Platinum-based chemotherapies used to treat many types of cancers are ototoxic. Ototoxicity management (OtoM) to mitigate the ototoxic outcomes of cancer survivors is recommended practice yet it is not a standard part of oncologic care. Although more than 10,000 patients each year are treated with platinum-based chemotherapies at the US Veterans Health Administration (VA), the current state of OtoM in VA is not well-defined. This study reports on a national survey of VA audiologists’ perceptions regarding OtoM in cancer patients.A 26-item online survey was administered to VA audiologists and service chiefs across the VA’s 18 regional systems of care. Descriptive statistics and deductive thematic analysis were used to analyze the data.The 61 respondents included at least one from each VA region. All reported they felt some form of OtoM was necessary for at-risk cancer patients. A pre-treatment baseline, the ability to detect ototoxicity early, and management of ototoxic effects both during and after treatment were considered high value objectives of OtoM by respondents. Roughly half reported routinely providing these services for patients receiving cisplatin and carboplatin. Respondents disagreed regarding appropriate hearing testing schedules and how to co-manage OtoM responsibilities with oncology. They identified barriers to care that conformed to three themes: care and referral coordination with oncology, audiology workload, and lack of protocols.Although VA audiologists value providing OtoM for cancer patients, only about half perform OtoM for highly ototoxic treatment regimens. The OtoMIC survey provides clinician perspectives to benchmark and address OtoM care gaps.Collaboration between oncology and audiology is needed to improve current OtoM processes, so that cancer survivors can have more control over their long term hearing health.The online version contains supplementary material available at 10.1007/s11764-022-01316-7. Platinum-based chemotherapeutics, such as cisplatin and carboplatin, are highly effective at treating a variety of common cancers including those of the bladder, bone, cervix, colon, endometrium, esophagus, head and neck, lung, ovaries, testes, pancreas, rectum, and stomach . UnfortuOtotoxicity monitoring guidelines were put in place by the American Speech-Language-Hearing Association (ASHA) nearly three decades ago . As showIn 2021, Konrad-Martin and colleagues evaluated the premise that OtoM should be the recommended standard of care for patients receiving cisplatin-based chemotherapy, using a randomized control trial conducted in the VA. The trial compared the efficacy of OtoM provided as a dedicated program using automated protocols that enabled patients to screen their own hearing in the oncology infusion unit, against a referral system for “usual care” ototoxicity monitoring administered through the audiology clinic. Although the research team made referrals to audiology for each participant in the usual care group, only one patient completed a monitoring visit prior to each cisplatin dose, the protocol recommended by US audiology governing bodies for patients receiving cisplatin , 28. In Many interventions shown to be effective in research studies fail to be successfully implemented in real-world healthcare settings. Barriers to successful implementation exist at multiple levels of healthcare delivery that must be understood and considered . The ConThis report documents the development of the “Ototoxicity Management Through Interdisciplinary Care (OtoMIC) Survey” . Follow-up emails to service chiefs/leads were sent to VISNs that lacked responses following the initial request for participation. Respondents were surveyed between November and December of 2020 using a VA-approved secure web-based application called Qualtrics, and the survey took approximately 15 min to complete. Sixty-one respondents completed survey questions, and 57/61 respondents provided their VISN or specific VA location  inne inne1 isThe face validity of the survey was established by two different review panels. The first review panel consisted of a VA Audiology Chief, an Oregon Health & Science University Audiologist, a VA Oncology Chief, a VA Oncologist, and a VA Oncology Nurse Practitioner to ensure that the questions captured the salient dimensions of OtoM. This prompted revisions to the response options for a few of the multiple-choice questions, in addition to other minor edits. The second review was conducted by an Implementation Science/Health Service Delivery expert to assess question clarity and fit to the conceptual framework. The final version of the OtoMIC survey The quantitative data obtained from the survey were analyzed using descriptive statistics. Quantitative responses from the survey are reported as absolute frequency (number of respondents that selected each option), relative frequency , or the median response . All data were securely stored in compliance with VA policy.A directed, deductive thematic analysis  was usedSixty-one respondents answered the demographic questions in the survey: VA name and geographic location, clinic type , and position (service chief/lead or staff member); of these, some chose not to provide specific location information. Forty-eight percent of the responses were from audiologists and the remaining 52% were from Speech Pathology and Audiology Service Chiefs, which corresponded with the expected response from one audiologist and one service chief or lead from each facility. Seventy-nine percent of respondents worked primarily at a VAMC only, and the other 21% worked at both a CBOC and a VAMC. Seventy-seven percent of the respondents had been practicing in their field for over 10 years and 15% of respondents had been practicing for 7–10 years. The geographical distribution of the 57 respondents who provided this information is shown in Appendix Questions related to the outer setting CFIR construct included those asking about Veterans OtoM needs and resources. Audiologists were asked approximately how many patients in their monthly caseload were receiving a platinum-based chemotherapy and/or radiotherapy. Appendix Respondents were also asked what percentage of their patients experienced new or increased hearing loss, tinnitus, balance changes, or decreased quality of life because of an ototoxic agent. The reported presentation and impact of ototoxicity symptoms varied substantially. Despite a large range in responses, respondents indicated similar median incidence of new or increased tinnitus (20%), balance problems (17%), and hearing loss (18%) in their OtoM caseloads. Finally, the respondents reported that 29% of their OtoM patients experienced reduced quality of life due to the ototoxic impacts of their cancer treatment. These estimates can be seen in greater detail in Appendix The inner setting domain includes questions on the tasks that providers perform related to OtoM and the prioritization of ototoxicity monitoring. Table Several questions asked about team member responsibilities for aspects of OtoM. As shown in Fig. Survey respondents ranked hearing loss and balance dysfunction as the most and second most important non-lethal cancer treatment side effects to manage, respectively Appendix . These sRespondents were asked to indicate the appropriate monitoring schedule for ototoxic medications based on drug type. Figure When asked about the main barriers associated with OtoM implementation, respondents cited several including factors related to interdisciplinary communication , identifying patients , resources, and the absence of national protocols. Table This survey study was conducted to characterize OtoM service gaps and barriers to care across the VA healthcare system from the audiologist’s perspective, with a focus on care provision for patients prescribed platinum-based chemotherapies and/or radiation for the treatment of cancer. The provision of OtoM is generally not standard practice for cancer patients despite the high rates of ototoxicity associated with platinum-based chemotherapy, the known adverse effects of ototoxicity on QoL, and the existence of position statements from medical professional organizations advocating OtoM e.g., , 44. TheThe aggregated survey results indicate that audiology providers in the VA believe certain aspects of OtoM are “extremely useful” or “very useful” for patient’s receiving platinum-based drugs, and that some form of monitoring is necessary for this population. However, only about half of respondents reported having fully implemented these valued OtoM services for highly ototoxic, cisplatin, and carboplatin-containing chemotherapies. The most frequently reported barriers to implementing OtoM were a lack of integrated interdisciplinary care, referral issues, no standardized protocol to guide care, and insufficient resources. Lastly, there were inconsistencies in the respondents’ knowledge regarding ototoxicity symptoms, and differing opinions about the responsibilities of audiologists and oncologists for OtoM care. Audiologists were primarily deemed responsible for monitoring hearing during treatment and providing patients with hearing aids and rehabilitation, but the oncology team was considered the main source for informing patients about the risks of ototoxicity, monitoring patient-reported symptoms, counseling patients who develop ototoxicity, as well as referring patients for OtoM services.The CFIR constructs used to guide each stage of this research were those that Damschroder et al.  determinThe variation in the audiologists’ perspectives on when ototoxicity should be monitored may reflect the need to expand and refine existing guidance on OtoM protocols , 32. PatSurvey results further indicate that barriers such as unclear referral pathways are exacerbated by a lack of confidence that oncology teams would value and utilize information about ototoxicity in their patients. Audiologists also point to the need for alignment across audiology and oncology care providers regarding their responsibilities for OtoM. While results indicated a small number of “unsure” responses, more respondents indicated that no provider was specifically assigned to key tasks or that multiple providers were. This underscores the need for interdisciplinary discussion, and perhaps formalized agreements, between care teams to clarify roles for different elements of OtoM. This could ensure that patients do not miss key opportunities to improve their long-term hearing, tinnitus, and balance outcomes.Approximately 14 studies from five of the six global regions defined by WHO have collected patient data or surveyed health care providers on aspects of OtoM implementation in cancer patients. A list of these publications can be found in Appendix Understanding how OtoM fits into the VA can inform integration into other healthcare systems and structures; however, applying similar analyses will be necessary to identify locally available resources and barriers to care in the many other contexts in which patients are treated with ototoxic drugs. The VA survey respondents may have been biased toward those who prioritize OtoM, in which case actual care gaps could be greater than indicated in this report. The current report also is limited to the VA audiology community. Ongoing work for this project includes surveying VA oncology teams . A better understanding of what purpose OtoM serves for the oncology team will be crucial for better integrating OtoM into oncology care. This report does not provide any data on the perspectives of patients receiving OtoM, a necessary element to ensure the care is relevant and valuable for the patient and to increase buy-in from a multidisciplinary team of providers as well as organizational leadership.The OtoMIC survey provides stakeholder perspectives to benchmark and address OtoM care gaps. The implications of this report add to the growing body of evidence that shows OtoM is not consistently provided for cancer patients across clinical settings, healthcare structures, and global regions. Perspectives from VA audiologists gained through this nationwide survey have clarified factors that are barriers to implementing OtoM in the largest organized healthcare system in the USA . CollaboSupplementary file1 (DOCX 439 KB)Below is the link to the electronic supplementary material.


Background and Objectives: Various predisposing factors for lateral patellar dislocation (LPD) have been identified, but the relation between femoral rotational deformity and the tibial tubercle–Roman arch (TT-RA) distance remains elusive. Materials and Methods: We conducted this study including 72 consecutive patients with unilateral LPD. Femoral anteversion was measured by the surgical transepicondylar axis (S-tAV), and the posterior condylar reference line (P-tAV), TT-RA distance, trochlear dysplasia, knee joint rotation, patellar height, and hip–knee–ankle angle were measured by CT images or by radiographs. The correlations among these parameters were analyzed, and the parameters were compared between patients with and without a pathological TT-RA distance. Binary regression analysis was performed, and receiver operating characteristic curves were obtained. Results: The TT-RA distance was correlated with S-tAV , but the correlation between P-tAV and the TT-RA distance was not significant. S-tAV had an AUC of 0.711 for predicting a pathological TT-RA, with a value of >18.6° indicating 54.8% sensitivity and 82.9% specificity. S-tAV revealed an OR of 1.13  with regard to the pathological TT-RA distance by an adjusted regression model. Conclusions: S-tAV was significantly correlated with the TT-RA distance, with a correlation coefficient of 0.360, and was identified as an independent risk factor for a pathological TT-RA distance. However, the TT-RA distance was found to be independent of P-tAV. As a common sports-related disorder, lateral patellar dislocation (LPD) has a morbidity of about 108 per 100,000 individuals ,3. NotabAccurately evaluating the anatomic abnormalities of patients with LPD is of great significance. In 2022, a systematic review highlighted the importance of an accurate radiological evaluation to perform an individualized surgical strategy . Using tA controversy exists in the literature with regard to the relation between femoral anteversion and the lateralization of the tibial tubercle. Wang et al.  found thGiven that the relation between femoral rotational deformity and the parameters for evaluating tibial tubercle lateralization remains controversial in the literature, this study aimed to verify the relationship between the TT-RA distance and femoral anteversion in patients with LPD. We hypothesized that the TT-RA distance could be directly correlated with S-tAV.The ethics committee of our hospital approved this study and waived the informed consent . In total, 135 patients were initially identified from January 2016 to December 2021 in our institution from the Electronic Medical Records System based on the inclusion criterion of unilateral and recurrent patellar dislocators with skeletal maturity. Patients were excluded from this study if they were without sufficient or standard radiological data, had hip developmental dysplasia, previously suffered from trauma or surgery, or presented with distal femoral condyle epiphysitis, which could influence the reliability of the measurements.In total, 36 patients did not have CT scans of the hip, femur, and knee joint simultaneously; 13 patients had nonstandard weight-bearing full-leg anteroposterior radiographs; 3 patients suffered from trauma or surgery; 2 patients presented severe condyle epiphysitis; 4 patients showed hip developmental dysplasia. Finally, 77 patients were enrolled in this study for radiological assessment.A CT scanner  was used to obtain images of the patients ranging from the ilium to the toes. All the patients were supine on the examination bed during the CT scan, the knee joints were fully extended, and the ankle joints were in a neutral position. Important scanning parameters: according to the size of the extremities of the patients, the field of view varied from 220 to 450 mm; both the scanning layer thickness and the layer spacing were 1 mm, with a matrix of 512 × 512 pixels.We included 77 patients with LPD for radiological assessment. All the measurements were retrospectively conducted by a radiologist and an orthopedist on CT images and radiographs via a picture archiving and communication system (PACS). The observers received professional training regarding the measuring method of each parameter. Major disputes of the measuring results, especially on the Dejour classification of trochlear dysplasia, were discussed until consensus was reached. In this study, the anatomic parameters were retrospectively evaluated by PACS, and the accuracy of each measurement was one digit behind a comma.According to the method described previously, the segmental torsion parameters of the femur were measured by CT images . Three dTrochlear dysplasia includes four subtypes identified by axial CT slice according to the Dejour classification . Type A Referring to the method that we described previously, axial CT images were used to measure the TT-RA distance . In shorKnee joint rotation (KJR) is defined as the angle formed between the PCRL and the proximal tibial condyle reference line in the slice with visualization of the intact posterior tibial condyles  Figure . The InsCoronal malalignment was assessed by hip–knee–ankle (HKA) angle on weight-bearing full-leg radiographs. It is defined as the angle between the femoral mechanical axis and the tibial mechanical axis  Figure . Valgus p < 0.05 represents statistical significance.We calculated the interclass correlation coefficient (ICC) to evaluate the inter-observer reliability of each measurement; a value higher than 0.75 indicates an excellent agreement. To exclude abnormal values from the final analysis, box plot analysis was conducted. The average value of each parameter was utilized, and all statistical analyses were performed by an experienced orthopedist via the SPSS software . We performed the Shapiro–Wilk normality test to verify if the data conformed to the normal distribution. Spearman or Pearson correlation analysis was conducted to deal with the relation between the anatomic parameters. Chi-square test, Wilcoxon rank-sum test , and unpaired t-test  were used to identify the differences in the anatomic parameters between the two subgroups. GraphPad Software  was used to conduct receiver operating characteristic curves (ROC) analysis. The areas under the curves (AUC) and the Youden index were calculated to determine the ability of the parameters to predict a pathological TT-RA distance. We established a binary logistic regression model to identify the relationship between femoral anteversion and the TT-RA distance. The power of this study was calculated by G-Power software . For the effective size of 0.36 calculated by the correlation coefficient between the TT-RA distance and S-tAV in this study, the sample size was 72, and the alpha value was set to 0.05; this study obtained a power of 0.94.Five patients with abnormal data were excluded from the final statistical analysis by box plot. A total of 72 subjects were eventually enrolled in the statistical analysis; they included 57 females and 15 males (mean age ± SD 21.9 ± 8.4). The detailed demographic data are shown in p = 0.013), similar to what observed for the relation between P-tAV and P-dAV . S-tAV was associated with the TT-RA distance  and the HKA angle . P-tAV was correlated with patellar height  and HKA angle . The correlation between P-dAV and the HKA angle showed statistical significance . S-tAV was correlated with S-dAV in patients with LPD . The difference in P-tAV between the two subgroups showed no statistical significance. There were no significant differences in the rest of the parameters between the two subgroups (p > 0.05).According to the TT-RA distance, the patients with a value higher than 26 mm and smaller than 26 mm were designed as group A and group B, respectively. The results of a different analysis of the parameters between the two subgroups are shown in p = 0.002), with a value of >18.6° indicating 54.8% sensitivity and 82.9% specificity. P-tAV had an AUC of 0.644 for a pathological TT-RA distance (p = 0.038) (p = 0.002) for predicting a pathological TT-RA distance by simple binary regression analysis. A multivariable analysis (the HKA angle and S-dAV were included) showed that S-tAV was associated with the TT-RA distance, with an OR of 1.13   . S-tAV h= 0.003) .The most significant findings of this study are here described. The TT-RA distance was directly correlated with S-tAV but was independent of P-tAV in patients with LPD. S-tAV had a fair diagnostic ability for predicting a pathological TT-RA distance and was also verified as an independent risk factor for a pathological TT-RA distance. When the value of S-tAV was greater than 18.6°, the sensitivity to identify a pathological TT-RA distance was 54.8%. As S- tAV increased by one degree, the risk of a pathological TT-RA distance was 1.13-fold higher. These findings indicate the significant correlation between the lateralization of the tibial tubercle and femoral malrotation.Femoral rotational malformation was reported as a significant etiology for LPD by decreasing the patellofemoral congruence and increasing the force on the lateral patellofemoral facet ,21. If fOne of the reasons for such discrepancies might be that the parameters selected to evaluate a specific deformity could not accurately reflect the studies malformation. The measurement of the TT-TG distance is significantly dependent on trochlear morphology, because the lowest point of the trochlea is hard to identify, especially in patients with severe trochlear dysplasia. Because of the impact of the morphology of the posterior femoral condyles, P-tAV could potentially over-evaluate a femoral rotational deformity ,25. ThenPrakash et al.  found thThe literature regarding the relation between the TT-TG distance and distal femoral anteversion is scarce. Distal femoral anteversion was considered a contributor to excessive total femoral malrotation in patients with LPD . In thisAs it stands, femoral rotational abnormalities in patients with LPD could be alleviated via DDFO to some extent . NeverthTrochlear dysplasia has been accepted as the most significant predisposing factor for LPD, and the Dejour classification and LTI are commonly used to evaluate trochlear dysplasia . P-dAV sKnee valgus deformity contributes to patellar instability by increasing the Q angle and lateral vector on the patella, and the HKA angle is an accepted parameter for evaluating the coronal malalignment of the lower extremities . Li et aPatella alta was also considered an important risk factor for LPD . ResearcOur study has some limitations. First, not all segmental femoral torsion parameters were analyzed, such as neck and mid femoral anteversion. Second, the tibial morphology was not included, which has been demonstrated to be associated with LPD . Third, S-tAV was significantly correlated with the TT-RA distance, with a correlation coefficient of 0.360, and appeared as an independent risk factor for a pathological TT-RA distance. However, P-tAV was shown to be independent of the TT-RA distance.


Treponema pallidum into the central nervous system. In recent years, with the increase in the latent syphilis infection rate, the incidence of neurosyphilis has gradually increased, the typical symptoms of neurosyphilis have decreased, atypical manifestations have increased, and the clinical manifestations have become increasingly diverse. Cerebrospinal fluid testing plays an important role in the diagnosis of neurosyphilis. In recent years, there have been many advances in cerebrospinal fluid testing. This review focuses on the current and potential laboratory indicators of neurosyphilis in cerebrospinal fluid, aiming to provide a reference for clinical application and ideas for future experimental research of neurosyphilis.Neurosyphilis is a chronic infectious disease caused by the invasion of  Treponema pallidum , and humans are the only host. T. pallidum is highly neuroinvasive and can invade the central nervous system and result in neurosyphilis at any time after the initial infection. Studies have shown that T. pallidum can disseminate to the central nervous system of rabbits within hours to days after inoculation . First, the CSF of an individual suspected of having neurosyphilis was injected into the testes of normal New Zealand rabbits. One week after inoculation, the testicular size of rabbits was examined, and blood was used for serological testing  test and rapid plasma response (RPR) test). If the results of the rabbit serological tests were positive, the animal was considered positive. CSF-RIT could provide direct evidence of T. pallidum invasion of the nervous system  is becoming increasingly important in the detection of infectious disease pathogens. Molecular assays with NAATs of T. pallidum DNA are used for direct detection to improve diagnostic sensitivities. There are various NAATs, such as PCR, nested PCR, quantitative PCR, and reverse transcriptase PCR   –10. AmonT. pallidum DNA in CSF by NAATs has been assessed as a potential additional tool for the diagnosis of neurosyphilis. A total of 124 patients with positive T. pallidum serological results were recruited and classified according to the 2008 European syphilis management guidelines. Among these patients, Tp47 and polA NAATs were positive in 25 (76%) and 23 (70%) of 33 neurosyphilis patients and 12 (13%) and 7 (8%) of 91 patients without neurosyphilis, respectively  test, toluidine red unheated serum test (TRUST) and RPR test  released against lipid antigens  and non-specific antibodies produced by RPR test . The meaThe CSF-VDRL test has been considered the gold standard for neurosyphilis diagnosis for a long time and is the main diagnostic test for neurosyphilis in domestic and foreign guidelines –21. It iThe RPR test uses the same antigen as the VDRL test except it is bound to carbon particles and uses charcoal particles as the visualizing agent. Studies have reported that the CSF-RPR test sensitivity ranged from 51.5 to 81.8%, and the specificity ranged from 81.8 to 100% , 27. TheOne study focused on the performance of a non-treponemal test in CSF neurosyphilis specimens and found that the sensitivity and specificity of the CSF-VDRL test, CSF-RPR test and CSF-TRUST were similar. Therefore, the CSF-RPR test and CSF-TRUST could be considered alternative tests for neurosyphilis in HIV-negative patients, especially when the CSF-VDRL test is unavailable . HoweverAt present, there is no unified view on the sensitivity and specificity of the CSF-VDRL test, CSF-RPR test and CSF-TRUST, and it is unlikely that the role of the CSF-VDRL test could be completely replaced by the CSF-RPR test and CSF-TRUST in the diagnosis of neurosyphilis. There are also some different opinions about the role of CSF non-treponemal tests in the diagnosis of neurosyphilis among different country guidelines. The guidelines for the Treatment of Sexually Transmitted Diseases of the United States Centers for Disease Control and Prevention (CDC) emphasize that CSF-VDRL test positivity could be used as an important diagnostic criterion for symptomatic neurosyphilis patients, but CSF-VDRL test negativity does not exclude a neurosyphilis diagnosis . The EurCSF non-treponemal test results are the most important indicators for the diagnosis of neurosyphilis at present. However, this test is difficult to automate, the results observed by the naked eye are relatively subjective, and the sensitivity is not high. Biological false positives due to cross reactivity may be related to various infectious and non-infectious diseases, and the anterior band phenomenon may cause false-negative results. Therefore, it is necessary to determine more sensitive laboratory indicators as supplementary tests for CSF non-treponemal tests.T. pallidum extract or recombinant T. pallidum protein as a specific antigen to detect serum anti-T. pallidum IgG or IgM antibodies. At present, treponemal tests mainly include the fluorescent treponemal antibody absorption (FTA-ABS) test, Treponema pallidum haemagglutination assay (TPHA), TPPA test and enzyme immunoassay (EIA). The FTA-ABS, TPHA and TPPA tests are used to detect total antibodies against T. pallidum antigen. EIA mainly detects IgG and IgM antibodies against recombinant T. pallidum proteins . The tests mentioned above can be used to detect anti-T. pallidum IgG or IgM antibodies in CSF. Studies have reported that the sensitivity of the CSF-FTA-ABS test is 90.9–100%, and the specificity is 100%  is a multieffect immunoregulatory cytokine with a unique structure. MIF plays an important role in innate immunity, immune cell recruitment and inflammation. Therefore, it has become a relevant indicator of the inflammatory response in various diseases. MIF is a key indicator of central nervous system infection. Studies have shown that the sensitivity of CSF MIF concentration for neurosyphilis diagnosis was 74.42%, and the specificity was 67.74% (Interleukins are cytokines produced by multiple cells that act on multiple cells. Interleukins play an important role in immune function modulation. Studies have shown that the level of IL-17A in the CSF of patients with asymptomatic neurosyphilis is significantly higher than that in patients without neurosyphilis . In anot6/L), with >20 × 106/L used as the cut-off value to improve the specificity of neurosyphilis diagnosis  and protein > 500 mg/L, with no other evident causes of these abnormalities. (2) Positive CSF-VDRL test (or RPR test/TRUST) or FTA-ABS test (or TPPA/TPHA test) (The CSF white blood cell (WBC) count and total protein test, as traditional laboratory indicators for the diagnosis of central nervous system infection, also play an important role in the diagnosis of neurosyphilis. Abnormalities in the routine biochemical examination of CSF are considered important laboratory evidence for the diagnosis of neurosyphilis in many national guidelines. The European guidelines for the diagnosis and treatment of neurosyphilis specifically suggest that CSF examination must include total protein, monocyte count, and treponemal and non-treponemal tests. If there is an abnormal CSF examination result (high protein levels and/or increased number of cells), CSF analysis must be repeated after treatment (6 weeks-6 months) . The Ameiagnosis . In the HA test) . AnotherHA test) . HoweverTau protein is the main microtubule-associated protein in neurons and is located mostly in the axons of neurons. A study found that there was a significant difference in CSF Tau protein content between neurosyphilis and Alzheimer's disease patients. The Tau protein level in the CSF of neurosyphilis patients was significantly higher than that of non-neurosyphilis patients, suggesting that Tau protein is helpful for the diagnosis of neurosyphilis with a history of syphilis and cognitive decline , 48. Howβ-Amyloid precursor protein lyase (BACE1) is a key enzyme responsible for the cleavage of pathological amyloid β-protein precursors . The stuin vitro (Triggering receptor expressed on bone marrow cells 2 (TREM2) is a cell surface receptor protein. For the brain, the focus is on the expression of TREM2 in microglia, which promotes phagocytosis, inhibits toll-like receptor-induced inflammatory cytokine production, and enhances anti-inflammatory cytokine transcription in vitro , 52. Itsin vitro .β2-microglobulin is a protein composed of 11 polypeptide chains that is one of the light chain components of major histocompatibility complex class I molecules and is associated with aging-related cognitive impairment and Alzheimer's disease . The levT. pallidum in CSF was detectable by metagenomic sequencing. However, it is difficult to use metagenomic sequencing as a conventional screening tool due to its high cost. For neurosyphilis patients with atypical symptoms or negative results as detected by conventional methods, mNGS could be used as a supplementary diagnostic method.Increasing data have shown that metagenomic sequencing can play a role in neurological infectious diseases , and metagenomic next-generation sequencing (mNGS) analysis of CSF can quickly detect pathogens. A recent study showed that Metabolomics is a quantitative analysis of all metabolites in organisms and a search for the relative relationship between metabolites and physiological and pathological changes. Metabolomics provides a large amount of information on energy metabolism, physiology and possible pathogen diagnostic biomarkers and intervention strategies. A metabolic analysis of CSF in patients with neurosyphilis showed that bilirubin, L-histidine, prostaglandin E2, α-mannuronic acid, butyryl L-carnitine and palmitoyl L-carnitine were significantly increased in the CSF of neurosyphilis patients. The metabolism of CSF may provide a new way to explore the pathogenesis of neurosyphilis . In anotT. pallidum DNA in CSF by NAATs has gradually become possible, and CSF cytokines as indicators for neurosyphilis diagnosis continue to be defined. CSF CXCL13, which shows good diagnostic efficacy, is most likely to be applied in clinical practice. Interleukin, MIF, Tau protein, BACE1, sTREM2, and β2-microglobulin and metagenomic and metabolomic factors are considered to be potential markers in the CSF detection of neurosyphilis. However, the specificity of these indicators is not high, and the related studies are few; therefore, further study is needed . The funders played no role in the study design, data collection and analyses, decision to publish, or manuscript preparation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Discogenic microspurs are calcified outgrowths from the intervertebral disc which can perforate the dura, causing a leak of cerebrospinal fluid (CSF). Spontaneous leaks of the CSF present a recognized cause of spontaneous intracranial hypotension (SIH). Moreover, subdural hematomas (SDH) are a potentially severe complication of SIH.We present a case of a bilateral subdural hematoma without orthostatic headaches caused by a discogenic microspur protruding from the T1-2 intervertebral disc. The microspur is conjectured to be the culprit of the leak by ventrally perforating the dura and catalyzing the causal chain leading to the formation of the subdural hemorrhage.A 79-year woman noticed a progressive gait disturbance accompanied by a decline of short-term memory over several months without experiencing orthostatic headaches. Magnetic resonance imaging (MRI) showed extensive bilateral subdural fronto-parietal hematoma, signs of CSF hypotension (dilated venous compartments), and computed tomography (CT) myelography revealed a CSF leak originating at the T1-2 level.The leakage site was treated with microsurgical duraplasty leading to a regression of the symptoms and complete resolution of the subdural hematomas within five postoperative months.Discogenic microspurs can perforate the dura causing a CSF leak, leading to spontaneous intracranial hypotension, finally resulting in a bilateral subdural hematoma. This constellation of symptoms does not necessarily induce orthostatic headaches and can be treated with microsurgical duraplasty. •Discogenic microspur perforating the dura and inducing a liquor leak.•Discogenic microspur leading to spontaneous intracranial hypotension.•Discogenic microspur leading to bilateral subdural hematoma.•Liquor leak treated by microsurgical duraplasty.•Bilateral subdural hematoma retraction after microsurgical duraplasty. These can span a wide range from entirely asymptomatic to orthostatic headaches to neurological abnormalities up to death . A well-Spinal fluid leakage is increasingly recognized to contribute to SIH . WheneveRecently established MRI-based scores may aid in quantifying the likelihood of having a CSF leak due to SIH, warranting further myelography , 2022. HA discogenic microspur (DM) is a calcified outgrowth of the intervertebral disc, which can surface as calcification of the disc progresses, accompanied by a reaction to increased mechanical stress . ProtrusIn most cases with dural tear, a DM is found to be involved , and noWe present a case where the following events act as a causal chain: A DM ventrally produces a dural tear, which induces a CSF leak at the T1-2 level, leading to SIH, and finally resulting in a chronic bilateral subdural hematoma without orthostatic headaches.2A 79-year-old woman noticed a progressive gait disturbance accompanied by a short-term memory decline over several months, along with a mild tension in the head without a history of trauma. Her gait followed a broad-based pattern, accompanied by a neurogenic bladder dysfunction. Her performance on the Montreal Cognitive Assessment indicated a mild cognitive impairment and corroborated a deficit of short-term memory. She experienced no orthostatic headaches, no focal deficits, and showed no pyramidal-tract signs. As the patient had been suffering from secondary progressive multiple sclerosis (MS) for over twenty years, with the last episode over twenty years ago, brain magnetic resonance imaging (MRI) was used to search for changes stemming from an acute episode of MS or some other neurodegenerative process.Surprisingly, a brain MRI revealed a bilateral subdural hematoma in the fronto-parietal region with sizes ranging from 18 mm width on the left side and 13 mm width on the right side, leading to a compression of both cerebral hemispheres and a reactive supra- and infratentorial dural thickening without a midline shift . FurtherTo search for the cause of the SIH, the patient underwent an MRI of the entire spinal column, which exposed a circular CSF extravasation around the dural sac from the C3- to the T10 level . In a suA DM-induced dural tear revealed a persistent mechanical problem. Neither conservative treatment nor an EBP would have promised relief. Therefore, it was decided to perform an endoscopically assisted microsurgical closure of the ventral dural dehiscence by duraplasty accessed through an interarcuate fenestration at the T1-2 level .Fig. 3InA CT of the skull on the second postoperative day revealed no change in the volume of the SDH. Subdural bifrontal and interhemispheric air inclusions were spotted, most likely due to a postoperative reallocation of air. Five days later, the MRI of the skull showed a reduction of the SDH by 4 mm on the left side and 2–3 mm on the right side with a normalization of the ventricular system and reappearance of frontoparietal cerebral sulci .The patient reported a general improvement and experienced less tension in the head, despite the SDH not fully receding during the hospital stay. The patient was discharged on the 13th day of hospitalization without new neurological deficits. Four weeks after surgery, the CSF extravasation subsided slightly, and there was no recurrence detected on brain MRI . In the 3The etiology of CSF leaks often remained undetermined or was prone to initial misdiagnosis in the past, delaying appropriate therapy . IncreasSeveral risk factors can contribute to dural tear. For instance, a weak area around the dura mater, spinal trauma, and connective tissue disorders . MoreoveDural lesions due to microspurs or osteophytes were found widely between C5 and L1, with most lesions at the cervicothoracic level . In a scThe various etiologies of CSF leaks complicate diagnostics and choice of intervention. In our case, the first MRI of the skull only exposed the bilateral SDH, while its underlying cause remained hidden. Based on this finding alone, the neurosurgical guidelines would have mandated evacuating the SDH, only to have found it resurge down the road due to the persisting dural leak. Moreover, postponing an intervention might have introduced further procedures down the line. The cause and location of the CSF leak were revealed in spinal imaging, and the decision for surgical intervention with duraplasty was made.SIH has an annual incidence of 5 per 100,000 of SIH . With thWhenever SIH occurs, it may result in SDH. The Monroe-Kellie doctrine states that the voluminal sum of intracranial blood, CSF, and cerebral tissue remains constant within an intact cranium . Hence, Whenever the loss of CSF from the spine outweighs the compensatory capacity of the vascular components, hematomas may ensue. As the intracranial pressure decreases due to an efflux of CSF, the loss of CSF buoyancy can lead to a downward displacement of the brain, resulting in a rupture of bridging veins pulled away from the dura . The samA small study found that in two-thirds of patients, a CSF leak led to a SDH, which was bilateral in 62.5% of cases . AnotherAlthough orthostatic headaches appear as a clinical hallmark for SIH diagnosis, nearly half of patients suffering from SIH have atypical headaches . Surpris4We describe a case with spontaneous intracranial hypotension due to a discogenic microspur at the thoracic spine perforating the dura, resulting in chronic bilateral subdural hematoma without orthostatic headaches, which was successfully treated with microsurgical closure by duraplasty.The authors received no financial support for the research, authorship, and/or publication of this article.The authors have no conflict of interest to declare.


We evaluated the correlation between cerebrospinal fluid (CSF) cytokine levels and central nervous system (CNS) involvement in adult acute myeloid leukemia (AML).The study sample consisted of 90 patients diagnosed with AML and 20 with unrelated CNS involvement. The AML group was divided into two sub-groups: those with  and without CNS involvement . We used a cytometric bead assay to measure CSF interleukin (IL)-2, IL-4, IL-6, and IL-10, tumor necrosis factor-α, interferon-γ, and IL-17A. We used receiver operating characteristic curves to evaluate the ability of CSF cytokine levels to identify CNS involvement in adult AML.CSF IL-6 levels were significantly higher in CNS+adult AML patients and positively correlated with the lactate dehydrogenase levels  and white blood cell (WBC) count  in the blood, and the protein  as well as WBC count in the CSF . Using a CSF IL-6 cut-off value of 8.27 pg/ml yielded a diagnostic sensitivity and specificity was 80.00% and 88.46%, respectively . After treating a subset of tested patients, their CSF IL-6 levels decreased. Consequently, the elevated CSF IL-6 levels remaining in CNS+ adult AML patients post-treatment were associated with disease progression.CSF IL-6 is a promising marker for the diagnosis of adult AML with CNS involvement and a crucial dynamic indicator for therapeutic response. Central nervous system (CNS) involvement is a well-known and serious extramedullary disease in adults with acute myeloid leukemia (AML). However, it is less common than acute lymphoblastic leukemia (ALL) –3. The thas superior specificity and sensitivity in detecting CNS leukemia compared to conventional cytology (CC)  by LPs, as well as radiographic imaging, which may be used independently or in combination . The LPsogy (CC) –11. Howeogy (CC) . In addiogy (CC) , 13. ThuCSF biomolecules can be used as biomarkers to promote the diagnosis of CNS disease –16. EpstThus, in this study, we retrospectively analyzed cytokine expression in the CSF of adult AML patients at CNS relapse. We explored the correlation between CSF cytokine levels and clinical characteristics of CNS involvement in these patients. We evaluated the diagnostic significance of CSF IL-6 and examined the cytokine levels after treatment to evaluate the dynamics of treatment-induced alteration of the IL-6 expression. Collectively, we aimed to identify a new and effective diagnostic tool for CNS involvement in adult patients with AML.Ninety AML patients admitted to the First Affiliated Hospital, College of Medicine, Zhejiang University, were enrolled in the study from January 2021 to February 2022. Clinical and laboratory data were collected from the hospital electronic databases. All patients underwent peripheral blood microscopic evaluations, bone marrow and flow cytometric analyses to diagnose AML and classify its morphology. None of the patients had the presence of other diseases that may affect the change of central immune status, such as other tumor, infection, acute trauma to the brain, cerebrovascular disease and a history of immunodeficiency etc. Twenty patients diagnosed with other CNS diseases, such as autoimmune encephalitis (n=6), metastatic brain tumor of lung cancer (n=3), neurosyphilis (n=2), HIV encephalopathy (n=2), viral meningitis (n=3), and headache of unknown cause (n=4), were included for comparison. This study protocol was approved by the ethics committee of the First Affiliated Hospital, College of Medicine, Zhejiang University.All AML patients underwent diagnostic and follow-up LPs to identify CNS involvement at different time points after their first prophylactic intrathecal chemotherapy therapy with cytarabine (50 mg), dexamethasone (5 mg), and methotrexate 10 mg. To diagnose CNS involvement, we used a cell counting chamber to confirm the presence of >5 white blood cells (WBCs) of CSF. To this end, we also confirmed the presence of leukemic blast cells in the CSF with CC or FCM analysis after cytocentrifugation. Intrathecal therapy for AML in CNS+ patients consisted of intrathecal injection twice a week until CSF blast clearance and minimal residual disease (MRD) FCM were negative.CSF samples  were obtained from 90 AML patients and 20 subjects with unrelated CNS involvement. The levels of seven cytokines , interferon-γ (IFN-γ), and IL-17A were quantitatively determined immediately with the use of a cytometric bead array kit . The minimum and maximum limits of detection for all 6 cytokines were 0.10 and 5000 pg/ml, respectively. Samples were analyzed using a BD FACS Canto II flow cytometer . The data were generated in graphical and tabular format using FCAP Array software .2 test or Fisher’s exact test. We evaluated the correlation of clinical features and CSF cytokines with Spearman’s correlation analysis (GraphPad Prism 5.0). The Kolmogorov–Smirnov test on these cytokines revealed a non-normal distribution, thus the Mann–Whitney U test was used to compare the concentrations of seven cytokines among the three groups. The sensitivity, specificity, cut-off value, the area under the curve (AUC), and 95% confidence interval (CI) of CSF cytokine levels to identify CNS involvement was assessed using receiver operating characteristic (ROC) curves (GraphPad Prism 5.0). All tests were two-tailed, and statistical significance was set at p<0.05.Statistical analyses were performed using SPSS version 23.0 . The Mann–Whitney U test was used to the compare the differences of non-normal distribution data between CNS involvement group and non-CNS involvement group, categorical values were analysed by χNinety adult AML patients and 20 individuals diagnosed with other CNS disease were included in this study (N=110). Patients with AML were divided into those with CNS involvement  and those without CNS involvement . Patients with CNS involvement were significantly older than those without CNS involvement and had a higher proportion of CNS symptoms/signs and adverse cytogenetic risk. Based on the French-American British (FAB) morphology classification scheme, M5 morphologywas associated with CNS involvement. In addition, among the 30 AML patients with CNS+ in this study, 21 cases of FCM of CSF and 18 cases of CC of CSF were positive. Significant differences were observed in white blood cell WBC count, lactate dehydrogenase (LDH) level, CSF protein level, and CSF WBC count, but not in sex, bone marrow status and chemotherapy regimens between the two groups Table 1.As shown in To evaluate the potential correlation between CSF IL-6 levels and clinical features, pairwise Spearman’s rank coefficients were calculated. The data in The diagnostic efficacy of CSF IL-6 was assessed using the ROC curve. With the CSF IL-6 cut-off at 8.27 pg/ml, the diagnostic sensitivity and specificity for AML with CNS involvement were 80.00% and 88.46%, respectively  Figure 3Additionally, we explored the relationship between CSF IL-6 levels and disease status. CSF IL-6 concentrations were available before and after intrathecal treatment in 16 AML patients with CNS involvement. The cytokine levels after chemotherapy treatment decreased in 12 patients, four of whom were in partial remission (PR), whereas the rest were in complete remission (CR). The other four had CSF-IL-6 levels elevation, despite having completed intrathecal chemotherapy treatment; Notably, two of them experienced early death (<12 months), and two reached “progressive disease” status during follow-up visits Figure 4CNS involvement in AML remains a clinical challenge related to therapeutic obstacles and confers a poor prognosis . In adulCytokines are involved in various malignancies. IL-6, a pleiotropic cytokine, plays a role in various cancers, including hematological malignancy –31. IL-6However, the cellular origin of CSF IL-6 in this study is unclear. In this study, IL-6 expression in peripheral blood (PB) samples did not differ between AML patients wtih CNS involvement and without CNS involvement, which suggesting that the high expression of CSF IL-6 might not be derived from the peripheral circulation. IL-6 is produced by macrophages  as well Furthermore, we examined the CSF IL-6 levels after intrathecal therapy to evaluate the treatment-induced alteration dynamics of IL-6 expression over time. Our results demonstrated that the CSF IL-6 concentration after treatment was significantly connected with the therapeutic response in adult AML with CNS involvement. Moreover, four patients after intrathecal therapy who were negative for CSF CC/FCM but with an elevated CSF IL-6 concentration exhibited a progressive form of the disease in the subsequent follow-up. Thus, our findings suggest that measurement of IL-6 levels in the CSF could be combined with cytologic/FCM analysis to better assess the therapeutic response as well as to help clinicians determine further treatment. However, whether post-treatment IL-6 levels in the CSF of patients with CR or PR affect PFS requires further investigation.The present study still had several limitations. First, since CNS involvement is uncommon in adult AML, the sample size was small. Second, as a retrospective study, we lack CSF samples of CNS involvement in adult AML at initial diagnosis; thus, future studies are needed to investigate whether the CSF IL-6 levels in adult AML at initial diagnosis could predict CNS status. Finally, owing to a lack of exploration of the relationship between CSF IL-6 and survival analysis, an accumulation of prospective studies is necessary to provide definitive conclusions on the influence of CSF IL-6 on the prognosis of adult AML with CNS involvement.In conclusion, our study provides the first description of CSF IL-6 as a promising diagnostic biomarker for CNS involvement in adult AML patients. We also revealed the correlation between CSF IL-6 level and clinical features of CNS involvement in adult with AML. In addition, we demonstrated that CSF IL-6 level, after intrathecal treatment, correlated with the therapeutic response. Further studies are required to validate CSF IL-6 level as a highly sensitive and specific diagnostic marker for adult AML with CNS involvement in. The molecular mechanisms underlying the cytokine network in the CNS involvement in adult AML require further investigation.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics committee of the First Affiliated Hospital, College of Medicine, Zhejiang University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JG and XH was involved in the conception design, analysis and interpretation of the data, and drafting the manuscript. YZ, CB and ZZ collected and analyzed the data and assisted in manuscript drafting. JJ and HT developed the conception design, analyzed and interpreted the data, and revised the manuscript critically for intellectual content. All authors approved the final of the version of the manuscript to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Like in many other pathologies, oxidative stress is involved in the development of neurodegenerative disorders. Human serum albumin (HSA) is the main protein in different body fluids including cerebrospinal fluid (CSF). By its redox state in terms of cysteine-34, albumin serves as marker for oxidative burden. We aimed to evaluate the redox state of HSA in patients with multiple sclerosis in serum and CSF in comparison to controls to identify possible correlations with disease activity and severity. Samples were stored at −70 °C until analysis by HPLC for the determination of albumin redox state in terms of the fractions of human mercaptalbumin (HMA), human nonmercaptalbumin1 (HNA1), and human nonmercaptalbumin2 (HNA2). Albumin in CSF showed significantly higher fractions of the reduced form HMA and decreased HNA1 and HNA2. There was no difference between albumin redox states in serum of patients and controls. In CSF of patients HNA2 showed a trend to higher fractions compared to controls. Albumin redox state in serum was associated with physical disability in remission while albumin redox state in CSF was related to disease activity. Thus, albumin redox state in serum and CSF of patients in relation to disease condition merits further investigation. Oxidative challenges have been reported to occur during the development of neurodegenerative diseases in general, including in multiple sclerosis (MS) ,2,3. MS Alb), serves as a measure for the leakage of the blood–brain barrier (BBB) [The role of oxidative stress as cause or consequence of pathological changes is not yet fully understood. Different markers can be used to monitor the oxidative burden in different body compartments. In this respect, human serum albumin (HSA) is a quite interesting molecule for MS as well as for oxidative stress in general. HSA is the main protein in multiple body fluids, e.g., vitreous humor and cerebrospinal fluid (CSF) ,9. However (BBB) . The reder (BBB) . Whereaser (BBB) ,15,16,17It has been reported that the redox state of albumin in CSF differs from that in serum and that in Alzheimer’s disease (AD), CSF albumin is significantly shifted to the oxidized state . Data coWe evaluated albumin redox state in serum and CSF of 20 MS patients and 21 controls . The patp = 0.76; r = 0.32, p = 0.164; r = 0.20, p = 0.20; HNA1: r = 0.264, p = 0.26; r = 0.331, p = 0.14; r = 0.225, p = 0.16; HNA2: r = −0.121, p = 0.61; r = 0.495, p = 0.02; r = 0.195, p = 0.22).The redox state of serum and CSF albumin was evaluated in all patients and controls. No significant differences between patients and controls were found for HMA and HNA1 in either compartment . In CSF,p = 0.007), which was mainly driven by the control group . No such correlation was present when analyzing solely the MS patient group . In CSF of patients and controls, together, we found a moderate linear correlation of HMA with the age at sampling . In the control group there was also a correlation of HNA2 in CSF with age . Likewise, these correlations were not observed when examining only the patient group . No significant correlation of HNA1 with the age at sampling was observed in either of the groups. Detailed data on correlations of albumin redox state with the age at sampling are given in In the combined analysis of patients and controls, we found a significant correlation of serum HNA2 with the age at sampling  but not with HNA2 in serum . However, these correlations were lost when correcting for age .Within our patient group, albumin redox state in serum but not in CSF was associated with the extent of physical disability in remission. Patients with lower HMA and higher HNA1 and HNA2 serum levels had significantly higher Expanded Disability Status Scale (EDSS) scores in remission compared to patients with higher HMA and lower HNA1 serum levels . Furtherp = 0.04)  . HoweveThere are (only) two other studies reporting albumin redox state in terms of HMA, HNA1, and HNA2 in CSF. One investigated AD patients and controls , the othThe conversion of HMA to HNA1 is reversible and the ratio depends on the environment of the albumin molecule in terms of the concentrations of thiols such as cysteine or GSH, and disulfides such as cystine or GSSG. Although it has been reported that microglia may synthesize albumin in cell culture, the significance thereof is not yet established . HSA in Several studies report the total thiol content and only a few the disulfide content of CSF in MS patients and controls. However, the methods applied and the results are quite divergent and data concerning the ratio of thiols and disulfides are scarce. Nanomolar  and micrAn increase in HNA2 indicates the occurrence of reactive species, despite the high levels of HMA. On the other hand, the loss of HNA2 in CSF compared to serum is perplexing as the oxidation of Cys-34 to the sulfinic and sulfonic acid form is thought to be irreversible. The data concerning the slight reduction of HNA2 by astrocytes in cell culture does not appear to fully explain the loss of HNA2 . PerhapsBased on previous reports, one can expect a correlation of serum HMA and HNA1 with age in healthy subjects, while no such correlation might be present with HNA2 ,25. For There were no differences in the HSA redox state between patients and controls in serum. Furthermore, the fractions of HMA and HNA1 in CSF were essentially identical in both groups. Only HNA2 showed a trend to increased values in the patient group. Although not significant, this is in agreement with a decreased antioxidative capacity in CSF of MS patients . While HConnections of HSA redox state with the disease pattern in MS were found in serum and in CSF. Remarkably, higher physical disability, indicated by higher EDSS in remission, was associated with lower HMA and higher HNA1 and HNA2 in serum and not in CSF. However, in RRMS patients who suffered a relapse within the last 14 days before sample collection, HNA2 in CSF was significantly higher compared to patients with stable disease within this time interval. The current study had some limitations. Our data are based on a small patient cohort and it is necessary to confirm our findings in a larger group. Furthermore, most of the patients were in early stages of disease and had a relapsing–remitting disease course, whereas only three patients had primary progressive MS. This limits the comparison of albumin redox states in serum and CSF between patients with different disease phenotypes. Therefore, it would be especially interesting to investigate albumin redox state in serum and CSF from a higher number of patients with progressive disease in a longitudinal prospective study. Although the availability of CSF material is limited, the knowledge concerning HSA characteristics is also of interest with the background of albumin infusion as part of therapies for neurodegenerative disorders such as AD . To obtaIn summary, our data confirm the view that oxidative processes are involved in the progress of MS. It is quite interesting that HNA2 can be increased while the thiol/disulfide ratio is shifted to the reduced side. This happens in an environment that is very dynamic and presents HSA as a fascinating analyte for the investigation of redox processes in CSF. Our results provide a reliable basis for future studies with larger patient cohorts to further investigate the clinical significance of altered albumin redox fractions in patients with MS or the suitability as prognostic markers.This study was approved by the ethics committee of the Medical University of Graz, Austria .Twenty patients aged 18–52 years  at time of sampling with a confirmed diagnosis of multiple sclerosis according to McDonald’s 2017 criteria  were enrExclusion criteria for MS patients and controls were administration of corticosteroids within the previous 28 days, erythrocyte concentration in CSF greater than 500 per µL, and usage of disease-modifying MS therapy prior to sampling (MS patients only). Further exclusion criteria were presence of other inflammatory neurological diseases or active liver or kidney diseases, with known influence on the albumin redox state. Alb) [All CSF and serum samples were collected, processed, and stored according to international consensus guidelines . SamplinAlb) . IntrathAlb)  and qualAlb) . RoutineDemographic and clinical parameters including age, sex, disease onset and duration, Expanded Disability Status Scale (EDSS) score, and annualized relapse rate were recorded by experienced neurologists at time of diagnosis and at scheduled clinical follow-up visits. A relapse was defined as a monophasic clinical episode with patient-reported symptoms and objective findings typical of multiple sclerosis, reflecting a focal or multifocal inflammatory demyelinating event in the CNS, developing acutely or subacutely, with a duration of at least 24 h, with or without recovery, and in the absence of fever or infection . The EDSv/v; mobile phase B) at a flow rate of 1 mL/min applied by an Hitachi Elite LaChrom gradient pump (Hitachi High-Tech Corporation). A linear gradient (5–25 min) of 0 to 60% mobile phase B and additional 5 min at 60% B was used for elution. The column was kept at 35 °C in a Shimadzu CTO-10AC VP column oven (Shimadzu). Detection was carried out by fluorescence at 280/340 nm with a Jasco 821FP fluorescence detector  and quantification was based on the area of the individual peaks as determined using Peak Fit software  by fitting Gaussian curves to the chromatograms. Examples of chromatograms obtained in serum and CSF of MS patients are shown in To determine the redox state of albumin in serum and CSF, albumin was separated into its different fractions  by high-performance liquid chromatography (HPLC) as described by Hayashi et al. . In brieHMA, QHNA1, QHNA2). Absolute amounts of HMA, HNA1, and HNA2 in CSF and serum were calculated from the percentage of the respective albumin redox fraction and the total albumin concentration in CSF and serum, whereof the quotients were formed.To estimate the ratio of reduced and oxidized albumin in CSF to serum we calculated HMA, HNA1, and HNA2 quotients  or IBM SPSS Statistics .Results are presented as means ± SD or medians and interquartile ranges, depending on their distribution as assessed by Kolmogorov–Smirnoff test. Differences between the groups were assessed applying Student’s t-tests or Mann–Whitney U tests, as appropriate. Pearson or Spearman  correlations between variables were performed. Differences are considered statistically significant for


In Parkinson’s disease (PD), levels of cerebrospinal fluid (CSF) biomarkers and progression of non-motor symptoms are associated, but the specifics are not yet clear.The aim of this study was to investigate the associations of non-motor symptoms with CSF biomarkers in PD.1–42), and total tau (t-tau) levels. Multiple linear regressions were used in baseline analysis and linear mixed-effects models in longitudinal analysis. Analyses of mediating effects between cognition and CSF biomarkers were also performed.We assessed 487 individuals from the Parkinson’s Progression Markers Initiative (PPMI), consisting of 155 healthy controls (HCs) and 332 individuals with PD. Patients with PD were grouped according to non-motor symptoms and compared CSF α-synuclein (α-syn), amyloid-beta 1-42 (AβP = 0.0469), Aβ , and t-tau  levels than PD patients without cognitive impairment (PDCU). Moreover, a faster decline of α-syn  and Aβ  and a faster rise of t-tau  have been found in longitudinal analysis. The Aβ positive group showed an earlier decline in cognitive performance  compared with the negative Aβ group in both analyses. In addition, we found that PD patients with probable rapid eye movement sleep behavior disorder (pRBD) showed decreased CSF α-syn  levels. Finally, mediation analysis demonstrated that olfactory function partially mediated the relationship between cognition and CSF biomarkers levels.At baseline, PD patients with cognitive impairment (PDCI) exhibited significantly lower CSF α-syn (β = −0.1244; Our study shows that CSF biomarkers are associated with cognition at baseline and longitudinally. Cognitive impairment is more severe in patients with a heavier Aβ burden. CSF α-syn decreased in PD patients with pRBD. This study suggests that early recognition of the increased risk of non-motor symptoms is important for disease surveillance and may be associated with the pathological progression of CSF markers. Parkinson’s disease (PD) is a chronic neurodegenerative disorder that affects the central nervous system, second only to Alzheimer’s disease (AD). The main pathological feature of PD is the deposition of α-synuclein (α-syn) and fibrillar translocation from the brainstem to the limbic system as formation of Lewy bodies (LBs) . AdditioMild cognitive impairment (MCI) is defined as cognitive decline that can be observed through neuropsychological scales, in the intermediate stages of subjective cognitive decline (SCD) and dementia . PatientRapid eye movement sleep behavior disorder (RBD) occurs during rapid eye movement (REM) sleep and manifests as enacting dreams and loss of muscle atonia, leading to violent, aggressive movements, and may injure oneself and a bed partner . The occBiofluid markers can be useful in shedding light on the pathology and variability of PD in the long term. However, the deep correlation of non-motor symptoms with CSF biomarker levels has not been appropriately explored. Therefore, we modeled using data from the PPMI database to explore the association of non-motor symptoms with CSF biomarker levels in patients through baseline and longitudinal analysis. In addition, we investigated the possible links by using mediating effect analyses.1 The PPMI is a longitudinal, observational cohort study of participants with PD and healthy controls (HCs). It is beneficial to dig into further evidence supporting the diagnosis of PD and CSF biomarkers of progression and their intrinsic associations. Subjects underwent assessments including motor, non-motor, imaging, and donated biological samples including CSFs. Of the 495 enrolled subjects, 487 subjects (155 HCs and 332 PD) who agreed to donate CSF samples at baseline visits were included in our study. Subjects who were recruited into the PD group were at the disease threshold. They needed to meet the criteria of (1) untreated for PD and (2) having an asymmetric resting tremor or asymmetric bradykinesia or two of bradykinesia, resting tremor, and rigidity with a diagnosis within 2 years. For more details on the PPMI inclusion and exclusion criteria, please visit the official website. Every subject selected for the baseline analyses has completed the non-motor assessments . Moreover, to ensure the accuracy of the biomarker data, individuals with hemoglobin above the measurable value were excluded. To avoid fluctuations in the effect on olfaction and sleep, people with severe neurological disorders that may interfere with sleep and those who were taking antidepressants were excluded. Participants without baseline or follow-up data of CSF biomarkers  were excluded. Participants were informed and written informed consent was obtained prior to the start of the study. All studies related to PPMI have been approved by the local Institutional Review Board prior to commencement.All data for this research were obtained from the PPMI database.1–42 test for comparative analysis, we took 683.45 pg/ml as the threshold to distinguish between Aβ1–42 high and low groups  Score, the Symbol Digit Modalities Test (SDMT) Score, and the Hopkins Verbal Learning Test Delayed Recall (HVLT-R). In this study, a MoCA score of 26 was used as a cutoff value to distinguish MCI groups, and the PD with cognitive impairment group was identified as a score less than the cutoff value . This clw groups .The RBDSQ questionnaire was used to screen for RBD . Using a1–42, and t-tau .The collection and processing of cerebrospinal fluid (CSF) follows a standardized procedure, refer to the PPMI Biologics Manual for details. Each subject’s CSF specimen corresponds to its unique code. The samples were frozen and stored in the PPMI Biorepository Core Laboratory until they were transferred to the University of Pennsylvania Center for Bioanalysis at the time of analysis. We assessed CSF for α-syn , Aβ1–42, and t-tau transformations via the “car” package of R software. The mean ± standard deviation (SD) was used to represent continuous variables. The categorical variables were expressed as the number of patients and their percentage. Differences between groups were compared using the Mann–Whitney–Wilcoxon test for continuous variables and the chi-square test for categorical variables. The association between CSF biomarkers  and cognition was analyzed at baseline using multiple linear regression equations. The model was corrected for age, gender, years of education, and hemoglobin when used. Further longitudinal analysis of cognition and CSF biomarkers were explored using linear mixed-effects models. The above two analyses are also applied in the analysis of the relationship between sleep behavior and α-syn. Multiple linear regression was used to calculate the correlation between the mean rate of change in CSF levels and the longitudinal change in cognitive correlation scale scores. The rate of change is obtained using the “arm” package in R software through 10,000 repetitions. To further explore the relationship of CSF biomarkers and cognition decline or α-syn and sleep behavior mediated by PD pathology, mediation analyses were used. The mediation effect is based on the method of causal-steps approach and the Sobel test. Furthermore, the indirect effect is estimated, with the significance determined using 10,000 bootstrapped iterations (“mediate” package in R 4.1.0 software). The indirect effect P-value was statistically significant.Statistical analysis and figures were performed using the R (version 4.1.0) software. Biomarker values with a right-skewed distribution underwent logarithmic α-syn, AβP < 0.05.The Bonferroni correction was used for multiple comparisons. All tests used a significance level of P = 0.98), gender (P = 0.79), and education year (P = 0.09). All participants were well-educated, with an average of approximately 15 years of education. Patients with PD exhibited a greater loss of olfactory function  and greater burden of cognition  and sleep behavior disorder  compared with HCs. There were significant differences in processing speed  and delayed verbal recall  in cognitively related markers, except for working memory . Control subjects had higher CSF Aβ1–42 (P < 0.01), α-syn (P < 0.01), and t-tau (P < 0.01) than those of the patients with PD.P = 0.0469)  (P = 0.0131) (P = 0.0107)  (P = 0.0330)  , Aβ1–42  0.0447) , and t-t 0.0131) . These r 0.0107)  and Aβ1– 0.0089) . Besides 0.0330) . Convers1–42 showed significantly lower MoCA  (P = 0.0384)   scores a 0.0384) , whereasn = 284; PD patients with cognitive impairment, PDCI: n = 48; high CSF Aβ1–42: n = 244; low CSF Aβ1–42: n = 88) individuals were included in the model fit during 3-year follow-up beyond baseline measurements, including at least one follow-up measurement. In a linear mixed model (LME) adjusted for age, gender, education, and baseline diagnosis, the cognition impaired predicted a decline in CSF biomarker level over time. Compared with PD patients without cognition impairment group, the PD patients with cognition impairment were significantly associated with Aβ1–42  (P = 0.0374) (P = 0.0274) (P = 0.0362) in PDCU; α-syn and MoCA  in PDCI; and SDMT and Aβ1–42  in PDCI, but not in all participants with PD.A total of 332  , α-syn ( 0.0374) , and t-t 0.0274) . Associa1–42 patient group showed a more pronounced downward trend in the test of global cognitive functioning (MoCA)  (P = 0.0341)   (P = 0.6637) (The low CSF Aβ 0.0180)  and work 0.0341)  than tho 0.1284)  and dela 0.6637) .P = 0.0412) (P = 0.0033)  group had lower CSF α-syn   biomarke 0.0033)  level, wP = 0.0001) and that the UPSIT scores were significantly associated with CSF Aβ1–42  (P = 0.0340)  . Moreove 0.0340) , and cogBased on the results of the analysis, an association was shown between biomarker levels and progression of non-motor symptoms. At this stage, CSF biomarkers cannot be used alone as diagnostic and typing criteria for the diagnosis of PD. However, assessing its association with non-motor symptoms provides a clue to the progression of non-motor symptoms and may explain the pathological progression of the CSF marker.1–42 and α-syn levels. In contrast, CSF t-tau levels increased with disease progression. All three CSF biomarkers were lower in PDCI than in PDCU at baseline. At the same time, baseline CSF Aβ1–42 level can also predict cognition function changes. PD patients with low CSF Aβ1–42 showed a faster decline of MoCA and SDMT than those with high CSF Aβ1–42 at baseline. Only the MoCA and LNS are meaningful in the CSF grouping in longitudinal data analysis. Besides, PD with RBD shows low CSF α-syn levels.Our analyses demonstrated that cognition has a high predictive value for progressive reductions in CSF AβConsistent with our findings, a decrease in CSF α-syn was observed in patients with PD, and further results were found in the study that analyzed a complete dataset of patients with cognitive impairment who showed greater changes over the course of the disease than those without cognitive impairment . On the 1–42 level is the most common CSF biomarker associated with cognitive impairment  and olfactory bulb, according to Braak staging . A possiIn addition, we observed a mediation effect of the UPSIT score on the relationship between global cognition and CSF biomarkers, although the exact mechanism was not clear. It has been reported that the progression of Aβ pathology in the olfactory bulb reflects the severity of respective pathologies in other brain areas, which results from large mortem studies . OlfactoThere are several limitations to our study. First, due to the PPMI database only including data from patients with early onset PD, our study lacked biomarker data for patients with advanced PD, which could have an impact on the accuracy of the longitudinal analysis. Changes in biomarkers may be masked. Second, the questionnaires assessing non-motor symptoms, including MoCA and RBDSQ, were self-reported without objective measures, so the results need to be further validated in the pathology. Third, cognition in patients with PD may worsen over time, becoming dementia or returning to normal, which also needs to be considered. In addition, there may be overlaps in the distribution of CSF biomarkers between PD groups with and without cognitive impairment, affecting their utility. Taken together, although the variability of this study was limited, our analysis showed that changes in CSF biomarkers were associated with cognitive decline in patients with PD, and pRBD would be associated with lower CSF α-syn. The PPMI study is expected to mature with long-term longitudinal follow-up observations that will resolve these limitations. Future research is needed to draw more robust conclusions and obtain new evidence on the underlying relationship between CSF biomarker levels and non-motor symptoms.1–42 as well as RBD and α-syn. In addition, olfaction may mediate the associations between CSF biomarkers and cognition. Changes in biomarkers may be associated with non-motor symptoms. These findings still need to be further analyzed and validated in future models that incorporate more sample-fit optimizations.Taken together, our study helps to reveal the association between non-motor symptoms and CSF biomarkers, specifically in cognitive impairment and AβThe data were sourced from the Parkinson’s Progression Markers Initiative (PPMI) database. The original contributions presented in this study are included in the article/AX and BH responsible for the conception and design of the study. MT, KD, and YX performed the data analysis. MT and KD contributed to the design of the study and drafted the manuscript. All authors contributed to the article and approved the submitted version.


Post-operative cerebrospinal fluid (CSF) leak is a known complication in spine surgery. This mostly iatrogenic issue is typically treated using a variety of modalities , CSF diversion methods, or primary repair. The use of an external ventricular drain to treat this post-operative complication has been infrequently reported. We describe a case of a CSF leak after thoraco-lumbar surgery treated using an external ventricular drain and a review of the literature regarding this treatment modality. A 70-year-old man presented to our clinic with a recent diagnosis of multiple myeloma with progressive thoracic kyphosis and spinal stenosis. He developed progressive neurological deficits over the course of several weeks. Radiological studies showed significant thoracic kyphosis and severe cord compression in the thoraco-lumbar area. The patient underwent a T9-L4 posterior instrumentation and fusion with decompression surgery that developed post-operative wound infection and a CSF leak. An external ventricular drain (EVD) was used successfully as a CSF diversion method where direct thoracolumbar approaches were not feasible. Given the effectiveness of EVD placement in treating this post-operative complication, we concluded that the use of an EVD can be a potentially safe and effective way to treat thoracolumbar CSF leakage when lumbar or cervical drainage is not feasible. Iatrogenic cerebrospinal fluid (CSF) leakage is a common concern in spinal surgery following any procedure involving this region . It is eWe present a case of a 70-year-old man who underwent T9-L4 posterior instrumentation and fusion surgery and later developed a post-operative CSF leak. The patient subsequently developed a wound infection and was treated successfully with an EVD.A 70-year-old man presented to our clinic with a recent diagnosis of multiple myeloma with progressive thoracic kyphosis. He developed two weeks of bowel and bladder incontinence along with increased difficulty ambulating over the course of several months. On physical exam, the patient had marked distal lower extremity weakness and no rectal tone. Radiological studies showed significant thoracic kyphosis Figure  and seveBecause of progressive neurological symptoms along with the radiological findings, the patient underwent T9-L4 posterolateral fusion with screw cement augmentation with focal decompression at T11-T12, T12-L1, and L1-L2 Figure . The surgery proceeded without complication. The night following surgery, the patient was noted to be confused with altered mental status. A head CT scan Figure  was perfDiscussion with the family and confirmation by urine testing revealed the patient had used cocaine immediately preoperatively which had not been previously disclosed. Symptoms resolved on post-operative day 2 with observation and return to his neurological baseline. On the sixth day following surgery, the incision was inspected and was found to be leaking a non-purulent clear fluid from the inferior aspect. The presence of recent surgery, small amounts of pneumocephalus on post-operative brain imaging, and clear fluid raised concern for a CSF leak. The fluid was sent for beta-2 transferrin testing which came back positive, confirming CSF leakage.Due to a large recent thoracolumbar surgery with evidence of lumbar wound dehiscence/infection, a lumbar drain was not feasible as a CSF diversion method. Further, the patient’s clinical status continued to worsen rapidly, suggesting a septic clinical picture. Specifically, the patient's clinical status suggested urosepsis which was immediately treated with broad-spectrum antibiotics. However, acutely, the patient’s status became critical and was subsequently evaluated by palliative care for the potential withdrawal of treatment. Additional imaging studies were desired in order to clearly elucidate the exact site of the CSF leak, however, the patient’s clinical status continued to deteriorate, and an urgent procedure was needed. Given that the patient had become systemically ill, a larger open lumbar surgical exploration and repair was not possible due to the patient’s unlikely ability to tolerate the larger procedure. The authors were aware of diversion techniques involving the placement of a cervical CSF diverting drain , howeverThe patient drained approximately 10 cc of CSF per hour for seven days and the CSF leak was resolved. A three-day clamp trial was done with no further signs of spinal fluid leakage. The EVD was removed and the patient was discharged to the Spinal Cord Injury Rehabilitation unit with no subsequent complications related to CSF leakage.While primary dural closure and the use of lumbar or cervical drains are common ways to treat thoracolumbar CSF leakage, there are no established guidelines on how to deal with this post-operative complication. It is generally agreed upon that closing the dura primarily in a “watertight” manner when a leak is noted intra-operatively along with post-operative bed rest should be the first step to treat a CSF leak . In a stWe proceeded with an EVD as a CSF diversion method to allow the site of dural injury to heal. There are few reports of an external ventricular drain used to treat thoracolumbar CSF leakage in the literature. In a study published by Galgano et al., an EVD successfully treated an individual who underwent multiple surgeries for a recurrent ependymoma that developed persistent CSF leakage . Yeager Our case adds to the experiences reported in the literature to support the use of an EVD as a CSF diversion method to treat complex CSF leaks after spinal procedures in patients who are not candidates for cervical or lumbar cerebrospinal fluid drains. A larger prospective study could elucidate its safety and effectiveness over a long-term period.The use of an EVD to treat CSF leaks following spinal procedures is infrequently reported in the literature. In our case study, the patient underwent CSF drainage for seven days and was subsequently discharged with no further complications. Although a CSF leak was not originally avoided, the subsequent diversion method proved to be effective in mitigating this common post-operative complication. While this only represents one case, our favorable outcome suggests that neurosurgeons may consider the use of an EVD as a safe option to treat thoracolumbar CSF leakage when more traditional methods are not feasible.


In liver transplantation, older donor age is a well-known risk factor for dismal outcomes, especially due to the high susceptibility of older grafts to ischemia-reperfusion injury. However, whether the factors correlating with impaired graft and patient survival following the transplantation of older grafts follow a linear trend among elderly donors remains elusive. In this study, liver transplantations between January 2006 and May 2018 were analyzed retrospectively. Ninety-two recipients of grafts from donors ≥65 years were identified and divided into two groups: (1) ≥65–69 and (2) ≥ 70 years. One-year patient survival was comparable between recipients of grafts from donors ≥65–69 and ≥70 years (78.9% and 70.0%). One-year graft survival was 73.1% (donor ≥65–69) and 62.5% (donor ≥ 70), while multivariate analysis revealed superior one-year graft survival to be associated with a donor age of ≥65–69. No statistically significant differences were found for rates of primary non-function. The influence of donor age on graft and patient survival appears not to have a distinct impact on dismal outcomes in the range of 65–70 years. The impact of old donor age needs to be balanced with other risk factors, as these donors provide grafts that offer a lifesaving graft function. In orthotopic liver transplantation (oLT), donor organ shortage to a variable extent is a challenge for many centers and procurement organizations. The unmet need for life-sustaining grafts demands the utilization of so-called extended criteria donors, e.g., those with pre-existing diseases, donation after cardiac arrest or cardiac death, prolonged intensive care stay, etc. . Among t2019-473-f-S). All retrospectively collected data were from patients’ charts, Eurotransplant Network Information System (ENIS), or in-house transplant data files. Before analysis, all data were de-identified. All allografts were procured from donation after brain death donors.All adult patients who underwent oLT at the Department of General, Visceral and Transplant Surgery, University Hospital Münster, Germany between January 2006 and May 2018 were screened for inclusion. Ninety-two patients with donors ≥ 65 years were identified and included in the final analysis. Based on the donor age, the eligible patients were further stratified into two groups: (1) ≥65–69 and (2) ≥70 years. The study design was a retrospective single-center study with a follow-up period of 12 months. The study was conducted as per the ethical principles stated in the Declaration of Helsinki and all patients provided consent for the routine recording of clinical data. Specific study approval was obtained from the local ethics committee  as well as donor center , and a donor risk index (DRI) was calculated, as described . BaselinThe primary outcome for this study was one-year patient survival, estimated by the Kaplan–Meier methodology and compared using Log-Rank testing. The secondary outcome parameters encompassed one-year overall and death-censored graft survival, as well as 30-day and 90-day patient and graft survival, primary non-function  resulting in death or re-transplantation within 30 days of the initial oLT). Additional secondary outcome measures were the rates of biopsy-proven acute rejections (BPAR), early allograft dysfunction as defined by Olthoff et al. , peak sep-values < 0.05 were considered statistically significant. Additionally, Cox proportional hazards regression models were used to investigate the influence of different variables on one-year patient survival, death-censored graft survival, and overall graft survival. The univariate analysis included donor age ), recipient age, HCV status, cold and warm ischemia time, labMELD, PNF, BPAR, re-operation, number of readmissions, and stay at ICU. Thereafter, a stepwise selection was used to identify the relevant variables in a multivariable Cox regression analysis. Results are shown as hazard ratios (HR) with a 95% confidence interval (CI) and p-value of the likelihood ratio test. All statistical analyses were performed with SAS 9.4, SAS Institute, Cary, NC, USA.Continuous variables were presented as mean and standard deviation and the number of reoperations and the length of readmissions as median (minimum and maximum). Categorial variables were presented as absolute and relative frequencies. Comparisons between the two groups were done either by Wilcoxon rank-sum test for continuous variables or using the Fisher exact test for categorial variables. Survival between groups was compared using the Log-Rank test and p = 0.005) as well as the number of HU oLTs . Next, the 92 patients who received a liver graft from donors ≥ 65 were further stratified based on the donor age into two groups: (1) ≥65–69  and (2) ≥70  years (p = 0.073) and alcoholic cirrhosis , whereas more cases had ALF . In addition, the mean labMELD score, warm and cold ischemia times, as well as the percentage of HCV-positive donors showed no differences between the two groups  patients received grafts from a donor younger than 65, while 92 (22.7%) patients were transplanted with a graft from a donor ≥ 65 years old. When comparing baseline recipient characteristics , signifi%) years . While to groups .p < 0.001). Accordingly, younger donors had significantly lower DRI .The primary outcome was one-year patient survival, and the Kaplan–Meier analysis was used to generate survival curves. When analyzing the entire cohort of 406 patients, one-year patient survival was found to be 77.1% (donor < 65) and 75.0%  nor donor age ≥ 65–69 in comparison to donor age ≥ 70  were found to be significantly associated with the endpoint. However, re-operation and the number of readmissions revealed a significant influence on one-year patient survival , BPR , and rates of re-transplantation  within the first year were all comparable between the two groups (p = 0.898), peak enzyme levels (AST and ALT), frequency of ITBL , number of reoperations, and initial hospital stay or stay at ICU  according to Cassuto et al.  and the p = 0.069) among the two elderly donor age categories, even though the difference was insignificant, most likely due to the limited number of cases. This finding is as per the CTS and Eurotransplant data and could be attributed to the prioritization of ALF candidates in the allocation. The percentage of HCV-positive recipients of grafts from donors exceeding 69 years was higher compared to recipients of grafts from donors of ≥65–69 years , without reaching the level of significance. Since DAAs were available only by the end of the study period, this finding runs counter to the traditionally avoided combination of HCV and older donors. With the introduction of DAAs, HCV-positive recipients achieve outcomes comparable to HCV-negative patients after oLT [It is debatable whether center-specific conclusions can be drawn from large multicenter prospective studies like the CTS, or analyses from national registries like UNOS ,5. Therefter oLT . Moreovefter oLT . The higher rate of HCC recipients in the older category in our study is also as per CTS and Eurotransplant data. In our opinion, allocating older grafts to HCC recipients is justified, as it was shown that especially older HCC recipients show the least impairment of graft survival by receiving elderly grafts . AllocatAs our study did not reveal any entirely new, previously unreported findings, the interpretation of the data obviously does not lead to changes in the clinical routine. Nevertheless, as mentioned above, the acceptance of grafts in our program is decided based on individual consideration of recipient- and donor-based risk factors. Therefore, we believe that it is essential to know the exact impact of increased donor age in our individual circumstances. This is especially relevant, as we are confronted with a severe donor shortage, forcing us to commonly evaluate marginal grafts, which is reflected by the rather high DRI above 2 in our cohort. Notably, the impact of the routine implementation of normothermic machine perfusion (NMP) on the outcome of older grafts, and likewise marginal grafts, will be the future focus of the transplant community . There iSince older liver grafts are highly susceptible to cold-storage-elicited injury, it is recommended to keep the CIT as short as possible (preferably below 8 h ), to minOur study has not obtained insights that are entirely different from the previously published work in this matter. One-year patient survival in our study was unimpaired comparing donors below 65 and 65–69 years (77.1% vs. 78.5%) The survival rates for recipients of grafts exceeding 70 years were inferior to those receiving grafts in the donor age range of 65–69 years, even though the difference was insignificant due to the limited numbers in this single-center analysis. Having established elevated donor age as a risk factor for graft failure in our Cox proportional hazards regression models, it appears conceivable that well-conducted risk balancing might mitigate donor-associated risk factors, since age-stratified Log-Rank analysis revealed no significant differences in graft survival between donors ≥ 65–69 and ≥70 years of age. Given the aforementioned observation that the impact of increasing donor age is linear over the entire age range, one has to conclude that differences are very minute in comparing 65–69 years old donors to those exceeding 70. Accordingly, the meta-analysis of Dasari et al. has not identified 70 years as a donor age threshold predicting impaired graft or patient survival rates in LT . ConfirmIn summary, our results confirm previous findings that an absolute cut-off age threshold for donors does not exist. Elevated donor age should rather be considered as one of the several parameters in the decision-making process for allocation and individualized acceptance of grafts for oLT. Elderly donors, especially in the range of 65–69 years, are substantially helping to reduce the burden of donor organ shortage and waitlist mortality.


This study presents the clinical and electrophysiological findings of four subjects with a pathogenic heterozygous GDAP1 variant causing Charcot–Marie–Tooth disease 2K (CMT2K) and one additional subject with an uncertain GDAP1 variant and clinical findings of CMT 2K. The study evaluated these five subjects using clinical, laboratory, electrophysiological, and genetic testing. The findings showed that clinical features demonstrated no pes cavus, no significant weakness in the hands or feet, normal reflexes in four out of the five subjects, and mild to normal electrodiagnostic findings. The variant was associated with painful and numb feet with diminished sensation to pinprick. This study suggests that GDAP1 variants may be associated with very mild, predominantly sensory Charcot–Marie–Tooth disease, warranting continuing research for this type of the disease. Charcot–Marie–Tooth disease (CMT) reflects a group of inherited neuropathies affecting 1 in 2,500 individuals . CMT typGenetic advances have allowed the classic CMT phenotype to be expanded and evaluated for idiopathic unexplained neuropathies . The rarGDAP1 mutations can present in both heterozygous and homozygous forms , 6. GDAPAlthough the homozygous presentation is typically very severe with early childhood onset with motor and sensory involvement and possible vocal fold paresis, the heterozygous form seems much less severe with a late-onset mild sensory presentation .This study further describes the clinical presentation of GDAP1 mutations and adds to the knowledge of heterozygous GDAP1 mutations.All subjects received care at the AdventHealth Orlando Neuroscience Institute. All had neurological records evaluated. In addition, four out of the five individuals had electrodiagnostic testing performed. Genetic testing for inherited neuropathies was performed through Invitae  . Three pAs a child, this subject had no difficulties with running, walking, roller skating, or biking. She was not athletic and was the slowest runner compared to her peers at school but was healthy and active. Her symptoms first started in her 50s when she started to have difficulty with fatigue and numbness in her toes. Occasionally, she will have pain. She has no weakness but does have some difficulty with climbing stairs. Her son was diagnosed with CMT at age 10 due to high arches, which prompted her evaluation for CMT.In her youth, she had no difficulties with running, walking, balance, or athletics. She was a slow runner in general and had weak ankles. Her symptoms started in her 20s when she experienced burning foot pain after standing for prolonged periods. In her 40s, she felt that she started to develop numbness in her feet and mild difficulty with dexterity in her hands. Examination revealed absent Achilles reflexes.As a child, she had no difficulties with running, walking, roller skating, or biking. Although she was not athletic, she was a fast walker. She had some mild tremors throughout her life. She developed burning, tingling, and extreme sensitivity to cold at age 67. She has numbness in her thumbs and paresthesias in her hands and feet. Neurological examination is intact except for absent Achilles reflexes. Both her father and her daughter have CMT 2K.Daughter of the As a child, he was athletic. In his early 50s, he started to develop constant daily pain in both plantar aspects of his feet below the middle toe area. He also has a numb feeling as if someone wrapped duct tape around his foot. Despite pain relieving interventions, including neurontin, pregabalin, marijuana, and acupuncture, he has not had pain relief. He has difficulty walking due to his balance. He had a ruptured Achilles tendon. He walks and rides his bike daily. EMG/NCS showed minor abnormalities to suggest a possible sensorimotor polyneuropathy. Exam is significant only for absent ankle jerk reflexes and pinprick sensation decreased up to ankle.CMT can have various symptoms and signs, including mild paresthesias, as evidenced in this study. In some cases, genetic testing can reveal underlying causes of idiopathic mild neuropathies.The findings from the subjects with a heterozygous pathogenic GDAP1 missense variant  demonstrPrevious studies of heterozygous GDAP1 variants suggest a late-onset, slowly progressive, and mild neuropathy , 9. AnotThe GDAP1 variant is a rare CMT variant in which autosomal recessive and dominant forms can be seen . The GDAClassical CMT2 is an axonal CMT with reduced amplitudes . Our subOur subjects were comprised of four women and one man. Men may need to be separately investigated as there might be a gender difference or variability among this population .In summary, CMT should be considered a possible differential in mild late-onset sensory neuropathies with normal to borderline abnormal nerve conduction studies.