculography , 71. HowConsequently, exercise-based cardiac imaging techniques may be useful for characterizing CTRCD. However, these techniques come with a number of advantages and disadvantages that need to be considered when determining their utility for detecting CTRCD , representing the amount of flow passing through a given area which can be used to calculate stroke volume SV; , which cn = 10, 12, and 75) of patients with HFpEF and/or exertional dyspnoea have shown that compared to resting Doppler assessment, the inclusion of E/e' >13–15 during exercise had a sensitivity of 67–90% for detecting an abnormal increase in LV filling pressures or pulmonary capillary wedge pressures  to provide an estimate of LV filling pressures , 82. A hressures . Whilst ressures  found a ressures  also demThe assessment of tricuspid regurgitant velocities using Doppler imaging can be used to estimate changes in systolic (sPAP) and mean pulmonary artery pressures (mPAP), and thereby identify impairment in pulmonary vascular and diastolic reserve. Evaluating the slope of the increase in sPAP relative to CO during exercise is considered a reasonably accurate marker of impaired pulmonary vascular reserve . A revie2D echocardiography provides cross-sectional images of the heart. Integration of image slices from different viewing orientations enables measurement of ventricular dimensions and appreciation of global as well as regional myocardial function. Using 2D echocardiography, ventricular volumes and ejection fraction can be determined using the biplane method of disks, applied on the apical 4- and 2-chamber view (modified Simpson's rule). To facilitate data acquisition during exercise, ventricular volumes can also be determined from a single plane 4-chamber view , with si3D echocardiography has some important theoretical advantages over 1D and 2D approaches for chamber visualization and quantification. The rapid acquisition of pyramidal datasets eliminates the need for geometrical assumptions and errors caused by foreshortened views. However, given that a full volumetric data acquisition is typically performed over at least 4–7 cardiac cycles, so-called “stitching artifacts” may appear between sub-volumes as a result of cardiac translation due to respiration. The recent development of single-beat 3D echocardiography should avoid these stitching artifacts, but, at present, image quality is limited. Whilst showing improved accuracy and repeatability over 2D echocardiography at rest , 97, curOne of the major constraints of using cardiac volume measures, such as LVEF, to assess myocardial performance is that these measures are strongly influenced by loading conditions. Measures of myocardial velocity and deformation (strain and strain rate) have gained increasing acceptance as accurate and reproducible measures of myocardial function. Assessments of GLS and strain rate during exercise has shown the ability to discriminate between athletic and sedentary individuals , identifThe most obvious question to arise after discussing the different echocardiographic techniques is: which is now the best echocardiographic method to assess cardiac volumes and function during exercise? The most commonly used echocardiographic techniques to assess SV and CO are Doppler echocardiography and 2D echocardiography. Christie et al.  comparedRadionuclide angiocardiography is a nuclear imaging technique that can evaluate ventricular performance during exercise. Most often, imaging is performed during supine or upright exercise on a bicycle ergometer. Radionuclide angiocardiography can be differentiated into two key techniques: (1) first-pass radionuclide angiocardiography (FPRNA) and (2) equilibrium radionuclide angiocardiography (ERNA).FPRNA comprises a rapid bolus injection of radiotracer, preferably Technetium99m diethylamine triamine pentaacetic acid because of its renal excretion, hence minimizing radiation exposure . After bIn ERNA, the radioactive tracer is attached to patients' red blood cells or human serum albumin and allowed to reach equilibrium in the vascular system before imaging is performed . Image aAn important advantage of RNA techniques is that measurements of ventricular EF are not dependent on geometrical assumptions, but are based on the assumption that LV volumes are proportional to LV counts throughout the cardiac cycle. Ventricular volumes can be derived by a counts-based or geometrically based method, but these measurements are not routinely performed in a clinical setting. RNA techniques provide very reproducible measurements of EF both at rest and during incremental exercise , 111. ImCMR is generally considered the gold standard technique for measurement of biventricular volumes and cardiac function at rest . Rather To overcome these problems, real-time exCMR imaging has been developed , 113. InAnother CMR method for determination of SV is CMR phase-contrast flow quantification . This teDespite several important advantages over other imaging techniques, CMR also has its limitations. The key disadvantages of exCMR are its high cost and limited availability. Furthermore, exercise imaging with CMR is confined to exercise in the supine body position. Usually, this is performed on a supine cycle ergometer attached to the CMR table, which allows for in-magnet exercise testing. Some groups have used treadmill exercise outside the scanner to achieve maximal cardiovascular stress, followed by post-exercise breath-hold cine imaging . However1-mediated increases in heart rate and contractility, and β2-mediated peripheral vasodilatation, thereby simulating some of the physiologic changes seen during exercise. An advantage of pharmacologic stress over exercise imaging is the improved image quality due to lack of movement. The utility of pharmacologic assessment of cardiac reserve in the heart failure setting has primarily been investigated by stress echocardiography, with studies investigating the utility of pharmacologic stress CMR primarily limited to the diagnosis and prognosis of coronary artery disease  comparing cardiac reserve in pediatric cancer survivors treated with cardiotoxic therapies, largely anthracycline chemotherapy, to matched healthy controls –145. ComThere are two studies that prospectively evaluated changes in exercise cardiac reserve among pediatric cancer survivors previously treated with anthracyclines , 145, hoThe potential role of dobutamine stress has been investigated in several studies of anthracycline-treated pediatric cancer survivors. Cross-sectional studies of asymptomatic pediatric cancer survivors assessed with dobutamine stress echocardiography a number of years following anthracycline treatment (median 5.3–7 years) have shown cancer survivors have reduced posterior LV wall thickening, LVEF, and LV fractional shortening, decreased ratio of early to late peak mitral velocity (E/A), and increased LV wall stress during exercise compared to matched control subjects—demonstrating impairments in both systolic and diastolic reserve , 149. FuOverall, it appears that there is sufficient evidence to suggest cardiac reserve is reduced in pediatric cancer survivors previously treated with cardiotoxic treatments (primarily anthracyclines), however more evidence is needed to prospectively evaluate changes in cardiac reserve following treatment and whether this can predict future CTRCD.n = 30–57) included in this systematic review compared cardiac reserve measured via 2D echocardiography among early stage breast cancer survivors previously treated with anthracyclines to age- and gender-matched controls (P = 0.06) (n = 48) prospective analysis of mixed adult and pediatric patients with advanced cancer undergoing high-dose anthracycline chemotherapy  . One of otherapy . This stThere have also been a handful of studies investigating the role of pharmacologic stress to assess cardiac reserve in adult cancer survivors. Civelli et al.  investigOverall these results suggest cardiac reserve is impaired in adult cancer survivors treated with anthracyclines, and may be a more sensitive marker of subclinical dysfunction given resting function was often relatively preserved. However, due to the relatively small sample sizes, these findings require validation in larger cohorts, which also investigate their potential relationship with other important cardiovascular and health outcomes. Furthermore, the utility of cardiac reserve to detect cardiac dysfunction induced by other cardiotoxic cancer therapies requires further evaluation.Cardiovascular conditions are emerging as a major cause of morbidity and mortality among cancer survivors. Consequently improved detection and treatment of CTRCD can have a profound impact on health outcomes following cancer treatment, however the current approach for identifying CTRCD is largely insensitive to early cardiac dysfunction. The use of non-invasive imaging techniques to assess cardiac function during exercise enables a more wholistic characterization of cardiac function, and may therefore provide a novel means of early identification of CTRCD. Whilst there is emerging data demonstrating patients previously exposed to cardiotoxic chemotherapy and/or radiotherapy have impairments in cardiac reserve (despite relatively preserved resting cardiac dysfunction), there are still a number of gaps that should be addressed before this approach can be incorporated into the clinical setting. There is a need for longitudinal studies to better understand the evolution of impairment in cardiac reserve, and its relationships with other cardiovascular endpoints. Furthermore, given the variety of imaging methods and measures available for quantifying cardiac reserve, there is a particular need to identify the optimal imaging method, measure, and associated cut-points for predicting these outcomes. Ultimately, we are hopeful that existing and new imaging modalities focused on assessing cardiac function during exercise will help to unravel many unresolved questions, ultimately improving morbidity and mortality outcomes for the growing cancer survivor population.All authors contributed to the conception, development, and critical appraisal of this 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.


The newly discovered functional integration of glioma cells into brain networks in mouse models provides groundbreaking insight into glioma aggressiveness and resistance to treatments, also suggesting novel potential therapeutic avenues and targets. In the context of such neuron-to-glioma communication, noninvasive brain modulation techniques traditionally applied to modulate neuronal function in neurological and psychiatric diseases  could now be tested in patients with brain tumors to suppress glioma’s activity and its pathological crosstalk with healthy brain tissue. Key Points• Gliomas have been found to be electrically active and integrate into the brain’s neural network.• Noninvasive brain neuromodulation safely suppressed or enhances the neuronal activity in humans.• Neuromodulation techniques may interfere with this neuron-to-glioma electrical communication.2 According to these seminal studies, gliomas are able to create electrical synapses with surrounding neural tissue and this communication drives tumor cell growth and migration, closing the circle with previously discovered influence of neuronal activity in regulating cancer growth.3 This groundbreaking novel molecular and pathophysiological framework could not only shed light on cancer proliferation and migration pathways, but also provide novel therapeutic opportunities aimed at inhibiting tumor-promoting neural activity. In this regard, noninvasive brain stimulation (NiBS) represents a group of techniques widely used in clinical and research settings to modify neuronal activity by means of transcranial magnetic or electrical fields applied on the scalp. Depending on shape, frequency, and intensity of stimulation, NiBS can lead to neuronal firing as in the case of transcranial magnetic stimulation (TMS), or cause an increase or decrease of membrane excitability as with transcranial direct current stimulation (tDCS). Interestingly, both TMS and tDCS can induce long-lasting effects especially when applied over multiple sessions, thanks to the modulation of synaptic plasticity and excitation/inhibition balance in the targeted regions4 . Moreover, as for the application of neuromodulation to inhibit neuronal activity induced glioma growth, new insight on tumor electrical property supporting a new context for NiBS application has been shared very recently, and still need to be fully received by the clinical neuro-oncological community. The discovery of this “electric” behavior in glioma cells opens intriguing scenarios, including whether NiBS could be used to interrupt the bidirectional signaling between healthy neuronal populations and cancer cells, therefore potentially slowing cancer growth and increasing patient survival.Gliomas have recently been found to contain electrically active tissue integrated into the brain’s neural network.regions4 . Given t2 The neuronal activity-regulated cancer growth acts via a specific pathway involving the synaptic protein neuroligin-3 (NLGN3), whose expression inversely correlates with the survival of patients with glioblastoma.3 Interestingly, NLGN3 was found to induce the expression of numerous synaptic genes in glioma cells, leading the investigators to explore whether glioma cells could also engage in synaptic connections with surrounding neuronal populations. Surprisingly, excitatory synaptic structures between neurons and glioma cells  were observed by two independent groups in the United States and Germany,2 who further revealed how these specific synapses shared the same molecular properties of a classical type of neuron-to-neuron synapses involving calcium-permeable AMPA (ionotropic glutamate) receptors. Electrical stimulation of neurons surroundings glioma cells implanted in mouse models elicited a rapid depolarization in tumor cells displaying such specific synaptic structures. A long-lasting depolarizing current was also observed in a glioma subpopulation, which even more surprisingly spreads through the entire glioma network via gap junctions. The depolarizing current caused a calcium-ion influx that ultimately promoted cancer cell migration and mitosis. These growth-supporting changes were strongly inhibited by pharmacological and genetic blockage of the glutamate synaptic transmission.2While the importance of tumor microenvironment in regulating glioma progression is well established, the dependence of gliomas on neuronal activity has been only recently demonstrated, with data showing how neuronal spiking promotes glioma growth and proliferation in vivo.1 To further shed light on this relation, Monje and colleagues explored fast oscillatory activity in the gamma frequency band  in patients with high-grade gliomas (HGGs) via intraoperative electrocorticography, finding increased high-gamma spectral power in infiltrated brain tissue with respect to macroscopically normal-appearing tissue.1On the other hand, neuron-to-glioma communication does not seem unidirectional. Gliomas, in fact, can increase neuronal spiking via numerous mechanisms, such as synaptogenic factors, glutamate secretion, as well as by reducing the number of inhibitory interneurons in its microenvironment.8 However, further research is needed to disentangle the mechanisms of tumor-induced neuronal hyperexcitability, considering that low-grade glioma (LGG)—and not HGGs, are more prone to cause epilepsy.9In summary, HGGs seem to be tightly integrated in the brain electrical network and further able to create a positive feedback loop with healthy neurons to promote spiking activity, and thus tumor viability. These recent findings are also in line with the evidence of hyperexcitability in glioma patients that frequently leads to seizures, as well as with the observation that progression of epilepsy, when present, is associated to progression of tumor.10), such as glutamatergic and calcium transmission, gene induction,11 brain-derived neurotrophic factor (BDNF)-dependent plasticity and modulation of multiple neurotransmitters13 (4 The application of repeated magnetic stimuli (repetitive TMS – rTMS) over a cortical site using so-called “low-frequency” rTMS protocols (<1Hz) usually causes a long-lasting decrease in cortical activity, whereas high-frequency stimulation  is commonly used to increase local excitability for various purposes, for example, boost cognitive function or modulate network connectivity.4 Recent evidence suggests a definite antidepressant efficacy of high-frequency rTMS over the left DLPFC.14 The rationale of NiBS application in depressed patients stems from the documented imbalance of neuronal activity between the bilateral DLPFC areas.16 In the case of drug-resistant OCD, hyperactivation of the supplementary motor area and/or other components of the cortico-striato-thalamo-cortical circuits is related to patient symptoms, and the application of inhibitory rTMS has been shown to ameliorate the symptoms for at least 6–12 weeks.18 Finally, in migraine with aura, single-pulse TMS is delivered to the occipital cortex at the beginning of symptomatology to interrupt the attack via inhibition of cortical spreading depression.19 When applied over time , TMS is able to induce long-lasting changes in brain connectivity and even affect structural brain properties.20Even if effective modulation of “glioma cells’ excitability” has not been tested via NiBS yet and is difficult to foresee at the present time, NiBS application on surroundings neuronal tissue to modulate excitability and decrease the mitotic stimuli induced in the tumor cells represents a feasible target for future research. Indeed, NiBS acts on multiple levels to induce long-term depression-like effects  in a target muscle recorded via electromyography.21 For language mapping, rTMS is delivered to the language network while participants perform a language task to transiently disrupt speech or other language functions and identify areas to be spared during surgery. Navigated TMS enormously increases the accuracy of TMS for surgical mapping, with its performance being equivalent to the gold standard represented by Direct Cortical Stimulation performed intraoperatively.21 This has led to a consensus about the use of navigated TMS for routine neurosurgical work-up, with identification of standardized protocols.21 Different TMS protocols have led to various TMS performance in terms of functional mapping across studies.22 Importantly, lesions themselves can influence the performance of TMS for surgical mapping, due to location  and type of tumor, considering that the typically slow LGG growth allows for functional plasticity and cortical rearrangement induced by neuronal damage. These changes are not often seen in HGG.22So far, TMS has been used only in the preoperative assessment of patients with brain tumors, to map eloquent cortical regions  by transiently exciting or suppressing their activity and thus guide surgical resection.3 spatial resolution), transiently suppressing local neural activity  could be tested to exert fine control of neuronal activity in regions surroundings the glioma .26 Differently from tDCS, TTF delivers alternating currents that oscillate at extraphysiological frequencies , therefore not affecting neuronal activity but rather impeding cancer cell mitosis by interfering with the formation of microtubules, making it not suitable for selective disruption of neuron-to-glioma communication. In this scenario, neuroimaging techniques  could be used to identify regions that would benefit from the application of inhibitory TMS/tDCS, for example, peri-tumoral regions displaying the strongest link with HGGs. More ambitiously, prediction of tumor spread based on imaging and electrophysiology data could be used to map migration trajectories and potentially prevent tumor expansion by suppressing distant regions at higher probability of tumor migration.On the other hand, tDCS, a recently developed form of NiBS, allows to deliver direct electrical current into the brain via scalp electrodes, with documented effects similar to those of TMS.27 Image-guided, personalized tDCS targeting the solid tumor mass has been recently demonstrated able to transiently modify tumor perfusion in patients with glioblastoma and lung metastasis by our group, both pre- and postsurgery.7 Based on similar evidence on bodily tumors  in which progressive perfusion reduction and necrosis have been observed after repetitive sessions of direct current stimulation delivered via electrodes directly inserted into the tumor, tDCS in gliomas may lead to long-lasting reduction of tumor perfusion and be leveraged to reduce tumor metabolism as well as growth.29 tDCS has also been shown to transiently increase permeability of the blood–brain barrier (BBB) to small and large molecules (up to 70 kDa) in rats and endothelial monolayers, using stimulation intensities similar to those applied in humans (1 mA).30 Enhancement/control of drug delivery into the brain  constitutes one of the major challenges in modern neuro-oncology, with combined tDCS-chemotherapy potentially offering a viable synergy for enhancing local drug delivery by means of modulation of BBB and perfusion in peritumoral regions .On top of modulating neuronal and tumor’s electrical activity, noninvasive approaches to selectively modulate perfusion of intra and peritumoral regions could be complementary to those acting on tumor’s electrical behavior . Gliomas16 tDCS application in patients with tumors is safe and feasible, but personalized biophysical models need to be created in order to realistically estimate current diffusion, as well as to effectively target the lesion and/or the peritumoral areas and reduce the risk for potential collateral effects  usually leads to long-term modulation of neuronal activity in neuropsychiatric populations.20 Along with the strong reduction of proliferation observed in mice models after inhibition of neuron-to-glioma communication,2 a reduction in the amount of tumor growth specifically caused by this mechanism could also be expected (corresponding to ~50% decrease in proliferation2) when accurate modeling and repeated neuromodulatory sessions are administered.Of note, currently available NiBS solutions could be immediately used in the context of clinical trials to explore the therapeutic potential of brain stimulation on brain tumors. As shown in a pilot study aimed at decreasing tumor perfusion, effects . TherefoOverall, growing evidence suggests an opportunity to investigate NiBS as a potential resource to slow down glioma progression, via suppression of tumor-promoting neuronal activity, modulation of perfusion, and enhanced drug permeability. Given the favorable safety profile, efficacy, noninvasiveness, and portability of TMS/tDCS devices, a conceptual framework for NiBS application in brain cancers should be thoroughly discussed and tested.Conflict of interest statement. All authors report no conﬂict of interest.


Cancer Cell, Carrot-Zhang et al. identified ancestry-specific molecular variants and expression changes among patients from The Cancer Genome Atlas (TCGA).1 Their study findings and limitations highlight the critical need to diversify populations represented in cancer genomics research.In a recent issue of  Cancer Cell, Carrot-Zhang et al. identified ancestry-specific molecular variants and expression changes among patients from The Cancer Genome Atlas (TCGA).1 Their study findings and limitations highlight the critical need to diversify populations represented in cancer genomics research.In a recent issue of  Ever since the “Philadelphia chromosome” was characterized as a leukemia-defining translocation, cancer has been considered a genetic disease. Molecular alterations can now inform diagnosis, treatment targets, and predictive and prognostic biomarkers across cancer types. Efforts such as The International Hapmap Project, the 1000 Genomes Project, and the Trans-Omics for Precision Medicine (TOPMed) Program have all emphasized the need to include participants from diverse international backgrounds, yet the vast trove of genomic and transcriptomic data in cancer genomics research continues to overwhelmingly represent patients of European ancestry. Of the major genomic datasets in oncology that offer publicly available ancestry information, The Cancer Genome Atlas (TCGA) includes 83% European ancestry patients compared to 6% each of African and East Asian patients,Prior work on genomic associations between ancestry and cancer has focused largely on the direct relationship between genomic alterations and disparities in outcomes. For example, patients of African ancestry with cancer have worse overall survival in spite of similar or decreased incidence rates relative to patients of European ancestry.Carrot-Zhang and colleagues are among only a handful of groups asking how genetic ancestry may influence cancer development. In their recently published article, they examined associations between ancestry (defined via population-specific genomic markers) and somatic (cancer-only) alterations, DNA methylation sites, messenger RNA (mRNA) expression, and microRNA (miRNA) expression across the 10,678 patients and 33 cancer types represented in TCGA. Their study expanded on prior work to include epigenetic and post-transcriptional regulation as well.PIK3CA mutations with European ancestry and TP53 mutations with African ancestry.,TP53 mutations in patients of African ancestry and subtypes also associates with higher risk of recurrence.Ignoring differential distributions of cancer-specific subtypes among patients of differing ancestral populations  introduces confounding, thus imperiling the translational significance of research findings. The Cancer Genetic Ancestry Atlas developed by Yuan et al. previously associated Also importantly, with their work on methylation and microRNAs, Carrot-Zhang and colleagues raise the larger question of how genes literally interact with geography and environment to influence cancer development. The group consistently saw more significant methylation sites and greater consistency in methylation when examining ancestry within specific cancer types compared to a pan-cancer analysis. Similarly, the largest effect sizes for ancestry-specific differences in miRNA expression were within specific cancer types. DNA methylation markers in cancer have been previously shown to perform well in differentiating geographic origins.The limitation consistently highlighted by Carrot-Zhang et al. across these interesting findings is power. To find genomic variants specific to African ancestry, the authors estimate 50% power to detect an association with a given cancer for a minimum odds ratio of 1.5, assuming a mutation frequency of 0.3. These standards will only detect the most obvious ancestry-specific associations. If we were to design an experiment to seek variants with ancestry-specific cancer associations at 80% power and a type-I error of 0.05, we would ideally need more than 15,000 patients of African ancestry to participate in research. The sum total of patients of African ancestry in TCGA is 651. That estimate does not even fully account for well-known analytic issues in genomics such as shorter linkage disequilibrium in patients of African ancestry (necessitating whole-genome sequencing to find disease-associated variants) and lack of full representation of African-specific variants in the reference human genome.every cancer patient in the world using genomic research, but also to use science and technology to promote equity.In the United States, we are now being asked to face the inequity in our healthcare system head-on, driven by the concurrent pandemics of systemic racism and COVID-19. Vulnerable populations face significant potential harm both from the growing global burden of cancer and the fact that the majority of individuals currently diagnosed with cancer will not benefit from either precision oncology-based preventative risk assessment or targeted therapies. Scientific collaborations and mutually beneficial international partnerships at intersection of patient care and research can be leveraged to actively engage diverse populations of patients in genetics research across racial, geographic, and economic barriers. Now more than at any time in history, we have the responsibility and capacity not only to ask how we can best serve


Lipomatous metaplasia is an infrequently discussed condition characterized by adipose tissue replacing scar tissue from ischemic events. Lipomatous metaplasia specifically of the myocardium is an adverse physiological result of myocardial infarction. In the past, several different imaging and diagnostic techniques were utilized to recognize lipomatous metaplasia of the myocardium. The aim of this study is to discuss an individual case with this condition to highlight several key aspects that are under-discussed in current literature, such as determining the most suitable modality for the recognition of lipomatous metaplasia. The clinical significance of lipomatous metaplasia remained unclear for a long time owing to the relatively little amount of literature about the topic in the past. More recently, however, there have been a few studies in the literature highlighting the association between lipomatous metaplasia and significant adverse cardiac conditions such as ventricular arrhythmia, infarct size, and heart failure . HoweverWe present a case of left ventricular (LV) lipomatous metaplasia after myocardial infarction evaluated with cardiac magnetic resonance imaging. A 56-year-old male with anterior myocardial infarction eight years ago presented with a transient ischemic attack. The patient underwent a transthoracic echocardiogram as part of the diagnostic evaluation, which suggested possible LV thrombus. He was referred to cardiac MRI to assess for possible LV thrombus and to quantify the LV function.Original cardiac MRI showed moderately impaired LV systolic function with hypokinesis of the mid to apical anteroseptal wall. There was a linear high signal lesion with surrounding low signal chemical shift artifact in balanced steady-state free precession (SSFP) cine sequences in the mid anteroseptum, mid anterior, and apical septal segments Figures , 1D. T1-Following a myocardial infarction, myofibroblasts lay connective tissue that serves as a protective agent against future myocardial rupture and prevents dilation of the infarcted area . HoweverThe bright signal in T1-weighted images without fat suppression and high signal lesion with chemical shift artifact in balanced SSFP sequences show lipomatous metaplasia without intravenous contrast media. Therefore, cardiac MRI, with its high contrast resolution capabilities and lack of ionizing radiation, is the most suitable modality to identify lipomatous metaplasia of the myocardium.


In general, trunk muscles onset of activity did not significantly differ between the groups. On the contrary, kayakers/canoeists showed higher RER mean values in all the observed muscles (p < 0.041), except in multifidus muscle during self-inflicted movements. Similarly, higher RER variability was observed in the majority of the observed muscles among kayakers/canoeists. Higher RER among kayakers/canoeists could represent a protective mechanism that ensures spine stability and prevents low back pain. Trunk stability functions play an important role in sport and everyday movements. The aim of this study was to analyze trunk strength, trunk muscles onset of activity, and rate of electromyographic rise (RER) in the case of self-inflicted and unexpected trunk loading. Thirty-two healthy young adults (16 elite kayakers/canoeists and 16 non-athletes) were measured with a multi-purpose diagnostic machine. Trunk strength was assessed in standing position. Trunk muscles onset of activity and RER were assessed through unexpected loading over the hands and rapid shoulder flexion, respectively. In comparison with non-athletes, kayakers/canoeists did not significantly differ in trunk strength and showed lower trunk extension/flexion strength ratio ( Elite athletes who compete in agility-based sports demonstrate greater strength and power outputs than endurance trained athletes or non-athletes . KayakinThe level of spinal stability depends on several factors. One of those is neuro-muscular control . AnticipWhen a sudden perturbation occurs to the spine, PRRs provide the first line of defense to ensure trunk stability . AlteredIn addition to quick onset of muscles activity, the rate of force development provides an important basis for spinal stability . The ratThe knowledge about the effectiveness of long-term training on trunk muscles onset of activity and RER the in case of unexpected and expected trunk loading in elite athletes is very limited. To the authors knowledge, there is no study that has investigated the effect of combined trunk sensory-motor training and upper body resistance exercise, such as in the case of kayaking and canoeing, on trunk muscles RER in elite athletes. In the present study, we tested the hypothesis that long-term wild water kayak/canoe practice and associated strength and conditioning training increases trunk strength and trunk muscles onset of activity and RER in the case of self-inflicted and unexpected trunk loading.The study was cross sectional, where we investigated trunk stability of elite kayakers/canoeists and physically inactive subjects. We hypothesized that long-term wild water kayak/canoe practice increases strength of trunk muscle groups as measured per trunk maximal isometric voluntary contractions (MIVC) in frontal  and sagittal planes (flexion and extension) and improves trunk stability responses. Trunk stability was assessed via muscles onset of activity and RER of several trunk muscles, triggered by self-inflicted and unexpected external loading.Thirty-two healthy young adults participated in the study. Sixteen subjects, members of the Slovenian national wild water kayak and canoe team (kayakers/canoeists), with a minimum of 4 years of regular training (average 3 times per week) and sixteen subjects without regular physical activity (non-athletes) took part. Inclusion criteria were controlled via self-reported questionnaire and were confirmed by athletes’ coaches. Eleven kayakers/canoeists had history of LBP. The structure of the participants, including age, gender, body mass, and body height is presented in A commercial multi-purpose trunk diagnostic machine  was used to measure trunk isometric strength  and trunThe data on trunk muscles PRRs were provided by the system which enables unexpected external loading over the hands  Figure . SubjectTo obtain the data from trunk muscles APAs, rapid shoulder flexion maneuver was used. All subjects handled a stick (300 g) which incorporated an accelerometer and were instructed to stand relaxed with feet parallel at hip width and arms extended in front of the hips. The subjects’ task was to flex the shoulders to 90° as fast as possible after ~2 s, following the acoustic signal, which randomly occurred between every 6 to 12 s. After rapid shoulder flexion and ~1 s of holding the accelerometer at eye level, the subjects slowly returned it into the initial position and waited for the next acoustic signal. In both PRR and APA, the subjects performed 2 sets of 10 repetitions (~1 min rest between sets).Electrical activity of trunk muscles was measured with surface EMG. EMG signals were 1500-times amplified  and captured via an analog-digital card  with a frequency of 4000 Hz. An anti-aliasing analog filter was implemented using a low-pass filter with a bandwidth of 1 kHz. Signal acquisition and processing was done by custom software . All signals were displayed in real time and stored in a personal computer for further analysis. In order to measure muscle activation during both stability tasks, we used the bipolar setup of surface EMG pairs of electrodes . A pair of electrodes were embedded in a thin plastic plate, enabling good fixation to the body using two-sided adhesive tape and placed in accordance with previous studies  on obliqCustom developed software  was used for signal post-processing. For MIVC assessment, only the repetition with the highest mean force output within 1 s time interval was included into the further analysis. The vertical center-to-center distance between the two bars represented the lever arm, used for torque calculation in the MIVC trials (Torque (Nm) = Force (N) × Lever arm (m)). The onset of trunk muscles activity during PRR and APA analyses were defined by a computer protocol and represented the point when the target muscle EMG amplitude increased by two standard deviations above the baseline value . The latp < 0.05 and effect size (ES) estimation  is presented. Statistical analyses were done in SPSS .The normality of distribution and homogeneity of variances of all outcome variables were verified by Shapiro–Wilk and Levene’s test, respectively. In the case of normal distribution, the T-test for independent samples was used to test the differences between the two groups of subjects. When variables were not normally distributed, we used a nonparametric, Mann–Whitney test. To avoid type I error, we corrected p-values for multiple pairwise comparisons using the Benjamini–Hochberg correction method. Results (mean and variability) are reported as mean ± standard deviation. The level of statistical significance was set to All results are presented in In the case of PRR, mean and variability values of trunk muscles onset of activity did not significantly differ between kayakers/canoeists and non-athletes in any of the observed muscles. In contrast with muscles onset of activity, mean values of RER and variability of RER differ significantly between the groups among all muscles, except in variability of MF.In the case of APA, mean values of trunk muscles onset of activity did not significantly differ between kayakers/canoeists and non-athletes in any of the observed muscles except ESR. Variability of trunk muscles onset of activity was significantly higher among non-athletes in ESR while MF, ESL, and OE did not significantly differ between the groups.RER mean values were significantly higher among kayakers/canoeists in all observed muscles except in MF. Similarly, kayakers/canoeists showed higher RERvariability in all observed muscles except in ESR and MF.The purpose of our study was to investigate trunk strength and trunk stability functions between elite kayakers/canoeists and physically inactive subjects. We hypothesized that in comparison with physically inactive subjects, kayakers/canoeists will express greater trunk strength output, earlier muscles onset of activity, and higher RER during APA and PRR tests. The results only partly support our hypothesis. Elite kayakers/canoeists showed significantly higher RER mean values . Trunk strength and trunk muscles onset of activity did not significantly differ between the groups.Kayakers/canoeists who participated in our study performed on average 11 training sessions per week and did not significantly differ in maximal torque values from non-athletes. These surprising results could be explained in several ways. The time that paddlers need to complete their racing course indicates that wild water kayaking/canoeing has an important aerobic component. Training that produces muscle fatigue favors slow muscle fibers, which could affect maximal torque production. A history of LBP, which was present in the majority of our kayakers/canoeists, could represent another trigger for a decreased peak torque outcome. Hodges and Richardson  demonstrTrunk sudden loading showed that kayakers/canoeists had 13.3%/s to 9.3%/s higher RER of back muscles than non-athletes. The latter finding is in accordance with the literature, where investigators demonstrated greater neural excitability during the early phase of rate of force development after high intensity strength training . BesidesTo the authors knowledge, there has been no study that demonstrated improved muscles onset of activity after exercise in healthy adults . SimilarIn comparison with mean values, a variability of RER and muscles onset of activity is not well understood. Our results showed that kayakers/canoeists had significantly higher RER variability in the majority of analyzed muscles. Pain , nerves Our study has several limitations which relate to group homogeneity and familiarization with the testing protocol. The majority of kayakers/canoeists tested in our study had a history of LBP, which could result in decreased torque output and delayed reflex response. The subjects did not undergo a separate preliminary learning visit (familiarization with the equipment and testing protocol), which could influence lower reliability of outcome force values.Higher RER among kayakers/canoeists could represent a protective mechanism that ensures spine stability and prevents LBP. Unstable sitting with additional pulling exercises should be a subject for future research due to its potential to develop proximal stability in young adults. Despite the onset of muscles activity, future research should investigate how fast muscles develop strength in conditions of unexpected trunk loading.


It remains unclear whether infection events before entering end stage renal disease (ESRD) have a long-term negative impact on patients with advanced chronic kidney disease (CKD) who survive to permanent dialysis. We enrolled 62,872 patients with advanced CKD who transitioned to maintenance dialysis between January 1, 2004 and December 31, 2013. We used multivariable Cox as well as Fine and Gray models to determine the association of pre-dialysis infection exposure with all-cause mortality after starting dialysis. Compared with no infection during advanced CKD, the presence of infection exposure during that period was independently associated with a higher risk of all-cause mortality in the first year of dialysis  and also during the entire follow-up period . The increased risks of all-cause mortality increased incrementally with higher annual number of infections during advanced CKD. Similar results were found for all other adverse outcomes, e.g. post-ESRD infection-related hospitalization and major cardiac and cerebrovascular events. In conclusion, infection events during advanced CKD was associated with increased risks of adverse outcomes after dialysis has been started. Timely interventions in such a vulnerable group may help attenuate these risks. Other than cardiovascular causes, approximately 50% of mortality in patients with CKD can be attributed to non-cardiovascular causes; infection is now increasingly recognized as one of these causes, particularly as some such infection events may be preventable5. Infection is also a common cause of hospitalization in patients with CKD and studies have shown a strong graded association between the incidence of infection and reduced kidney function9.Advanced chronic kidney disease (CKD) is associated with a marked increase in the risk of all-cause mortality and morbidity, frequently necessitating hospitalization10 and 21%–34% were readmitted within 30 days13, and even that IRH increased the risk of subsequent cardiovascular events14, cumulatively constituting a substantial burden on the health care system. Hence, identifying dialysis patients at risk of IRH is of paramount importance.Infection events in patients receiving dialysis not only contributes to a higher risk of death but is also associated with substantial morbidity. For example, research has reported that 15.3% of patients with infection-related hospitalization (IRH) required an intensive care unit stay while 28.6% required prolonged hospitalization15. However, it remains unclear whether infection events before entering ESRD have a long-term negative impact on patients with advanced CKD who survive to permanent dialysis. To address this knowledge gap, we investigated the association of infection exposure during advanced CKD and adverse outcomes, e.g. all-cause mortality, recurrent IRH, major cardiac and cerebrovascular events (MACCE), after dialysis initiation by using a nationwide representative population with advanced CKD transitioning to ESRD. We hypothesized that infection exposure in advanced CKD might not only lead to a higher risk of adverse outcomes before ESRD but also have a persistently negative impact after transitioning to permanent dialysis.Few studies have addressed the consequences of an infection event in non-dialysis patients with advanced CKD. A recent analysis of the Canadian prospective cohort (CanPREDDICT) comprising 2,370 patients with advanced CKD showed that an infection episode was independently associated with an increased risk of end-stage renal disease (ESRD) or other adverse outcome before dialysis, such as cardiovascular events and deathThe study population selection process is shown in Fig. Table Figure There were 25,475 (40.5%) deaths during a mean follow-up of 3.6 years (standard deviation: 2.4 years) following dialysis initiation. As shown in Table After starting dialysis, 34,711 (55.2%) patients experienced at least one IRH during the entire follow-up, with a crude incidence rate of 22.9 events per 100 person-years. Among the patients who experienced IRH, 17,342 (50%) of them had it during their first year of dialysis. The infection group had significantly higher cumulative incidences  into four quartiles based on annual number of infections during pre-dialysis advanced CKD. As shown in Table In subgroup analyses, the pattern of associations between pre-ESRD infection exposure and post-ESRD IRH was generally consistent across selected subgroups. However, age and dialysis modalities significantly modified this association: the effect of pre-ESRD infection exposure on the risk of post-ESRD IRH was significantly greater among the older patients and those with hemodialysis, particularly among patients with tunneled-catheter as their initial dialysis access Fig. .Figure 4During follow-up, 20,472 32.6%) patients experienced MACCE, including 13,072 cardiovascular deaths. The presence of pre-ESRD infection exposure was associated with a slightly higher risk of MACCE compared with the absence of any infection episodes . Little is known about the long-term negative impact of infection events or recurrent infections among advanced CKD patients who survive to permanent dialysis, particularly among Asians, who appear to have higher rates of entering permanent dialysis16. Herein, we provide further evidence of an association between infection exposure during advanced CKD and post-ESRD adverse outcomes irrespective of all-cause mortality, IRH, or MACCE.Accumulating evidence indicates that infection is a frequent event in patients with non-dialysis advanced CKD and that reduced estimated glomerular filtration rate (eGFR) is associated with a higher risk of subsequent short-term mortality. In a study of 25,675 participants from a single Canadian health region, individuals with eGFRs of less than 30 mL/min/1.73 m17. Therefore, early identification of patients with a higher risk of IRH would likely minimize the overall health care expenditure on dialysis patients, as each IRH can spiral into a vicious cycle resulting in substantial adverse consequences, including worsening nutritional status18, readmission13, and cardiovascular event14. Similar to previous studies, we found that older age, diabetes, heart failure, chronic obstructive pulmonary disease, and prior cerebrovascular disease are risk factors for IRH in incident dialysis patients irrespective of their initial dialysis modality20. The finding that catheter as initial vascular access was associated with a higher risk of IRH is also consistent with previous observations21. In addition, our results extend observation of Drew et al.22, showing that dementia can independently contribute to a higher risk of not only death but also IRH. Furthermore, we report the novel finding that after adjustment for relevant confounders, the presence of any infection event during advanced CKD was associated with a 30% higher risk of post-ESRD IRH.Our finding regarding the substantial burden of infection in dialysis patients is consistent with the results of a previous analysis of 333,453 incident dialysis patients from the U.S. Renal Data System, which showed a 31% cumulative incidence rate of IRH in the first year and 52.5% at 3 years23, cardiovascular medication nonadherence24, and abrupt decline in kidney function25, have a sustained impact on post-ESRD outcome. Our report adds to this literature by elucidating the impact of pre-dialysis infection. The aggravated negative impact of infection exposure we identified in the first year of dialysis therapy also supports the notion that incident dialysis patients experience the highest morbidity and mortality within the first year after starting dialysis26. This observation raises the possibility that infection events during advanced CKD directly affects clinical outcomes or that infection events are simply a surrogate marker for the severity of uremia that itself affects clinical outcomes. However, our study showed that the negative impact of infection exposure was not only restricted to the first year of dialysis but remained significant throughout the entire mean 3.6 years of follow-up period, indicating that uremia alone is not sufficient to interpret our whole results. Notably, Fig. 27. As infection or other cause related AKI might confound our findings, we repeated our primary analysis excluding patients who had AKI during advanced CKD period and the effect estimates of the infection exposure were similar.Our findings for the short- and long-term negative impact of infection events during advanced CKD on post-ESRD outcome expand on the emerging theory that pre-ESRD conditions, such as blood pressure control29. Notably, this link is further supported by another finding of the current study, namely the independent association between pre-dialysis infection exposure and MACCE after dialysis initiation.The underlying mechanisms linking infection events during advanced CKD to a higher risk of post-ESRD IRH or other adverse outcomes are likely to be multifactorial. In our study, the patients with advanced CKD who experienced at least one infection event had a higher prevalence of comorbidities. The progression of these comorbidities may conceivably serve as a link between pre-dialysis infection event and post-ESRD adverse outcomes. Alternatively, any infection event during advanced CKD may serve as a marker for patients with particularly poor control of these comorbidities. However, after adjustment for all the studied comorbidities, the risk of post-ESRD adverse outcomes was attenuated but remained statistically significant, supporting the idea that infections may trigger other risk factors, such as hypercatabolic state or chronic inflammation, leading to worse outcomes. Systemic inflammation has been shown to contribute to the link between infection and cardiovascular events31. Notably, our study found that a higher number of nephrologist visits during advanced CKD was associated with a lower risk of post-ESRD IRH, irrespective dialysis modality. Our finding that a higher risk of post-ESRD IRH is linked with pre-dialysis infection exposure among older patients and patients using tunneled-catheter is also supported by previous reports21, suggesting timely arteriovenous fistula creation. Moreover, incident dialysis patients with infection exposure or recurrent infections during advanced CKD appear particularly vulnerable to infections or other adverse events and may benefit from timely preventive strategies, such as nutrition resilience assessment32 and/or nutrition supplementation33, immunization against influenza and pneumococcus35, blood stream infection prevention collaborative interventions36, or appropriate management of comorbidities37. Further research is needed to confirm the beneficial effect of the aforementioned multifaceted interventions for such high-risk patients. Although this study provides novel information on the relationship between pre-dialysis infection exposure and post-ESRD adverse outcomes, they must be weighed against the potential limitations of the investigation. First, we excluded advanced CKD patients with a malignancy, an autoimmune disease, liver cirrhosis, or history of organ transplant because they may have had other factors linking infection and post-ESRD adverse outcomes. Therefore, our results may not be generalizable to the entire dialysis population. Second, our study design raises the possibility of selection bias as patients needed to survive those infection events and initiate dialysis to be included in the study. Third, we defined infection events by identifying only hospitalization and emergency department visits but some patients with a mild infection may have been treated in the outpatient setting, which led to underestimate the infection events. However, some disease can mimic a mild infection at initial presentation and those cases are difficult to ascertain due to either uncertain diagnostic accuracy or lack of definite information of infection type, potentially introducing misclassification bias. Fourth, our study was limited by the use of only principal discharge diagnoses to define infections; the true incidence of infection events may have been underestimated. We used diagnostic codes rather than validated clinical criteria to ascertain infection types, potentially resulting in some misclassifications. However, the primary objective of this study was to heighten awareness among clinicians regarding the significance of pre-dialysis infection events, like pre-dialysis cardiovascular disease, as potential risk factors for post-ESRD adverse outcomes and thus deserving of routine assessment. As such, misclassifications may not affect the relevance or accuracy of our results. Finally, although we adjusted for a large number of patient characteristics, we cannot rule out the possibility of residual confounding such as baseline nutritional status, exact eGFR at enrollment and speed of eGFR decline, or vaccination status. The observational nature of the study also makes it impossible to prove a causal link between the occurrence of infections and adverse outcome later on, meaning that the results should be regarded as hypothesis generating only and require further investigation.Another factor involved in the higher risk of post-ESRD adverse outcomes might be the result of insufficient handling of these advanced CKD patients after an infection event, potentially highlighting the importance of early intervention for these populations. Early referral to a nephrologist after any infection event in a patient with advanced CKD might be necessary because nephrologists are more likely to comprehensively manage worsening nutritional status, anemia, and volume status complicated by an infection event. Several observational studies have demonstrated that the quality of pre-dialysis CKD care independently predicts post-dialysis mortalityIn conclusion, the results of this study indicated that infection is a frequent event in patients with non-dialysis advanced CKD and that infection exposure during advanced CKD can lead to higher risks of post-ESRD adverse outcomes irrespective of all-cause mortality, IRH, or MACCE. Timely multifaceted preventive strategies among such high-risk incident dialysis patients may lead to improved outcomes and a lower burden on the health care system.This study was conducted in accordance with the Declaration of Helsinki. Because no identifiable personal information is included in the NHIRD, the Research Ethics Committee agreed that no informed consent was required. All experimental protocols were performed following the relevant guidelines and was approved by the Institutional Review Board of Chang Gung Memorial Hospital (IRB No.201701186B0).2or less and a hematocrit level below 28%. This definition of advanced CKD has been widely reported in previous NHIRD-based studies39. In addition, when patients with advanced CKD start permanent dialysis, they can receive a catastrophic illness certificate verified by the Bureau of National Health Insurance, exempting them from related copayments. Thus, the ESRD registry in the NHIRD is notably comprehensive and our selected cohort was highly representative of patients with advanced CKD who entered permanent dialysis.We analyzed longitudinal data from Taiwan’s National Health Insurance Research Database (NHIRD), which contains anonymized health care information collected prospectively from approximately 99.9% of Taiwan’s population. Only patients who had advanced CKD and then started permanent dialysis were included as the source population. Hence, we selected individuals who had a primary diagnosis of CKD and received erythropoiesis-stimulating agent (ESA) treatment. According to the reimbursement regulations of Taiwan’s National Health Insurance program, ESA is to be initiated when patients with CKD have an eGFR of 15 mL/min/1.73 m12. To avoid double counting of the same infection, the infections recorded in emergency departments and those recorded for hospitalization were combined into one single infection episode if the admission date was within two weeks of the emergency visit date.The primary exposure of interest was the number of infection episodes during pre-dialysis advanced CKD. An episode of infection was ascertained by identifying either hospitalizations or emergency department visits with a principal discharge diagnosis of selected infection-related International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes as indicated previously  by using the independent sample t test. The categorical data between groups were compared using the chi-square test. The association between infection exposure prior to ESRD transition and risk of all-cause mortality was investigated using univariate and multivariable Cox proportional hazard models. The association between infection exposure and risk of other time to event outcomes  was studied using a Fine and Gray subdistribution hazard model in which all-cause mortality during follow-up was a competing risk. Furthermore, to determine the robustness of our results and as a sensitivity analysis, we analyzed the risk of post-ESRD adverse outcomes according to four quartiles based on the annual number of infection episodes during pre-dialysis advanced CKD. We then examined linear trends by modeling the quartiles of these infection exposures as a continuous variable with and without adjustment for covariates. To compare the effect of pre-dialysis infection exposure on early and late post-ESRD adverse outcomes, the analyses were performed with the follow-up time restricted to the first year or with the entire follow-up period. The covariates adjusted for in the multivariable analyses were age, sex, CKD duration, number of nephrologist outpatient visits in the previous year, dialysis modality, 11 baseline comorbidities, 14 medications, and the index year .A sensitivity analysis was done by excluding patients who had AKI during advanced CKD because rapid decline of renal function caused by infection or other etiology might confound the primary analysis. At last, we also conducted subgroup analyses to examine whether the hazard of pre-dialysis infection exposure was consistent across different levels of the 4 pre-specified subgroups . A two-sided P value of less than 0.05 was considered statistically significant and no adjustment for multiple testing (multiplicity) was made. All statistical analyses were performed using SAS version 9.4 , including the procedure ‘phreg’ for survival analysis and the macro ‘%cif’ for cumulative incidence functions.Supplementary information.


A new entity termed multilayered pigment epithelial detachment is seen to occur with the use of multiple intravitreal anti-VEGF agents. A distinct appearance of a spindle-shaped elevation with bands of hyporeflective and hyperreflective tissue is seen on optical coherence tomography. We describe a novel finding on optical coherence tomography angiography which includes a large type 1 choroidal neovascular membrane underlying this elevation. A large vascular network is seen. It is thought to be protective in nature and may prevent further degeneration. Neovascular age-related macular degeneration (AMD) can present with various types of retinal pigment epithelial detachments (PED). In the era of dye-based angiography with fluorescein (FA) or indocyanine green (ICGA) dye, they were broadly classified into serous or fibrovascular PED, wherein serous PED showed a smooth filling pattern, and fibrovascular PED showed a notched appearance on FA or a hot spot on ICGA. With the advent of optical coherence tomography (OCT), exact three-dimensional structural details were revealed with better resolution and higher depth penetration. With this knowledge, further morphologic classifications were made which divided the PED into fibrovascular PED, vascular serous PED, drusenoid PED, etc. More recently, another term called multilayered PED has been coined . This teWe imaged two patients with neovascular AMD who had a history of treatment with anti-vascular endothelial growth factor (VEGF) injections. They included a 48-year-old female who had received 2 injections of bevacizumab in both eyes before the presentation to us. Her vision was 20/30 in both eyes. The macular area showed a solid yellowish-orange colored subretinal elevation in both eyes, surrounded with patchy areas of grey and a few small black pigmented patches of superficial scarring (Figure 1A, B Another case was that of a 77-year-old man with a history of 6 anti-VEGF injections in the right eye and 8 in the left eye. His visual acuity was 20/200 with a fibrovascular PED in both eyes. The retinal examination revealed a slightly raised, yellowish subretinal lesion with a few pigmented patches superiorly. The left eye showed an orange-red subretinal mildly elevated lesion which appeared to be active (Figure 3A, B Multilayered PED is a recently introduced term to describe the peculiar morphologic appearance of organized layers of hyperreflective bands within the vascularized PED. These develop through a sequential layering of hyperreflective bands of fibrovascular and fibrocellular tissue beneath the RPE in chronic fibrovascular PED . They arBeneath the multilayered complex, a hyporeflective cavity is seen, referred to as pre-choroidal cleft. This is presumed to have been formed by the horizontal contraction of the multilayered tissue complex and was seen in about 65% of the eyes in a study . These cAlthough the multilayered PED is known to harbor a type 1 CNV, the vascular component has never been demonstrated so clearly. The FA in such a situation would show a patchy hyperfluorescence, a so-called occult CNV, whereas the ICGA would result in a hot spot or plaque. Here, the large net of vessels comprising the CNV is very dramatically seen in the SSOCTA. The central stalk of blood vessel branches out in a fan-like manner. Notably, no subretinal fluid was seen.Although more dramatic-looking, the multi-layered PED generally have a better visual acuity and a lower probability of developing a high-grade retinal pigment epithelium tear , 3]. Th. Th3]. TIn conclusion, we present the SSOCTA features of a multilayered PED which typically reveal a large fan-shaped vascular network sans any subretinal fluid or hemorrhage.Written informed consent has been obtained from all patients.Both authors contributed to the data collection, analysis, writing and reviewing of the manuscript.The authors declare that they have no competing interests.