NF2-related schwannomatosis and other schwannomatosis: an updated genetic and epidemiological study.

OBJECTIVES: New diagnostic criteria for NF2-related schwannomatosis (NF2) were published in 2022. An updated UK prevalence was generated in accordance with these, with an emphasis on the rate of de novo NF2 (a 50% frequency is widely quoted in genetic counselling). The distribution of variant types among de novo and familial NF2 cases was also assessed. METHODS: The UK National NF2 database identifies patients meeting updated NF2 criteria from a highly ascertained population cared for by England's specialised service. Diagnostic prevalence was assessed on 1 February 2023. Molecular analysis of blood and, where possible, tumour specimens for NF2, LZTR1 and SMARCB1 was performed. RESULTS: 1084 living NF2 patients were identified on prevalence day (equivalent to 1 in 61 332). The proportion with NF2 inherited from an affected parent was only 23% in England. If people without a confirmed molecular diagnosis or bilateral vestibular schwannoma are excluded, the frequency of de novo NF2 remains high (72%). Of the identified de novo cases, almost half were mosaic. The most common variant type was nonsense variants, accounting for 173/697 (24.8%) of people with an established variant, but only 18/235 (7.7%) with an inherited NF2 pathogenic variant (p<0.0001). Missense variants had the highest proportion of familial association (56%). The prevalence of LZTR1-related schwannomatosis and SMARCB1-related schwannomatosis was 1 in 527 000 and 1 in 1.1M, respectively, 8.4-18.4 times lower than NF2. CONCLUSIONS: This work confirms a much higher rate of de novo NF2 than previously reported and highlights the benefits of maintaining patient databases for accurate counselling.

Analysis of the Structure of 14 Therapeutic Antibodies Using Circular Dichroism Spectroscopy.

Understanding the impact of the manufacturing environment on therapeutic monoclonal antibody (mAb) structures requires new process analytical technology. Here, we describe the creation of a new reference set for the circular dichroism (CD) spectra of mAbs. Data sets of the highest quality were collected by synchrotron radiation CD for 14 different mAbs in both native and acid-stressed states. Deconvolution of far-UV spectra for the mAb cohort identified two current reference sets (SP175 and SMP180) as assigning accurate secondary structures, irrespective of the analysis program employed. Scrutiny of spectra revealed significant variation in the far-UV and especially near-UV CD of the 14 mAbs. Two spectral features were found to be sensitive to changes in solution pH, i.e., the far-UV positive peak at 201-202 nm and the near-UV negative exciton couplet around 230-240 nm. The latter feature offers attractive possibilities for in-line CD-based monitoring of the mAb structure during manufacture.

Nocturnal pulse oximetry for the detection and prediction of acute mountain sickness: An observational study.

Acute mountain sickness (AMS) is a well-studied illness defined by clinical features (e.g., headache and nausea), as assessed by the Lake Louise score (LLS). Although obvious in its severe form, early stages of AMS are poorly defined and easily confused with common travel-related conditions. Measurement of hypoxaemia, the cause of AMS, should be helpful, yet to date its utility for identifying AMS susceptibility remains unclear. This study quantified altitude-induced hypoxaemia in individuals during an ascent to 4800 m to determine the utility of nocturnal pulse oximetry measurements for prediction of AMS. Eighteen individuals (36 ± 16 years of age) ascended to 4800 m over 12 days. Symptomology of AMS was assessed each morning via LLS criteria, with participants categorized as either AMS-positive (LLS ≥ 3 with headache) or AMS-negative. Overnight peripheral oxygen saturations (ov- S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_2}}}$ ) were recorded continuously (1 Hz) using portable oximeters. Derivatives of these recordings were compared between AMS-positive and -negative subjects (Mann-Whitney U-test). Exploratory analyses (Pearson's) were conducted to investigate relationships between overnight parameters and AMS severity. Overnight derivatives, including ov- S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_2}}}$ , heart rate/ov- S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_2}}}$ , variance, oxygen desaturation index, hypoxic burden and total sleep time at <80% S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_2}}}$ , all differed significantly between AMS-positive and -negative subjects (all P < 0.01), with cumulative/relative frequency plots highlighting these differences visually. Exploratory analysis revealed that ov- S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_2}}}$ from 3850 m was correlated with peak LLS at 4800 m (r = 0.58-0.61). The findings highlight the potential for overnight oximetry to predict AMS susceptibility during ascent to high altitude. Further investigation is required to develop, evaluate and optimize predictive models to improve AMS management and prevention.

The impact of myasthenia gravis severity on work and daily activities.

INTRODUCTION/AIMS: People with myasthenia gravis (MG) experience impaired quality of life. However, the impact of MG symptoms on work productivity has not been well-studied. We aimed to evaluate this impact and to examine associations between disease severity and the degree of impairment. METHODS: Data were drawn from the Adelphi MG Disease-Specific Programme™, a multinational (USA, France, Germany, Italy, Spain, UK) survey completed by physicians and their patients with MG in 2020. Patient-reported measures included the Work Productivity and Activity Impairment (WPAI): Specific Health Problem questionnaire. RESULTS: The WPAI questionnaire was completed by 330 patients. Among those currently employed, the mean percentage of work time missed (absenteeism) was 13.3% (N = 116), percentage impairment of productivity at work (presenteeism) was 26.7% (N = 121), and overall work impairment was 30.0% (N = 110). Across all patients, impairment of non-work-related activities due to health problems (ADL impairment) was 39.2% (N = 330). Regression analysis indicated that impairment differed according to MG Foundation of America (MGFA) class (p = .0147, p < .0001, p < .0001 and p < .0001 for absenteeism, presenteeism, overall work impairment and ADL impairment, respectively). Being MGFA class III/IV was a predictor of presenteeism, overall work impairment and ADL impairment in a predictor model. DISCUSSION: Patients with MG experience substantial work impairment particularly those with more severe symptoms, highlighting an important way in which patient quality of life is negatively affected. More effective treatment strategies would enable patients to lead more productive lives and could impact decisions relating to work and career.

Influence of therapeutic plasma exchange treatment on short-term mortality of critically ill adult patients with sepsis-induced organ dysfunction: a systematic review and meta-analysis.

INTRODUCTION: The impact of therapeutic plasma exchange (TPE) on short-term mortality in adult patients with sepsis-induced organ dysfunction remains uncertain. The objective of the study is to assess the effect of adjunct TPE in this setting through a comprehensive literature review. METHODS: The National Library of Medicine's Medline, Ovid (Embase), the Cochrane Library database and clinicaltrial.gov from January 01, 1966, until October 01, 2022, were searched for terms: therapeutic plasma exchange, plasmapheresis, sepsis, and septic shock. We reviewed, selected and extracted data from relevant randomized clinical trials (RCTs) and matched cohort studies (MCSs) comparing short-term mortality in critically ill adult septic patients treated with standard therapy versus those receiving adjunct TPE. Risk of bias was assessed in the RCTs using Cochrane Collaboration tool and in MCSs using ROBINS-I tool. Summary statistics, risk ratios (RRs), and confidence intervals (CIs) were calculated using random effects model. RESULTS: This systematic review included 937 adult critically ill septic patients from five RCTs (n = 367) and fifteen MCSs (n = 570). Of these total, 543 received treatment with TPE in addition to standard care. The meta-analysis includes all five RCTs and only six MCSs (n = 627). The adjunct TPE treatment (n = 300) showed a significant reduction in short-term mortality (RR 0.59, 95% CI 0.47-0.74, I2 3%) compared to standard therapy alone (n = 327). The systematic review of all 20 trials revealed that adding TPE to the standard therapy of critically ill septic patients resulted in faster clinical and/or laboratory recovery. CONCLUSIONS: Our comprehensive and up-to-date review demonstrates that adjunct TPE may provide potential survival benefits when compared to standard care for critically ill adult patients with sepsis-induced organ dysfunction. While results of this meta-analysis are encouraging, large well-designed randomized trials are required to identify the optimal patient population and TPE procedure characteristics prior to widespread adoption into practice.

Microbial exposure at birth and the development of behavioral temperament during the first three years of childhood.

We investigated cross-sectional and longitudinal associations between neonate microbial exposure and emerging behavioral temperament measures at the ages of 1, 2, and 3 years. Infants and mothers (n = 335) were extracted from the Kuopio Birth Cohort Study. Temperament was assessed using the Infant Behavioral and Early Childhood Behavioral Questionnaires. Microbial samples were collected from oral cavity at birth and the bacterial profiles were assessed using 16S rRNA gene sequencing. Microbial diversity was characterized using alpha and beta diversity metrics. Analyses were performed for the most abundant genera. The sample was analyzed as a whole, as well as divided into subgroups representing no antibiotic use during birth (n = 198) and those with antibiotic use during birth (n = 137). No significant associations were observed between microbial profiles and behavioral measures after Bonferroni corrections. Nevertheless, our pre-correction results indicated an association between increased behavioral temperament surgency in the first year and beta diversity (high abundance of Bacteroides, Faecalibacterium and Blautia, low abundance of Lactobacillus) in the antibiotic use group. Additionally, pre-corrections, a high relative abundance of Staphylococcus was associated with increased surgency through years 1, 2, and 3 in the no antibiotics group, prompting consideration into a possible link between antibiotic use and emerging behavioral temperament.

A longitudinal study combining the Double Diamond framework and Behavior Change Wheel to co-create a sedentary behavior intervention in police control rooms.

BACKGROUND: Police work can be sedentary and stressful, negatively impacting health and wellbeing. In a novel co-creation approach, we used the Behavior Change Wheel (BCW) and Double Diamond (DD) design framework to guide the collaborative design and development of a sedentary behavior intervention in the control rooms of two British police forces. METHODS: Multiple stakeholders participated in four phases of research. In Phase 1, a literature review, focus groups (n = 20) and interviews (n = 10) were conducted to 'discover' the relationship between physical activity and wellbeing in the police. In Phase 2, a steering group consolidated Phase 1 findings to 'define' a specific behavior for intervention. Phases 3 and 4 'developed' the intervention across six workshops with control room workers and six steering group workshops. RESULTS: The co-creation process identified contextual sedentary behavior as the target behavior, driven by behavioral regulation, social influence and social norms. The sedentary behavior intervention targeted these drivers and aimed to engage control room workers in short bursts of physical activity throughout their shifts. Key intervention features targeted involvement of staff in decision-making and embedding physical activity into work practices. CONCLUSIONS: The BCW and DD can be combined to co-create evidence-based and participant-informed interventions and translate science into action.

Debunking Mental Health Misperceptions in Short-Form Social Media Videos: An Experimental Test of Scientific Credibility Cues.

In recent years, short-form social media videos have emerged as an important source of health-related advice. In this study, we investigate whether experts or ordinary users in such videos are more effective in debunking the common misperception that talking about suicide should be avoided. We also explore a new trend on TikTok and other platforms, in which users attempt to back up their arguments by displaying scientific articles in the background of their videos. To test the effect of source type (expert vs. ordinary user) and scientific references (present or absent), we conducted a 2 × 2 between-subject plus control group experiment (n = 956). In each condition, participants were shown a TikTok video that was approximately 30 seconds long. Our findings show that in all four treatment groups, participants reduced their misperceptions on the topic. The expert was rated as being more authoritative on the topic compared to the ordinary user. However, the expert was also rated as being less credible compared to the ordinary user. The inclusion of a scientific reference did not make a difference. Thus, both experts and ordinary users may be similarly persuasive in a short-form video environment.

Halved contrast medium dose in lower limb dual-energy computed tomography angiography-a randomized controlled trial.

OBJECTIVES: To compare vascular attenuation (VA) of an experimental half iodine-load dual-layer spectral detector CT (SDCT) lower limb computed tomography angiography (CTA) with control (standard iodine-load conventional 120-kilovolt peak (kVp) CTA). METHODS: Ethical approval and consent were obtained. In this parallel RCT, CTA examinations were randomized into experimental or control. Patients received 0.7 vs 1.4 mL/kg of iohexol 350 mgI/mL in the experimental- vs the control group. Two experimental virtual monoenergetic image (VMI) series at 40 and 50 kiloelectron volts (keV) were reconstructed. PRIMARY OUTCOME: VA. SECONDARY OUTCOMES: image noise (noise), contrast- and signal-to-noise ratio (CNR and SNR), and subjective examination quality (SEQ). RESULTS: A total of 106 vs 109 were randomized and 103 vs 108 were analyzed in the experimental vs, control groups, respectively. VA was higher on experimental 40 keV VMI than on control (p < 0.0001), but lower on 50 keV VMI (p < 0.022). Noise was higher on experimental 40 keV VMI than on control (p = 0.00022), but lower on 50 keV VMI (p = 0.0033). CNR and SNR were higher than the control on experimental 40 keV VMI (both p < 0.0001) and 50 keV (p = 0.0058 and p = 0.0023, respectively). SEQ was better on both VMIs in the experimental group than in the control (both p < 0.0001). CONCLUSIONS: Half iodine-load SDCT lower limb CTA at 40 keV achieved higher VA than the control. CNR, SNR, noise, and SEQ were higher at 40 keV, while 50 keV showed lower noise. CLINICAL RELEVANCE STATEMENT: Spectral detector CT with low-energy virtual monoenergetic imaging performed halved iodine contrast medium (CM) lower limb CT-angiography with sustained objective and subjective quality. This facilitates CM reduction, improvement of low CM-dosage examinations, and examination of patients with more severe kidney impairment. TRIAL REGISTRATION: Retrospectively registered 5 August 2022 at clinicaltrials.gov NCT05488899. KEY POINTS: • Contrast medium dosage may be halved in lower limb dual-energy CT angiography with virtual monoenergetic images at 40 keV, which may reduce contrast medium consumption in the face of a global shortage. • Experimental half-iodine-load dual-energy CT angiography at 40 keV showed higher vascular attenuation, contrast-to-noise ratio, signal-to-noise ratio, and subjective examination quality than standard iodine-load conventional. • Half-iodine dual-energy CT angiography protocols may allow us to reduce the risk of PC-AKI, examine patients with more severe kidney impairment, and provide higher quality examinations or salvage poor examinations when impaired kidney function limits the CM dose.

Indirect CT venography of the lower extremities: impact of scan delay and patient factors on contrast enhancement and examination quality.

OBJECTIVES: Indirect computed tomography venography (CTV) is often the next imaging modality for deep vein thrombosis (DVT) when sonography is inconclusive. Our aim was to investigate the impact of scan delay and patient factors on contrast enhancement (CE) and examination quality in CTV. METHODS: Patients with clinical suspicion or clinical mimics of DVT in one large hospital were enrolled. Age, sex, body weight, height, heart rate, systolic blood pressure and cardiac output were registered. CTV of the popliteal veins was obtained at 30 s intervals at 30-210 s delays. The proportions of examinations with CE exceeding predefined cut-offs were estimated and subjective examination quality was rated. Changes in CE with time, and associations between patient factors and time to peak contrast enhancement (TPCE) were modelled with mixed effects non-linear and linear regression, respectively. RESULTS: The CE increased with increasing scan delay and reached a plateau from 120 to 210 s. The percentages of examinations achieving enhancement above cut-offs across all thresholds from 70 to 100 HU were higher at 120 s compared to 90 s (p < 0.001). After 120 s, there were no differences across scan delays for any thresholds. No patient factors showed a significant effect on TPCE. The percentage of examinations rated as acceptable was higher at 120 s compared to 90 s (p < 0.001). After 120 s, there were no statistically significant differences across scan delays. CONCLUSIONS: No patient factors were associated with TPCE in CTV. A fixed scan delay of 120-210 s yielded the best examination quality. KEY POINTS: • Contrast enhancement reached a plateau at scan delay between 90 and 120 s. • A scan delay of 120-210 s yielded the best examination quality. • No patient factors were associated with time to peak contrast enhancement.

Treatment and outcome of gastrointestinal bleeding due to peptic ulcers and erosions - (BLUE study).

OBJECTIVES: Peptic ulcers and erosions are the most common causes of upper gastrointestinal bleeding. The aim of this study was to investigate the management and outcomes of these patients. MATERIALS AND METHODS: A total of 543 patients with endoscopically confirmed bleeding from peptic ulcers and erosions were included from March 2015 to December 2017. The patient characteristics, endoscopic findings, Forrest classification and endoscopic treatment were recorded. Moreover, the rebleeding rates, repeated endoscopies and transcatheter angiographic embolization and surgery incidences were registered. A follow-up endoscopy after discharge from the hospital was scheduled. RESULTS: Among the patients, high-risk stigmata ulcers were present in 36% (198/543) and low-risk stigmata ulcers and erosions in 60% (327/543) at first endoscopy. Endoscopic therapy was performed in 30% (165/543) of the patients, and hemostasis was achieved in 94% (155/165). The incidence of rebleeding was 9% (49/543) for the whole cohort and 14.8% (23/155) for those patients who had received successful endoscopic treatment. Moreover, rebleeding was significantly more frequent in duodenal ulcers than in gastric ulcers (11.9% vs 4.0%, p = .004). In a multivariable analysis, rebleeding was significantly related to comorbidity and Forrest classification. Transcatheter angiographic embolization and surgery were required in 6% (34/543) and 0.07% (4/543) of patients, respectively. Complete peptic ulcer healing was found at follow-up in 73.3% (270/368) of patients. CONCLUSIONS: Endoscopic hemostasis was achieved in the majority of patients with high-risk ulceration, although the occurrence of rebleeding is a significant challenge, especially in patients with duodenal ulcers. Clinical trial registration: Bleeding Ulcer and Erosions Study (BLUE Study), ClinicalTrials.gov identifier: NCT03367897.

Correlation between MRI morphological response patterns and histopathological tumor regression after neoadjuvant endocrine therapy in locally advanced breast cancer: a randomized phase II trial.

PURPOSE: To correlate MRI morphological response patterns with histopathological tumor regression grading system based on tumor cellularity in locally advanced breast cancer (LABC)-treated neoadjuvant with third-generation aromatase inhibitors. METHODS: Fifty postmenopausal patients with ER-positive/HER-2-negative LABC treated with neoadjuvant letrozole and exemestane given sequentially in an intra-patient cross-over regimen for at least 4 months with MRI response monitoring at baseline as well as after at least 2 and 4 months on treatment. The MRI morphological response pattern was classified into 6 categories: 0/complete imaging response; I/concentric shrinkage; II/fragmentation; III/diffuse; IV/stable; and V/progressive. Histopathological tumor regression was assessed based on the recommendations from The Royal College of Pathologists regarding tumor cellularity. RESULTS: Following 2 and 4 months with therapy, the most common MRI pattern was pattern II (24/50 and 21/50, respectively). After 4 months on therapy, the most common histopathological tumor regression grade was grade 3 (21/50). After 4 months an increasing correlation is observed between MRI patterns and histopathology. The overall correlation, between the largest tumor diameter obtained from MRI and histopathology, was moderate and positive (r = 0.50, P-value = 2e-04). Among them, the correlation was highest in type IV (r = 0.53). CONCLUSION: The type II MRI pattern "fragmentation" was more frequent in the histopathological responder group; and types I and IV in the non-responder group. Type II pattern showed the best endocrine responsiveness and a relatively moderate correlation between sizes obtained from MRI and histology, whereas type IV pattern indicated endocrine resistance but the strongest correlation between MRI and histology.

The importance of genetic counseling and screening for people with pathogenic SMARCE1 variants: A family study.

Clear cell meningioma (CCM) is a rare variant of meningioma. In recent years, an association between cranial and spinal CCMs and germline loss of function mutations in the SMARCE1 gene (SWI/SNF chromatin remodeling complex subunit gene) has been discovered. We report a family with an incidental large spinal clear cell meningioma in a young adult following reflex screening for a germline loss of function pathogenic variant (PV) in the SMARCE1 gene. The index patient's mother and maternal grandfather were both also tested positive presymptomatically for SMARCE1. His mother developed intracranial and spinal meningiomas and his maternal grandfather developed a spinal CCM 4 years following a clear spinal MRI scan which required surgical excision. In this report we particularly emphasize the importance of genetic counseling and screening in siblings, parents and offspring of patients who are diagnosed with intracranial or spinal CCM in the context of SMARCE1 PVs. We recommend brain and spine Imaging screening of asymptomatic SMARCE1 PV carriers at least every 3 years, even if the baseline scan did not show any tumors.

Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing.

PURPOSE: To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2). METHODS: Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing. RESULTS: The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma <20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant. CONCLUSION: This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

Automated High-Throughput Capillary Circular Dichroism and Intrinsic Fluorescence Spectroscopy for Rapid Determination of Protein Structure.

Assessing the physical stability of proteins is one of the most important challenges in the development, manufacture, and formulation of biotherapeutics. Here, we describe a method for combining and automating circular dichroism and intrinsic protein fluorescence spectroscopy. By robotically injecting samples from a 96-well plate into an optically compliant capillary flow cell, complementary information about the secondary and tertiary structural state of a protein can be collected in an unattended manner from considerably reduced volumes of sample compared to conventional techniques. We demonstrate the accuracy and reproducibility of this method. Furthermore, we show how structural screening can be used to monitor unfolding of proteins in two case studies using (i) a chaotropic denaturant (urea) and (ii) low-pH buffers used for monoclonal antibody (mAb) purification during Protein A chromatography.

Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing.

PURPOSE: We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). METHODS: Two large databases of individuals fulfilling NF2 criteria (n = 1361) and those tested for NF2 variants with criteria short of diagnosis (n = 1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the positive predictive value (PPV) with regard to definite diagnosis. RESULTS: There was no evidence for usefulness of old criteria "glioma" or "neurofibroma." "Ependymoma" had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced PPV (80%). Siblings as a first-degree relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with unilateral VS plus ≥2 nondermal schwannomas reduced PPV to 67%. CONCLUSIONS: The present study confirms important deficiencies in NF2 diagnostic criteria. The term "glioma" should be dropped and replaced by "ependymoma." Similarly "neurofibroma" should be removed. Dropping "sibling" from first-degree relatives should be considered and testing of LZTR1 should be recommended for unilateral VS.

Aortic Pulsatility Propagates Intracranially and Correlates with Dilated Perivascular Spaces and Small Vessel Compliance.

INTRODUCTION: To test the hypotheses that changes in the aortic pulse-wave produced by arterial stiffening are (1) propagated into cerebral small vessels, (2) associated with reduced compliance of small cerebral arterial vessels, and (3) associated with the presence of dilated perivascular spaces (PVS). METHODS: Fifteen volunteers and 19 patients with late-onset depression (LOD) were prospectively recruited, of which 6 fulfilled the criteria for treatment-resistant depression (TRD). Aortic pulse-wave velocity (PWV) was determined using Carotid-Femoral Doppler. Pulse-wave analysis (PWA) was performed using a SphygmoCor system. White-matter lesion load and PVS were scored on established MRI scales. Cerebral arterial and aqueductal cerebrospinal fluid (CSF) flow patterns were studied using quantitative phase-contrast angiography. RESULTS: Depressed patients had more PVS (P < .05) and prolongation of the width of the arterial systolic pulse-wave in the carotid arteries (P < .01). There was no significant group difference for any PWV or PWA measurement. TRD patients showed more PVS than other LOD patients (P < .05). The fractional width of the arterial systolic peak correlated significantly with augmentation index (AIx) and heart rate-corrected augmentation index (AIx75; R2 = 0.302, P < .01and R2 = 0.363, P < .01 respectively). Arterial-aqueductal delay showed a negative correlation with estimated aortic systolic pressure (PWVsys; R2 =  0.293; P < .01), AIx (R2 = -0.491; P < .01) and AIx75 (R2 = -0.310; P < .01). PVS scores correlated with AIx (R2 = 0.485; P < .01) and AIx75 (R2 = -0.292; P < .01). CONCLUSION: Our findings support the hypothesis that increased arterial pulsatility resulting from central arterial stiffness propagates directly into cerebral vessels and is associated with the development of microvascular angiopathy, characterized by dilated PVS and decreased compliance of small arterial vessels.

Schwannomatosis: a genetic and epidemiological study.

OBJECTIVES: Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2. METHODS: Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available. RESULTS: Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%-2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004). CONCLUSIONS: Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

Magnetic hydrophobic-charge induction adsorbents for the recovery of immunoglobulins from antiserum feedstocks by high-gradient magnetic fishing.

BACKGROUND: The extraction of biopharmaceuticals from plasma and serum often employs overly complicated antiquated procedures that can inflict serious damage on especially prone protein targets and which afford low purification power and overall yields. This paper describes systematic development of a high-gradient magnetic fishing process for recovery of immunoglobulins from unclarified antiserum. RESULTS: Non-porous superparamagnetic particles were transformed into hydrophobic-charge induction adsorbents and then used to recover immunoglobulins from rabbit antiserum feedstocks. Comprehensive characterisation tests conducted with variously diluted clarified antiserum on a magnetic rack revealed that immunoglobulin binding was rapid (equilibrium reached in <45 s), strong (Kd < 0.1 mg mL-1), of high capacity (Qmax = 214 mg g-1), and pH and ionic strength dependent. In a high-gradient magnetic fishing process conducted with the same adsorbent, and a conventional 'magnetic filter + recycle loop' arrangement, >72% of the immunoglobulin present in an unclarified antiserum feed was recovered in 0.5 h in >3-fold purified form. CONCLUSIONS: Fast magnetic particle based capture of antibodies from an unclarified high-titre feed has been demonstrated. Efficient product recovery from ultra-high titre bioprocess liquors by high-gradient magnetic fishing requires that improved magnetic adsorbents displaying high selectivity, ultra-high capacity and operational robustness are used with 'state-of-the-art' rotor-stator magnetic separators. © 2018 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Adsorption of Fibronectin Fragment on Surfaces Using Fully Atomistic Molecular Dynamics Simulations.

The effect of surface chemistry on the adsorption characteristics of a fibronectin fragment (FNIII8⁻10) was investigated using fully atomistic molecular dynamics simulations. Model surfaces were constructed to replicate self-assembled monolayers terminated with methyl, hydroxyl, amine, and carboxyl moieties. It was found that adsorption of FNIII8⁻10 on charged surfaces is rapid, specific, and driven by electrostatic interactions, and that the anchoring residues are either polar uncharged or of opposing charge to that of the targeted surfaces. On charged surfaces the presence of a strongly bound layer of water molecules and ions hinders FNIII8⁻10 adsorption. In contrast, adsorption kinetics on uncharged surfaces are slow and non-specific, as they are driven by van der Waals interactions, and the anchoring residues are polar uncharged. Due to existence of a positively charged area around its cell-binding region, FNIII8⁻10 is available for subsequent cell binding when adsorbed on a positively charged surface, but not when adsorbed on a negatively charged surface. On uncharged surfaces, the availability of the fibronectin fragment's cell-binding region is not clearly distinguished because adsorption is much less specific.