Exploring the kynurenine pathway in mild traumatic brain injury: A longitudinal study.

A potential source of novel biomarkers for mTBI is the kynurenine pathway (KP), a metabolic pathway of tryptophan (Trp), that is up-regulated by neuroinflammation and stress. Considering that metabolites of the KP (kynurenines) are implicated in various neuropsychiatric diseases, exploration of this pathway could potentially bridge the gap between physiological and psychological factors in the recovery process after mTBI. This study, therefore, set out to characterize the KP after mTBI and to examine associations with long-term outcome. Patients were prospectively recruited at the emergency department (ED), and blood samples were obtained in the acute phase (<24 h; N = 256) and at 1-month follow-up (N = 146). A comparison group of healthy controls (HC; N = 32) was studied at both timepoints. Trp, kynurenines, and interleukin (IL)-6 and IL-10 were quantified in plasma. Clinical outcome was measured at six months post-injury. Trp, xanthurenic acid (XA), and picolinic acid (PA) were significantly reduced in patients with mTBI relative to HC, corrected for age and sex. For Trp (d = -0.57 vs. d = -0.29) and XA (d = -0.98 vs. d = -0.32), larger effects sizes were observed during the acute phase compared to one-month follow-up, while for PA (d = -0.49 vs. d = -0.52) effect sizes remained consistent. Findings for other kynurenines (e.g., kynurenine, kynurenic acid, and quinolinic acid) were non-significant after correction for multiple testing. Within the mTBI group, lower acute Trp levels were significantly related to incomplete functional recovery and higher depression scores at 6 months post-injury. No significant relationships were found for Trp, XA, and PA with IL-6 or IL-10 concentrations. In conclusion, our findings indicate that perturbations of the plasma KP in the hyperacute phase of mTBI and 1 month later are limited to the precursor Trp, and glutamate system modulating kynurenines XA and PA. Correlations between acute reductions of Trp and unfavorable outcomes may suggest a potential substrate for pharmacological intervention.

Frequency and predictors of headache in the first 12 months after traumatic brain injury: results from CENTER-TBI.

BACKGROUND: Headache is a prevalent and debilitating symptom following traumatic brain injury (TBI). Large-scale, prospective cohort studies are needed to establish long-term headache prevalence and associated factors after TBI. This study aimed to assess the frequency and severity of headache after TBI and determine whether sociodemographic factors, injury severity characteristics, and pre- and post-injury comorbidities predicted changes in headache frequency and severity during the first 12 months after injury. METHODS: A large patient sample from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study was used. Patients were stratified based on their clinical care pathway: admitted to an emergency room (ER), a ward (ADM) or an intensive care unit (ICU) in the acute phase. Headache was assessed using a single item from the Rivermead Post-Concussion Symptoms Questionnaire measured at baseline, 3, 6 and 12 months after injury. Mixed-effect logistic regression analyses were applied to investigate changes in headache frequency and associated predictors. RESULTS: A total of 2,291 patients responded to the headache item at baseline. At study enrolment, 59.3% of patients reported acute headache, with similar frequencies across all strata. Female patients and those aged up to 40 years reported a higher frequency of headache at baseline compared to males and older adults. The frequency of severe headache was highest in patients admitted to the ICU. The frequency of headache in the ER stratum decreased substantially from baseline to 3 months and remained from 3 to 6 months. Similar trajectory trends were observed in the ICU and ADM strata across 12 months. Younger age, more severe TBI, fatigue, neck pain and vision problems were among the predictors of more severe headache over time. More than 25% of patients experienced headache at 12 months after injury. CONCLUSIONS: Headache is a common symptom after TBI, especially in female and younger patients. It typically decreases in the first 3 months before stabilising. However, more than a quarter of patients still experienced headache at 12 months after injury. Translational research is needed to advance the clinical decision-making process and improve targeted medical treatment for headache. TRIAL REGISTRATION: ClinicalTrials.gov NCT02210221.

Accuracy of Labeling of Galantamine Generic Drugs and Dietary Supplements.

This study examines the accuracy of labeling for galantamine products formulated as both generic drugs and dietary supplements, as well as tests for contamination with microorganisms.

Substandard and falsified ivermectin tablets obtained for self-medication during the COVID-19 pandemic as a source of potential harm.

In 2019, a global viral pandemic, due to the SARS-CoV-2 virus, broke out. Soon after, the search for a vaccine and/or antiviral medicine began. One of the candidate antiviral medicines tested was ivermectin. Although several health authorities warned the public against the use of this medicine outside clinical trials, the drug was widely used at the end of 2020 and in 2021. Simultaneously, several reports started to emerge demonstrating serious adverse effects after self-medicating with ivermectin. It stands to reason that the self-administration of substandard or falsified (SF) medicines bearing harmful quality deficiencies have contributed to this phenomenon. In order to have a better view on the nature of these harmful quality deficiencies, SF ivermectin samples, intercepted in large quantities by the Belgian regulatory agencies during the period 2021-2022, were analyzed in our official medicines control laboratory. None of the samples (n = 19) were compliant to the quality criteria applicable to medicinal products. These SF products either suffered from a systematic underdosing of the active pharmaceutical ingredient or were severely contaminated with bacteria, two of which were contaminated with known pathogens that cause gastrointestinal illness upon oral intake. In addition to the direct risks of self-medicating with such a product, the improper usage and dosage of ivermectin medication might also facilitate ivermectin tolerance or resistance in parasites. This may have detrimental consequences on a global scale, certainly as the number of newly developed active pharmaceutical ingredients that can safely be used to combat parasites is rather scarce.

Retrospective surveillance of viable Bacillus cereus group contaminations in commercial food and feed vitamin B2 products sold on the Belgian market using whole-genome sequencing.

Bacillus cereus is a spore-forming bacterium that occurs as a contaminant in food and feed, occasionally resulting in food poisoning through the production of various toxins. In this study, we retrospectively characterized viable B. cereus sensu lato (s.l.) isolates originating from commercial vitamin B2 feed and food additives collected between 2016 and 2022 by the Belgian Federal Agency for the Safety of the Food Chain from products sold on the Belgian market. In total, 75 collected product samples were cultured on a general medium and, in case of bacterial growth, two isolates per product sample were collected and characterized using whole-genome sequencing (WGS) and subsequently characterized in terms of sequence type (ST), virulence gene profile, antimicrobial resistance (AMR) gene profile, plasmid content, and phylogenomic relationships. Viable B. cereus was identified in 18 of the 75 (24%) tested products, resulting in 36 WGS datasets, which were classified into eleven different STs, with ST165 (n = 10) and ST32 (n = 8) being the most common. All isolates carried multiple genes encoding virulence factors, including cytotoxin K-2 (52.78%) and cereulide (22.22%). Most isolates were predicted to be resistant to beta-lactam antibiotics (100%) and fosfomycin (88.89%), and a subset was predicted to be resistant to streptothricin (30.56%). Phylogenomic analysis revealed that some isolates obtained from different products were closely related or even identical indicating a likely common origin, whereas for some products the two isolates obtained did not show any close relationship to each other or other isolates found in other products. This study reveals that potentially pathogenic and drug-resistant B. cereus s.l. can be present in food and feed vitamin B2 additives that are commercially available, and that more research is warranted to assess whether their presence in these types of products poses a threat to consumers.

Dexamethasone versus Surgery for Chronic Subdural Hematoma.

BACKGROUND: The role of glucocorticoids without surgical evacuation in the treatment of chronic subdural hematoma is unclear. METHODS: In this multicenter, open-label, controlled, noninferiority trial, we randomly assigned symptomatic patients with chronic subdural hematoma in a 1:1 ratio to a 19-day tapering course of dexamethasone or to burr-hole drainage. The primary end point was the functional outcome at 3 months after randomization, as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Noninferiority was defined by a lower limit of the 95% confidence interval of the odds ratio for a better functional outcome with dexamethasone than with surgery of 0.9 or more. Secondary end points included scores on the Markwalder Grading Scale of symptom severity and on the Extended Glasgow Outcome Scale. RESULTS: From September 2016 through February 2021, we enrolled 252 patients of a planned sample size of 420; 127 were assigned to the dexamethasone group and 125 to the surgery group. The mean age of the patients was 74 years, and 77% were men. The trial was terminated early by the data and safety monitoring board owing to safety and outcome concerns in the dexamethasone group. The adjusted common odds ratio for a lower (better) score on the modified Rankin scale at 3 months with dexamethasone than with surgery was 0.55 (95% confidence interval, 0.34 to 0.90), which failed to show noninferiority of dexamethasone. The scores on the Markwalder Grading Scale and Extended Glasgow Outcome Scale were generally supportive of the results of the primary analysis. Complications occurred in 59% of the patients in the dexamethasone group and 32% of those in the surgery group, and additional surgery was performed in 55% and 6%, respectively. CONCLUSIONS: In a trial that involved patients with chronic subdural hematoma and that was stopped early, dexamethasone treatment was not found to be noninferior to burr-hole drainage with respect to functional outcomes and was associated with more complications and a greater likelihood of later surgery. (Funded by the Netherlands Organization for Health Research and Development and others; DECSA EudraCT number, 2015-001563-39.).

Evaluation of Clinical Characteristics and CT Decision Rules in Elderly Patients with Minor Head Injury: A Prospective Multicenter Cohort Study.

Age is variably described as a minor or major risk factor for traumatic intracranial lesions after head injury. However, at present, no specific CT decision rule is available for elderly patients with minor head injury (MHI). The aims of this prospective multicenter cohort study were to assess the performance of existing CT decision rules for elderly MHI patients and to compare the clinical and CT characteristics of elderly patients with the younger MHI population. Thirty-day mortality between two age groups (cutoff ≥ 60 years), along with clinical and CT characteristics, was evaluated with four CT decision rules: the National Institute for Health and Care Excellence (NICE) guideline, the Canadian CT Head Rule (CCHR), the New Orleans Criteria (NOC), and the CT Head Injury Patients (CHIP) rule. Of the 5517 MHI patients included, 2310 were aged ≥ 60 years. Elderly patients experienced loss of consciousness (17% vs. 32%) and posttraumatic amnesia (23% vs. 31%) less often, but intracranial lesions (13% vs. 10%), neurological deterioration (1.8% vs. 0.2%), and 30-day mortality (2.0% vs. 0.1%) were more frequent than in younger patients (all p < 0.001). Elderly patients with age as their only risk factor showed intracranial lesions in 5% (NOC and CHIP) to 8% (CCHR and NICE) of cases. The sensitivity of decision rules in the elderly patients was 60% (CCHR) to 97% (NOC) when age was excluded as a risk factor. Current risk factors considered when evaluating elderly patients show lower sensitivity to identify intracranial abnormalities, despite more frequent intracranial lesions. Until age-specific CT decision rules are developed, it is advisable to scan every elderly patient with an MHI.

The cognitive status of chronic subdural hematoma patients after treatment: an exploratory study.

OBJECTIVE: Chronic subdural hematoma (CSDH) is a common neurological condition, often affecting the elderly. Cognitive impairment is frequently observed at presentation. However, the course and longer term aspects of the cognitive status of CSDH patients are unknown. In this study, we aim to explore the cognitive status of CSDH patients after treatment. METHODS: An exploratory study in which CSDH patients were assessed 3 months after treatment and compared to healthy controls. A total of 56 CSDH patients (age 72.1 SD ± 10.8 years with 43 [77%] males) and 60 healthy controls were included (age 67.5 ± SD 4.8 with 34 [57%] males). Cognitive testing was performed using the Telephonic Interview of Cognitive Status-modified (TICS-m), a 12-item questionnaire in which a total of 50 points can be obtained on several cognitive domains. RESULTS: Median time between treatment and cognitive testing was 93 days (range 76-139). TICS-m scores of CSDH patients were significantly lower than healthy controls, after adjusting for age and sex: mean score 34.6 (95% CI: 33.6-35.9) vs. 39.6 (95% CI: 38.5-40.7), p value < 0.001. More than half (54%) of CSDH patients have cognitive scores at follow-up that correspond with cognitive impairment. CONCLUSION: A large number of CSDH patients show significantly worse cognitive status 3 months after treatment compared to healthy controls. This finding underlines the importance of increased awareness for impaired cognition after CSDH. Further research on this topic is warranted.

Validation of a Targeted LC-MS/MS Method for Cereulide and Application in Food and Faeces.

Cereulide is an emetic toxin produced by some strains of Bacillus cereus. This bacterial toxin, a cyclic 1.2 kDa dodecadepsipeptide, is stable to heat and acids and causes nausea and vomiting when ingested via contaminated food. This work aimed to develop and validate a targeted analytical method applying liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify this toxin in food and human faeces. Samples were extracted with acetonitrile in the presence of 13C6-cereulide, a labelled internal standard, and purified by centrifugation and filtration. The limits of quantification were 0.5 and 0.3 µg kg-1 for food and faeces, respectively. The linearity of the method was very good, with calculated R2 values above 0.995. The mean recovery of the method was within the acceptable range of 70.0%-120.0%, the repeatability was not higher than 7.3%, and the highest intra-laboratory reproducibility was 8.9%. The estimated range for the expanded measurement uncertainty was between 5.1% and 18.0%. The LC-MS/MS method was used to analyse one food sample (rice) from a Belgian foodborne outbreak and five faecal samples from patients with clinical symptoms after consumption of the contaminated rice. The levels of cereulide were 12.22 µg g-1 for food and between 6.32 and 773.37 ng g-1 for faecal samples.

Mortality after chronic subdural hematoma is associated with frailty.

PURPOSE: Chronic subdural hematoma (CSDH) is a common neurological disease often affecting the elderly. Long-term excess mortality for patients after CSDH has been suggested but causes of death are unknown. We hypothesize that excess mortality of CSDH patients is related to frailty. In this article, we describe mortality rates and causes of death of CSDH patients compared with the general population and assess the association of frailty with mortality. METHODS: A cohort study in which consecutive CSDH patients were compared to the general population regarding mortality rates. Furthermore, the association of six frailty indicators (cognitive problems, frequent falling, unable to live independently, unable to perform daily self-care, use of benzodiazepines or psychotropic drugs, and number of medications) with mortality was assessed. RESULTS: A total of 1307 CSDH patients were included, with a mean age of 73.7 (SD ± 11.4) years and 958 (73%) were male. Median follow-up was 56 months (range: 0-213). Compared with controls CSDH patients had a hazard ratio for mortality of 1.34 (95% CI: 1.2-1.5). CSDH patients more often died from cardiovascular diseases (37% vs. 30%) and falls (7.2% vs. 3.7%). Among CSDH patients frequent falling (HR 1.3; 95% CI: 1.0-1.7), inability to live independently (HR 1.4, 95% CI: 1.1-1.8), inability to perform daily self-care (HR 1.5; 95% CI: 1.1-1.9), and number of medications used (HR 1.0; 95% CI: 1.0-1.1) were independently associated with mortality. CONCLUSIONS: CSDH patients have higher mortality rates than the general population. Frailty in CSDH patients is associated with higher mortality risk. More attention for the frailty of CSDH patients is warranted.

Highlights mild traumatic brain injury 2021.

PURPOSE: Mild traumatic brain injury (TBI) is one of the most common causes of morbidity worldwide. Patients at risk of unfavourable outcome may benefit from additional attention and help but identification of these patients necessitates the development of diagnostic methods to assess indices of brain injury at an early stage. The aim of this overview is to highlight studies that reflect the growing scientific attention to the early diagnosis and prognostication of mild TBI. RECENT FINDINGS: The value of serum biomarkers for the diagnosis of TBI severity has been acknowledged in recent studies. The diagnostic and prognostic utility of several biomarkers of brain injury, such as glial fibrillary acidic protein, and of inflammation, such as interleukin (IL)-6 and IL-10, holds promise for application in daily clinical practice in a point-of-care platform. Besides head CT imaging, early advanced MRI brain imaging has been reported as a tool for assessment of injury severity and prognostication. The introduction of direct oral anticoagulants (DOACs) has raised new challenges for the treatment of intracranial traumatic haemorrhage at the Emergency Department. SUMMARY: Promising findings of new diagnostic markers of brain injury severity highlight the potential prognostic value of serum biomarkers and early MRI imaging. The accurate assessment of patients at risk of incomplete recovery after mTBI will enhance more timely and individualized treatment.

Acute serum free thiols: a potentially modifiable biomarker of oxidative stress following traumatic brain injury.

Serum concentrations of free thiols (key components of the extracellular antioxidant machinery) reflect the overall redox status of the human body. The objective of this exploratory study was to determine the concentrations of serum free thiols in the acute phase after traumatic brain injury (TBI) and their association with long-term outcome. In this observational cohort study, patients with TBI of various severity were included from a biobank of prospectively enrolled TBI patients. Further eligibility criteria included an available blood sample and head computed tomography data, obtained within 24 h of injury, as well as a functional outcome assessment (Glasgow Outcome Scale Extended (GOSE)) at 6 months post-injury. Serum free thiol concentrations were markedly lower in patients with TBI (n = 77) compared to healthy controls (n = 55) (mean ± standard deviation; 210.3 ± 63.3 vs. 301.8 ± 23.9 µM, P < 0.001) indicating increased oxidative stress. Concentrations of serum free thiols were higher in patients with complete functional recovery (GOSE = 8) than in patients with incomplete recovery (GOSE < 8) (median [interquartile range]; 235.7 [205.1-271.9] vs. 205.2 [173-226.7] µM, P = 0.016), suggesting that patients with good recovery experience less oxidative stress in the acute phase after TBI or have better redox function. Acute TBI is accompanied by a markedly lower concentration of serum free thiols compared to healthy controls indicating that serum free thiols may be a novel biomarker of TBI. Future studies are warranted to validate our findings and explore the clinical applicability and prognostic capability of this candidate-biomarker.

Update of the CHIP (CT in Head Injury Patients) decision rule for patients with minor head injury based on a multicenter consecutive case series.

OBJECTIVE: To update the existing CHIP (CT in Head Injury Patients) decision rule for detection of (intra)cranial findings in adult patients following minor head injury (MHI). METHODS: The study is a prospective multicenter cohort study in the Netherlands. Consecutive MHI patients of 16 years and older were included. Primary outcome was any (intra)cranial traumatic finding on computed tomography (CT). Secondary outcomes were any potential neurosurgical lesion and neurosurgical intervention. The CHIP model was validated and subsequently updated and revised. Diagnostic performance was assessed by calculating the c-statistic. RESULTS: Among 4557 included patients 3742 received a CT (82%). In 383 patients (8.4%) a traumatic finding was present on CT. A potential neurosurgical lesion was found in 73 patients (1.6%) with 26 (0.6%) patients that actually had neurosurgery or died as a result of traumatic brain injury. The original CHIP underestimated the risk of traumatic (intra)cranial findings in low-predicted-risk groups, while in high-predicted-risk groups the risk was overestimated. The c-statistic of the original CHIP model was 0.72 (95% CI 0.69-0.74) and it would have missed two potential neurosurgical lesions and one patient that underwent neurosurgery. The updated model performed similar to the original model regarding traumatic (intra)cranial findings (c-statistic 0.77 95% CI 0.74-0.79, after crossvalidation c-statistic 0.73). The updated CHIP had the same CT rate as the original CHIP (75%) and a similar sensitivity (92 versus 93%) and specificity (both 27%) for any traumatic (intra)cranial finding. However, the updated CHIP would not have missed any (potential) neurosurgical lesions and had a higher sensitivity for (potential) neurosurgical lesions or death as a result of traumatic brain injury (100% versus 96%). CONCLUSIONS: Use of the updated CHIP decision rule is a good alternative to current decision rules for patients with MHI. In contrast to the original CHIP the update identified all patients with (potential) neurosurgical lesions without increasing CT rate.

Long-Term Stability of Blood Serum Biomarkers in Traumatic Brain Injury: A Feasibility Study.

Few studies on traumatic brain injury (TBI) have investigated the stability of blood serum biomarkers after long-term storage at low temperatures. In the current feasibility study we analyzed acute phase serum samples from patients with mild TBI as well as patients with moderate and severe TBI that were collected more than 10 years ago (old samples). We were particularly interested in mild TBI, because injury effects are more subtle in this category as compared to moderate-severe TBI. Therefore, the primary objective was to find out whether several biomarkers were still detectable for these patients. Additionally, we examined whether biomarker levels varied as a function of injury severity. For comparison, we also analyzed samples from an ongoing mTBI cohort (new samples) and healthy controls. Samples were treated with care and were not being subjected to freeze-thaw cycles. We measured concentrations of interleukins (IL6 and 10) and brain specific markers (total tau, UCH-L1, GFAP, and NF-L). No significant differences in biomarker concentrations were found between old and new mild TBI samples. For IL6, IL10, and UCH-L1 higher concentrations were found in moderate and severe TBI as compared to mild TBI. In conclusion, our study shows that long-term storage does not rule out the detection of meaningful biomarker concentrations in patients with TBI, although further research by other laboratories is warranted.

Incomplete recovery in patients with minor head injury directly discharged home from the emergency department: a prospective cohort follow-up study.

OBJECTIVES: To determine the frequency of post-traumatic complaints and recovery rate of non-hospitalised patients with minor head injury (MHI) and their relationship with demographic and injury characteristics. We also evaluated the differences between patient groups in this least severe category of brain and head injury. DESIGN: Prospective cohort follow-up study. SETTING: Patients admitted to the emergency department (ED) of a tertiary hospital in the Netherlands. PARTICIPANTS: 242 patients with MHI (n=100 with head injury only and n=142 with mild traumatic brain injury (mTBI)) discharged home directly after evaluation at the ED. OUTCOME MEASURES: The primary outcome measure was incomplete recovery at 3 months measured by the Glasgow Outcome Scale-Extended score <8. Secondary outcome measures were number of post-traumatic complaints assessed 2 weeks and 3 months postinjury by a standardised questionnaire. Also the number of patients that visited their general practitioner because of persistent complaints was determined. RESULTS: Three months postinjury 48% of patients reported more than one post-traumatic complaint. Half (51%) of patients showed incomplete recovery. Incomplete recovery was associated with headache directly postinjury (OR 3.27, 95% CI 1.28 to 8.34), age (OR 1.02, 95% CI 1.00 to 1.05) and the number of post-traumatic complaints (OR 1.24, 95% CI 1.09 to 1.40) and depression (OR 6.31, 95% CI 1.24 to 32.00) 2 weeks postinjury. Incomplete recovery was comparable between the head injury only and mTBI group (55% vs 50%, 95% CI -12.5 to -23.0). In total 36 MHI patients (28%) visited their general practitioner because of complaints related to their head injury. CONCLUSION: Half of the non-hospitalised patients with MHI experienced incomplete recovery after 3 months without differences between head injury only and mTBI patients. Therefore, early identification of patients at risk for incomplete recovery must be started at the ED to provide appropriate aftercare to avoid long-term post-traumatic complaints.

External validation of prognostic models predicting outcome after chronic subdural hematoma.

BACKGROUND: Several prognostic models for outcomes after chronic subdural hematoma (CSDH) treatment have been published in recent years. However, these models are not sufficiently validated for use in daily clinical practice. We aimed to assess the performance of existing prediction models for outcomes in patients diagnosed with CSDH. METHODS: We systematically searched relevant literature databases up to February 2021 to identify prognostic models for outcome prediction in patients diagnosed with CSDH. For the external validation of prognostic models, we used a retrospective database, containing data of 2384 patients from three Dutch regions. Prognostic models were included if they predicted either mortality, hematoma recurrence, functional outcome, or quality of life. Models were excluded when predictors were absent in our database or available for < 150 patients in our database. We assessed calibration, and discrimination (quantified by the concordance index C) of the included prognostic models in our retrospective database. RESULTS: We identified 1680 original publications of which 1656 were excluded based on title or abstract, mostly because they did not concern CSDH or did not define a prognostic model. Out of 18 identified models, three could be externally validated in our retrospective database: a model for 30-day mortality in 1656 patients, a model for 2 months, and another for 3-month hematoma recurrence both in 1733 patients. The models overestimated the proportion of patients with these outcomes by 11% (15% predicted vs. 4% observed), 1% (10% vs. 9%), and 2% (11% vs. 9%), respectively. Their discriminative ability was poor to modest (C of 0.70 [0.63-0.77]; 0.46 [0.35-0.56]; 0.59 [0.51-0.66], respectively). CONCLUSIONS: None of the examined models showed good predictive performance for outcomes after CSDH treatment in our dataset. This study confirms the difficulty in predicting outcomes after CSDH and emphasizes the heterogeneity of CSDH patients. The importance of developing high-quality models by using unified predictors and relevant outcome measures and appropriate modeling strategies is warranted.

Slow Channel Syndrome Revisited: 40 Years Clinical Follow-Up and Genetic Characterization of Two Cases.

BACKGROUND: The slow channel syndrome is a rare hereditary disorder caused by a dominant gain-of-function variant in one of the subunits of the acetylcholine receptor at the neuromuscular junction. Patients typically experience axial, limb and particularly extensor finger muscle weakness. OBJECTIVE: Age at diagnosis is variable and although the long-term prognosis is important for newly diagnosed patients, extensive follow-up studies are rare. We aim to provide answers and perspective for this patient group by presenting an elaborate description of the lifetime follow-up of two slow channel syndrome patients. METHODS: We describe 40 years follow-up in two, genetically confirmed cases (CHRNA1; c.866G > T p.(Ser289Ile)(legacy Ser269Ile) and CHRNE; c.721C > T p.(Leu241Phe)(legacy Leu221Phe) variants). RESULTS: We find that the disease course has a fluctuating pattern and is only mildly progressive. However, hormonal imbalances, (psychological) stress or excessive hot or cold environments are often aggravating factors. Quinidine and fluoxetine are helpful, but ephedrine and salbutamol may also improve symptoms. CONCLUSION: Slow channel syndrome is mildly progressive with a fluctuating pattern. The observations reported here provide a lifespan perspective and answers to the most pressing questions about prognosis and treatment options for newly diagnosed patients.

An endemic species flock of Cypridopsinae (Crustacea, Ostracoda) from the ancient Lake Malawi (Africa), with the description of a new genus and three new species.

We describe Malawidopsis gen. nov., a new genus of Cypridopsinae Kaufmann, 1900 from the African ancient Lake Malawi. The genus comprises at least 17 new species, which makes it a significant ostracod radiation in this lake, parallel to a similar (but independent) cypridopsine radiation in Lake Tanganyika. Three of these new species are here described: Malawidopsis stellae gen. et. sp. nov., the type species of the new genus; M. ruwaydae gen. et. sp. nov. and M. antoniae gen. et. sp. nov.. The other new species are briefly illustrated and described, but are left in open nomenclature (sp. A, B, C, etc.). Cypridopsis cunningtoni Sars, 1910 and Potamocypris fuelleborni Daday, 1910 are transferred to Malawidopsis gen. nov. and are identical to Malawidopsis spec. F and Malawidopsis spec. N, respectively. The new tribe Plesiocyprisopsini trib. nov. is erected, and comprises the cypridopsine genera previously in the Cypridopsini s.l. with the right valve overlapping the left valve, at least anteriorly. Potential drivers of speciation within this endemic clade in Lake Malawi are briefly discussed. Bathymetry might have been important, with most species being restricted to shallower depths and only four species also occurring at depths of 75 m or more, but very few specimens were retrieved from greater depths. Most species occurred on coarse sand, but this sediment category coincides with shallower stations. Overall, most species appear to have a wide geographical distribution in the lake, so no geographical parapatric speciation is apparent. The occurrence of all species in sexual populations and the significant differences in the male sexual organs and the valves suggest that sexual selection might have been the most important driver in the speciation process of this species flock, but this should be further explored. Following deep coring results in Lake Malawi, the present clade could be (at least) c one million years old.

Surgery After Primary Dexamethasone Treatment for Patients with Chronic Subdural Hematoma-A Retrospective Study.

BACKGROUND: We aimed to quantify the need for additional surgery in patients with chronic subdural hematoma (CSDH) primarily treated with dexamethasone and to identify patient characteristics associated with additional surgery. METHODS: Data were retrospectively collected from 283 patients with CSDH, primarily treated with dexamethasone, in 3 hospitals from 2008 to 2018. Primary outcome was the need for additional surgery. The association between baseline characteristics and additional surgery was analyzed with univariable and multivariable logistic regression analysis and presented as adjusted odds ratios (aOR). RESULTS: In total, 283 patients with CSDH were included: 146 patients (51.6%) received 1 dexamethasone course (DXM group), 30 patients (10.6%) received 2 dexamethasone courses (DXM-DXM group), and 107 patients (37.8%) received additional surgery (DXM-SURG group). Patients who underwent surgery more often had a Markwalder Grading Scale of 2 (as compared with 1, aOR 2.05; 95% confidence interval [CI] 0.90-4.65), used statins (aOR 2.09; 95% CI 1.01-4.33), had a larger midline shift (aOR 1.10 per mm; 95% CI 1.01-1.21) and had larger hematoma thickness (aOR 1.16 per mm; 95% CI 1.09-1.23), had a bilateral hematoma (aOR 1.85; 95% CI 0.90-3.79), and had a separated hematoma (as compared with homogeneous, aOR 1.77; 95% CI 0.72-4.38). Antithrombotics (aOR 0.45; 95% CI 0.21-0.95) and trabecular hematoma (as compared with homogeneous, aOR 0.31; 95% CI 0.12-0.77) were associated with a lower likelihood of surgery. CONCLUSIONS: More than one-third of patients with CSDH primarily treated with dexamethasone received additional surgery. These patients were more severely affected amongst others with larger hematomas.