Prehospital Blood Pressure and Clinical and Radiological Outcomes in Acute Spontaneous Intracerebral Hemorrhage.

BACKGROUND: High blood pressure (BP) is associated with poor outcome in acute spontaneous intracerebral hemorrhage. Little is known about the predictive value of prehospital BP in intracerebral hemorrhage. We aimed to investigate the relationship between prehospital BP and clinical and radiological outcomes. METHODS: This is a retrospective, hospital-based study of all adult intracerebral hemorrhage patients admitted within 24 hours of symptom onset to a large primary stroke centre during 2012 to 2019. The first prehospital and on-admission BP were recorded as systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. The absolute differences between prehospital and on-admission BP were calculated (BPchange). Primary outcomes were in-hospital death, early neurological deterioration, and hematoma expansion. Associations between prehospital BP, BPchange, and outcomes were explored by regression with adjustment for relevant confounders. RESULTS: We included 426 patients aged median 76 (interquartile range 67-85) years and 203 (48%) were female. Median prehospital systolic BP was 179 (interquartile range 158-197) and diastolic BP was 100 (interquartile range 86-112) mm Hg. In-hospital death occurred in 121/426 (28%), early neurological deterioration in 107/295 (36%), and hematoma expansion in 50/185 (27%) patients. There were linear associations between 5 mm Hg increment of prehospital systolic BP (odds ratio 1.06, [95% CI, 1.01-1.12]) and mean arterial pressure (odds ratio 1.08, [95% CI, 1.01-1.15]) and in-hospital death, and between 5 mm Hg increment of prehospital diastolic BP (odds ratio 1.10, [95% CI, 1.00-1.21]) and mean arterial pressure (odds ratio 1.09, [95% CI, 1.00-1.18]) and hematoma expansion. There was a nonlinear association between prehospital systolic BP and in-hospital death. No consistent associations between prehospital BPchange and outcomes were found. CONCLUSIONS: In patients with acute intracerebral hemorrhage, elevated prehospital BP parameters were associated with in-hospital death and hematoma expansion. Changes in prehospital BP were not consistently associated with outcome. A possible U-shaped association between prehospital BP and in-hospital death needs further investigation.

Pooled Subject-Reported Outcomes From 2 Phase 3 Studies of OnabotulinumtoxinA for Simultaneous Treatment of Forehead and Glabellar Lines.

BACKGROUND: Understanding the subjects' perspective is critical for successfully treating upper facial lines. OBJECTIVE: To understand subjects' self-perception and overall satisfaction after onabotulinumtoxinA treatment for forehead and glabellar lines. METHODS: This analysis pooled data from two 12-month, pivotal phase 3 studies in which toxin-naive subjects received onabotulinumtoxinA 40 U or placebo for treatment of upper facial lines. OnabotulinumtoxinA was administered as 0.1-mL injections at 10 prespecified sites (frontalis: 20 U; glabellar complex: 20 U). Each study used 3 reliable and validated patient-reported outcome instruments to evaluate subject satisfaction and appearance-related psychological effects: the Facial Line Satisfaction Questionnaire (FLSQ), the Facial Line Outcomes (FLO-11) Questionnaire, and the Self-Perception of Age (SPA) Questionnaire. In total, data for 865 subjects (608, onabotulinumtoxinA 40 U; 257, placebo) were analyzed. RESULTS: Treatment with onabotulinumtoxinA 40 U resulted in significant and sustained improvements across all pooled FLO-11 items and FLSQ items compared with placebo. SPA results demonstrated that a significant proportion of subjects in the pooled analysis felt they looked younger after treatment than at baseline (all, p < .0001 vs placebo). CONCLUSION: This study demonstrates a high level of treatment satisfaction and significantly improved appearance-related psychological outcomes among toxin-naive subjects after onabotulinumtoxinA 40 U treatment.

Phase 3 Study of OnabotulinumtoxinA Distributed Between Frontalis, Glabellar Complex, and Lateral Canthal Areas for Treatment of Upper Facial Lines.

BACKGROUND: Although commonly practiced, simultaneous onabotulinumtoxinA injections to multiple facial areas have not been investigated in prospective studies. OBJECTIVE: Evaluate safety and efficacy of onabotulinumtoxinA for treatment of forehead lines (FHL) distributed between the frontalis (20 U) and glabellar complex (20 U), with or without simultaneous lateral canthal areas (crow's feet lines [CFL], 24 U) treatment. METHODS: Subjects with moderate to severe FHL were randomized (2:2:1) to onabotulinumtoxinA 40 U, onabotulinumtoxinA 64 U, or placebo. After 180 days, subjects could receive up to 2 additional open-label onabotulinumtoxinA 64 U treatments. RESULTS: The intent-to-treat (ITT) population comprised 787 subjects, and the modified ITT (mITT) population (subjects with psychological impact) comprised 568. After 30 days, onabotulinumtoxinA 40 U and 64 U significantly improved investigator- and subject-assessed FHL severity by at least 2 Facial Wrinkle Scale (FWS) grades in 45.6% and 53.0% of ITT subjects, respectively, versus 0.6% receiving placebo (both, p < .0001). Significantly more mITT subjects receiving onabotulinumtoxinA achieved investigator- and subject-assessed FWS ratings of none/mild versus placebo (p < .0001). OnabotulinumtoxinA was well tolerated. CONCLUSION: OnabotulinumtoxinA distributed between the frontalis and glabellar complex, with or without additional CFL injections, was safe and effective for treatment of moderate to severe FHL.

Reaccumulation of globotriaosylceramide in podocytes after agalsidase dose reduction in young Fabry patients.

BACKGROUND: Agalsidase-α 0.2 mg/kg every other week (eow) and agalsidase-ß 1.0 mg/kg/eow are licensed in Europe as equipotent treatment of the α-galactosidase deficiency in Fabry disease. This case series describes the effects of agalsidase dose adjustments in serial kidney biopsies in switch patients. METHODS: All treatment-naïve patients with classical Fabry disease in our centre started on agalsidase-ß 1.0 mg/kg/eow and subsequently switched to agalsidase-α 0.2 mg/kg/eow were included ( n = 3). The median age at enzyme replacement therapy start was 11 (range 7-18) years. Kidney biopsies were performed at baseline, after 5 years of agalsidase-ß 1.0 mg/kg/eow and after 3 subsequent years of agalsidase-α 0.2 mg/kg/eow. One patient was re-biopsied 2 years after reswitch to agalsidase-ß 1.0 mg/kg/eow. The scoring system of the International Scoring Group of Fabry Nephropathy was used. RESULTS: The patients completely cleared globotriaosylceramide (GL3) from mesangial and endothelial cells and partly cleared podocytes on agalsidase-ß 1.0 mg/kg/eow. Reaccumulation of GL3 in podocytes, but not in the mesangium or endothelium, occurred after 3 years of agalsidase-α 0.2 mg/kg/eow. Subsequent reduction of podocyte GL3 was observed in the single patient rebiopsied 2 years after reswitch to agalsidase-ß 1.0 mg/kg/eow. CONCLUSION: Partial clearance, reaccumulation and renewed partial clearance of podocyte GL3 deposits in serial kidney biopsies over 8-10 years were seen in parallel with agalsidase dose adjustments. Repeated kidney biopsies may impact therapeutic choices in Fabry disease.

Forehead Line Treatment With OnabotulinumtoxinA in Subjects With Forehead and Glabellar Facial Rhytids: A Phase 3 Study.

BACKGROUND: Effacement of horizontal forehead lines (FHL) with onabotulinumtoxinA has not been investigated in prospective Phase 3 studies. OBJECTIVE: To evaluate safety and efficacy of onabotulinumtoxinA treatment of FHL together with glabellar lines (GL). MATERIALS AND METHODS: A 12-month, Phase 3 study randomized subjects with moderate-to-severe FHL and GL to onabotulinumtoxinA 40 U or placebo, distributed between the frontalis (20 U) and glabellar complex (20 U). After Day 180, subjects could receive up to 2 additional open-label onabotulinumtoxinA treatments. Efficacy was assessed using the Facial Wrinkle Scale (FWS) and Facial Line Outcomes questionnaire. RESULTS: The intent-to-treat (ITT) population included 391 subjects, and the modified ITT (mITT) population (subjects with psychological impact) included 254 subjects. After 30 days, onabotulinumtoxinA significantly improved the investigator- and subject-assessed appearance of FHL severity by at least 2 FWS grades in 61.4% of ITT subjects versus 0% of placebo subjects (p < .0001). In the mITT population, 94.8% of onabotulinumtoxinA subjects and 1.7% of placebo subjects achieved investigator- and subject-assessed FWS ratings of none/mild (p = .0003). Patient-reported outcomes were consistent with FWS ratings. OnabotulinumtoxinA was well tolerated. CONCLUSION: OnabotulinumtoxinA 40 U distributed between the frontalis and glabellar complex was safe and effective for treatment of moderate-to-severe FHL.

Changes in neuronal dopamine homeostasis following 1-methyl-4-phenylpyridinium (MPP+) exposure.

1-Methyl-4-phenylpyridinium (MPP(+)), the active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, selectively kills dopaminergic neurons in vivo and in vitro via a variety of toxic mechanisms, including mitochondrial dysfunction, generation of peroxynitrite, induction of apoptosis, and oxidative stress due to disruption of vesicular dopamine (DA) storage. To investigate the effects of acute MPP(+) exposure on neuronal DA homeostasis, we measured stimulation-dependent DA release and non-exocytotic DA efflux from mouse striatal slices and extracellular, intracellular, and cytosolic DA (DAcyt) levels in cultured mouse ventral midbrain neurons. In acute striatal slices, MPP(+) exposure gradually decreased stimulation-dependent DA release, followed by massive DA efflux that was dependent on MPP(+) concentration, temperature, and DA uptake transporter activity. Similarly, in mouse midbrain neuronal cultures, MPP(+) depleted vesicular DA storage accompanied by an elevation of cytosolic and extracellular DA levels. In neuronal cell bodies, increased DAcyt was not due to transmitter leakage from synaptic vesicles but rather to competitive MPP(+)-dependent inhibition of monoamine oxidase activity. Accordingly, monoamine oxidase blockers pargyline and l-deprenyl had no effect on DAcyt levels in MPP(+)-treated cells and produced only a moderate effect on the survival of dopaminergic neurons treated with the toxin. In contrast, depletion of intracellular DA by blocking neurotransmitter synthesis resulted in ∼30% reduction of MPP(+)-mediated toxicity, whereas overexpression of VMAT2 completely rescued dopaminergic neurons. These results demonstrate the utility of comprehensive analysis of DA metabolism using various electrochemical methods and reveal the complexity of the effects of MPP(+) on neuronal DA homeostasis and neurotoxicity.

Agalsidase benefits renal histology in young patients with Fabry disease.

The effect of early-onset enzyme replacement therapy on renal morphologic features in Fabry disease is largely unknown. Here, we evaluated the effect of 5 years of treatment with agalsidase alfa or agalsidase beta in 12 consecutive patients age 7-33 years (median age, 16.5 years). We performed renal biopsies at baseline and after 5 years of enzyme replacement therapy; 7 patients had additional biopsies after 1 and 3 years. After a median of 65 months, biopsy findings from all patients showed total clearance of glomerular endothelial and mesangial cell inclusions, and findings from 2 patients showed complete clearance of inclusions from epithelial cells of the distal tubule. The 4 patients who received the highest dose of agalsidase exhibited substantial clearance of podocyte inclusions, and the youngest patient had nearly complete clearance of these inclusions. Linear regression analysis showed a highly significant correlation between podocyte globotriaocylceramide clearance and cumulative agalsidase dose (r=0.804; P=0.002). Microalbuminuria normalized in five patients. In summary, long-term enzyme replacement therapy in young patients can result in complete globotriaocylceramide clearance of mesangial and glomerular endothelial cells across all dosage regimens, and clearance of podocyte inclusions is dose-dependent.

Intracerebral haemorrhage in patients taking different types of oral anticoagulants: a pooled individual patient data analysis from two national stroke registries.

BACKGROUND: We investigated outcomes in patients with intracerebral haemorrhage (ICH) according to prior anticoagulation treatment with Vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or no anticoagulation. METHODS: This is an individual patient data study combining two prospective national stroke registries from Switzerland and Norway (2013-2019). We included all consecutive patients with ICH from both registries. The main outcomes were favourable functional outcome (modified Rankin Scale 0-2) and mortality at 3 months. RESULTS: Among 11 349 patients with ICH (mean age 73.6 years; 47.6% women), 1491 (13.1%) were taking VKAs and 1205 (10.6%) DOACs (95.2% factor Xa inhibitors). The median percentage of patients on prior anticoagulation was 23.7 (IQR 22.6-25.1) with VKAs decreasing (from 18.3% to 7.6%) and DOACs increasing (from 3.0% to 18.0%) over time. Prior VKA therapy (n=209 (22.3%); adjusted ORs (aOR), 0.64; 95% CI, 0.49 to 0.84) and prior DOAC therapy (n=184 (25.7%); aOR, 0.64; 95% CI, 0.47 to 0.87) were independently associated with lower odds of favourable outcome compared with patients without anticoagulation (n=2037 (38.8%)). Prior VKA therapy (n=720 (49.4%); aOR, 1.71; 95% CI, 1.41 to 2.08) and prior DOAC therapy (n=460 (39.7%); aOR, 1.28; 95% CI, 1.02 to 1.60) were independently associated with higher odds of mortality compared with patients without anticoagulation (n=2512 (30.2%)). CONCLUSIONS: The spectrum of anticoagulation-associated ICH changed over time. Compared with patients without prior anticoagulation, prior VKA treatment and prior DOAC treatment were independently associated with lower odds of favourable outcome and higher odds of mortality at 3 months. Specific reversal agents unavailable during the study period might improve outcomes of DOAC-associated ICH in the future.

Antithrombotic Treatment, Prehospital Blood Pressure, and Outcomes in Spontaneous Intracerebral Hemorrhage.

Background In acute intracerebral hemorrhage, both elevated blood pressure (BP) and antithrombotic treatment are associated with poor outcome. Our aim was to explore interactions between antithrombotic treatment and prehospital BP. Methods and Results This observational, retrospective study included adult patients with spontaneous intracerebral hemorrhage diagnosed by computed tomography within 24 hours, admitted to a primary stroke center during 2012 to 2019. The first recorded prehospital/ambulance systolic and diastolic BP were analyzed per 5 mm Hg increment. Clinical outcomes were in-hospital mortality, shift on the modified Rankin Scale at discharge, and mortality at 90 days. Radiological outcomes were initial hematoma volume and hematoma expansion. Antithrombotic (antiplatelet and/or anticoagulant) treatment was analyzed both together and separately. Modification of associations between prehospital BP and outcomes by antithrombotic treatment was explored by multivariable regression with interaction terms. The study included 200 women and 220 men, median age 76 (interquartile range, 68-85) years. Antithrombotic drugs were used by 252 of 420 (60%) patients. Compared with patients without, patients with antithrombotic treatment had significantly stronger associations between high prehospital systolic BP and in-hospital mortality (odds ratio [OR], 1.14 versus 0.99, P for interaction 0.021), shift on the modified Rankin Scale (common OR, 1.08 versus 0.96, P for interaction 0.001), and hematoma volume (coef. 0.03 versus -0.03, P for interaction 0.011). Conclusions In patients with acute, spontaneous intracerebral hemorrhage, antithrombotic treatment modifies effects of prehospital BP. Compared with patients without, patients with antithrombotic treatment have poorer outcomes with higher prehospital BP. These findings may have implications for future studies on early BP lowering in intracerebral hemorrhage.

Antithrombotic treatment after intracerebral hemorrhage: Surveys among stroke physicians in Scandinavia and the United Kingdom.

Background and Aims: It is unclear whether patients with previous intracerebral hemorrhage (ICH) should receive antithrombotic treatment to prevent ischemic events. We assessed stroke physicians' opinions about this, and their views on randomizing patients in trials assessing this question. Methods: We conducted three web-based surveys among stroke physicians in Scandinavia and the United Kingdom. Results: Eighty-nine of 205 stroke physicians (43%) responded to the Scandinavian survey, 161 of 180 (89%) to the UK antiplatelet survey, and 153 of 289 (53%) to the UK anticoagulant survey. In Scandinavia, 19 (21%) stroke physicians were uncertain about antiplatelet treatment after ICH for ischemic stroke or transient ischemic attack (TIA) and 21 (24%) for prior myocardial infarction. In the United Kingdom, 116 (77%) were uncertain for ischemic stroke or TIA and 115 (717%) for ischemic heart disease. In Scandinavia, 32 (36%) were uncertain about anticoagulant treatment after ICH for atrial fibrillation, and 26 (29%) for recurrent deep vein thrombosis or pulmonary embolism. In the United Kingdom, 145 (95%) were uncertain about anticoagulants after ICH in at least some cases. In both regions combined, 191 of 250 (76%) would consider randomizing ICH survivors in a trial of starting versus avoiding antiplatelets, and 176 of 242 (73%) in a trial of starting versus avoiding anticoagulants. Conclusion: Considerable proportions of stroke physicians in Scandinavia and the United Kingdom were uncertain about antithrombotic treatment after ICH. A clear majority would consider randomizing patients in trials assessing this question. These findings support the need for such trials.

Hesitant adopters: COVID-19 vaccine hesitancy among diverse vaccinated adults in the United States.

Background: Despite the United States (US) having an abundant supply of COVID-19 vaccines, vaccination rates lag behind other high-income countries, suggesting that vaccine hesitancy and attitudes play a greater role in public health measures than pure supply and access. With the acknowledgment that vaccination attitudes and status may or may not be correlated, this study examined COVID-19 vaccine hesitancy among vaccinated US adults by asking: 1) What is the prevalence of COVID-19 vaccine hesitancy among the vaccinated? 2) Does COVID-19 vaccine hesitancy vary across sociodemographic characteristics? 3) Does COVID-19 vaccine hesitancy vary by healthcare access and influenza vaccination over the past 5 years? Methods: Data were collected through an online survey of 2022 US adults with a final analytic sample of 1383 vaccinated respondents. Results: Overall, 48.8% of vaccinated adults reported some level of hesitancy, while a slight majority reported they were "not at all hesitant". Younger respondents, women, and Black and American Indian or Alaska Native participants had greater adjusted odds of being more hesitant towards receiving the COVID-19 vaccine. Respondents who had a primary care physician had greater adjusted odds than those who did not have a primary care physician of being more hesitant towards receiving the COVID-19 vaccine. Conclusions: This is the first population-based national sample study examining COVID-19 vaccine hesitancy among vaccinated individuals from subgroups of distinctive backgrounds in order to inform targeted strategies for reducing vaccine hesitancy. Findings can assist in efforts to increase vaccination rates and also decrease vaccine hesitancy at the national level.

Synthesis and Development of Highly Selective Pyrrolo[2,3-d]pyrimidine CSF1R Inhibitors Targeting the Autoinhibited Form.

Colony-stimulating factor-1 receptor (CSF1R) is a receptor tyrosine kinase that controls the differentiation and maintenance of most tissue-resident macrophages, and the inhibition of CSF1R has been suggested as a possible therapy for a range of human disorders. Herein, we present the synthesis, development, and structure-activity relationship of a series of highly selective pyrrolo[2,3-d]pyrimidines, showing subnanomolar enzymatic inhibition of this receptor and with excellent selectivity toward other kinases in the platelet-derived growth factor receptor (PDGFR) family. The crystal structure of the protein and 23 revealed that the binding conformation of the protein is DFG-out-like. The most promising compounds in this series were profiled for cellular potency and subjected to pharmacokinetic profiling and in vivo stability, indicating that this compound class could be relevant in a potential disease setting. Additionally, these compounds inhibited primarily the autoinhibited form of the receptor, contrasting the behavior of pexidartinib, which could explain the exquisite selectivity of these structures.

Effects of oral anticoagulation in people with atrial fibrillation after spontaneous intracranial haemorrhage (COCROACH): prospective, individual participant data meta-analysis of randomised trials.

BACKGROUND: The safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation. METHODS: In this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133. FINDINGS: We identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA2DS2-VASc score ≤4, and 163 [40%] with CHA2DS2-VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42-1·10]; I2=0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events (nine [4%] of 212 vs 38 [19%] of 200; pooled HR 0·27 [95% CI 0·13-0·56]; I2=0%). There was no significant increase in haemorrhagic major adverse cardiovascular events (15 [7%] of 212 vs nine [5%] of 200; pooled HR 1·80 [95% CI 0·77-4·21]; I2=0%), death from any cause (38 [18%] of 212 vs 29 [15%] of 200; 1·29 [0·78-2·11]; I2=50%), or death or dependence after 1 year (78 [53%] of 147 vs 74 [51%] of 145; pooled odds ratio 1·12 [95% CI 0·70-1·79]; I2=0%). INTERPRETATION: For people with atrial fibrillation and intracranial haemorrhage, oral anticoagulation had uncertain effects on the risk of any stroke or cardiovascular death (both overall and in subgroups), haemorrhagic major adverse cardiovascular events, and functional outcome. Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events, which can inform clinical practice. These findings should encourage recruitment to, and completion of, ongoing trials. FUNDING: British Heart Foundation.

Association of grit and overall survival in patients undergoing nephrectomy for renal cell carcinoma.

Background: Quantifying grit with the Short Grit Scale (Grit-S) has shown ability to predict success in various academic and professional domains. Grit has yet to be analyzed in patients with cancer. Methods: This study is a longitudinal analysis of prospectively distributed Grit-S surveys to patients undergoing radical or partial nephrectomy. Patients who completed a preoperative Grit-S survey with confirmed renal cell carcinoma (RCC) were included in the analysis. The relationship between preoperative grit scores and overall survival (OS) was determined using Cox proportional-hazard models and Kaplan-Meier analysis. Results: A total of 323 patients with RCC that completed the Grit-S survey prior to nephrectomy were included in the study. Median Grit score was 3.9. Most patients were male (67.5%), White (69.3%), and greater than 60 years old (57.0%) with a median age of 62 at the time of surgery. Patients scoring above or below the median grit score had similar baseline characteristics. As a binary variable, lower preoperative grit was significantly associated with shorter OS [hazard ratio (HR) =2.02, 95% confidence interval (CI): 1.12-3.63, P=0.019] on multivariable analysis. Unit changes in grit were not significantly associated with OS (HR =0.77, 95% CI: 0.53-1.14, P=0.193). Conclusions: Lower grit scores may predict decreased OS in RCC patients undergoing nephrectomy. The Grit-S survey may have utility in preoperative evaluation. Further research assessing grit in other malignancies and how to psychologically optimize patients prior to surgery are needed.

Feasibility of Outpatient Stem Cell Transplantation in Multiple Myeloma and Risk Factors Predictive of Hospital Admission.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains the standard of care for multiple myeloma (MM) patients. Although outpatient ASCT has been shown to be safe and feasible, the procedure is overall rare with most patients in the US undergoing inpatient ASCT. Furthermore, hospitalization rates for patients that undergo outpatient ASCT remain high. Adequate markers that predict hospitalization during outpatient ASCT are lacking, yet would be of great clinical value to select patients that are suited to outpatient ASCT. In this study we aimed to elucidate differences between planned outpatient and inpatient ASCT and further evaluated clinical characteristics that are significantly associated with hospitalization during planned outpatient hospitalization. Factors that were significantly associated with a planned inpatient ASCT included an advanced MM disease stage, worse performance status as well as non-Caucasian race, while low albumin levels and female gender were significantly associated with hospitalization during outpatient ASCT. The results of this analysis provide crucial knowledge of factors that are associated with planned inpatient ASCT and hospitalization during outpatient ASCT and could guide the treating physician in decision-making and further facilitate outpatient transplantation.

[A young man with acute, generalised oedema]. / En ung mann med akutte generaliserte ødemer.

BACKGROUND: Ménétrier disease is an uncommon, idiopathic disease characterized by development of chronic protein loss from marked gastric foveolar hyperplasia. A literature search identified several reports of self-limiting, cytomegalovirus-associated Ménétrier disease in children. Some cases have also been reported in adults. CASE REPORT: A formerly healthy man was admitted to hospital with a serum albumin level of 11 g/l and generalised oedema. Transabdominal ultrasound and endoscopy revealed a folded thickening of the (abdominal) ventricular wall; indications of Ménétrier disease. Histological examination of endoscopic biopsies showed moderate hyperplasia in foveolar epithelium, but also suggested an infectious cause. Intranucleal inclusion bodies, CMV-specific immunology, PCR and special stains all supported cytomegalovirus infection. The patient recovered quickly on antiviral treatment. CONCLUSION: Our case demonstrates that cytomegalovirus may cause severe, Ménétrier-like gastritis with protein loss in non-immune-compromised adults.

STudy of Antithrombotic Treatment after IntraCerebral Haemorrhage: Protocol for a randomised controlled trial.

BACKGROUND AND AIMS: Many patients with prior intracerebral haemorrhage have indications for antithrombotic treatment with antiplatelet or anticoagulant drugs for prevention of ischaemic events, but it is uncertain whether such treatment is beneficial after intracerebral haemorrhage. STudy of Antithrombotic Treatment after IntraCerebral Haemorrhage will assess (i) the effects of long-term antithrombotic treatment on the risk of recurrent intracerebral haemorrhage and occlusive vascular events after intracerebral haemorrhage and (ii) whether imaging findings, like cerebral microbleeds, modify these effects. METHODS: STudy of Antithrombotic Treatment after IntraCerebral Haemorrhage is a multicentre, randomised controlled, open trial of starting versus avoiding antithrombotic treatment after non-traumatic intracerebral haemorrhage, in patients with an indication for antithrombotic treatment. Participants with vascular disease as an indication for antiplatelet treatment are randomly allocated to antiplatelet treatment or no antithrombotic treatment. Participants with atrial fibrillation as an indication for anticoagulant treatment are randomly allocated to anticoagulant treatment or no anticoagulant treatment. Cerebral CT or MRI is performed before randomisation. Duration of follow-up is at least two years. The primary outcome is recurrent intracerebral haemorrhage. Secondary outcomes include occlusive vascular events and death. Assessment of clinical outcomes is performed blinded to treatment allocation. Target recruitment is 500 participants.Trial status: Recruitment to STudy of Antithrombotic Treatment after IntraCerebral Haemorrhage is on-going. On 30 April 2020, 44 participants had been enrolled in 31 participating hospitals. An individual patient-data meta-analysis is planned with similar randomised trials.

Severe nephritis as initial sign of Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia (WM), characterized with monoclonal immunoglobulins of type M and lymphoplasmacytic lymphoma, is a rare clonal Bcell disorder. WM usually present as an indolent lymphoma, and renal involvement is, in contrast to multiple myeloma, very rarely seen. We present a patient presenting with severe nephritis and nephrotic range proteinuria of more than 9 g/day as initial manifestations of WM. Furthermore, we discuss diagnostic and therapeutic approaches for this rare manifestation of the disease, in the light of recent research and treatment recommendations.

Bedside Stereomicroscopy of Fabry Kidney Biopsies: An Easily Available Method for Diagnosis and Assessment of Sphingolipid Deposits.

BACKGROUND/AIMS: A previous case report found stereomicroscopic changes typical for Fabry disease in a kidney biopsy. This case series evaluates an expanded diagnostic capacity of the method. METHODS: Bedside stereomicroscopy was performed in a cross-sectional prospective study of 31 consecutive enzyme-treated or treatment-naïve male (n = 14) and female Fabry disease patients. The burden of glomerular storage material was scored semiquantitatively on a visual analog scale (range 0-3) and a blinded comparison was done with a reference histologic method. RESULTS: Significant correlations (p < 0.001) were found between the stereomicroscopic scoring of glomerular characteristic white storage material and the amount of podocyte globotriaosylceramide (Gb3) deposits scored by standardized light microscopy. The bedside method correctly identified the variability of podocyte Gb3 accumulation after 10 years of identical agalsidase therapy in 2 brothers aged 24 and 27 years, and also identified tubular cell deposits. Stereomicroscopy correctly verified the absence of sphingolipid deposits in the biopsy of a female index patient with a genetic variant of unknown significance, and the diagnosis of Fabry disease was finally discarded. CONCLUSIONS: Bedside stereomicroscopy of kidney biopsies is an easily available, low-cost microscopy method handled by the clinician. The method carries a high diagnostic sensitivity for Fabry disease, reducing the risk of misdiagnosis in previously unknown cases. An expanded yield of the method is suggested, including the grading of the podocyte Gb3 burden and assessment of effectiveness of enzyme replacement therapy. We recommend the method as complementary to current standard histologic evaluation of Fabry kidney biopsies.

Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis.

Alpha-synuclein (alpha-syn), a protein implicated in Parkinson's disease pathogenesis, is a presynaptic protein suggested to regulate transmitter release. We explored how alpha-syn overexpression in PC12 and chromaffin cells, which exhibit low endogenous alpha-syn levels relative to neurons, affects catecholamine release. Overexpression of wild-type or A30P mutant alpha-syn in PC12 cell lines inhibited evoked catecholamine release without altering calcium threshold or cooperativity of release. Electron micrographs revealed that vesicular pools were not reduced but that, on the contrary, a marked accumulation of morphologically "docked" vesicles was apparent in the alpha-syn-overexpressing lines. We used amperometric recordings from chromaffin cells derived from mice that overexpress A30P or wild-type (WT) alpha-syn, as well as chromaffin cells from control and alpha-syn null mice, to determine whether the filling of vesicles with the transmitter was altered. The quantal size and shape characteristics of amperometric events were identical for all mouse lines, suggesting that overexpression of WT or mutant alpha-syn did not affect vesicular transmitter accumulation or the kinetics of vesicle fusion. The frequency and number of exocytotic events per stimulus, however, was lower for both WT and A30P alpha-syn-overexpressing cells. The alpha-syn-overexpressing cells exhibited reduced depression of evoked release in response to repeated stimuli, consistent with a smaller population of readily releasable vesicles. We conclude that alpha-syn overexpression inhibits a vesicle "priming" step, after secretory vesicle trafficking to "docking" sites but before calcium-dependent vesicle membrane fusion.