OBJECTIVE:Patient self-report is known to be an inaccurate reflection of true seizure frequency in persons with epilepsy. The current study aimed to assess the safety and performance of the Minder system, a bilateral subscalp electroencephalographic (EEG) acquisition system for continuous long-term EEG recording. METHODS:This prospective, multicenter first-in-human study enrolled adult patients with focal or generalized epilepsy and at least two seizures per month. The primary outcome was adverse events (AEs) in the first 6 months of implantation. Secondary analyses determined whether normal neurophysiological signals, interictal discharges, and seizures seen on scalp video-EEG monitoring were identifiable on subscalp recordings, and signals were rated for clarity on subscalp and two-channel scalp EEG recordings (1 = not recognizable, 5 = clear). Subscalp data were reviewed in relation to events reported in 6-month seizures diaries. RESULTS:Twenty-six subjects were implanted between November 2019 and July 2023. No serious device- or implant procedure-related AEs were reported. The most common device-related AEs were mild or moderate postsurgical pain, headache, or scalp pain/paresthesia (9/26, 35%). All sleep spindles, chewing artifacts, interictal discharges, and electrographic seizures observed on scalp recordings (25 seizures from eight patients) were identified on subscalp recordings and given higher clarity ratings compared to two-channel scalp recordings (median seizure clarity rating was 3 for both scalp and subscalp EEG, range = 1-5, p = .0025). Subscalp recordings captured seizures from diverse seizure focus locations, including frontal and mesial temporal seizure foci and hypothalamic hamartoma. Bilateral recording revealed clinically relevant findings not possible with unilateral recordings (6/26 patients, 23%). Findings of potential clinical utility were identified on manual review of 6-month recordings in most patients (23/26, 88%). SIGNIFICANCE:This study demonstrates the safety and performance of the Minder bilateral subscalp EEG acquisition system for long-term seizure monitoring in patients with epilepsy. Bilateral hemisphere coverage captured seizures in a diverse patient group and permitted lateralization of events.

Abdominal aortic aneurysm (AAA) is a vascular disease process whereby the aorta expands to apoint where rupture may occur. This serious condition is diagnosed in approximately 200,000 people in the United States per year and accounts for over 15,000 deaths annually. The only medical intervention proven to reduce the risk of AAA rupture is surgical repair; however, such repair is associated with high risk of death, reduced quality of life, and high expense. AAA is caused by the weakening of the artery wall due to inflammation-induced destruction of its structural components. Our clinical data shows increased levels of circulating elastin degradation products in patients with AAA, especially smokers, compared to risk factor matched controls. This observation led us to hypothesize that an immune reaction to elastin fragments initiates the inflammatory cascade in the aorta that leads to AAA formation. To test this hypothesis, C57BL/6 mice were injected with poly(lactide-co-glycolide) nanoparticle-encapsulated IL-10 to induce immune tolerance or nanoparticle-encapsulated control ovalbumin. Injection of elastin fragments was performed 7 days later to induce an immune response. AAA of the infrarenal aorta was induced by topical application of elastase during laparotomy procedure 14 days after nanoparticle injection. Aorta diameter was measured 16 days post-operatively with Microfil. Immunologic changes were evaluated by cytokine analysis, Tr1/Th17 cell ratio inperipheral blood, and splenic Th17 and Tr1 response to elastin. Based on prior work, we expect that induction of elastin tolerance using poly(lactide-co-glycolide) nanoparticle-encapsulated IL-10 will suppress abdominal aortic aneurysm expansion and promote an anti-inflammatoryenvironment characterized by increased Tr1/Th17 cell ratio, increased levels of anti-inflammatory cytokines, and decreased pro-inflammatory cytokine expression.

Purpose: Many systematic reviews have summarised evidence from randomised controlled trials (RCTs) on the clinical effectiveness of knee bracing for knee osteoarthritis (OA). However, a detailed synthesis of the descriptions of the actual bracing interventions tested is lacking. The absence of full descriptions of these complex interventions could limit efforts to replicate and extend research findings as well as hamper reliable implementation in clinical practice. We therefore aimed to synthesise and critically evaluate the content and quality of intervention descriptions in published RCTs of bracing for knee OA according to the Template for Intervention Description and Replication (TIDieR) guidelines.

ABSTRACT:Mast cell skin disease is rarely described after external beam radiation therapy in patients with breast carcinoma, with only 7 previous reports in the literature. Skin changes typically occur within (but are not limited to) the radiation field. We present a 64-year-old woman with postradiotherapy cutaneous mastocytosis on the left breast and adjacent chest wall. The clinical and laboratory findings in all reported patients, including the current case, are reviewed. No clear mechanism has been presented to explain disease pathogenesis; although, mast cell accumulation secondary to local mediators produced in response to radiation damage and/or koebnerization phenomenon have been proposed. Cutaneous/systemic mastocytosis is not widely recognized and may be underdiagnosed in the setting of postradiation for breast cancer. It is important for clinicians and pathologists to be aware of this diagnosis for patients presenting with rashes after radiotherapy.

Key points Providing access to an online psychological therapy program in cancer care did not result in significant uptake and engagement by patients, or referrals by cancer care professionals Despite many opportunities for referral by cancer care professionals, only 2% resulted in a referral to the program. None of these referrals were taken up Twenty five patients self‐referred, however only seven (28%) matched the recommended criteria for the program of mild to moderate psychological distress Patient engagement in the program was low, with 11/25 (44%) patients completing at least one lesson Cancer care professionals reported numerous barriers to use including patient barriers such as fatigue, and personal barriers such as forgetting to refer

Objective. Long-term electroencephalogram (EEG) recordings can aid diagnosis and management of various neurological conditions such as epilepsy. In this study we characterize the safety and stability of a clinical grade ring electrode arrays by analyzing EEG recordings, fluoroscopy, and computed tomography (CT) imaging with long-term implantation and histopathological tissue response.Approach. Seven animals were chronically implanted with EEG recording array consisting of four electrode contacts. Recordings were made bilaterally using a bipolar longitudinal montage. The array was connected to a fully implantable micro-processor controlled electronic device with two low-noise differential amplifiers and a transmitter-receiver coil. An external wearable was used to power, communicate with the implant via an inductive coil, and store the data. The sub-scalp electrode arrays were made using medical grade silicone and platinum. The electrode arrays were tunneled in the subgaleal cleavage plane between the periosteum and the overlying dermis. These were implanted for 3-7 months before euthanasia and histopathological assessment. EEG and impedance were recorded throughout the study.Main results. Impedance measurements remained low throughout the study for 11 of 12 channels over the recording period ranged from 3 to 5 months. There was also a steady amplitude of slow-wave EEG and chewing artifact (noise). The post-mortem CT and histopathology showed the electrodes remained in the subgaleal plane in 6 of 7 sheep. There was minimal inflammation with a thin fibrotic capsule that ranged from 4 to 101μm. There was a variable fibrosis in the subgaleal plane extending from 210 to 3617μm (S3-S7) due to surgical cleavage. One sheep had an inflammatory reaction due to electrode extrusion. The passive electrode array extraction force was around 1 N.Significance. Results show sub-scalp electrode placement was safe and stable for long term implantation. This is advantageous for diagnosis and management of neurological conditions where long-term, EEG monitoring is required.

To the Editor: Dermatitis herpetiformis (DH) is a papulovesicular skin disease that is diagnosed on the basis of clinical–histopathological correlation and direct immunofluorescence (DIF) findings from perilesional skin.1 A spectrum of DIF findings in skin biopsies from patients with DH has been described.1 Classically, granular Immunoglobulin A (IgA) deposition in the upper papillary dermis is seen.1 We report a case of DH with fibrillary IgA deposits in the upper papillary dermis, which has rarely been described and may represent a distinct clinical–histopathological variant of DH.1–8 A 52-year-old Pakistani man presented to the dermatology clinic with a 3-year history of an intermittent, intensely pruritic eruption. The rash initially developed in 2017 while the patient lived in Pakistan, and recurred in 2020 after he had moved to the United States. The patient reported lesions on his arms, legs, chest, and neck. He denied any new household contacts, other travel, or changes in personal care products. He had no known history of intestinal malabsorption or gluten-sensitive enteropathy. His medications were metoprolol and naproxen, which he had taken at the same doses for at least 5 years. Physical examination revealed 1–2-mm crusted papules and rare intact papulovesicles on the posterior neck and back. He had more widespread hyperpigmented patches on his trunk and extremities, consistent with postinflammatory changes from his eruption. A punch biopsy taken from his left back showed a subepidermal blister, papillary dermal neutrophilic infiltrate, and perivascular inflammation (Fig. 1). DIF studies revealed fibrillary “fern-like” papillary dermal deposition of IgA. IgG, IgM, C3, and fibrinogen were negative. Special stains for microorganisms were also negative. A diagnosis of DH was made. No HLA typing or electron microscopy was performed. A celiac disease antibody panel was ordered; however, the patient was lost to follow-up. An interesting, but rare finding in some patients with DH is the presence of fibrillary IgA deposits in the superficial papillary dermis on DIF studies.1–8 The fibrillary pattern differs from the more common granular pattern in that IgA reactivity is identified as linear streaks (we describe as ‘fern-like’) rather than fine grains in the papillary dermis. By electron microscopy, fibrillary deposits of IgA are localized to microfibrils within the dermal papillae.2 The fibrillary IgA pattern has been described in different demographic groups, including 1.2% of diagnosed DH patients in the United Kingdom,3 2.6% in Spain,1 4.5% in China,4 and 9% in Poland,5 in addition to small case series.2,6 These percentages contrast with the high prevalence (36.3%–56%) of fibrillary IgA deposition reported in Japanese patients with DH.7,8 Mixed fibrillary–granular patterns have also been detected in 5.8%–7.7% of Japanese patients.7,8FIGURE 1.: Subepidermal blister, papillary dermal neutrophilic infiltrate, and perivascular inflammation on hematoxylin and eosin staining (A–B). Fibrillary “fern-like” papillary dermal deposition of IgA on direct immunofluorescence studies (C–D). (A, original magnification ×40; B and D, original magnification ×200; C, original magnification ×100).The light microscopic findings and DIF results confirmed the diagnosis of DH in our patient. Previous reports have suggested that fibrillary IgA deposition in the papillary dermis can be associated with atypical clinical features in DH, such as psoriasiform and urticarial eruptions and lesions suggestive of bullous pemphigoid, linear IgA bullous dermatosis, erythema multiforme, and nodular vasculitis.1–8 Japanese patients demonstrating the fibrillary pattern commonly show more generalized involvement of the trunk and limbs.7,8 In addition, lack of circulating autoantibodies to tissue transglutaminase or endomysium, HLA-B8/DR3/DQ2 haplotype, and/or absence of gluten-sensitive enteropathy in some patients, also suggest that the fibrillary IgA pattern reflects a separate clinical–histopathological subtype of the disease.1–8 The unusual cutaneous findings (ie, sparing of typical predilection sites), absence of gastrointestinal symptoms, and presence of fibrillary IgA deposits in the upper papillary dermis support this distinct variant of DH in our patient. The true molecular basis and biological significance of a fibrillary pattern of IgA deposition on DIF studies in cases of DH remains to be determined.

Ischemic wound complications of below-the-knee amputation (BKA) will necessitate conversion to above-the-knee amputation (AKA) in ≤36% of cases. Loss of the knee joint has deleterious effects on patient rehabilitation. Cell therapy has demonstrated proangiogenic benefits in patients with peripheral arterial disease, which might allow for improved wound healing after BKA. We assessed the use of cell therapy in BKA wound healing through a safety and feasibility study. A nonrandomized, parallel-assignment, open-label safety and feasibility study was conducted at a single institution from 2017 to 2020. Patients undergoing semi-elective BKA because of untreaTable Rutherford class 4 to 5 ischemia were recruited. The participants were assigned to one of three treatment arms: allogeneic bone marrow-derived mesenchymal stem cells (MSCs), autologous bone marrow cells (BMCs), and control. Allogeneic MSCs were obtained from healthy female donors. Autologous BMCs were obtained via bone marrow aspiration and then concentrated in a closed centrifugation system. The cell product was injected at multiple sites within the gastrocnemius muscle 7 to 21 days before the BKA. The control patients did not receive a placebo injection. The patients were followed up for 24 weeks after amputation. The primary outcome was treatment-related adverse events. The secondary outcomes were conversion to AKA and the use of a prosthetic limb. A total of 34 patients were recruited. Of the 34 patients, 13 had received allogeneic MSC treatment, 6 had received autologous BMC treatment, and 15 had received no treatment. The demographic and disease-related characteristics are listed in Table I. No treatment-related adverse events occurred. Revision-free survival was 79.4% at 24 weeks. This metric was significantly reduced in the allogeneic MSC treatment group but not in the autologous BMC group or the combined cell therapy treatment arm (Table II). Death, conversion to AKA, and the use of a prosthetic limb did not differ between the groups. These results have demonstrated an encouraging safety profile, with no treatment-related adverse events. No significant differences were found in the secondary outcomes of amputation conversion and walking status, although our pilot study was not powered to detect such differences. Given the potential benefit regarding ambulation and quality of life, these results support the performance of a larger phase II randomized trial.Table IDemographic and disease-related characteristicsCharacteristicControl (n = 15)Allogeneic MSCs (n = 13)P valueAutologous BMCs (n = 6)P valueAge, years62.8 ± 6.764.9 ± 7.1.42663.0 ± 5.8.947Male sex15 (100)9 (69.2).0206 (100)1.000Ethnicity African American5 (33.3)6 (46.2)0.4881 (16.7).445 White (non-Hispanic)10 (66.7)7 (53.8)0.4885 (83.3).445 White (Hispanic)0 (0)0 (0)>.9990 (0)>.999Rutherford category 40 (0)1 (7.7).2741 (16.7).105 515 (100)12 (92.3).2745 (83.3).105Smoking status Current5 (33.3)3 (23.1).5494 (66.7).163 Former7 (46.7)7 (53.8).7052 (33.3).577 Never3 (20)3 (23.1).8430 (0).237Comorbidity Diabetes mellitus14 (93.3)8 (61.5).0416 (100).516 Myocardial infarction2 (13.3)2 (15.4).8770 (0).347 TIA or stroke1 (6.7)2 (15.4).4571 (16.7).481 Coronary artery disease4 (26.7)3 (23.1).8270 (0).160 Congestive heart failure5 (33.3)3 (23.1).5490 (0).105 DVT in index leg2 (13.3)2 (15.4).8770 (0).347 Chronic kidney disease8 (53.3)9 (69.2).3902 (33.3).407 Hypertension15 (100)11 (84.6).1155 (83.3).105Systolic blood pressure, mm Hg136.7 ± 16.8114.4 ± 20.5.005103.7 ± 13.9<.001Diastolic blood pressure, mm Hg76.1 ± 12.466.4 ± 16.7.09854.8 ± 11.9.004Cardioprotective medication Statin11 (73.3)13 (100).0445 (83.3).627 Antiplatelet9 (60)12 (92.3).0495 (83.3).306 Anticoagulation8 (53.3)7 (53.8).9781 (16.7).125 Beta-blocker8 (53.3)9 (69.2).3902 (33.3).407 Calcium channel blocker4 (26.7)2 (15.4).4684 (66.7).088 ACE inhibitor1 (6.7)3 (23.1).2164 (66.7).004ACE, Angiotensin-converting enzyme; BMCs, bone marrow cells; DVT, deep vein thrombosis; MSCs, bone marrow-derived mesenchymal stem cells; TIA, transient ischemic attack.Data presented as mean ± standard deviation or number (%).Boldface P values represent statistical significance. Open table in a new tab Table IIPrimary and secondary outcomes of control and treatment groups at 24 weeksOutcomeControl (n = 15)Allogeneic MSCs (n = 13)P valueAutologous BMCs (n = 6)P valueCombined treatment groups (n = 19)P valueRevision-free survival14 (93.3)7 (53.8).0166 (100).51713 (68.4).074Conversion to AKA1 (6.7)4 (30.8).0970 (0).5174 (21.1).240Death0 (0)2 (15.4).1150 (0)>.9992 (10.5).195Walking with prosthesis6 (40)3 (23.1).3391 (16.7).3064 (21.1).229AKA, Above-the-knee amputation; BMCs, bone marrow cells; MSCs, bone marrow-derived mesenchymal stem cells.Data presented as number (%).Boldface P values represent statistical significance. Open table in a new tab

Objectives: To determine the long-term outcomes in patients undergoing intracranial EEG (iEEG) evaluation for epilepsy surgery in terms of seizure freedom, mood, and quality of life at St. Vincent's Hospital, Melbourne. Methods: Patients who underwent iEEG between 1999 and 2016 were identified. Patients were retrospectively assessed between 2014 and 2017 by specialist clinic record review and telephone survey with standardized validated questionnaires for: 1) seizure freedom using the Engel classification; 2) Mood using the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E); 3) Quality-of-life outcomes using the QOLIE-10 questionnaire. Summary statistics and univariate analysis were performed to investigate variables for significance. Results: Seventy one patients underwent iEEG surgery: 49 Subdural, 14 Depths, 8 Combination with 62/68 (91.9%) of those still alive, available at last follow-up by telephone survey or medical record review (median of 8.2 years). The estimated epileptogenic zone was 62% temporal and 38% extra-temporal. At last follow-up, 69.4% (43/62) were Engel Class I and 30.6% (19/62) were Engel Class II-IV. Further, a depressive episode (NDDI-E > 15) was observed in 34% (16/47), while a 'better quality of life' (QOLIE10 score < 25) was noted in 74% (31/42). Quality of life (p < 0.001) but not mood (p = 0.24) was associated with seizure freedom. Significance: Long-term seizure freedom can be observed in patients undergoing complex epilepsy surgery with iEEG evaluation and is associated with good quality of life. (c) 2021 Elsevier Inc. All rights reserved.

Accurate identification of seizure activity, both clinical and subclinical, has important implications in the management of epilepsy. Accurate recognition of seizure activity is essential for diagnostic, management and forecasting purposes, but patient-reported seizures have been shown to be unreliable. Earlier work has revealed accurate capture of electrographic seizures and forecasting is possible with an implantable intracranial device, but less invasive electroencephalography (EEG) recording systems would be optimal. Here, we present preliminary results of seizure detection and forecasting with a minimally invasive sub-scalp device that continuously records EEG. Five participants with refractory epilepsy who experience at least two clinically identifiable seizures monthly have been implanted with sub-scalp devices (Minder®), providing two channels of data from both hemispheres of the brain. Data is continuously captured via a behind-the-ear system, which also powers the device, and transferred wirelessly to a mobile phone, from where it is accessible remotely via cloud storage. EEG recordings from the sub-scalp device were compared to data recorded from a conventional system during a 1-week ambulatory video-EEG monitoring session. Suspect epileptiform activity (EA) was detected using machine learning algorithms and reviewed by trained neurophysiologists. Seizure forecasting was demonstrated retrospectively by utilizing cycles in EA and previous seizure times. The procedures and devices were well-tolerated and no significant complications have been reported. Seizures were accurately identified on the sub-scalp system, as visually confirmed by periods of concurrent conventional scalp EEG recordings. The data acquired also allowed seizure forecasting to be successfully undertaken. The area under the receiver operating characteristic curve (AUC score) achieved (0.88), which is comparable to the best score in recent, state-of-the-art forecasting work using intracranial EEG.

Objective: This paper offers clinical insights and practical guidelines for clinicians about how internet-delivered cognitive behaviour therapy (iCBT) can be safely and effectively integrated into routine psychological therapy practice, in a 'blended' care model. Method: For over a decade, the Clinical Research Unit for Anxiety and Depression (CRUfAD) has developed, tested, and disseminated iCBT programs for anxiety and depression, into routine care settings. This paper outlines examples of the available iCBT options for clinicians and details the advantages of integrating iCBT for anxiety and/or depression into psychological practice. We address common barriers to using iCBT, offer practical solutions based on our research and clinical experience, and present the lived experiences of 'real-world' clinicians using iCBT in their private practises and specialist clinics. Considerations associated with risk management, funding arrangements, and flexible models of care (e.g., stepped, blended and adjunct care) are discussed. Results: Flexible and judicious use of iCBT in our outpatient routine care clinic has reduced treatment waitlists and enabled clinicians to dedicate more time to sophisticated therapeutic interventions (e.g., experiential work) and to support clients with complex needs. Conclusion: iCBT can be safely and effectively integrated into routine psychological practice, and enhance client care. What is already known about this topic: (1) Internet cognitive behavioural therapy (iCBT) is effective for treating anxiety and depression. (2) iCBT includes psychoeducation and core CBT components (e.g., thought challenging) delivered over the internet. (3) To date, most iCBT programs have been used as stand-alone interventions, either as self-help or under guidance from a clinician. What this paper adds: (1) Outlines examples of iCBT options, their advantages and disadvantages, indications and contraindications. (2) Outlines a variety of ways to integrate iCBT into routine clinical practice settings, including prequel to therapy, as an adjunct, and relapse prevention tool. (3) Offers practical solutions to address common barriers and concerns to using iCBT in routine practice.

Background/ Objective: Abdominal aortic aneurysm (AAA) is an epigenetic event characterized by chronic inflammation and degeneration of the aortic wall leading to catastrophic rupture. Cigarette smoke exposure is the greatest environmental risk factor associated with AAA development. MicroRNAs (miRNA) regulate gene expression and may play a role in smoking-induced aortic inflammation. Epigenetic changes could include dysregulation of miRNA, causing post-transcriptional abnormalities pathogenic to AAA. Methods: miRNA was extracted from plasma of 24 AAA patients and 7 risk factor matched (RFM) patients and analyzed by RNA sequencing. We compared previous (PS) and current smokers (CS) within and between both patient cohorts. Differential expression of miRNAs was analyzed by ANOVA (p≤ 0.05). Potential targets of significant differentially expressed miRNAs were predicted using cross-analysis of TargetScan and miRanda databases. Results: Analysis revealed 7 significantly different miRNAs between AAA CS and AAA PS and 6 significantly different miRNAs between RFM CS and RFM PS. Of greatest significance, hsa-miR-223-3p was significantly downregulated as an effect of smoking cessation in AAA PS compared to AAA CS (p=0.000263), while also showing clinically relevant expression levels. Target genes of hsa-miR-223-3p include pro-inflammatory factors IL-6, TNFα, TGFβ, and MCP-1. Speculatively, as tissue levels of miR-223 tend to inversely correlate with plasma levels, we could hypothesize that the observed plasma upregulation of hsa-miR-223-3p in AAA CS contributes to the pro-inflammatory microenvironment of aortic tissue. Conclusion: Cigarette smoke contributes to epigenetic changes impacting factors of immune regulation or inflammation, eventually leading to disease states such as AAA. Inflammatory-related hsa-miR-223-3p is upregulated in AAA CS, suggesting its potential role in the disease course. Implications: Upregulation of hsa-miR-223-3p in AAA CS offers a link between disease state and the number one environmental factor attributed to AAA. This signature miRNA could serve as a biomarker for AAA or as a potential therapy target.

Existing murine models of abdominal aortic aneurysms (AAAs) include pressurized intraluminal infusion of elastase, subcutaneous injection of angiotensin II in the apolipoprotein E knockout background, and periaortic application of calcium chloride. However, none of these models duplicate the periadventitial inflammation that is T helper 17 (Th17) cell dominant and might be the obstacle in developing effective strategies to prevent AAA initiation and expansion. Our previous work has demonstrated that patients with AAA have elevated plasma levels of elastin fragments, anti-elastin antibodies, and significantly elevated levels of Th17 cells sensitized to elastin degradation products (EDPs), the sum of which suggests that AAA is the result of an autoimmune response targeting elastin in the aorta.

Background A clinical feasibility study was undertaken at a single center of long-term intra-cerebroventricular drug delivery of the anti-seizure medication valproic acid, into the cerebrospinal fluid (CSF) in order to treat drug resistant focal seizures, using an implantable infusion system. The primary objective was to establish the dose range of VPA administered in this manner. Secondarily, safety, pharmacokinetics (PK) and a preliminary estimate of effectiveness were evaluated. Methods In this single arm study, five adult subjects, with 29234 focal onset seizures per month from a seizure focus involving the mesial temporal lobe were implanted with the system (clinicaltrials.gov identifier NCT02899611). Oral valproic acid (VPA) had previously been ineffective in all subjects. Post-surgery, pharmacokinetic studies of CSF infused VPA were performed. Valproic acid doses were increased stepwise in a standardised protocol. Findings The procedure and implantation were well-tolerated by all subjects. Four subjects responded with > 50% seizure reduction at the highest tested dose of 160 mg/day. Two subjects experienced extended periods of complete seizure freedom. All five subjects reported significant quality of life improvement. No clinical dose limiting side effects were encountered and there was no evidence of local periventricular toxicity in three subjects who were evaluated with imaging (T2 MRI). Side effects included nausea and appetite loss but were not dose-limiting. Mean CSF valproic acid levels were 45 mu g per ml (range 20120 mu g per ml), with corresponding serum levels of 414 mu g per ml. Subjects have received therapy for up to 2.5 years in total . The efficacy analysis presented focuses on the period of time with the current pump with a mean 12.5 months, range 11.515 months. Pump failure requiring reimplantation was a significant initial issue in all subjects but resolved with use of pumps suitably compatible with long-term exposure to valproic acid. Interpretation The study demonstrated that chronic intraventricular administration of valproic acid is safe and effective in subjects with medically refractory epilepsy over many months. The procedure for implanting the infusion system is safe and well-tolerated. High CSF levels are achieved with corresponding low serum levels and this therapy is shown to be effective despite unsuccessful earlier use of oral valproate preparations. Drug side effects were minimal. (C) 2020 The Author(s). Published by Elsevier Ltd.

Whereas fractional flow reserve has been a “gold standard” to determine the severity of coronary stenosis, the trans-stenotic pressure gradient (TSPG) might be an alternative to assess the severity of iliac arterial stenoses. Because it is determined by the proximal (Pa) and distal (Pd) pressure to a stenosis, we developed a novel method to evaluate the four-dimensional (space and time) in vivo blood flow (pressure, velocity, and wall shear stress) in stenosed aortoiliac arteries based on computed tomography angiography and Doppler ultrasound. Such a means not only can quantify in vivo blood pressure noninvasively but also enable massive studies to determine whether TSPG can assess the true severity of iliac stenosis. We employ a patented in-house computational platform, InVascular, to quantify the four-dimensional (space and time) hemodynamics (velocity and pressure) in a stenosed iliac artery. Clinically acquired computed tomography angiography images are used to anatomically extract the three-dimensional flow domain, and the flow information is obtained from the velocity waveforms of Doppler ultrasound. Through the integration of advanced computational modeling and cutting-edge parallel computing technique, InVascular can quickly compute the proximal (Pa) and distal (Pd) pressure to a stenosis, schematized in Fig, a. Thus, TSPG (= Pa − Pd) is obtained. Three cases with five iliac stenoses are studied, in each of which Pa and Pd are measured during angiography. Fig, b compares the cardiac pressure waveforms of Pa (top) and Pd (bottom) between noninvasive computation (line) and invasive measurement (symbols), respectively. The good agreements indicate the accuracy of InVascular. Statistical analysis for the correlation between computed and measured pressures (systolic, diastolic, and mean arterial values) is shown in the Table. Both paired sample t-test (P > .05) and Pearson correlation (P < .05) reveal the significant correlation between computed and measured pressures. InVascular is a new and reliable means for noninvasive evaluation of in vivo pressure in stenosed aortoiliac arteries, from which TSPG can be obtained. With the outstanding feature of fast computation, InVascular will have an impact on the development of a new noninvasive gold standard to determine the true severity of iliac stenosis.TableStatisticsVariableMean pressure difference measured vs calculatedStandard deviationt valueP valueCorrelation coefficientP valuePressure systolic5.107.362.19.060.973.00E-6Pressure diastolic3.908.391.47.180.66.04Mean arterial pressure4.306.482.10.070.921.75E-4 Open table in a new tab