TM meningitis panel, real-time polymerase chain reaction (PCR) was used to test for the presence of 12 common viruses. PTC patients  had mean opening pressure of 41.9 ±10.2 mmH2O. All PTC patients had papilledema, and 25 (93%) had PTC symptoms. No viruses were found in the PTC group, while in the control group, one patient tested positive for Epstein–Barr virus and another for human herpesvirus type 6. Overall, in our study, PTC was not found to be associated with the presence of viruses in CSF. Pseudotumor cerebri (PTC) in children is a rare condition whose underlying cause remains largely unknown. No study has yet systematically examined viral infection as a cause of PTC. The current study aimed to characterize PTC in children and investigate the possible role of acute viral infection of the central nervous system in its pathogenesis. A prospective, cross-sectional study was conducted in three centers in Israel. Participants were 50 children aged 0.5–18 years, of whom 27 had a definitive diagnosis of pseudotumor cerebri (the study group) and 23 comprised a control. Data collected included clinical presentation, imaging, treatment, ophthalmic findings, and cerebrospinal fluid (CSF) analysis. Using the ALLPLEX Pseudotumor cerebri usually presents with such symptoms as headache, nausea, vomiting, blurred vision, and irritability [Pseudotumor cerebri (PTC), also known as idiopathic intracranial hypertension (IIH), is an uncommon condition in children, with a reported incidence of 0.60–0.71 per 100,000 children. The revised Freidman criteria [Infections, such as meningitis and encephalitis, are known causes of intracranial pressure. However, the basic criterion of normal CSF content  should eThere is a relative paucity of literature on viral central nervous system infection as a potential cause of increased ICP in PTC. It should be emphasized that the absence of CSF pleocytosis does not rule out CNS infection. Only case reports or small case series have been described, relating variously to the hepatitis E virus , hepatitThe aim of the current study was to characterize PTC in children and to investigate the possible role of acute viral infections of the central nervous system in the pathogenesis of pseudotumor cerebri.TM meningitis panel, real-time PCR was used to test for the presence of 12 viruses that are known to cause infections of the central nervous system: cytomegalovirus, Epstein–Barr virus, herpes simplex virus 1 and 2, human herpesvirus 6 and 7, varicella–zoster virus, adenovirus, parvovirus B19, human parechovirus, measles, and hepatitis E . Twenty-three pediatric CSF samples without PTC or known infection were also tested using the ALLPLEXTM meningitis panel and served as controls. The samples were kept at −80 Celsius, and the PCR panel was performed at the end of the study. All precipitants were vaccinated against varicella–zoster virus but not against any other pathogen included in the study.The present prospective, cross-sectional study was conducted in three centers in Israel: the Bnai Zion, Hillel Yaffe, and Schneider Children’s Medical Centers. Twenty-seven children aged 0.5–18 years with pseudotumor cerebri were prospectively studied. Ethical approval was obtained from each hospital, and all participants or caregivers provided written informed consent. All children were examined by a pediatric neurologist and ophthalmologist. The data collected included clinical presentation, imaging, treatment, ophthalmic findings, and CSF analysis. The CSF was taken as part of the PTC diagnosis at the time of measuring the opening pressure. Using the ALLPLEXWe collected and analyzed CSF samples from 50 children, of whom 27 had a definitive diagnosis of pseudotumor cerebri, and 23 served as a control group.No viral infections were found in the PTC group. In the control group, one patient tested positive for Epstein–Barr virus and another for human herpesvirus type 6.In our study, we looked at whether an acute CNS infection can be a cause of PTC in children. We studied the CSF of children with PTC and compared them to the CSF of a control group. In our study, we performed the PCR of 12 common CNS viral pathogens and found no pathogens in the PTC group. It must be emphasized that our study, although conducted in three different medical centers, was conducted in Israel, and other regions or populations may have different common viral pathogens that we have not sought out.The pathogenesis of pseudotumor cerebri is still unknown . AlthougAlthough both Dandy’s original criteria  and the Viral infection of the CNS increases the levels of inflammatory cells such as chemoattractants, neutrophils, CD8 T cells, and monocytes, suggesting the stimulation of the immune system. The immune response is mediated by cytokines such as IL-1β IL-6 and INF-γ in CSF . This inSome case reports have connected PTC to viral infections. Tamer et al.  report fKonrad et al.  reportedRavid et al.  describeThe only papers that reported PTC during acute illness are Millichap  and McMiOur study systematically examined the cerebrospinal fluid of a group of children with PTC using PCR to test for common viruses. In our study, no viruses were found in the CSF of children diagnosed with PTC. Our findings thus support the initial assumption that PTC is not caused directly by a viral pathogen.Limitations: Our paper has some limitations. The sample is small. We studied only CSF and not blood samples. Hepatitis A and enterovirus that previously have been connected to PTC were not part of our panel. Although PCR is a good choice for acute infection, it does rule out a post-infection process.In conclusion, in our study, based on real-time PCR, pseudotumor cerebri was not found to be associated with the presence of viruses in CSF, as compared to a control group. Our study has two main limitations. First, we examined a specific, although common, panel of viruses. Second, we examined CSF for the presence of viruses after the patient was diagnosed with PTC. Thus, our findings do not rule out the possibility that PTC was caused by a prior infection where the pathogen was no longer present in the CSF.


Transfusion exposure increases the risk of death in critically ill patients of all ages. This was thought to relate to co-morbidities in the transfusion recipient. However, donor characteristics are increasingly recognised as critical to transfusion recipient outcome with systematic reviews suggesting blood donor sex influences transfusion recipient health. Originally focusing on plasma and platelet transfusions, retrospective studies report greater risks of adverse outcomes such as transfusion related acute lung injury in those receiving products from female donors. There is increasing awareness that exposure to red blood cells (RBCs) poses a similar risk. Recent studies focusing on transfusion related outcomes in extremely preterm newborns report conflicting data on the association between blood donor sex and outcomes. Despite a renewed focus on lower versus higher transfusion thresholds in neonatal clinical practice, this group remain a heavily transfused population, receiving on average 3–5 RBC transfusions during their primary hospital admission. Therefore, evidence supporting a role for better donor selection could have a significant impact on clinical outcomes in this high-risk population. Here, we review the emerging evidence for an association between blood donor sex and clinical outcomes in extremely preterm newborns receiving one or more transfusions. The risk of death in critically ill patients, both short- and long-term mortality increases with each red blood cell (RBC) transfusion exposure ,2. In thThe preterm newborn has a developmentally unique immune system which contributes to their vulnerability to adverse transfusion-related effects. Preterm birth is associated with multifaceted abnormalities, resulting in multi-system immaturity. Chronic fetal inflammation, frequently without a definite cause, is associated with preterm birth and preterm neonate complications , with feResearch efforts have predominantly focused on factors influencing blood quality to improve post-transfusion clinical outcomes. Much attention has been given to the age of transfused blood and the development of storage lesions . StorageMore recently, interest has turned to the influence of donor characteristics on adverse post-transfusion responses . InitialHere we review recent additions to the neonatal literature focusing on the role of donor sex on transfusion recipient outcomes. Furthermore, we discuss the underlying biological mechanisms that could potentially contribute to the association between donor sex and incidence of significant neonatal morbidities and mortality. Finally, we address design considerations needed for future large-scale studies of the impact of transfusion exposure in this highly transfused population. Such studies are required to definitively address uncertainty about the safety of transfusion in the preterm newborn and will represent important steps towards personalised transfusion therapy. Two types of donor sex comparison are commonly reported in the adult literature: single donor sex exposure and donor-recipient sex mismatch. For instance, transfusion with RBCs from female donors has been reported to be associated with greater mortality rates ,32,33, aCriticism of the data generated from these studies has focused on residual confounders, resulting in model misspecification , large pp = 0.03). However, the proportion of sex matched versus mismatched transfusions in each group was not reported. While this study focuses on an outcome other than mortality, the association between RBC transfusion exposure and NEC remains controversial. The most recent meta-analysis of available observational data found no such effect [The first report of donor sex specific outcomes in the preterm newborn was by Paul and colleagues, who described a retrospective cohort of 2311 patients in whom 122 (5.3%) developed NEC [h effect , while ah effect . p = 0.025) and a longer length of stay , this effect was no longer present following adjustment for the number of transfusions received. The potential for a dose-response effect of female blood was also investigated with an increase in the odds of any morbidity for each additional transfusion of female RBCs observed . More recently, Murphy and colleagues reported the findings of an exploratory, retrospective, cohort study which aimed to investigate the potential of RBC donor sex on a range of neonatal outcomes including BPD, IVH grade III or IV, spontaneous intestinal perforation (SIP), NEC Bell criteria stage 2 or greater, and death . The stuWhile this study has several strengths, including the exclusion of patients who received other blood products and assessment of the Morbidity Assessment Index for Newborns score on days 1 and 7 to limit the potential for confounding by illness severity, clear limitations remain. As for all studies of this design, no consideration of transfusion timing and its relation to diagnosis of the outcome/s of interest was possible. Clearly, a transfusion cannot be causative if it is administered as part of the therapeutic response to a clinical event. In addition, extrapolation of transfusion exposure to later development of BPD, defined at 36 weeks by conventional criteria or the need for pressure support >2 L/min , is probA different approach was taken by Patel and colleagues . Here thWhy are the findings of these studies’ contradictory while many of the limitations are common to both? The most obvious methodological difference is the inclusion, rather than exclusion, of infants who received both male and female donor RBCs in the Murphy study . Patel aFinally, the primary outcome differs between the two studies, potentially affecting any association between donor sex and morbidity and mortality. While IVH was included in the composite “any morbidity” outcome in the study by Murphy and colleagues, it was excluded in the Patel study. This was justified by the authors on the grounds that all transfusions were evaluated, including those occurring after the typical timing of IVH occurrence in their population of very low birth weight newborns . Currently, the biological mechanisms which underlie the association of donor sex and increased risk of adverse outcomes following exposure to RBCs remain poorly characterized. What is likely, however, is that multiple factors contribute to the influence of donor sex on recipient outcomes .RBC transfusion packs from male and female donors are inherently different with haematological and redox parameters differing between male and female donors during storage. Female donors have a greater proportion of younger RBCs at the time of donation, a difference greatest during reproductive age, when more young RBCs enter the circulation to compensate for blood loss through menstruation . As a reThere is some evidence that these differences may result in sex specific responses in the transfusion recipient. For female transfusion recipients, the delivery of larger amounts of free haemoglobin with RBC transfusions from male donors may result in the haptoglobin scavenging capacity of the reticuloendothelial system being overwhelmed . Excess We and others have reported an increase in circulating plasma pro-inflammatory cytokines and markers of endothelial activation concentration between 2 and 48 h after single transfusion exposures in the weeks following preterm birth ,44. FurtHow donor sex influences these immune responses is an area of growing interest, with immune cell activation by HLA antibodies , which aIntriguingly, there is emerging evidence that preterm newborns may themselves exhibit sex-specific inflammatory responses to RBC transfusion . In an aDonor sex related immunomodulation, with increases in pro-inflammatory cytokines, also contributes to endothelial activation. This is a potential predictive marker for transfusion associated adverse outcomes and has recently been shown to be increased with sex mismatched RBC transfusion exposure . In vitrExtracellular vesicles, specifically microparticles, transfused along with the RBCs are biological response modifiers that may play a significant immunomodulatory role in the transfusion recipient ,78. TheyIn summary, there is increasing data supporting biologically plausible pathways by which donor sex related differences in RBC characteristics, immunomodulatory and endothelial responses to transfusion exposure could result in adverse outcomes. However, further exploration of potential biological mechanisms should be an important consideration of future planned studies. Blood donors, RBC preparation and transfusion practice has been given significant attention. However, more work is required to unravel the complex linkage between these critical three determinants of transfusion safety. These three factors, termed the “transfusion continuum” , requireAs the available evidence supporting an effect of blood donor sex on outcomes in transfusion recipients is observational, there remains a compelling argument for further establishment and development of large ‘vein-to-vein’ data sets that would allow for robust evaluations of the clinical impact of donor characteristics. Linked donor/product and recipient data has been successfully used to explore the impact of donor sex on outcomes in adult transfusion recipients, yet this approach is under-utilized in the newborn. For example, even the most developed, The Scandinavian Donations and Transfusions (SCANDAT) database including over 21 million transfusion records and over 3.5 million donors, has yet to investigate donor effects in the preterm newborn . While one logical evolution of such resources would be real time capture and reporting, another approach is the use of a novel analytical methodology to interrogate large-scale retrospective datasets. Brunn-Rasmussen and colleagues have recently employed causal inference methodology and targeted machine learning approaches to emulate the large scale randomized controlled trials investigating donor sex and transfusion recipient outcomes that are currently lacking . The autn = 8850) randomised to receive male-only or female-only donor transfusions, [The fact that each donor’s blood is biologically different, rendering the standardization of blood products at any level extremely difficult , has confusions, . The priFinally, RCTs are typically based on a biological hypothesis with the trial designed to prove or refute the hypothesis. As the mechanism/s by which donor sex affects clinical outcomes may be complex and multifactorial, we propose that simultaneous exploration of potential biological mechanisms within the context of a trial would represent an efficient approach to address significant knowledge gaps. Further, there is emerging evidence of the potential for additional blood product processing, such as RBC washing, to protect against transfusion related immune responses in the preterm newborn . ConfirmWithin the newborn literature, the focus of transfusion research has predominantly been on factors influencing blood quality or the impact of strategies to control transfusion exposure. While there is ongoing controversy about the contribution of transfusion exposure to their adverse outcomes in the preterm newborn, donor characteristics are increasingly recognized as being potentially critical to transfusion recipient outcomes and are an emerging area of research. Systematic reviews have identified blood donor sex as one such factor that may influence transfusion recipient health, yet the limited evidence for such an effect in extremely preterm newborns remains conflicting. This is predominantly because all the available evidence is observational with inherent limitations. Furthermore, the biological mechanisms which could underlie the association of donor sex and increased risk of adverse outcomes following exposure to RBCs remain poorly characterized. Considering that preterm newborns remain a heavily transfused population, and that better donor selection may be one approach to significantly improving both morbidity and mortality in this high-risk group, further studies focusing on this specific question are warranted. Further larger cohort studies enabling the establishment and development of the large donor-recipient data sets would allow for further evaluation of the clinical impact of donor characteristics. However, the argument for well designed, adequately powered RCTs which allow for simultaneous exploration of potential biological mechanisms within the context of the trial is compelling. The knowledge generated from this type of research has the potential to change the way donors are selected and could improve patient outcomes. Such a practice change would entail significant operational changes for the blood supply but would represent a first step towards personalized transfusion therapy for the preterm newborn.


Corynebacterium striatum is a microorganism with an excellent capacity for biofilm production and thus has been correlated with nosocomial transmission and invasive infections. However, little is known about the mechanism of biofilm formation of this commensal pathogen. In this study, we aimed to investigate the biofilm formation abilities of multidrug-resistant Corynebacterium striatum clinical isolates and the roles of extracellular proteins, exopolysaccharides and extracellular DNA in mediating more robust biofilm formation by the isolates of C. striatum.C. striatum isolates were identified using VITEK-2 ANC card, matrix-assisted laser desorption/ionization-time of flight mass spectrometry and 16S rRNA sequencing. The antibiotic susceptibility test was performed using the broth microdilution method. The distribution of spaDEF genes among C. striatum isolates was detected by polymerase chain reaction, and pulsed-field gel electrophoresis typing was employed to analyze the genotypes of the isolates. Crystal violet staining and scanning electron microscopy techniques were used to detect biofilm production by C. striatum isolates. Biofilm degradation assay was performed to observe the effects of extracellular matrix degradative agents  on C. striatum biofilms.C. striatum isolates were enrolled in the study, and the resistance rates were the highest  against penicillin and ceftriaxone. Approximately 96.3% (26/27) C. striatum isolates were resistant to at least three different types of antimicrobial agents tested. All isolates were confirmed to be biofilm producers, and 74.07% (20/27) isolates presented moderate to strong biofilm production abilities. P7 genotype  was identified to as the predominant genotype, and all of isolates belonging to this genotype were multidrug-resistant and had stronger biofilm-forming abilities. Most C. striatum isolates  carry spaD, spaE, and spaF genes, which encode spa-type pili. However, the correlation between the expression of spa-type genes and the biofilm production abilities of the C. striatum isolates was not found. The biofilms of 80% (8/10), 90% (9/10), and 100% (10/10) C. striatum isolates with moderate to strong biofilm production abilities were significantly eliminated upon the treatment of dispersin B (20 μg/mL), DNase I (20 μg/mL), and proteinase K (20 μg/mL) (p < 0.05), respectively. For the combination groups with two kinds of biofilm-degradative agents, the combination of 20 μg/mL proteinase K/dispersin B showed the strongest biofilm-eliminating effects, when the biofilms of 90% (9/10) C. striatum isolates degraded more than 50%.Twenty-seven C. striatum isolates that belonged to the predominant genotype showed a multidrug resistance (MDR) phenotype and strong biofilm formation abilities. Extracellular matrix seems to be an essential determinant in mediating biofilm formation of MDR C. striatum, since extracellular matrix degradative agents  showed strong biofilm-eliminating effects toward multidrug-resistant C. striatum isolates. The findings of this study highlight new ideas/directions to explore the whole nature of biofilm formation of C. striatum and the function of extracellular matrix in this process.The The online version contains supplementary material available at 10.1186/s12941-022-00546-y. Corynebacterium striatum is a gram-positive, rod-shaped bacterium, opportunistic bacterial pathogen that has caused several types of invasive infections in the last two decades [C. striatum clinical isolates often show a high rate of multidrug resistance [ decades . C. strisistance , and itssistance , 4. UnfoC. striatum, especially for some kinds of chronic infections, including lower respiratory tract infections, catheter-related infections, and meningitis [C. striatum can produce biofilms on different types of abiotic surfaces, which may contribute to the enhancement of its virulence and invasion ability. For some well-known bacterial pathogens, the expression of bacterial surface structure and production of extracellular matrix were recognized to be two different kinds of crucial mechanisms contributing to biofilm formation. A recent report revealed that spa genes, encoding essential cellular surface structure pili, were highly expressed among C. striatum clinical isolates and were thought to correlate with cellular adhesion and biofilm production of C. striatum [C. striatum.Some recent reports revealed that production of biofilm was correlated with pathogenicity potential of ningitis . C. stristriatum . Complexstriatum –9, and cstriatum , 9. To dC. striatum clinical isolates and the roles of pili or anti-biofilm activities of extracellular matrix degradative agents in the regulating biofilm formation.Hence, this study aimed to explore the biofilm formation abilities of C. striatum strains were isolated from the patients admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2012 to July 2021. All isolates were identified by VITEK-2 ANC card  and were frozen at − 80℃. The isolates were sub-cultured on blood agar plates, incubated under 35 ℃ for 24 h, and validated by MALDI-TOF MS equipment  and 16S rRNA sequencing technology. Epidemiological data for the patients infected with C. striatum isolates were collected from the hospital information system.The antibiotic susceptibility test was performed using the broth microdilution method, and the antibiotics tested include penicillin (0.06–4 μg/mL),cefatriaxone (1–64 μg/mL),cefepime (1–4 μg/mL), meropenem (0.25–16 μg/mL), gentamicin (4–16 μg/mL), tetracycline (4–16 μg/mL), erythromycin (0.25–8 μg/mL), vancomycin (0.5–4 μg/mL), trimethoprim-sulfamethoxazole (0.5/9.5–4/76 μg/mL), ciprofloxacin (1–4 μg/mL), levofloxacin (2–8 μg/mL), clindamycin (0.25–4 μg/mL), daptomycin (0.5–1 μg/mL), and linezolid (1–2 μg/mL). The antimicrobial susceptibility test and data analysis were performed according to the Clinical and Laboratory Standards Institute guidelines (M45 A2 edition)  and the C. striatum isolates were inoculated on the blood agar medium at 35 ℃ for 24 h, and the colonies were picked out and transferred into a 1.5 mL Eppendorf tube with 0.5 mL sterile distilled water. Lysozyme (1 mg/ml) was added into each tube and mixed thoroughly by vortexing, and the tubes were placed into a water bath and incubated at 35 ℃ for 30 min. The total bacterial DNA was extracted according to the instructions of the bacterial genome DNA extraction kit . The information on the primers for spaD, spaE, and spaF used in this study is shown in Table C. striatum sequences were used as references .C. striatum isolates tested in this study was adjusted to 3.5–4.0 Mcf and digested with lysostaphin (1 mg/mL)  at 37 °C for 30 min. The bacterial chromosomal DNA of the isolates was extracted and cleaved using 40 U SwaI . The DNA of the S. braenderup H9812 standard strain was extracted and cleaved using 40 U XbaI  and used as the molecular mass standard. Electrophoresis was performed on the CHEF-Mapper XA PFGE system , and PFGE profiles were analyzed using the Bionumerics v.7.6 software. The isolates with 100% similarity were considered indistinguishable [The optical density of the bacterial cultures of the ostaphin  mg/mL  was added to each well and placed at room temperature for 20 min to dry, and 200 μl of crystal violet solution was added to each well and placed at room temperature for 5–10 min. Then, the plate was gently washed for three times with 200 μL PBS and was placed at room temperature until it was completely dry. Biofilm production was quantified by adding 160 μL glacial acetic acid to destain each well, and the solution was gently mixed for 10 min. The absorbance was measured at 620 nm to quantify the crystal violet present in the destaining solution. Each assay was performed in triplicate. Referring to Brahma U et al. [For U et al. , a cut-oC. striatum strains with strong and weak biofilm production in the logarithmic growth period were transferred to a 6-well plate containing TSB liquid medium . A sterile plastic coverslip (Thermanox™) was put into each well to collect the biofilm and incubate it aerobically at 35 ℃ for 24 h. After removing the culture medium, the coverslip was fixed in 0.1 M cacodylate sodium buffer (pH 7.2) with 2.5% glutaraldehyde at room temperature for 30 min, and in the same buffer with 1%OsO4 solution containing 2.5 mM CaCl2 at room temperature for 30 min. The biofilm was dehydrated in ascending acetone series and dried. Subsequently, the samples were observed with scanning electron microscope after drying [The r drying .C. striatum were investigated in this study, including protein degrading enzyme (proteinase K), polysaccharide poly-N-acetylglucosamine (PNAG): degrading enzyme (dispersin B), and eDNA degrading enzyme (DNase I). The assays were performed according to the protocols recommended previously [p < 0.05 was deemed statistically significant.The degrading activities of three kinds of well-known extracellular matrix degradative agents on the biofilm of eviously , 15. ProC. striatum was 54.63-years-old, and the male/female ratio was 22:5. The average time from admission to the isolation of C. striatum isolates was 24.04 days. Around 96.30% (26/27) of the patients received antimicrobial treatment two weeks before C. striatum isolation. The most frequently prescribed antimicrobials are β-lactam antibiotic/β-lactamase inhibitor combinations , followed by fluoroquinolones , carbapenems,  and cephalosporins . Two patients died during hospitalization, and the remaining patients were discharged after recovery. The detailed epidemiological data are summarized in Additional file Epidemiological data showed that the average age of twenty-seven patients infected with  66.67%, 8/27, folC. striatum isolates were all sensitive to vancomycin, linezolid, daptomycin, and the resistance rate to gentamicin was lower (7.41%). However, the resistance rates to penicillin, cefepime, meropenem, tetracycline and erythromycin were high , while the resistance rates to penicillin and ceftriaxone were the highest, reaching up to 100% (27/27). Around 96.3% (26/27) of C. striatum isolates were deemed multidrug-resistant (MDR) in at least three different kinds of the antimicrobials tested in this study. CS-14 isolate was the only non-MDR isolate resistant to penicillin and ceftriaxone.As shown in Table spaD, spaE and spaF genes were 81.48% (22/27), 85.19% (23/27), and 85.19% (23/27), respectively. Around 74.07% (20/27) of the C. striatum isolates carried spaD, spaE and spaF genes concurrently, while 7.41% (2/27) of C. striatum isolates did not carry any of spaD, spaE or spaF genes. Around 11.11% (3/27) of the isolates were positive with spaD and spaF genes, but the spaE gene was not detected. In addition, 7.41% (2/27) of the C. striatum isolates only carried the spaD gene.The PCR results revealed that the positive rates of C. striatum isolates were divided into eleven genotypes (P1 ~ P11), the P7 is the predominant genotype and accounted for 44.44% (12/27), as shown in Fig. C. striatum isolated from 31st, 2020 to 11th, 2021. Half of the samples were isolated from the intensive care unit (ICU), and 50% (6/12) of the specimens were isolated from qualified sputum samples. Six isolates were isolated from the cerebrospinal fluid , pus , and whole blood , respectively. In addition, most of the strains belonging to the P7 genotype presented stronger biofilm formation abilities and were all multidrug-resistant (MDR). Even worse, four isolates belonging to the P7 genotype were sequentially isolated from the patients admitted to ICU between March 31st and April 21st, 2020, indicating a potential nosocomial outbreak. Also, the isolates belonging to another genotype (P4) with weak biofilm formation ability accounted for 14.8% (4/27), three of which were collectively isolated from the patients admitted to ICU from February 8th to May 5th, 2020, which indicated a possible nosocomial transmission.Based on the discrimination standard for PFGE genotyping proposed by Tenover et al., twenty-notypes P ~ P11, tC. striatum strains were all biofilm producers but the biofilm production abilities differed significantly. Eight isolates were potent biofilm producers , twelve were medium biofilm producers , while the remaining seven isolates showed weak biofilm production abilities . Most isolates  were isolated from the lower respiratory tract samples and all the strong biofilm producers belonged to the P7 genotype. The SEM results confirmed the presence of mature and high-density of biofilm in the strong biofilm producers , respectively. The degradation efficiency of the above three agents differed significantly, when proteinase K showed the most potent degrading effects, followed by dispersin B and DNase I . A dominant genotype, P7, was identified during this study, triggering a nosocomial outbreak among ICU patients between March and April, 2020. Furthermore, all of the isolates belonging to P7 genotype were confirmed to be medium or strong biofilm producers and multidrug-resistant. Rapid and accurate discrimination of predominant C. striatum clones may help clinicians implement more potent measures to control its nosocomial transmission or treat of infections caused by C. striatum.In this study, almost all of the  studies , 16, 17.C. striatum could produce mature biofilms on several kinds of surfaces, such as medical catheters [C. striatum clones to some widely used biocides , especially for biofilm-associated forms of C. striatum [C. striatum seems to be urgent. In this study, all C. striatum isolates were confirmed to be biofilm producers, and 74.1% (20/27) isolates were confirmed to have medium and strong biofilm producing abilities. Also, the isolates belonging to the same PFGE type or closely similar types presented identical or similar biofilm formation abilities. However, the consistency between resistance features and clonality of the isolates was not observed, which is inconsistent with another previous study [Some previous studies revealed that MDR atheters , leadingstriatum . ExploraCorynebacterium spp. was generally mediated by fimbriae, which is usually encoded by three separate fimbriae gene clusters, spaDEF gene. Also, C. striatum fimbriae can also mediate its specific adhesion to host cells. Sana Alibi et al. revealed that Spa-type genes were detected in all C. striatum strains. However, not all the C. striatum strains  carried spaD, spaE, and spaF genes in this study. In addition, eight C. striatum strains with strong biofilm-forming ability carried spaDEF. At the same time, five C. striatum strains with weak biofilm-forming ability were also positive with spaDEF genes, which indicates an indefinite relationship between biofilm formation abilities and expression of pili in C. striatum. For some well-known gram-positive bacteria , the bacterial extracellular matrix has been recognized to be an essential determinant in mediating biofilm formation and participating in the protection process from external insults [Corynebacterium glutamicum, which suggests a nucleic acids’ potential role in regulating biofilm formation in Corynebacterium spp. [C. striatum and the potential roles of biofilm matrix degradative agents was not reported yet.Biofilm formation ability is essential for some bacterial pathogens . Cellula insults , 22. The insults , 23–25.  insults –28. A prium spp. . NeverthC. striatum biofilm degrading assays, all of which were commonly used in the assays for some other well-known bacterial pathogens, such as S. aureus [C. striatum biofilm was observed during this study, which suggests a significant strain or clonal heterogenicity of the composition of extracellular matrix in C. striatum. Specific constituents of the extracellular matrix in determining the biofilm formation capability of C. striatum and possible molecular mechanisms need to be further investigated, especially for extracellular proteins, which may be potent anti-biofilm targets.In this study, biofilm-degradative agents  were employed in . aureus , 15. IntC. striatum isolates accounted for the most of the isolates investigated in this study. The predominant clone identified in this study presented a more potent biofilm formation ability, and a nosocomial outbreak was observed. Also, this study firstly revealed the potential roles of the extracellular matrix in mediating C. striatum biofilm formation, since significant biofilm-eliminating effects of extracellular matrix degradative agents toward C. striatum were observed, especially for protein degradative agents. Further exploration of the extracellular matrix composition of C. striatum and a deep understanding of the molecular mechanism of extracellular matrix in mediating the biofilm formation of C. striatum will pave a new way for us to control and treat of colonization or infections caused by biofilm-producing C. striatum strains.Multidrug-resistant Additional file 1: Table S1. Epidemiology of twenty-seven patients infected with multi-drug resistant Corynebacterium striatum.Additional file 2: Table S2. The results of statistical analysis of the biofilm eliminating effects of combinations of biofilm degrading agents .


Concern about a long-term effect of the delivery of intensity modulated radiation therapy (IMRT) for prostate cancer on serum testosterone levels remains unelucidated. We evaluated how IMRT for localized prostate cancer affects serum testosterone levels during a follow-up period of up to 10 years.We retrospectively evaluated data from 182 patients with localized prostate cancer who underwent definitive IMRT alone between 2007 and 2014. Serum total testosterone (TT) levels were measured by blood draws between 6 AM and 11 AM before treatment and at every posttreatment follow-up for 10 years. Pretreatment values and each posttreatment testosterone value were compared using a Wilcoxon signed rank test. The data set was stratified into 4 groups based on the pretreatment testosterone (pre-TT) values using quartiles.P < .0001). Subsequently, TT levels gradually recovered to nearly the pretreatment levels 24 to 36 months after IMRT. When analyzed according to the pre-TT quartile, median TT levels initially decreased at the 3- to 12-month period in all the quartiles; however, median TT levels increased from the 18-month period in the first and second quartile groups, whereas they were maintained at less than the pretreatment levels in the third and the fourth quartile groups throughout the entire decade after radiation therapy. The proportion of patients with hypogonadal status, defined as TT levels <3.00 ng/mL, did not increase over time.The median absolute or relative changes in TT levels from pretreatment were –0.42 ng/mL or –12.0% at 3 months after radiation therapy (A transient and modest decrease of TT levels after IMRT spontaneously recovered to the pretreatment levels at the 24- to 36-month period except in patients in the higher quartile of pre-TT. This might have been partly owing to a variable sensitivity of individual testicular function to scattered radiation. Patients with lower pre-TT did not demonstrate a progressive overall rate of hypogonadism until 10 years after radiation therapy. Elective pelvic nodal radiation was not delivered. Of the 615 eligible patients, we excluded 33 patients with missing pretreatment TT (pre-TT) values; to avoid the known diurnal variability of TT levels, we also excluded 400 patients whose pre-TT values were determined by blood draws that took place after 12 PM.Altogether, 181 patients (99.5%) received a total dose of 76 Gy IMRT at 2 Gy per fraction with 6 million electron-volt (MV) photons to the prostate gland. The original dose of 76 Gy was reduced to 72 Gy in a single patient owing to the patient's concerns regarding radiation-related complications.Prostate-specific antigen (PSA) recurrence was defined based on the Phoenix criteriaP < .05 was considered statistically significant.A Wilcoxon signed rank test or Kruskal-Wallis test was used to compare changes in pretreatment and posttreatment TT values. All statistical tests were performed using SPSS Statistics, version 25 , and This study was approved by the institutional ethics review board of Edogawa Hospital and carried out in accordance with the Declaration of Helsinki, and all the patients provided informed consent before participating in the study.The median follow-up period was 96 months . Recurrence of PSA occurred in 31 patients (17.0%) within a median of 63 (14-121) months after IMRT. The overall 5- and 10-year PSA recurrence-free survival was 91.0% and 78.6%, respectively. None of the patients subsequently received any kind of hormone therapies until PSA recurrence was evident, at which point the TT levels of those patients with hormone therapies were excluded from the database of the study. The characteristics of the 182 patients stratified according to their pre-TT levels per quartile (pre-TT Q1-Q4) are shown in P < .0001). The subsequent absolute and relative changes in TT values at each period are shown in P < .0001; P < .001) until the 30-month period , median TT levels initially decreased at the 3- to 12-month period in all the quartiles; however, median TT levels increased from the 18-month period in the first and the second quartile groups .,P < .001), whereas men with an average or below average baseline testosterone level had no significant change. The authors discussed that the lack of testosterone suppression in their cohort could be explained partly by the very low radiation scatter dose to the testicles from brachytherapy, which they estimated to be 0.02 Gy over the life of an implant.This study evaluated the effect of IMRT for localized prostate cancer on serum testosterone changes during long-term follow-up. We found that IMRT for prostate cancer was associated with a median 12.0% reduction in testosterone levels 3 months after treatment. Further, testosterone suppression was only transient and significantly depended on the pretreatment levels of testosterone. To our knowledge, this is the first and largest study to evaluate long-term serial TT changes in patients receiving definitive IMRT for localized prostate cancer. Our results are consistent with those of previous studies that demonstrated transient TT depression immediately after photon irradiation for prostate cancer.,Some studies have previously attempted to estimate the amount of scattered radiation to the testes in the setting of prostate IMRT.Compared with the germ cells, Leydig cells are relatively resistant to the effects of radiation.,The transient decline in testosterone is consistent with the findings of most studies on photon-based radiation therapy for prostate cancer. The current consensus is that low-dose scatter radiation outside of the beam path has a deleterious effect on testicular Leydig cell function.Kubo and Shipley reported that a gonadal shield and scrotal block significantly reduced the photon scatter dose to the testes to less than 0.1% of the prescribed midplane dose during retroperitoneal therapy with 10 MV x-ray.In the current study, the standard IMRT for prostate cancer did not induce significant hypogonadal status overall; however, a cautious follow-up of sexual function as well as clinical management and counseling are recommended, especially in patients with TT levels equal to or more than 4.23 ng/mL.This study has some limitations. First, TT levels are known to be susceptible to diurnal variation. Our findings were based on TT levels determined between 6 AM and 11 AM. Despite the inherent bias in this retrospective study, the proper sample size, strictly excluding the data derived from blood draws after 12 PM, ensures robustness of the present findings. Second, we did not evaluate the adverse effect of IMRT on testicular function. We made every effort to correlate changes in TT levels with changes in sexual function according to the International Index of Erectile Function questionnaire sheet. Because this was a retrospective observational study, the limited number of patients with data on sexual function  precluded a more in-depth statistical evaluation. Lastly, the current study lacked a control arm without radiation effects. It would be ideal to include an age-matched group of patients with prostate cancer treated with other modalities such as surgery to compare spontaneous changes in testosterone levels together with luteinizing hormone and follicle stimulating hormone, which are pivotal hormones for supporting the hypothesis of a primary impairment in testicular function over time.Recently, Nichols et al published that passive-scatter proton therapy was not associated with testosterone suppression at 5 years, and they suggested that protons may cause less out-of-field scatter radiation than x-rays.In conclusion, TT levels and absolute/relative changes in TT consistently decreased between 3 and 12 months after IMRT. However, the changes were modest and recovered to nearly pretreatment levels at the 24- to 36-month period, except in patients with higher pre-TT levels (4.23 ≤ ng/mL). The difference in TT changes may be partly owed to a variable sensitivity of individual testicular function to scattered radiation during IMRT. Importantly, the proportion of patients with hypogonadal status determined according to TT level did not increase over time until 10 years after IMRT.


Eluxadoline is a mixed μ‐opioid, κ‐opioid receptor agonist, and δ‐opioid receptor antagonist, approved in the United States for adults with diarrhea‐predominant irritable bowel syndrome. This phase 1, single‐center, open‐label, single‐sequence study was conducted on 30 healthy participants to establish whether steady‐state eluxadoline increases systemic exposure of the cytochrome P450 (CYP) 3A4 substrate midazolam. Participants received oral midazolam 4 mg on day 1 with a 7‐day washout period. On days 8‐16, oral eluxadoline 100 mg was administered twice daily. On day 15, midazolam 4 mg was coadministered with the eluxadoline 100‐mg morning dose. Primary outcome measures were pharmacokinetic parameters of midazolam and 1‐hydroxy‐midazolam. The midazolam and 1‐hydroxy‐midazolam geometric mean ratios and 90%CIs for maximum plasma drug concentration were 99.0% (91.6‐107.0) and 113.8% (104.9‐123.5), respectively, and area under the plasma concentration–time curves were 90.5% (83.9‐97.6) and 105.1% (99.8‐110.7), respectively, demonstrating the 2 treatments were bioequivalent, and there was no clinically significant drug interaction. All treatment‐emergent adverse events were treatment related, mild in intensity, with no serious adverse events. These results suggest that eluxadoline has no clinically significant effect on CYP3A4 activity and is, therefore, unlikely to affect the pharmacokinetics of other CYP3A4 substrates. Eluxadoline is a mixed μ‐opioid and κ‐opioid receptor agonist and δ‐opioid receptor antagonist that has local gastrointestinal (GI) activity and low oral bioavailability.The effectiveness of eluxadoline to treat the symptoms of IBS‐D was demonstrated in 2 large, randomized, phase 3 clinical studies.max) reached at a median time of maximum plasma drug concentration (tmax) of 1.5 hours.max of eluxadoline is ≈2‐4 ng/mL, and the area under the plasma concentration–time curve (AUC) is 12‐22 ng • h/mL after a 100‐mg dose.Eluxadoline is minimally absorbed following oral administration, with peak plasma concentrations  in volunteers with hepatic impairment compared with healthy volunteers.In human and nonrodent cell lines, the predominant in vitro metabolic pathway is direct glucuronidation of the methoxy‐benzoic acid moiety to form the acyl glucuronide M11. M11 is also the major metabolite identified in human intestinal microsomal incubations. In vivo metabolism studies found the majority of eluxadoline is excreted in the feces of animals unchanged, while the major metabolite, M11, is seen in the urine of rats, primates, and humans. M11 was also detected in plasma samples from monkeys (data not published).In vitro studies indicate that eluxadoline is neither an inducer of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, or CYP3A4, nor an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant systemic concentrations. Although CYP2E1 was slightly inhibited by eluxadoline , clinically meaningful interactions are unlikely. In an additional in vitro study using human liver and intestinal microsomes investigating the potential of eluxadoline to inhibit the metabolism of concomitantly administered drugs, eluxadoline demonstrated a metabolism‐dependent  inhibition of CYP3A4/5 activity .max of the 100‐mg therapeutic dose, and by multidrug resistance protein‐2 at all tested concentrations (4‐400 ng/mL).Eluxadoline was shown to be transported by organic anion transporter (OAT) 3, OATP1B1, and bile salt export pump at 400 ng/mL, which is 133 times the CMidazolam is a short‐acting imidazobenzodiazepine, which is extensively metabolized by CYP3A in the liver and intestine.This was a phase 1, single‐center, open‐label, single‐sequence study in healthy participants, conducted from November 2016 to January 2017. The main inclusion criteria were healthy men and women aged 18‐45 years. The full inclusion and exclusion criteria are listed in Table am on day 1 following a standard breakfast given at 7:30 am. This was followed by a 7‐day washout period  dose of midazolam on day 1 (treatment A), which was administered with 240 mL of water, starting at ≈8:00 This study was conducted in accordance with the International Council for Harmonisation E6 guideline for good clinical practice and the principles of the Declaration of Helsinki. The institutional review board (IntegReview IRB) approved the study protocol for the site , and written informed consent was obtained from all participants at the first study visit.The dose of eluxadoline 100 mg twice daily on days 8‐16 was selected to ensure the maximum possible CYP3A4 inhibition by eluxadoline. Comparison of midazolam PK on day 1 vs day 15 helped to estimate the CYP3A4 inhibition potential of eluxadoline. A single 4‐mg dose of midazolam was chosen for the study based on a previous food‐effect study that tested a 15‐mg oral dose, and suggested that a 4‐mg dose would have an adequate safety margin in the event of increased midazolam exposure due to potential CYP3A4 inhibition by eluxadoline.The primary objective of the study was to evaluate the effect of eluxadoline on the single‐dose PK of midazolam in healthy participants. The secondary objectives were to evaluate the safety and tolerability of single‐dose midazolam when administered alone and in combination with eluxadoline.max, tmax, terminal elimination rate constant, terminal elimination half‐life, and apparent total body clearance of drug from plasma after extravascular administration (for midazolam only). In addition, the ratio of 1‐hydroxy‐midazolam to midazolam for Cmax and AUC were calculated following treatments A and B2. Sampling for eluxadoline plasma concentration was performed before the morning doses on days 8, 13, 14, and 15 (see Primary outcome measures were PK parameters of midazolam and 1‐hydroxy‐midazolam (α‐hydroxy‐midazolam) metabolite derived from plasma concentrations following treatments A (day 1) and B2 (day 15) (see Safety measures included adverse events (AEs), clinical laboratory determinations, vital sign parameters, electrocardiogram (ECG) results, and physical examination findings .max and AUC) of midazolam with and without coadministration of eluxadoline are within 80%‐125%. This was based on the assumption of a within‐subject coefficient of variation of 22% for Cmax and AUC of midazolam, and a true ratio of test to reference geometric means of ≈1.07. A total of 30 participants were enrolled to account for possible dropouts.A sample size of 24 participants was determined to provide 95% power to show that the 90%CIs for the point estimate of the ratio of geometric mean PK parameters . Plasma concentrations below the limit of quantification were treated as 0 for all PK calculations. The actual sampling times were used in the calculations of PK parameters in this study .Descriptive statistics were provided by treatment for plasma concentrations of midazolam and 1‐hydroxy‐midazolam metabolite for participants in the PK population. Descriptive statistics were also provided for plasma eluxadoline concentrations.max, AUC from time 0 to time t, and AUC from time 0 to infinity) of midazolam and 1‐hydroxy‐midazolam metabolite were compared using a linear mixed‐effects model with treatment as a fixed effect and participant as a random effect. The 2‐sided 90%CI for the ratio of AUC and Cmax geometric means between treatments were constructed. The difference in median tmax between midazolam plus eluxadoline vs midazolam alone was determined.PK parameters  experienced treatment‐emergent AEs (TEAEs) following administration of treatment A; 9 participants 31.0%) experienced TEAEs following treatment B1; and 8 participants (27.6%) experienced TEAEs following treatment B2  sponsored the study.AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial‐level data , as well as other information , as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.https://www.abbvie.com/our‐science/clinical‐trials/clinical‐trials‐data‐and‐information‐sharing/data‐and‐information‐sharing‐with‐qualified‐researchers.html.This clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan and execution of a Data Sharing Agreement. Data requests can be submitted at any time, and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: Supplemental InformationClick here for additional data file.


Intraventricular hemorrhage is recognized as a leading cause of hydrocephalus in the developed world and a key determinant of neurodevelopmental outcome following premature birth. Even in the absence of haemorrhagic infarction or posthaemorrhagic hydrocephalus, there is increasing evidence of neuropsychiatric and neurodevelopmental sequelae. The pathophysiology underlying this injury is thought to be due to a primary destructive and secondary developmental insult, but the exact mechanisms remain elusive and this has resulted in a paucity of therapeutic interventions. The presence of blood within the cerebrospinal fluid results in the loss of the delicate neurohumoral gradient within the developing brain, adversely impacting on the tightly regulated temporal and spatial control of cell proliferation and migration of the neural stem progenitor cells within the subventricular zone. In addition, haemolysis of the erythrocytes, associated with the release of clotting factors and leucocytes into the cerebrospinal (CSF), results in a toxic and inflammatory CSF microenvironment which is harmful to the periventricular tissues, resulting in damage and denudation of the multiciliated ependymal cells which line the choroid plexus and ventricular system. The ependyma plays a critical role in the developing brain and beyond, acting as both a protector and gatekeeper to the underlying parenchyma, controlling influx and efflux across the CSF to brain interstitial fluid interface. In this review I explore the hypothesis that damage and denudation of the ependymal layer at this critical juncture in the developing brain, seen following IVH, may adversely impact on the brain microenvironment, exposing the underlying periventricular tissues to toxic and inflammatory CSF, further exacerbating disordered activity within the subventricular zone (SVZ). By understanding the impact that intraventricular hemorrhage has on the microenvironment within the CSF, and the consequences that this has on the multiciliated ependymal cells which line the neuraxis, we can begin to develop and test novel therapeutic interventions to mitigate damage and reduce the associated morbidity. In the UK around 60,000 babies are born prematurely each year with a degree of hemorrhage seen in around one third, equating to around 20,000 cases of neonatal intraventricular hemorrhage per year. The high metabolic demand of the developing brain, in association with fragile and underdeveloped cerebral vasculature and parenchyma, combine to make the premature neonate prone to hemorrhage within the germinal matrix (GMH) , 2; its Despite advances in neonatal care, premature birth remains common with up to 15 million babies born preterm (<37 weeks gestation) every year worldwide. Indeed, over the last two decades, studies indicate that rather than decreasing, the incidence of premature birth has actually increased in almost all countries with reliable data , 5. The In the majority of cases, neonatal intraventricular hemorrhage occurs within the first 4–5 days of life. This can lead to life threatening cardiovascular instability, indeed neonatal intraventricular hemorrhage (NIVH) remains a leading cause for the withdrawal of care. Following the identification of hemorrhage, early management priorities are supportive with no active therapy instigated. Twice weekly transfontanelle ultrasound scanning is used to monitor the anatomy of the ventricular system, and in those neonates who develop radiological signs  or symptIncremental and focused research efforts over the past four decades have significantly reduced the incidence of severe NIVH , howeverWithin this review I will discuss the clinical and experimental evidence implicating that NIVH elicits a secondary injury process to the developing brain, specifically focusing on the role that damage to the ependymal lining of the ventricle may play in this process. The aim of this review paper is to stimulate interest in promoting research into maintaining ependymal health as a potential therapeutic avenue following neonatal intraventricular hemorrhage.Since Volpe's seminal paper in 2009  it is wiDespite improvements in perinatal care, neonatal intraventricular hemorrhage (NIVH) remains a leading cause of neurodevelopmental delay in childhood and the commonest cause of hydrocephalus in the developed world .Outcome studies following premature birth consistently show that a key determinant is the presence or absence of intraventricular hemorrhage . With hiThe variability seen in neurodevelopmental outcomes is multifactorial with comorbidity and parental socioeconomic status  playing in vivo analysis of the microstructural changes which accompany normal and abnormal brain development, while functional MRI enables the impact of these changes upon functional connectivity to be examined (With the advent of modern magnetic resonance imaging (MRI) modalities has come the ability to analyse the developing brain in previously unobtainable detail. Diffusion weighted imaging (DWI) allows the examined . Newer mexamined , MR elasexamined  and multexamined  may alsoNormal maturation in the perinatal period is correlated with a number of changes on DWI. These are thought to represent the loss of radial glia with an increase in myelination and dendritic arborisation during this period , 45. TheIn those born prematurely, imaging abnormalities are characterized by cerebellar, cortical and subcortical volume loss, with associated abnormalities of thalamocortical connections , 47, 50.GMH-IVH is associated with widespread imaging abnormalities in addition to those associated with prematurity. These include abnormalities within central, parietal and occipital white matter tracts and cerebellar volume reduction , 53. ManIn an attempt to negate the deleterious impact of intraventricular blood, the DRIFT study  was set up to establish if continuous ventricular irrigation over 72 h, to wash out bloodstained CSF and breakdown residual clot, could reduce the rate of progressive hydrocephalus and improve neurological outcome . IrrigatThe DRIFT study was discontinued due to concerns related to the safety of prolonged ventricular irrigation and the incidence of re-bleeding related to use of the thrombolytic agent tissue plasminogen activator (t-PA). Although the DRIFT study did not demonstrate a reduction in the requirement for a permanent VP shunt, cognitive and motor follow up at 2 and 10 years did demonstrate a significant reduction in the rate of death and severe disability in the DRIFT group compared to the group that received standard treatment , 25. ImpBuilding on the findings of the DRIFT trial, neuroendoscopic clot lavage at the time of temporizing intervention  has been proposed  Figure . This apIt is also important to consider that ventricular irrigation is undertaken on average between 20 and 30 days following hemorrhage. This is due to the intrinsic instability of the premature neonate and the high risk of intervening at earlier time points. In addition, intervention is currently only considered in neonates with progressive ventriculomegaly or signs and symptoms indicative of raised intraventricular pressure. As such, current therapeutic trials, focused on ventricular irrigation after the bleed, will have no impact on prior toxic damage. Nor will it be of any benefit to those neonates with isolated IVH i.e., without progression to post haemorrhagic hydrocephalus. By understanding the mechanisms through which early toxicity impacts on the periventricular tissue, early therapeutic strategies to limit brain injury and improve neurological outcome in babies with IVH can be developed.The timing of temporizing intervention in the treatment of NIVH remains contentious with two schools of thought persisting. The first advocates for so-called ‘early intervention’, guided by the size of the ventricles as measured by transfontanelle cranial ultrasound scan (cUSS). An increase in the ventricular index (VI) beyond the 97th+4 mm centile (based on the Levene chart) would in the first instance trigger a lumbar puncture, if this fails to prevent ventricular enlargement a temporizing intervention would then be inserted [ventricular subgaleal shunt (VSGS) or ventricular access device (VAD)]  with regThe weight of evidence would seem to insinuate that early intervention before the onset of symptoms improves outcome , with twFor the purposes of this review, it is plausible that prolonged exposure to blood-stained CSF, under higher than physiological pressure, increases the potential for harm to the ciliated ependyma. This in turn may increase the degree of ependymal denudation, as such I postulate that earlier intervention i.e., prior to the onset of symptoms, has the effect of preserving the ciliated ependymal border and this, in part, may contribute to the improved outcome seen in the early intervention groups.Throughout embryological and fetal development, the neuraxis is expanded and populated by cells derived from the ventricular and subventricular zones of the developing brain  Figure . Cell inThe microenvironment surrounding the NSPC within the subventricular zone of the periventricular region, is in part reliant on the composition of the CSF generated by the choroid plexus and periventricular epithelial cells  and the Evidence to support the neurohumoral gradient within the CSF comes from the differences seen between the ventricular and lumbar CSF , the regIn addition to the modulation of the microenvironment within the SVZ, the neural stem cells (NSC)  arising from the germinal matrix within the subventricular zone extend primary cilia through the ependymal lining of the ventricle , 78 and As such I postulate that changes in the proximal/apical domain  caused bIn addition to disturbing the delicate neurohumoral gradients with the CSF (as described above), NIVH also causes profound and toxic changes to the CSF microenvironment. The parenchymal origin of the hemorrhage classically lies within the germinal matrix around the head of the caudate nucleus. As the bleed ruptures through the ependymal wall of the ventricle it releases whole blood into the CSF. As a result, erythrocytes containing hemoglobin, plasma components, products of the coagulation cascade, platelets and leukocytes are all released into the CSF and all have been implicated in the pathogenesis of injury following intraventricular hemorrhage .Haemolysis of the erythrocytes within the ventricular CSF leads to the release of hemoglobin which is further broken down through the activity of haem oxygenase resulting in the release of iron into the CSF, which has been shown to be raised in the CSF following neonatal IVH . The relIn addition to the erythrocytes, the release of TGFβ from the platelets has been shown and the presence of leucocytes in the CSF causes a short-lived local tissue reaction. In this regard, it is intriguing to note the association between chorioamnionitis and the increased risk of developing of posthaemorrhagic hydrocephalus (PHH), it is plausible that this pathological process is exacerbated by the release of inflammatory mediators from the serum into the CSF causing an inflammatory reaction.+ K+ & Cl− and decreased glucose  interface . As suchInterspersed between the E1 cells, other highly specialized cell types are also recognized. These differ from the E1 cells in that rather than multiple cilia (multiciliated), these cells exhibit single (monociliated) or paired (biciliated) cilia and in contrast to the motile cilia seen on the E1 cell, these cilia are non-motile or so-called primary cilia. These non-motile cilia are thought to play a sensory role, acting as biosensors, detecting changes in mechanical and chemical stimuli within the CSF , 90. In The wall of the ventricular system is therefore though to play a significant role in maintaining brain homeostasis, both through its protective function, as a continuous border between the CSF and the parenchyma, and as a gatekeeper, controlling influx and efflux between the CSF and the brain interstitial fluid (BIF), but also in a more nuanced fashion sensing and modulating the composition of the CSF and relaying this information to distant targets within the brain.During embryological development, the neural tube is lined with neuroepithelial cells which, through a combination of cell intrinsic and microenvironmental cues, symmetrically and asymmetrically divide to produce further stem cells and progenitor cells which populate the parenchyma. Late in the second trimester  around tThis switch from neuroepithelial progenitor cell to multiciliated ependymal cell necessitates that the neuroepithelial cell which contains one single centrosome and associated primary cilia, is transformed into a polarized cell with tens of centriolar structures nucleating a functional motile ciliary tuft . Whilst In brief this process is thought to be reliant on Notch inhibition which results in an upregulation of multicilin, a protein required for the formation of multiciliated cells . Three eMulticiliated E1 Cells are CD24, S100β, FoxJ1, Sox2 and CD133 positive, and Nestin & GFAP negative. They are cuboidal in shape with a large spherical nucleus surrounded by multiple mitochondria. The lateral processes are interdigitated and held together by apical adherin junctions, tight junctional complexes and gap junctions  Figure .In contrast to other multiciliated cells in the body , which eThe individual cilia also exhibit rotational polarity, this refers to the fact that the cilia all align in the same orientation within the cilial tuft, such that they beat in the same direction to ensure coordination in the direction of travel of CSF flow.The cilia themselves are microtubule based hair-like organelles  which prThe 9 + 2 arrangement is referred to as the ciliary axoneme and is evolutionarily well-maintained throughout phylogeny . Up to 52B receptor  may be responsive to changes in the CSF microenvironment, for example the metabolic peptide melanin concentrating hormone (MCH), has been shown to regulate cilial beat frequency . Similarreceptor  and throreceptor , respectAs discussed above, around 90–95% of the surface of the ventricle is covered by the E1 ependymal cells but interspersed between the tufts of motile cilia are non-motile cilia arising from different specialized cell types . MonocilAs discussed above, the ependymal cells lining the ventricular system arise embryologically at around 25 weeks gestation from terminal differentiation of the neuroepithelial cells of the primitive neural tube. Lying on the basal surface, deep to the ependymal layer, is the subventricular zone, this layer is recognized as a germinal zone containing neural stem progenitor cells of the developing brain.In the mouse, whole mount staining of the wall of the lateral ventricle with β-catenin, to show the apical adherin junctions between the ependymal cells, and γ-tubulin to show the position of the cilia, demonstrates an elegant pinwheel structure with the primary cilium of the B-cell surrounded by the multiple motile cilia of the ependymal cells  Figure . This arActivity of the B-cells has been shown to be influenced through changes in the CSF microenvironment, for example fibroblast growth factor (FGF) & epidermal growth factor (EGF) infusions have been shown to increase proliferation, whilst other soluble factors within the CSF, including: Insulin like growth factor 2-IGF2; Bone morphogenetic proteins (BMPs); Wnts; sonic hedgehog (SHH) & retinoic acid, have also been shown to influence neural stem progenitor cell (NSPC) behavior in the subventricular zone (SVZ) , a proceTanycytes are bipolar mono-ciliated cells with microvilli on the apical/ventricular surface. They are found predominantly in the walls of third ventricle although a few have been observed in the lateral walls of the lateral ventricles  and in dThe long basal process of the tanycytes arising from the wall of the third ventricle connect with the thalamus and hypothalamus and are thought to play a role in regulating their function . It has The term denudation has been used to describe the stripping away of the ependymal lining from the wall of the lateral ventricle. It was first coined by Jiménez et al.  in referUnlike other ciliated epithelial surfaces, the ciliated ependymal lining of the brain ventricular surface undergoes minimal repair or renewal in response to aging or injury  in this In vivo animal studies modeling NIVH  causes a reduction in neurogenesis . Similarthe NSPC .In addition to the loss of the E1 ependymal cell, IVH also potentially impacts on the primary non-motile cilia of the B-cells, E2 cells and tanycytes. Several G protein coupled receptors have been identified in primary cilium [for example sonic hedgehog ] which aIn addition to direct injury to the NSPC in areas of ependymal denudation (as discussed above), it has been shown that damage to the motile cilia may impact on cell migration out of the SVZ . Using wThe majority of cells generated by the SVZ in the third trimester and early postnatal period are thought to be interneurons  with thrHistorically it was believed that blood products within the CSF caused a communicating hydrocephalus due to a blockage of CSF reabsorption at the arachnoid granulations. Whilst this may play a contributory role, the fact that arachnoid granulations are not developed in the neonate implies that other mechanisms may also be responsible.Fundamental shifts in our understanding of the etiology of hydrocephalus, CSF physiology and the role of CSF movement through the brain parenchyma and neuraxis , 70 haveOther potential mechanisms linking ependymal damage to the pathogenesis of hydrocephalus include disruption of a proposed feedback loop between the cilia of the ependyma and choroid plexus and consequently on CSF production. For example Banizs et al. demonstrated that in the Tg737orpk mouse, which has defects in cilia assembly secondary to a mutation in the Polaris gene, hydrocephalus was present before the motile cilia were formed . FurtherExposure of the ependyma and choroid to blood products results in changes in aquaporin RNA expression and protein expression , 132 a pDamage to the ependyma results in astrogliosis within the periventricular tissues  and the Finally, an important and evolving concept is the finding of inflammation induced choroid plexus hypersecretion secondary to intraventricular hemorrhage. Using a mouse IVH model, Karimy et al.  demonstrDespite concerted efforts to reduce the incidence of premature birth and the incidence and severity of neonatal intraventricular hemorrhage, it remains a fact that NIVH is still a frequent problem encountered by neonatologists and pediatric neurosurgeons alike. Given the extreme vulnerability and fragility of this patient group, the optimal treatment regime is not clear and NIVH remains the most common cause of hydrocephalus in the pediatric population  and a significant cause of neurodisability in children.Brain development in the final trimester and early postnatal period is reliant on both the maintenance of a neurohumoral gradient within the CSF  and the Traditional treatment paradigms based on a temporizing surgical intervention, with CSF diversion only in cases of symptomatic ventriculomegaly/raised intraventricular pressure have recently been challenged by new evidence showing that washing away bloodstained CSF , 22 and These are undoubtedly important and thought-provoking developments in the field, but by virtue of the fact that these neonates are extremely fragile and ventriculomegaly takes time to evolve, surgical intervention will not normally be considered until around 20–30 days of life. As such, this paradigm of surgical intervention, does not address the potential early toxicity caused due to the release of blood into the CSF.In order to develop new therapies to combat the early toxicity of NIVH more research is needed to understand both the changes that occur in the CSF secondary to hemorrhage and further to this, the impact that these changes have on the developing brain. Specifically, we need to increase our understanding of the mechanisms underlying ependymal denudation and the consequences that this process has on the underlying periventricular cells within the subventricular zone.The concept of earlier intervention prior to the development of symptoms  i.e., inDeveloping new therapies to treat the CSF with the intention of; reducing its toxicity, re-establishing haemostasis, and protecting the functional integrity of the ependyma, may herald new horizons in treatment. Given the difficulties associated with early surgical intervention, it may be that a staged treatment protocol would be most beneficial. For example, early medical treatment with the intention of buying time, whilst mitigating damage to the ciliated ependymal lining of the ventricle, followed by early instigation of endoscopic washout, timed to optimize the chance of facilitating clot and bloodstained CSF removal, whilst limiting potential risk to the neonate.WD is responsible for the conception, curation, writing of this manuscript, and production of the figures.This work was supported by Pump Priming Grants from the Royal College of Surgeons and is supported by the NIHR GOSH BRC.The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Emergency departments (ED) are rapidly replacing conventional troponin assays with high-sensitivity troponin tests. We sought to evaluate emergency physician utilization of troponin tests before and after high-sensitivity troponin introduction in our ED.We retrospectively examined 9,477 ED encounters, identifying the percentage in which physicians ordered a serum troponin both before and after our institution adopted a high-sensitivity troponin test.After introduction of high-sensitivity troponin testing, the percentage of ED encounters in which physicians ordered troponin studies decreased , with the drop most pronounced in admitted patients Introduction of high-sensitivity troponin testing was associated with a decrease in troponin ordering. While the reasons for this are unclear, it is possible that physicians became more selective in their ordering behavior because of the lower specificity of high-sensitivity troponin. Introducing high-sensitivity cardiac troponin (hs-cTn) in emergency departments (ED) often improves ED length of stayWe performed a retrospective analysis of ED operational data. Our institutional review board provided an exemption from full review.The Mayo Clinic Arizona ED is a tertiary care facility serving approximately 34,000 patients yearly with 26 rooms and up to nine hallway spaces in Phoenix, AZ, staffed by residency-trained EPs. There is no fast track or ED observation unit. Our EPs acquire patients on a rotational assignment basis, with no practical discretion as to which patients they evaluate. As EPs receive patients to individual queues when patients arrive in triage, we employ no triage physicians. The EPs place triage orders on their assigned patients to expedite care prior to physical assessment. Due to this front-end workflow, we rarely use nursing-initiated order sets outside of protocol activations such as acute stroke or ST-elevation myocardial infarction. Residents rotate through the ED and see approximately 5% of patients. No nurse practitioners or physician assistants work in our department.Our ED replaced conventional Roche fourth generation troponin T with Roche fifth generation hs-cTn on July 17, 2018. We reviewed all ED encounters seen by full-time EPs from July 17–September 16, 2018 (the “after” period). We chose this end date as it coincided with the rollout of a new electronic health record (EHR), which we believed would introduce additional confounders to our analysis. To account for seasonal variability, we matched this timeframe with a similar period one year prior, examining all ED encounters staffed by full-time EPs from July 17–September 16, 2017 (the “before” period). To limit the influence of different EP ordering practices,We obtained general characteristics of patient encounters in both groups including age, gender, race, Emergency Severity Index (ESI), ED length of stay (LOS), and admission rates. We examined the percentage of encounters receiving ED orders for a troponin test, either conventional troponin T before or hs-cTn after. We determined this percentage for all ED patients and then split the data to separately examine discharged and admitted  patients. To determine whether overall EP testing behavior changed, we performed this same analysis for hemoglobin, a common ED test. We selected hemoglobin since the data was readily available in our operational database.arsenal package.We used descriptive statistics , chi-square tests, and Kruskal-Wallis test by ranks where appropriate to examine differences in demographics in the before and after groups, as well as rates of troponin and hemoglobin ordered before and after hs-cTn overall and by type of encounter (discharge vs admission). Confidence intervals (CI) for the differences in rates of testing between groups were constructed using the Chan-Zhang exact method for calculating CIs for differences of binomial proportions.We report counts and rates of ED encounters receiving a troponin test in the before and after hs-cTn groups in Unlike troponin ordering, hemoglobin ordering did not change after hs-cTn introduction . Hemoglobin ordering behavior remained the same when examining subcategories of discharged  and admitted  encounters.Our results demonstrate a significant decrease in ED encounters receiving a troponin test after introduction of hs-cTn. We believe our EPs became more selective in their troponin ordering behavior. One study examining conversion to hs-cTn’s impact on laboratory workload noted a decrease in troponin tests after conversion to hs-cTn, with a decline in test orders of over 10% despite an increase in total ED visits, with an overall decrease in percentage of ED encounters receiving a troponin study.Decisions made by EPs change throughout a shift, with EPs picking up fewer patients and making more decisions that shorten ED LOS near end of shift (EOS).Increased ED troponin-ordering selectivity may be harmful or beneficial to patients. Although classic teaching recommends maintaining high suspicion for ACS, especially in patient groups who present atypically, some evidence suggests that EPs may overtest.If so, this approach may have pitfalls. Although the above method may be safe in geriatric patients with nonspecific complaints, ED patients presenting with chest pain are another matter. In a separate study, physician gestalt, even combined with an ECG, did not identify all ACS cases.Our study suffers from several limitations. The first is the capability of our EHR: the free-text nature of chief complaints at the time of data collection limited our ability to determine the percentage of ED visits with chest pain and potential ACS equivalents. Fewer patients with chief complaints suspected to be ACS equivalents may have presented to our ED in the after period. However, Patients in the after group were more likely to be labeled ESI 1 and 2, which we believe would typically prompt more orders for troponins, the opposite of our observed trend. Hemoglobin ordering, unlike troponin ordering, did not decrease after introduction of hs-cTn, suggesting that overall resource utilization remained similar before and after hs-cTn. We believe that matching the time of year when selecting the comparison period mitigated any effect of seasonal variability of complaints, and excluding encounters seen by part-time physicians and physicians employed during only one time period mitigated individual physician-ordering variability. We performed no specific interventions or community outreach programs during this time which would have changed the nature of presenting complaints.A second limitation is that ours is a single center, retrospective review; thus, we can comment on correlation but not causation. However, our findings do align with other studies noting a decrease in percentage of ED encounters receiving a troponin study after introduction of hs-cTn.After introduction of hs-cTn, the percentage of ED patients receiving troponin studies decreased. We suspect that emergency physicians became more selective in their ordering behavior to account for the lower specificity of hs-cTn.


Schizophrenia is essentially related to one’s self-perception and the relationship to the world. One possible explanation for symptoms of schizophrenia in activities is the disruption of timing, which can develop into a disorder of activity perception and attribution.Our study aimed to investigate the specificity of time perception disorder within the schizophrenia-bipolar spectrum, within the time interval around one second.In the study, N = 15 schizophrenic , N = 9 bipolar , N = 10 schizoaffective  patients with compensated clinical condition and N = 28 healthy control subjects  participated. Time processing was examined with a perceptual (discrimination) and a productive (synchronization) task.Concerning the interval discrimination, patients with schizophrenia and schizoaffective disorder lag behind controls in the majority of indicators (0.373–0.772). In terms of production and reproduction, the deviation of schizoaffective patients indicates a moderate difference, but subjects with schizophrenia show a large effect size, and subjects with bipolar disorder demonstrate a small effect size.Our results suggest that the schizophrenic group exhibits a comprehensive time-processing disorder and in this respect can be distinguished from the bipolar affective and the control group. People with schizoaffective disorder show an intermediate performance in reproduction between the schizophrenic and bipolar groups, while in the case of discrimination deficit, they approach schizophrenics.No significant relationships.


Hyperventilation resulting in hypocapnic alkalosis (HA) is frequently encountered in spontaneously breathing patients with acute cerebrovascular conditions. The underlying mechanisms of this respiratory response have not been fully elucidated. The present study describes, applying the physical–chemical approach, the acid-base characteristics of cerebrospinal fluid (CSF) and arterial plasma of spontaneously breathing patients with aneurismal subarachnoid hemorrhage (SAH) and compares these results with those of control patients. Moreover, it investigates the pathophysiologic mechanisms leading to HA in SAH.2), weak noncarbonic acids (ATOT), and pH were measured in CSF and arterial blood samples.Patients with SAH admitted to the neurological intensive care unit and patients  undergoing elective surgery under spinal anesthesia were enrolled. CSF and arterial samples were collected simultaneously. Electrolytes, strong ion difference (SID), partial pressure of carbon dioxide (PCOp < 0.001) and PCO2 , whereas no differences in ATOT  and pH  were observed. The reduced CSF SID was mainly caused by a higher lactate concentration . A linear association  was found between CSF SID and arterial PCO2. A higher proportion of patients with SAH were characterized by arterial HA, as compared with controls . A reduced CSF-to-plasma difference in PCO2 was observed in nonhyperventilating patients with SAH .Twenty spontaneously breathing patients with SAH and 25 controls were enrolled. The CSF of patients with SAH, as compared with controls, was characterized by a lower SID (23.1 ± 2.3 vs. 26.5 ± 1.4 mmol/L, Patients with SAH have a reduction of CSF SID due to an increased lactate concentration. The resulting localized acidifying effect is compensated by CSF hypocapnia, yielding normal CSF pH values and resulting in a higher incidence of arterial HA.The online version contains supplementary material available at 10.1007/s12028-022-01450-1. Cerebrospinal fluid (CSF) in normal conditions is a clear fluid surrounding the brain, characterized by a very low concentration of proteins. It is produced mainly by the choroid plexus and reabsorbed by the arachnoid villi  is expressed in mmol/L, [Alb] is the plasma concentration of albumin expressed in g/L, [Pi] is the plasma concentration of phosphates expressed in mmol/L, and pH denotes arterial or cerebrospinal pH.where [ATOT] was calculated, rearranging the dissociation equation as reported in Eq. A is equal to 6.8 and represents the negative logarithm to base 10 of the dissociation constant of noncarbonic buffers.The total amount of weak acids ) was calculated from pH and PCO2 according to the Henderson–Hasselbalch equation  , 19 was Data analysis and statistical plans were written and filed with the institutional review board before data were accessed. We calculated that a sample of 40 patients (20 patients per group) would provide a statistical power of 0.9 with an α error of 0.05 to detect a difference in SID of 3 mEq/L, assuming a standard deviation of 2.5 mEq/L. Given the novelty of the measurement of some CSF variables, we decided to increase the number of control patients to 25.t-test or the Mann–Whitney rank-sum test, as appropriate. Differences between categorical variables were assessed using the χ2 test. The relationship between quantitative or categorical variables was investigated using linear and multilinear regression, as appropriate. Data are expressed as mean ± standard deviation or median and interquartile range, unless otherwise stated. Statistical significance was defined as p < 0.05. Analysis was performed with SAS v.9.2  and SigmaPlot v.12.0 . The Strengthening the Reporting of Observational Studies in Epidemiology checklist was used.Comparison between continuous variables was performed via Student’s 2/FiO2 = 352 ± 121). Twenty-five healthy controls were enrolled . Comorbidities of patients with SAH and controls are reported in Table S1.Patients were enrolled between February 2017 and October 2018. Twenty spontaneously breathing patients with aneurismal SAH  wereindex 24 –25, 8 pa2 and similar ATOT. No difference in CSF pH was observed. The reduced CSF SID was caused mainly by an increased lactate concentration (p < 0.001). On the plasma side  and phosphate  concentrations.Cerebrospinal and arterial acid–base findings are summarized in Tables 2, the CSF-to-plasma difference in PCO2, showed significantly different values between controls and patients with SAH . Measured osmolarity of both plasma (p < 0.001) and CSF (p = 0.001) was significantly higher in patients with SAH.The ΔSID, i.e., the difference between CSF and plasma SID, differed significantly between the two groups Fig. . Furtherp = 0.003).The incidence of HA was higher in spontaneously breathing patients with SAH, as compared with controls . Arterial and CSF acid–base characteristics of patients with HA and those without HA are summarized in Table S3 and Table p = 0.002) in patients with HA, CSF PCO2 and pH did not differ significantly between groups. Notably, CSF electrolytes did not differ significantly between patients with HA and those without HA. Regarding plasma, in addition to the differences in PCO2 and pH due to the selection criteria, arterial SID was significantly lower in patients with HA.Although CSF SID was lower .A lower ΔPCOHA Table . Of notep = 0.93) or CSF PCO2 (p = 0.13) and CSF pH.Linear and multilinear regression analyses were used to investigate the association between variables both in controls and in patients with SAH. In controls, no association was found at univariate analysis between CSF SID . Both variables remained independently associated at the multilinear regression analysis . At univariate analysis, CSF sodium , chloride , and lactate  were significantly associated with CSF pH. However, at multilinear regression analysis, only lactate was independently associated with CSF pH (Table S5). Lastly, in the overall SAH population, a positive correlation between CSF SID and arterial PCO2 was found .In patients with SAH, both CSF SID and PCOp = 0.64) was observed in GOS-E scores between patients with HA and those without HA. A good clinical outcome (GOS-E score ≥ 6) was observed in 10 of 16 patients. Patients with worse clinical outcomes had higher CSF lactate concentrations .Six patients with SAH experienced an episode of clinical vasospasm; two of these patients died in the ICU, and four patients were lost at follow-up. Plasma and CSF acid–base characteristics of patients who developed vasospasm did not differ significantly from those of patients who did not (Tables S6 and S7). No significant association was observed between CSF SID (or ΔSID) and the modified Fisher scale score by Pearson’s correlation (data not shown). The median 12-month GOS-E score was 6 (3–8). No difference  contains several physiologic information linked to spontaneous breathing activity and cerebral blood flow. In a patient population characterized by an acute neurologic condition, this fluid might even gain more importance, including, possibly, a prognostic role. Our limited sample size is of course insufficient to draw inferences about the prognostic role of a single value or of its time course. However, we think that it might be a good research question for future studies.Our data suggest that the response to a local CSF acidification might differ among patients with SAH and that cerebral metabolism, and therefore local CO2 and pH of the two sites are minimal in physiologic conditions [We need to acknowledge some limitations of our study. First, a higher presence of men characterized our controls, as compared with the SAH population. Although hormones certainly play a role in respiratory regulation, this is more evident during pregnancy, which was an exclusion criterion for our study. Second, we sampled CSF in different sites, i.e., lumbar in controls and ventricular in patients with SAH. Differences in PCOnditions . TherefoOn the contrary, meaningful differences between lumbar and ventricular CSF could be present in patients with SAH , 42, 43.2 is reduced to restore a normal CSF pH. This compensatory mechanism might explain the high incidence of arterial HA in patients with spontaneous SAH.Patients with SAH have a localized CSF acidosis, characterized by a reduced CSF SID and mainly caused by increased lactate concentrations. CSF PCOSupplementary file1 (DOCX 189 KB)Below is the link to the electronic supplementary material.


Polyorchidism is a rare congenital anomaly which describes the presence of more than two intra- or extrascrotal testes. Typically, the supernumerary testis is found incidentally during surgery for another condition but may present clinically as a painless paratesticular mass necessitating a radiological diagnosis. Polyorchidism carries an increased risk of testicular malignancy, with cryptorchidism the likely most important risk factor. Given, however, that the supernumerary testis likely contributes a reproductive function, surgical removal and definitive histopathological diagnosis is not always appropriate. We present a radiologically diagnosed supernumerary testis in a 40-year-old male with a history of surgically managed cryptorchidism in childhood. We present a radiologically diagnosed supernumerary testis in a 40-year-old male with a history of surgically managed cryptorchidism in childhood.Polyorchidism or the presence of more than two intra- or extrascrotal testes is a rare congenital anomaly with less than 200 cases described worldwide. Triorchidism, or the presence of three testes, is the most common type of polyorchidism, with the supernumerary testis typically found incidentally during surgery for another medical condition such as inguinal hernia (24%) and cryptorchidism (22%).A 40-year-old Caucasian male was referred by his GP to our urology service following a transient episode of left-sided testicular pain associated with a long-standing history of left hemi-scrotal swelling which had remained unchanged for over 10 years. His previous medical history was significant for left-sided cryptorchidism for which he underwent a left-sided orchidopexy for at the age of 10. On examination, the left testis examined slightly smaller than the right and a soft, mobile lump was palpated adjacent to the left testis. The clinical impression at the time was a likely scrotal lipoma and an ultrasound testes scan was arranged to further evaluate the lump.Ultrasound testes reported a normal left testis (3.6 × 1.5 × 3.1 cm) with no intraparenchymal abnormality other than an incidental simple cyst of the tunica albuginea measuring 0.9 × 0.4 cm. Within the left scrotal sac however, there was a well-defined 1.7 × 1.1 × 0.5 cm soft tissue mass lateral to the left testis with similar echogenicity and texture to the left testis . AppearaGiven the increased risk of testicular malignancy in supernumerary testis, testicular tumour markers were sent, and an MRI testes was arranged. This reported a T2 hyperintense, T1 hypointense oval-shaped lesion abutting the posterior aspect of the left testis, measuring 16 × 6 × 14 mm, with no restricted diffusion, and was similar in appearance to that of the adjacent testis .−1, αFP 2.3 IU ml−1, and LDH 236 U l−1) and MDT concluded that both ultrasonographic and MRI findings supported a diagnosis of left-sided supernumerary testis. The patient will be followed up clinically with early interval sonographic observation.Given the rarity of supernumerary testis, the case was discussed at a urology multidisciplinary team (MDT) meeting. The previously sent testicular tumour markers returned within normal range (βhCG < 1 IU l2 Importantly, malignant neoplasms such as rhabdomyosarcomas, leiomyosarcomas and liposarcomas must be considered in context of the patient’s age and ruled out.3 Moreover, polyorchidism itself carries an increased risk of testicular malignancy, with cryptorchidism the likely most important risk factor for malignancy.1 This is highlighted in our case whereby the left supernumerary testis appears to have been missed during childhood, both on clinical examination and surgical exploration. This is most likely due to its small size and rarity.Differential diagnosis of a paratesticular mass presents a significant diagnostic challenge given the rarity of polyorchidism and the wide spectrum of potential neoplastic and non-neoplastic lesions.3 may present as a painless mass or be encountered in the scrotum or inguinal canal during surgery for another condition. On ultrasonography, the supernumerary testis is often smaller in size and hypoechoic to the normal testis, which it may or may not be connected to, and on Doppler the vascularity is often less.3 The mediastinum testis and shared epididymis may be shown, or a supernumerary epididymis may be detected.3 With a sensitivity of nearly 100% for lesions detected in the scrotal area, and a specificity of 70–90% depending on the location and characteristics of the lesion, US is the method of choice and in most cases is diagnostic.2–4 However in complicated cases such as ours, where the patient had undergone orchidopexy for left-sided cryptorchidism in childhood, MRI should be utilised for definitive tissue characterisation.Polyorchidism, which is thought to occur because of division of the genital ridge by peritoneal bands,i.e., T2 hyper- and T1 hypo- to isointense, homogenous oval structure, with diffusion restriction, and surrounded by a T1/T2 hypointense tunica albuginea, a finding that is helpful for differentiating a supernumerary testis from another lesion.2On MRI, the signal intensity of the supernumerary testis is reported to be almost identical to that of the normal testis 5In summary, polyorchidism is a rare clinical entity which requires a combination of radiological modalities and protocols to make a definitive diagnosis, avoid surgery and preserve a potentially functioning supernumerary testis in uncomplicated cases where conditions such as cryptorchidism, torsion, or malignancy do not coexist. In our case, we did not proceed to surgery as the patient had previously been operated on in childhood for cryptorchidism and radiological work-up confirmed a scrotal location of both the left testis and supernumerary testis without any suspicious features. Our management is in keeping with current consensus whereby in the setting of uncomplicated polyorchidism, conservative expectant management with close sonographic follow-up is advised.Polyorchidism is a rare clinical entity which carries an increased risk of testicular malignancy, with cryptorchidism the likely most important risk factor.This case presents the radiological diagnosis of a supernumerary testis presenting as a scrotal lump in a middle-aged male with a prior history of orchidopexy in childhood for same-side cryptorchidism.In complicated cases such as ours, a multimodal radiological approach, including MRI, should be utilised for definitive tissue characterisation.Based on MDT discussion, and in the absence of any suspicious radiological features, surgery may be avoided in a previously cryptorchid supernumerary testis when a post-operative scrotal location can be radiologically confirmed.Supernumerary testis should be considered in the differential diagnosis of any paratesticular mass.