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In eukaryotes, conserved mechanisms ensure that cell growth is coordinated with nutrient availability. Overactive growth during nutrient limitation ("nutrient-growth dysregulation") can lead to rapid cell death. Here, we demonstrate that cells can adapt to nutrient-growth dysregulation by evolving major metabolic defects. Specifically, when yeast lysine-auxotrophic mutant lys- encountered lysine limitation, an evolutionarily novel stress, cells suffered nutrient-growth dysregulation. A subpopulation repeatedly evolved to lose the ability to synthesize organosulfurs (lys-orgS-). Organosulfurs, mainly reduced glutathione (GSH) and GSH conjugates, were released by lys- cells during lysine limitation when growth was dysregulated, but not during glucose limitation when growth was regulated. Limiting organosulfurs conferred a frequency-dependent fitness advantage to lys-orgS- by eliciting a proper slow growth program, including autophagy. Thus, nutrient-growth dysregulation is associated with rapid organosulfur release, which enables the selection of organosulfur auxotrophy to better tune cell growth to the metabolic environment. We speculate that evolutionarily novel stresses can trigger atypical release of certain metabolites, setting the stage for the evolution of new ecological interactions.

We aim to study the outcome of soft tissue releases by tendon elongations and osteotomies in fixed joint contractures by clinical examination and patient self-reported assessment on 20 patients (14 males and 6 females) with spastic diplegic cerebral palsy treated with single-event multilevel surgery (SEMLS) between 2000 and 2012. A questionnaire was used to collect information on problems encountered before and after surgery and decision on surgery. Comparing patients with Gross Motor Function Classification System class I/II, (N = 8), III (N = 8) and IV/V, patients of classes IV/V showed much slower mean recovery time than I/II group (14.00 vs. 4.38 months, p < 0.01). SEMLS in the treatment of patients with spastic diplegia had good mid-term results in most patients. The patients who had unfavourable outcomes are associated with mental retardation, general or local complications and previous selective dorsal rhizotomy surgery. Patient selection and good rehabilitations preoperation and postoperation provided the most favourable outcomes of SEMLS.

Abstract: The role of CD4+ T-cells in immunity against tuberculosis has been extensively studied. However, the function of CD8+ T-cells in co-infections of HIV-1 and M. tuberculosis (VIH/Mtb) is not well understood. To evaluate the functionality of CD8+ T-cells from HIV+ patients having active TB, several immunological parameters were assayed. Results indicate that both HIV+ groups (with and without active TB), having the same viral load and peripheral blood CD4+ T and amount of lymphocytes in the blood, displayed different alterations in the ex vivo frequency for CD95 and CD127 markers in CD8+ T-cells, naive and memory positive cells, while for the HLA-DR marker, differences were observed in the total cell population. Moreover, CD8+ T- cells from TB-active patients, cultured for 72 h in the presence of PPD, showed a low proliferation rate and a high frequency of induced apoptosis as well as lower production of IFN-y IL-10 and TNF-a cytokines compared to healthy control cells. These results support the hypothesis that CD8+ T-cells lose their functionality against Mtb during an HIV-1 infection, which could be responsible for the activation of TB in VIH/Mtb co-infected patients. Resumen: El papel de las células TCD4+ en la inmunidad contra la tuberculosis ha sido ampliamente estudiado. Sin embargo, la función de las células TCD8+ en la co-infección VIH-1 y M. tuberculosis (VIH/Mtb) no está bien comprendida. Para determinar la funcionalidad de estas células TCD8+ de pacientes VIH+ con TB (tuberculosis) pulmonar activa se usaron diferentes parámetros inmunológicos. Los resultados indican que ambos grupos de pacientes VIH+ (con o sin TB activa) con la misma carga viral y cantidad de linfocitos TCD4+ en sangre, presentaron diferentes alteraciones en la frecuencia ex vivo para las moléculas CD95 y CD127 en células TCD8+ totales, vírgenes y memoria positivas, mientras que para la molécula HLA-DR, las diferencias fueron observadas en la población celular total. Además, las células TCD8+ de los pacientes con TB activa cultivadas por 72 h en presencia de PPD, presentaron baja proliferación y alta frecuencia de apoptosis inducida, así como baja producción de IFN-y IL-10 y TNF-a en comparación a los Controles sanos. Estos datos sustentan la hipótesis que las células T CD8+ pierden su funcionalidad contra el Mtb durante la infección con VIH-1, lo cual puede ser responsable de la activación de la TB en los pacientes co-infectados.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measures microvascular perfusion by capturing the temporal changes of an MRI contrast agent in a target tissue, and it provides valuable information for the diagnosis and prognosis of a wide range of tumors. Quantitative DCE-MRI analysis commonly relies on the nonlinear least square (NLLS) fitting of a pharmacokinetic (PK) model to concentration curves. However, the voxel-wise application of such nonlinear curve fitting is highly time-consuming. The arterial input function (AIF) needs to be utilized in quantitative DCE-MRI analysis. and in practice, a population-based arterial AIF is often used in PK modeling. The contribution of intravascular dispersion to the measured signal enhancement is assumed to be negligible. The MR dispersion imaging (MRDI) model was recently proposed to account for intravascular dispersion, enabling more accurate PK modeling. However, the complexity of the MRDI hinders its practical usability and makes quantitative PK modeling even more time-consuming. In this paper, we propose fast MR dispersion imaging (fMRDI) to effectively represent the intravascular dispersion and highly accelerated PK parameter estimation. We also propose a deep learning-based, two-stage framework to accelerate PK parameter estimation. We used a deep neural network (NN) to estimate PK parameters directly from enhancement curves. The estimation from NN was further refined using several steps of NLLS, which is significantly faster than performing NLLS from random initializations. A data synthesis module is proposed to generate synthetic training data for the NN. Two data-processing modules were introduced to improve the model's stability against noise and variations. Experiments on our in-house clinical prostate MRI dataset demonstrated that our method significantly reduces the processing time, produces a better distinction between normal and clinically significant prostate cancer (csPCa) lesions, and is more robust against noise than conventional DCE-MRI analysis methods.

Low bone mineral density and impaired bone quality have been shown to be important prognostic factors for curve progression in adolescent idiopathic scoliosis (AIS). There is no evidence-based integrative interpretation method to analyze high-resolution peripheral quantitative computed tomography (HR-pQCT) data in AIS. This study aimed to (1) utilize unsupervised machine learning to cluster bone microarchitecture phenotypes on HR-pQCT parameters in girls with AIS, (2) assess the phenotypes' risk of curve progression and progression to surgical threshold at skeletal maturity (primary cohort), and (3) investigate risk of curve progression in a separate cohort of girls with mild AIS whose curve severity did not reach bracing threshold at recruitment (secondary cohort). Patients were followed up prospectively for 6.22 ± 0.33 years in the primary cohort (n = 101). Three bone microarchitecture phenotypes were clustered by fuzzy C-means at time of peripubertal peak height velocity (PHV). Phenotype 1 had normal bone characteristics. Phenotype 2 was characterized by low bone volume and high cortical bone density, and phenotype 3 had low cortical and trabecular bone density and impaired trabecular microarchitecture. The difference in bone quality among the phenotypes was significant at peripubertal PHV and continued to skeletal maturity. Phenotype 3 had significantly increased risk of curve progression to surgical threshold at skeletal maturity (odd ratio [OR] = 4.88; 95% CI, 1.03-28.63). In the secondary cohort (n = 106), both phenotype 2 (adjusted OR = 5.39; 95% CI, 1.47-22.76) and phenotype 3 (adjusted OR = 3.67; 95% CI, 1.05-14.29) had increased risk of curve progression ≥6° with mean follow-up of 3.03 ± 0.16 years. In conclusion, 3 distinct bone microarchitecture phenotypes could be clustered by unsupervised machine learning on HR-pQCT-generated bone parameters at peripubertal PHV in AIS. The bone quality reflected by these phenotypes was found to have significant differentiating risk of curve progression and progression to surgical threshold at skeletal maturity in AIS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: A direct-aspiration first-pass technique (ADAPT) in mechanical thrombectomy has been described in recent studies as an efficacious strategy compared with using a stent retriever (SR). We sought to evaluate for cost differences of ADAPT technique versus SR as an initial approach., Methods: We conducted a retrospective analysis of consecutive patients with mechanical thrombectomy at our institution between 2022 and 2023. Patients were grouped into ADAPT with/without SR as a rescue strategy and SR as an initial approach with allowance of concomitant aspiration. Direct cost data (consumables) were obtained. Baseline demographics, stroke metrics, procedure outcomes and cost, and last follow-up outcomes in modified Rankin Scale were compared between 2 groups., Results: Fifty-six patients were included. Thirty-seven (66.1%) underwent ADAPT, with 11 (29.7%) eventually requiring an SR. Mean age was 64.8 years. The average National Institutes of Health Stroke Scale score was 13.2 in the ADAPT group and 14.0 in the SR group (P = 0.68), with a similar proportion of tissue plasminogen activator (P = 0.53), site of occlusion (P = 0.66), and tandem occlusion (P = 0.69) between the groups. Recanalization was achieved in 94.6% of all patients, with an average of 1.9 passes, 89.3% being TICI 2B or above, with no differences between the 2 groups. Significantly lower cost (P < 0.01) was observed in ADAPT ($14,243.4) compared with SR ($19,003.6). Average follow-up duration was 180.2 days, with mortality of 23.2%. At last follow-up, 55.4% remained functionally independent (modified Rankin Scale score <3) with no difference (P = 0.56) between the ADAPT (59.5%) and SR (47.4%) groups., Conclusions: Outcomes were comparable between the ADAPT and SR groups. ADAPT reduced procedural consumables cost by approximately $5000 (25%), even if stent retrievers were allowed to be used for rescue. Establishing ADPAT as initial approach may bring significant direct cost savings while obtaining similar outcomes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The longitudinal management of unruptured brain arteriovenous malformation (bAVM) is crucial. To date, no study in the United States has evaluated the impact of socioeconomic status (SES) on bAVM outcome. Herein, the authors aimed to clarify the impact of SES, as indicated by the area deprivation index (ADI), on bAVM outcome., Methods: A retrospective analysis of an institutional bAVM database was conducted. Non-hereditary hemorrhagic telangiectasia patients with a single unruptured bAVM in the period from 1990 to 2021 were included in the analysis. The ADI was categorized as low (ADI ≤ 15th percentile), mid (15th percentile < ADI < 85th percentile), and high (ADI ≥ 85th percentile), with a low ADI indicating the most advantaged group. Patient baseline and follow-up data were analyzed. The primary outcome of interest was nonindependence (modified Rankin Scale [mRS] score > 2) at the last follow-up. A multivariable logistic regression model was performed., Results: A total of 589 patients with unruptured bAVMs were included in the study. The mean patient age at diagnosis was 37.2 years, and 283 patients (48.0%) were male. Of the bAVMs, 238 (40.4%) had a low Spetzler-Martin grade (SMG < III), 194 (32.9%) had a moderate grade (SMG III), and 157 (26.7%) had a high grade (SMG > III). Sixty-nine patients (11.7%) were in the low-ADI group, 476 (80.8%) in the mid-ADI group, and 44 (7.5%) in high-ADI group. Increasing age (OR 1.02, 95% CI 1.01-1.04, p < 0.001), poor baseline mRS score (OR 3.27, 95% CI 1.32-7.88, p = 0.008), treatment with surgery plus radiosurgery with or without embolization (OR 3.21, 95% CI 1.03-9.81, p = 0.041), mid SMG (OR 1.94, 95% CI 1.11-3.44, p = 0.021), high SMG (OR 2.08, 95% CI 1.13-3.88, p = 0.020), longer follow-up (OR 1.05, 95% CI 1.03-1.08, p < 0.001), and mid ADI (OR 3.08, 95% CI 1.34-8.39, p = 0.015) were significantly associated with a poor outcome. A high ADI tended toward a poor outcome (OR 2.93, 95% CI 0.92-9.88, p = 0.071). Eventual obliteration of a bAVM was the only protective predictor of poor outcome (OR 0.55, 95% CI 0.30-0.98, p = 0.046)., Conclusions: This study revealed that relatively disadvantaged patients with unruptured bAVMs are more likely to experience nonindependent outcomes at the last follow-up, after adjusting for confounding variables. An emphasis on social support may be beneficial for patients with a lower SES.

Background and Objectives: Natural history of hemorrhage in brain arteriovenous malformations (bAVM) is reported at 2%-4% per year. Published studies using survival analysis fail to account for recurrent hemorrhagic events. In this study, we present a large, single institution series to elucidate the natural history of bAVM using multivariable Poisson regression., Methods: This is a retrospective cohort study. All patients with bAVM seen at our institution from 1990 to 2021 were included. Hemorrhages after detection of bAVM during the untreated interval were recorded. Natural history of hemorrhage was calculated by dividing number of hemorrhages by untreated interval. The frequency of hemorrhages followed a Poisson distribution. Multivariable Poisson regression with an offset variable of untreated interval in patient-years was constructed. Model selection was through a stepwise Akaike information criterion method. Stratified hemorrhagic rate was presented using different combinations of significant factors., Results: A total of 1066 patients with nonhereditary hemorrhagic telangiectasia harboring a single bAVM were included. Ninety (8.44%) patients had 101 hemorrhages during an untreated interval of 3596.3344 patient-years, translating to an overall hemorrhagic rate of 2.81% per year. Significant factors increasing hemorrhage risk included ruptured presentation ( P < .001), increasing age ( P < .001), female sex ( P = .043), and deep location ( P = .040). Adult male patients with ruptured presentation and deep bAVMs sustained the highest annual risk at 10.81%, whereas no hemorrhages occurred in unruptured pediatric male patients or ruptured pediatric (younger than 18 years) male patients with superficial bAVMs., Conclusion: Hemorrhage after bAVM detection occurs in 8.41% of all patients, and the rate averages 2.81% per year. However, this risk varies from 0.00% to 10.81% per year depending on various risk factor combinations. Efforts should be made to stratify bAVM hemorrhage rate by risk factors for more precise estimation of bleeding risk if left untreated., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Introduction : Bracing is one of the first-line treatment for early-onset idiopathic scoliosis (EOIS) to control curves from progression. This study aimed to explore the determinants that govern bracing effectiveness in EOIS. Methods : One hundred and eleven patients with EOIS (mean age of 8.6 ± 1.25 at diagnosis) received bracing treatment and had a final follow-up beyond skeletal maturity were identified from records between 1988 and 2021. Demographic data and clinical features of spinal curvature were obtained for correlation analyses to determine the associations between curve outcomes and clinical features. Results : Most patients were female (85.6%) and had a major curve on the left side (67%). The mean baseline Cobb angle of major curves was 21.73 ± 7.92°, with a mean Cobb angle progression of 18.05 ± 19.11°. The average bracing duration was 5.3 ± 1.9 years. Only 26 (23.4%) of them underwent surgery. The final Cobb angle and curve progression at the final follow-up with a Cobb angle of ≥50° were positively correlated with the initial Cobb angle (r = 0.206 and r = 0.313, respectively) and negatively correlated with maturity parameters. The lumbar curve type was found to correlate with a smaller final Cobb angle. Conclusions : The majority of patients had a final Cobb angle < 50°, which was considered a successful bracing outcome. The final Cobb angle correlated with the initial Cobb angle and curve types observed in EOIS.

A large portion of volumetric medical data, especially magnetic resonance imaging (MRI) data, is anisotropic, as the through-plane resolution is typically much lower than the in-plane resolution. Both 3D and purely 2D deep learning-based segmentation methods are deficient in dealing with such volumetric data since the performance of 3D methods suffers when confronting anisotropic data, and 2D methods disregard crucial volumetric information. Insufficient work has been done on 2.5D methods, in which 2D convolution is mainly used in concert with volumetric information. These models focus on learning the relationship across slices, but typically have many parameters to train. We offer a Cross-Slice Attention Module (CSAM) with minimal trainable parameters, which captures information across all the slices in the volume by applying semantic, positional, and slice attention on deep feature maps at different scales. Our extensive experiments using different network architectures and tasks demonstrate the usefulness and generalizability of CSAM. Associated code is available at https://github.com/aL3x-O-o-Hung/CSAM.

Background Context: Abnormal energy metabolism such as lower body weight and body mass index (BMI) and less fat mass is widely reported in patients with adolescent idiopathic scoliosis (AIS) and has been implicated in deformity development. However, the underlying mechanism is largely unclear. LBX1 is one of the promising AIS predisposing genes validated by multicenter studies., Purpose: This study aimed to identify differentially expressed proteins (DEPs) relating to energy metabolism in AIS by using proteomic and metabolic analysis and to explore if the expression of these DEPs is associated with clinical parameters and modulated by LBX1., Study Design: This is a cross-sectional study using clinical data and biological samples followed by basic study using a cellular model., Patient Sample: Plasma samples were collected from Chinese girls with nonprogressive and progressive AIS (N=7 and 8, respectively) and age-matched healthy girls (N=50). Paraspinal muscle tissues were collected intraoperatively from concave and convex side of the apex of the major spinal curve in AIS (N=24) and either side from nonscoliosis patients (N=14)., Outcome Measures: Radiological Cobb angle and basic anthropometric data of recruited subjects were measured. The DEPs and metabolites were compared in plasma using proteomics and metabolomics technique. The relative expression of selected genes was measured in muscles., Methods: Plasma samples from AIS were collected at first clinical visit and were further divided into nonprogressive or progressive groups according to Cobb angle changes in 6-year follow-up. Age-matched healthy girls were recruited as control. High-performance liquid chromatography-mass spectrometry based proteomic analysis was carried out in three groups to identify DEPs and their annotated metabolic pathways. An independent cohort was used for validation by gas chromatography-mass spectrometry based metabolomic analysis. Paraspinal muscles were subjected to quantitative polymerase chain reaction (qPCR) followed by correlation analysis. Human skeletal muscle myoblast (HSMM) was used as the cellular model., Results: The likelihood of aberrant galactose metabolism and glycolysis was found to be associated with AIS curve progression as evidenced by the thirteen DEPs and seven related metabolites according to proteomic and metabolomic analysis. Some of the DEPs showed significantly altered expression in AIS concave and convex sides paraspinal muscles compared with those in nonscoliosis control. Four DEPs were found significantly and negatively correlated with LBX1 in AIS convex side paraspinal muscles. Overexpressing LBX1 in HSMM cells led to increased expression of three DEPs and decreased expression of three DEPs, respectively., Conclusions: This is the first integrated proteomic and metabolomic analysis on AIS. Our findings show dysregulated galactose metabolism and glycolysis pathways in progressive group of AIS, suggesting the presence of abnormal energy metabolism at early stage of this disease, and their association with higher risk of progressing into more severe curvature. Evidence from ex vivo study with human muscle biopsies and in vitro study with human myoblast cells propose the possible effect of LBX1 on these two pathways in skeletal muscles. The present study provides new evidence of LBX1 function in AIS via modulating effect on the expression of energy metabolism related genes. This study might provide new insights into etiopathogenesis and development of novel treatment strategy targeting on abnormal body weight and BMI in patients with AIS. Additionally, the plasma proteomic and metabolomic studies suggested new candidates as biomarkers for establishing predictive model for AIS onset/progression., Competing Interests: Declarations of Competing Interests The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Bone densitometry revealed low bone mass in patients with adolescent idiopathic scoliosis (AIS) and its prognostic potential to predict curve progression. Recent studies showed differential circulating miRNAs in AIS but their diagnostic potential and links to low bone mass have not been well-documented. The present study aimed to compare miRNA profiles in bone tissues collected from AIS and non-scoliotic subjects, and to explore if the selected miRNA candidates could be useful diagnostic biomarkers for AIS. Microarray analysis identified miR-96-5p being the most upregulated among the candidates. miR-96-5p level was measured in plasma samples from 100 AIS and 52 healthy girls. Our results showed significantly higher plasma levels of miR-96-5p in AIS girls with an area under the curve (AUC) of 0.671 for diagnostic accuracy. A model that was composed of plasma miR-96-5p and patient-specific parameters (age, body weight and years since menarche) gave rise to an improved AUC of 0.752. Ingenuity Pathway Analysis (IPA) indicated functional links between bone metabolic pathways and miR-96-5p. In conclusion, differentially expressed miRNAs in AIS bone and plasma samples represented a new source of disease biomarkers and players in AIS etiopathogenesis, which required further validation study involving AIS patients of both genders with long-term follow-up., (© 2022. The Author(s).)

Background: Adolescent idiopathic scoliosis (AIS) patients have lower physical activity levels than normal adolescents, and there is an association with poorer bone and muscle health. This study evaluated the effects of a home-based exercise intervention (E-Fit) on bone mineral density (BMD), muscle function, and quality of life (QoL) in AIS-affected girls., Methods: A total of 40 AIS females aged 11 to 14 years were randomly assigned to the E-Fit or control group. The E-Fit group performed modified 7-min high-intensity interval training (HIIT) 5 days per week for 6 months. Outcome measures including BMD using dual-energy X-ray absorptiometry (DXA), muscle strength and endurance tests, physical activity levels, and QoL using self-reported questionnaires were assessed at baseline and at 6-month and 12-month follow-up., Results: In total, 14 patients in the E-Fit and 16 in the control group completed the study. The E-Fit group showed a marginally significant interaction effect in the whole body areal BMD at the 6- ( p = 0.096) and 12-month follow-ups ( p = 0.085). The left arm lean mass in the E-Fit group showed a statistically significant interaction effect between the 6- and 12-month follow-ups ( p = 0.046). The E-Fit group showed improvements in physical activity participation, as measured by the Modified Baecke Questionnaire (MBQ), with a significant interaction effect in work index ( p = 0.043), sport index ( p = 0.050), and total score ( p = 0.016) from baseline to the 12-month follow-up. Improvement on self-image were noted in E-Fit group across time., Conclusions: The present results provided some evidence to support the positive benefits of E-Fit for bone health and muscle function in AIS girls.

Scoliosis screening is important for timely initiation of brace treatment to mitigate curve progression in skeletally immature children and adolescents. School scoliosis screening programs in Hong Kong follow the protocol of referring children screened positive with a scoliometer and Moiré topography for confirmatory standard radiography. Despite being highly sensitive (88%) in detecting those who require specialist referral, the screening program was found to have a false-positive rate >50%, which could lead to unnecessary X-ray radiation. Radiation-free ultrasound has been reported to be valid and reliable for quantitative assessment of curve severity in scoliosis patients. The aim of this prospective diagnostic accuracy study was to determine the accuracy of ultrasound in determining the threshold of referral that requires X-ray for children screened positive with the scoliometer and Moiré topography. Our study recruited 442 schoolchildren with a mean Cobb angle of 14.0 ± 6.6°. The sensitivity and specificity of ultrasound in predicting the correct referral status, confirmed by X-ray, were 92.3% and 51.6%, with positive and negative predictive values of 29.0% and 96.9%, respectively. Receiver operating characteristic curve analysis revealed area under the curve values of 0.735 for ultrasound alone and 0.832 for ultrasound in combination with measurement of angle of trunk rotation. The finding supports the accuracy of using ultrasound to determine referral status, which could result in a >50% reduction of unnecessary radiation for children undergoing scoliosis screening., Competing Interests: Conflict of interest disclosure Y.P.Z. has a number of patents related to the Scolioscan system, which have been licensed to Telefield Medical Imaging Limited through the Hong Kong Polytechnic University. Y.P.Z. also served as consultant to Telefield Medical Imaging Limited to improve the function of the Scolioscan system. All other authors declare no conflict of interest., (Copyright © 2021 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background/purpose of the Study: Changes in health-related quality of life (HRQOL) of AIS patients coming across both bracing and surgery have not yet reported. These patients received two major clinical interventions and their HRQOL might be different from previous articles. The aim of this study is to evaluate the changes of HRQOL of a specific group of AIS patients who experienced both bracing and surgery., Methods: One hundred and twenty-eight patients requiring surgery with prior bracing treatment were identified from the electronic record. SRS-22 questionnaire was completed at 7 time points crossing both interventions (namely "Before", "Bracing ≤ 1 year", "Bracing > 1 year", "Pre-op", "Post-op", "Post-op ≤ 1 year, and "Post-op 1-2 years")., Results: SRS-22 "Function", "Pain" and "Self-image" scores were decreased from "Before" to "Bracing ≤ 1 year" when started bracing and raised at "Bracing > 1 year". The 3 scores were dropped from "Bracing > 1 year" to "Pre-op", particularly on "Self-image". "Function" and "Pain" were significantly dropped from "Pre-op" to "Post-op" and kept raising until "Post-op 1-2 years". "Self-image" was improving after "Pre-op". "Mental" was relatively stable along the timeline., Conclusion: This study described the changes in HRQOL of a specific group of AIS patients. Scores were dropped after the two major clinical interventions and recovered afterwards. Medical professionals were able to plan and provide appropriate supports on the expected changes in HRQOL, especially on function, pain and mental., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Indian Orthopaedics Association 2021.)

Study Design: A retrospective longitudinal follow-up study., Objectives: The aim of this study is to evaluate the health-related quality of life (HRQOL) of post-operative AIS patients from less than 1 year to over 30 years using SRS-22 questionnaire. Some of our AIS patients who operated since the establishment of the scoliosis clinic have passed the 30th year. The HRQOL of patients many years after surgery had yet to be summarized and reported., Methods: SRS-22 questionnaire was conducted by 254 operated patients between the year 2016 and 2018. All post-operative patients who visited a specialized clinic for annual check-up within the study period completed SRS-22. The number of years since surgery per questionnaire was grouped per 1 year until the 10th year, and per 5 years afterwards. The 6 SRS-22 domain scores (function, pain, self-image, mental, satisfaction, mean) were compared across time period., Results: All SRS-22 domain scores in post-operative patients, except "Self-image", were relatively stable in the first 5 years until a steady drop starting from the 10th year. "Self-image" was statistically lower than "Function" and "Pain" from the 10th years to more than 30 years., Conclusions: HRQOL of post-operative AIS patients remained stable until 10 years after surgery and was steadily decreasing. "Self-image" was consistently and statistically lower than the other scores. Patients who have surgically treated for more than 25 years are now at their perimenopause. Specific medical and psychosocial cares for this kind of patients are recommended to provide during the routine medical check-up., Level of Evidence: II.

Background: Sacrificing the superior petrosal vein (SPV) is controversial during a microvascular decompression (MVD). There have been multiple reports of complications including life-threatening brainstem infarction and cerebellar edema., Objective: To analyze the potential for vascular complications when the SPV is sacrificed during an MVD., Methods: Retrospective chart review was performed to identify all MVDs for trigeminal neuralgia and hemifacial spasm from 2007 to 2018 at 1 institution. Cases with ≥1 mo of follow-up were included and SPV sacrifice was noted. The primary outcome was complications related to SPV sacrifice including sinus thrombosis, cerebellar edema, and midbrain or pontine infarction. Imaging was used to confirm all potential vascular complications noted in medical records. Fisher's exact test and unpaired t-tests were used to compare between groups., Results: A total of 732 MVD cases were identified and 592 met inclusion criteria with an average follow-up of 11.8 ± 16.4 mo and a male-to-female ratio of 1:2.2. The SPV was sacrificed in 217 cases and retained in 375 cases. No SPV-related vascular complications were found in this study. Two unrelated cases of vascular complications were identified and both were in the nonsacrificed group. One case involved cerebellar bleeding while the other was an ipsilateral transverse sinus thrombosis that was present preoperatively., Conclusion: In MVDs, there is no difference in the rate of vascular complications when the SPV is sacrificed compared to preserved. To best visualize a cranial nerve and optimize safe decompression, surgeons should feel free to sacrifice the SPV., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Radiation exposure with repeated radiography required at follow-up poses serious health concerns for scoliosis patients. Although spinous process angle (SPA) measurement of spinal curvatures with ultrasound has been reported with promising results, an evidence-based account on its accuracy for translational application remains undefined. This prospective study involved 952 idiopathic scoliosis patients (75.7% female, mean age 16.7 ± 3.0 y, Cobb 28.7 ± 11.6°). Among 1432 curves (88.1%) detected by ultrasound, there was good correlation between radiologic Cobb angles measured manually on EOS (E&#95;Cobb) whole-spine radiographs and automatic ultrasound SPA measurement for upper spinal curves (USCs) (r = 0.873, apices T7-T12/L1 intervertebral disc) and lower spinal curves (LSCs) (r = 0.740, apices L1 or below) (p < 0.001). Taller stature was associated with stronger correlation. For E&#95;Cobb <30°, 66.6% USCs and 62.4% LSCs had absolute differences between E&#95;Cobb and predicted Cobb angle calculated from SPA ≤5°. Ultrasound could be a viable option in lieu of radiography for measuring coronal curves with apices at T7 or lower and Cobb angle <30°., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previous reports indicated an association between hemorrhagic presentation and flow-related aneurysms in arteriovenous malformation (AVM) patients. However, it remains unclear whether these flow-related aneurysms result in the hemorrhage of AVM., Objective: To characterize this hemorrhage risk using our institutional experience over 25 yr., Methods: We retrospectively reviewed records of patients at our institution diagnosed with AVM from 1990 to 2015. Patients without associated aneurysms (AVM only) and those with flow-related aneurysms (AVM-FA) were compared. Those with intranidal or unrelated aneurysms were excluded. Annual risk of AVM-related hemorrhage was calculated using the birth-to-treatment approach and compared using Poisson rate ratio test., Results: Among 526 patients, there were 457 AVM only patients and 69 with flow-related aneurysms. AVM-FA patients were older (P = .005). AVMs with flow-related aneurysms were more likely located in the cerebellar vermis and hemispheres (P = .023 and .001, respectively). Presence of flow-related aneurysms increased the risk of presentation with subarachnoid hemorrhage (P < .001). Interestingly, no significant differences in presenting hemorrhage due to AVM rupture were found (P > .356). The majority of aneurysms were untreated (69.5%), and only 8 (9.8%) had ruptured presentation. At follow-up (mean = 5.3 yr), patients with flow-related aneurysms were less likely to develop seizures (P = .004). The annual risk of AVM hemorrhage was 1.33% and 1.05% for AVM only patients and AVM-FA patients, respectively (P = .248)., Conclusion: Despite increased risk of subarachnoid hemorrhage at presentation, there was no increased likelihood of rupture in AVMs with flow-related aneurysms. More studies are warranted, as clarifying the competing risks of AVM vs aneurysm rupture may be critical in determining optimal treatment strategy., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Aim: To report whether Bone Ninja (BN) is a reliable tool to teach the reverse planning method (RPM) for implantable intramedullary (IM) limb-lengthening devices and for deformity correction surgery., Background: Motorised fully implantable implantable intramedullary (IM) lengthening devices have been gaining popularity all over the world for limb-lengthening procedures. Multiple advantages have been demonstrated over external fixator-controlled lengthening. Mechanical axis deviation may result if careful preoperative planning and surgical intervention are not completed for femur cases. The RPM proposed by Baumgart has been shown to be an accurate means of arriving at the desired end point. The RPM addresses the ideal correction position accounting for length, angulation, and translation created during lengthening along the nail axis. The original description calls for the use of life-size paper tracings of the bone and large light boxes to allow planning. We propose an alternative method using a digital tool that is readily available. The BN mobile app was developed for patient/physician education and is available for the Apple iPad platform. Bone Ninja has been shown to have similar accuracy for measurements of the limb length and deformity angles when compared to the gold standard picture archiving and communication systems (PACSs)., Technique: We used BN (version 4.2) on an iPad mini to perform the same RPM steps, using the same terminology originally described by Baumgart., Conclusion: Bone Ninja is a simple validated deformity correction tool with accuracy comparable to PACS. It is a reasonable alternative to paper/pencil cutouts for applying RPM for IM limb lengthening and deformity correction surgery., Clinical Significance: We proposed a digitised RPM for internal limb-lengthening surgeries, which is highly feasible and practical to use conveniently without the need for the traditional tedious paper-cutting procedure and related equipment., How to Cite This Article: Hung AL-H, McClure PK, Franzone JM, et al. Bone Ninja Mobile App for Reverse Planning Method in Internal Limb Deformity and Lengthening Surgery. Strategies Trauma Limb Reconstr 2019;14(2):72-76., Competing Interests: Source of support: Nil Conflict of interest: Dr Herzenberg reports personal fees from OrthPediatrics, Orthofix, NuVasive Specialized Orthopedics, Smith and Nephew, and WishBone Medical, outside the submitted work. Dr Standard reports personal fees and other from NuVasive Specialized Orthopedics, Smith and Nephew, and Pega Medical, outside the submitted work. Dr Herzenberg, Dr McClure, and Dr Standard are employees of Sinai Hospital who publish the BN mobile app and their institution received support for an annual course for orthopedic surgeons from the following entities: Avitus Orthopaedics, CyMedica Orthopedics, DePuy Synthes, MHE Coalition, NuVasive Specialized Orthopedics, Orthofix, OrthoPediatrics, Paragon 28, Smith and Nephew, Stryker, Vilex, and Zimmer Biomet, (Copyright © 2019; Jaypee Brothers Medical Publishers (P) Ltd.)

Objective: Trigeminal neuralgia (TN) is a neuropathic pain disorder characterized by severe, lancinating facial pain that is commonly treated with neuropathic medication, percutaneous rhizotomy, and/or microvascular decompression (MVD). Patients who are not found to have distinct arterial compression during MVD present a management challenge. In 2013, the authors reported on a small case series of such patients in whom glycerin was injected intraoperatively into the cisternal segment of the trigeminal nerve. The objective of the authors' present study was to report their updated experience with this technique to further validate this novel approach., Methods: The authors performed a retrospective analysis of data obtained in patients in whom glycerin was directly injected into the inferior third of the cisternal portion of the trigeminal nerve. Seventy-four patients, including 14 patients from the authors' prior study, were identified, and demographic information, intraoperative findings, postoperative course, and complications were recorded. Fisher's exact test, unpaired t-tests, and Kaplan-Meier survival curves using Mantel log-rank test were used to compare the 74 patients with a cohort of 476 patients who received standard MVD by the same surgeon., Results: The 74 patients who underwent MVD and glycerin injection had an average follow-up of 19.1 ± 18.0 months, and the male/female ratio was 1:2.9. In 33 patients (44.6%), a previous intervention for TN had failed. On average, patients had an improvement in the Barrow Neurological Institute Pain Intensity score from 4.1 ± 0.4 before surgery to 2.1 ± 1.2 after surgery. Pain improvement after the surgery was documented in 95.9% of patients. Thirteen patients (17.6%) developed burning pain following surgery. Five patients developed complications (6.7%), including incisional infection, facial palsy, CSF leak, and hearing deficit, all of which were minor., Conclusions: Intraoperative injection of glycerin into the trigeminal nerve is a generally safe and potentially effective treatment for TN when no distinct site of arterial compression is identified during surgery or when decompression of the nerve is deemed to be inadequate.

Introduction: The pathophysiology of normal-pressure hydrocephalus and the correlation with its symptomatology is not well understood., Objective: To monitor and evaluate the enlargement patterns of the ventricular system for each ventricle and its correlation with the presenting symptoms., Methods: Bilateral kaolin injection into the subarachnoid space overlying the cranial convexities was done in 18 adult rats. Magnetic resonance imaging was performed on an 11.7-T scanner 15, 60, 90, and 120 days after injection. Volumes of the ventricular system were measured for each ventricle and correlated with biweekly behavioral findings., Results: There was a progressive increase in the ventricular volume for the lateral ventricles since day 15 in the kaolin-injected animals. There was a nonsignificant trend in volume growth for the third ventricle, but its enlargement was synchronous with the lateral ventricles. No significant change for the fourth ventricle. No symptoms were detected in the first 60 days. Association was found between the ventricular volume and locomotor changes. In addition, the odds of locomotor symptoms increased by 3% for every additional cubic millimeter of volume in the left (P < 0.001) and right (P = 0.023) ventricles, and for the total magnetic resonance imaging volume by 1% (P = 0.013)., Conclusions: Expansion of the lateral ventricles maintained similar proportions over time, accompanied by a synchronous third ventricular expansion with less proportion and a nonsignificant fourth enlargement. Lateral ventricles enlarged most in those animals that were to develop late locomotor deterioration. Further research using this animal model combined with different radiologic imaging techniques, such as diffusion tensor imaging and perfusion studies, is recommended., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Prospective randomized controlled trials and long-term studies are essential future directions for building -evidence-based practices in developmental dysplasia of the hip (DDH), however, sufficient attrition in data (> 20%) can introduce bias deteriorating research quality. Pelvic radiography is synonymous with DDH assessment and so are -Gonadal Shield (GS) recommendations with pelvic radiography. -Nonetheless, losses to diagnostic information and inadequate protection have been increasingly implicated to GS usage, with significantly worse implications in female patients. Understandably for DDH, a disease with 80% female prevalence, the impact of GS usage on quality of radiographs and readability of radiological data may be drastic. This study aims to objectively define the implications of GS recommendations in DDH patients., Methods: Pelvis radiographs of all DDH patients under the hip surveillance programme at a tertiary care hospital with a written protocol for GS usage were evaluated. Images were reviewed for gender, GS presence, adequate gonadal protection and obstruction of essential anatomical landmarks for pelvic indices., Results: In all, 131 pelvis radiographs with DDH diagnoses (age: 1.25 to 6 years; 107 female, 24 male pelvises) were reviewed. Only 42.67% (56) of pelvis radiographs used GS despite the presence of a clear protocol. Useful anatomical landmarks were obstructed in 58.9% of radiographs with GS present. Lost diagnostic information was more common in female patients than male patients (68.1% versus 11.1%, p < 0.01). GS was ineffective at gonadal protection in 73.2% (41) of the pelvises with worse protection in female patients (78.7% vs 44.4%; p = 0.03)., Conclusions: Ironically, essential anatomy was obstructed in all the adequately protected female pelvises. Routine GS usage results in substantial attrition of radiographic data in DDH patients., Level of Evidence: III.

Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

Background: The new simplified thumb ossification composite index (TOCI) based on ossification of the thumb epiphyses and adductor sesamoid has demonstrated simplicity, excellent reliability, and high accuracy for predicting skeletal maturity, comparable with the Sanders simplified skeletal maturity system (SSMS). It was our belief that, because the terminology of the SSMS system has been commonly used for skeletal maturity prediction in idiopathic scoliosis in publications over the past decade, the clinical applicability of the TOCI system would increase if the stages in the 2 systems were found to be interchangeable and highly correlated., Methods: Hand radiographs of 125 premenarchal girls with newly diagnosed adolescent idiopathic scoliosis who had been followed longitudinally until skeletal maturity were all scored with use of the Tanner-Whitehouse III (TW3) system (stages E through I), the TOCI, and the SSMS. The scores for the epiphyses of the ulnar 4 digits were compared with those for the thumb and correlated with the timing of peak height velocity. Correlations were analyzed with the chi-square test and Cramer V and Somers delta correlations., Results: Six hundred and forty-five hand radiographs (an average of 5 for each girl with idiopathic scoliosis) and 11,517 epiphyses were scored. The rate of concordance between TW3 stages F, G, and I for the thumb proximal phalangeal epiphysis and those for all of the epiphyses of the ulnar 4 digits were 72.5%, 72.5%, and 89.9%, respectively. The overall concordance rate (including all epiphyses) was 71.3%, with a very high Cramer V correlation and significance (p < 0.01). High interchangeability was demonstrated for the TOCI and SSMS stages, supported by a high Somers delta correlation (>0.8) with significance (p < 0.05)., Conclusions: The TOCI is highly practical for clinical use, and its stages are highly interchangeable with those of the SSMS., Clinical Relevance: The TOCI could serve as a simplified "marker" of skeletal maturity on hand radiographs and minimize the learning-curve problems associated with the SSMS in a busy clinical practice.

The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc + tumors, we found that TIGIT expression was upregulated on CD8 + and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

Background: Embolization has been discussed as a feasible single modality treatment for intracranial arteriovenous malformations (AVMs)., Objective: To compare hemorrhagic risk between embolization and conservative management in a multivariate survival analysis., Methods: We retrospectively reviewed records of patients with intracranial AVMs evaluated at our institution from 1990 to 2013. We included patients recommended to undergo embolization without other treatment modalities and patients managed conservatively. Multivariate Cox regression analysis of hemorrhage-free survival was performed, with the survival interval right-censored to date of either last follow-up or salvage treatment., Results: We identified 205 patients matching our inclusion criteria, with 160 patients in the noninterventional group and 45 in the embolization group. The average age of all patients was 40.2 ± 19.5 yr, with younger patients undergoing embolization more often (P = .026). Fifty-one (31.9%) conservatively managed patients and 13 (28.9%) patients treated by embolization (P = .703) presented with hemorrhage. Other baseline characteristics were similar between the 2 management groups. During an average follow-up period of 7.7 yr, 30 patients (14.6%) experienced hemorrhage recurrence. Multivariate Cox regression revealed older age (P = .031) and hemorrhagic presentation (P < .001) to be statistically associated with follow-up hemorrhage. In a subset analysis of unruptured AVMs, embolization was associated with a 4-fold hazard ratio of hemorrhage compared to conservative management (P = .044)., Conclusion: Older age and initial presentation with hemorrhage were associated with increased risk of hemorrhage during follow-up. Treatment of AVMs with embolization as the sole modality may increase hemorrhagic risk compared with conservative management, especially in unruptured AVMs.

Background: Posterior fossa arteriovenous malformations (AVMs) are associated with increased risk of rupture and severe consequences from such rupture. The hemorrhagic risk of prenidal aneurysms (anr) on the posterior inferior cerebellar artery (PICA) may exceed that of the AVM in posterior fossa AVMs fed by PICA (PICA-AVM)., Objective: To characterize the relative risks of aneurysm and AVM hemorrhage in patients with posterior fossa AVMs., Methods: We retrospectively reviewed patients diagnosed with AVM. Patients with posterior fossa AVMs were divided into 3 groups: PICA-AVM with prenidal aneurysm (PICA-AVM-anr group), PICA-AVM without prenidal aneurysm (PICA-AVM group), and AVMs without PICA feeder with/without aneurysm (AVM-only group). Patient and lesion characteristics and treatment outcomes were compared. ANOVA and chi squared tests were used for statistical analyses., Results: Our cohort included 85 patients. Mean age was 45.3 ± 18.1 yr, with 43(50.6%) female patients. Fifty-one patients (60.0%) had hemorrhagic presentation, and 27 (31.8%) experienced acute hydrocephalus. Patients in the PICA-AVM-anr group (n = 11) were more likely to present with aneurysmal subarachnoid hemorrhage (SAH; P = .005) and less likely to have AVM rupture (P < .001). Ten (90.9%) patients presented with hemorrhage, 6 (60.0%) of which resulted from aneurysm rupture. Of these 6, 5 (83.3%) had acute hydrocephalus. No patients with AVM rupture had hydrocephalus. Eight (72.7%) received aneurysm treatment prior to AVM treatment. There were no significant differences in post-treatment outcomes dependent on treatment order., Conclusion: In addition to relatively higher risk of AVM rupture from infratentorial location and prenidal aneurysm, a higher risk of aneurysm rupture rather than AVM rupture was observed in patients with PICA-AVM-anr complex.

Background: Neuropathic pain is a challenging condition often refractory to existing therapies. An increasing number of studies have indicated that the immune system plays a crucial role in the mediation of neuropathic pain. Exploration of the various functions of individual cytokines in neuropathic pain will provide greater insight into the mechanisms of neuropathic pain and suggest potential opportunities to expand the repertoire of treatment options., Methods: A literature review was performed to assess the role of pro-inflammatory and anti-inflammatory cytokines in the development of neuropathic pain. Both direct and indirect therapeutic approaches that target various cytokines for pain were reviewed. The current understanding based on preclinical and clinical studies is summarized., Results and Conclusions: In both human and animal studies, neuropathic pain has been associated with a pro-inflammatory state. Analgesic therapies involving direct manipulation of various cytokines and indirect methods to alter the balance of the immune system have been explored, although there have been few large-scale clinical trials evaluating the efficacy of immune modulators in the treatment of neuropathic pain. TNF-α is perhaps the widely studied pro-inflammatory cytokine in the context of neuropathic pain, but other pro-inflammatory (IL-1β, IL-6, and IL-17) and anti-inflammatory (IL-4, IL-10, TGF-β) signaling molecules are garnering increased interest. With better appreciation and understanding of the interaction between the immune system and neuropathic pain, novel therapies may be developed to target this condition., (Copyright © 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Background: The Spetzler-Martin grading system for brain arteriovenous malformations (AVMs) is based on size (S), eloquence (E), and deep venous drainage (V). However, variation exists due to subgroup heterogeneity. While previous studies have demonstrated variations in outcomes within grade III AVMs, no studies have focused on grade II AVM subtypes., Objective: We aim to delineate how functional outcomes differ among patients with subtypes of grade II AVMs., Methods: We retrospectively reviewed patients with AVMs evaluated at our institution from 1990 to 2013. Grade II AVMs were divided into 3 subtypes: group 1 (S2V0E0), group 2 (S1V0E1), and group 3 (S1V1E0). Baseline characteristics were compared, and functional status was assessed using the modified Rankin Scale (mRS) at pretreatment and last follow-up. Differences in mRS between the 2 time points were compared., Results: A total of 208 grade II patients (34.0%) were retrieved from 611 graded patients. After accounting for missing data, our cohort consisted of 137 patients. Mean age of all patients was 37.2 years, with 74 females (54.0%). No significant difference was observed across subgroups for pretreatment mRS ( P = .096), treatment modalities ( P = .943), follow-up durations ( P = .125), and mRS at last follow-up ( P = .716). In a subgroup analysis between group 1 and group 3, more patients with worsened mRS were observed in group 3 ( P = .039). This distinction was further confirmed in surgically treated patients ( P = .049), but not in patients treated with radiosurgery ( P = .863)., Conclusion: Subtypes of grade II AVMs portend different posttreatment gains in functional outcome. Group 1 (S2V0E0) patients had the best functional outcome gain from treatment, while group 3 (S1V1E0) patients fared less well, particularly with surgical treatment., (Copyright © 2017 by the Congress of Neurological Surgeons)

Glioblastoma (GBM) is an aggressive central nervous system cancer with poor prognosis despite maximal therapy. The recent advent of immunotherapy holds great promise for improving GBM survival and has already made great strides toward changing management strategies. A diverse set of biomarkers have been implicated as immunotherapeutic targets and prognostic indicators in other cancers. Some of the more extensively studied examples include cytokines (IL-4, IL-13, and TGF-β), checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, CD137, GITR, OX40), and growth/angiogenesis proteins (endoglin and EGFR). Emerging theories involving the tumor mutational landscape and microbiome have also been explored in relation to cancer treatment. Although identification of novel biomarkers may improve and help direct treatment of patients with GBM, the next step is to explore the role of biomarkers in precision medicine and selection of specific immunotherapeutic drugs in an individualized manner., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Seizure risk has not been fully characterized in pediatric patients with arteriovenous malformations (AVMs)., Objective: To describe the progression and risk factors of post-treatment seizure in children with AVMs., Methods: We retrospectively reviewed pediatric patients diagnosed with intracranial AVMs at our institution between 1990 and 2013. Clinical and angiographic variables were included in univariate and multivariate Cox proportional hazard models to explore risk factors associated with time-related seizure outcomes. The outcome event is defined as first seizure occurrence after initial treatment. Kaplan-Meier survival curve is depicted for each significant variable, and survival differences were confirmed by Log-rank test., Results: We included 90 pediatric patients with complete data in our study cohort. Average age is 13.3 ± 3.8 years with 43.3% male patients. Thirty-seven patients had a hemorrhagic presentation, and 39 patients presented with seizure. Post-treatment seizure occurred in 33 patients (36.7%) over an average follow-up period of 8.1 ± 10.6 years; average time to onset is 5.3 ± 8.2 years, with partial seizures as the most common presentation. Multivariate Cox proportional hazard regression revealed seizure presentation ( P = .005), male gender ( P = .026), and nonconservative treatment modality to be significantly associated with earlier onset of post-treatment seizure after adjusting for AVM location and deep venous drainage. Overall annualized seizure risk is 7.4% for patients with pretreatment seizure, and 1.4% for those without., Conclusion: Risk of seizure persists after treatment in pediatric AVM patients. Seizure presentation, male gender, and nonconservative management are associated with increased risk of post-treatment seizure. Early identification of these risk factors provides important information for determining seizure management strategies., (Copyright © 2017 by the Congress of Neurological Surgeons)

Background: Idiopathic normal pressure hydrocephalus (iNPH) is a devastating condition that affects the elderly population. Although ventriculoatrial (VA) shunts can be used to manage iNPH, concerns for associated cardiopulmonary and renal complications have decreased their use. However, the rate of these complications is not well understood within this population of patients., Patients and Methods: A retrospective review of the electronic medical records of patients diagnosed with iNPH by the senior author between 1993 and 2015 was performed. Demographic information and baseline symptoms were assessed. Complications including infection, shunt obstruction, overdrainage, cardiopulmonary events, renal dysfunction, and shunt revision were recorded. Complication rates were compared between VA and VP shunted patients. Statistical analysis using Chi-square test, Fisher's exact test, logistic regression, Wald t-test, Poisson regression, ANOVA, and ANCOVA was performed., Results: 496 Patients, including 150 receiving VA shunts and 346 receiving VP shunts, were included in the study. The median age was 74 and 73 for VA and VP shunted patients, respectively, with slight male predominance in both (58.0% and 58.4% for VA and VP groups, respectively). A total of 36.0% of VA shunted patients and 42.5% of VP shunted patients experienced at least one post-operative complication. Overdrainage was the most commonly experienced complication in both VA (27.4%) and VP patients (19.9%). Infection occurred in only 2.0% of patients, and renal complications occurred in 1.3%. No patients had cardiopulmonary complications. VA shunted patients were significantly less likely to experience shunt obstruction and require shunt revision compared to VP shunted patients (p=0.008 and <0.001, respectively). Only dizziness and gait disturbance at baseline were correlated with a shorter time to revision in VA shunted patients (p=0.002 for both)., Conclusion: Although cardiopulmonary and renal complications are serious concerns associated with VA shunt placement, they were uncommon in patients with iNPH. VA shunted patients were less likely to experience shunt obstruction and require shunt revision compared to VP shunted patients. Therefore, VA shunts should be considered as an alternative primary treatment option in the iNPH population., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Context: Regional citrate anticoagulation for continuous renal replacement therapy is associated with a longer filter-life, less bleeding events and improved mortality. Problems associated with using Prismocitrate 10/2 solution in continuous renal replacement therapy, include hypomagnesemia, hypophosphatemia and the need for additional bicarbonate infusion., Aims: This study uses the new Prismocitrate 18/0 solution for improved buffer balance and Phoxilium solution for a more favourable electrolyte profile., Settings and Design: A retrospective analysis of patients who underwent continuous venovenous hemofiltration (CVVH) using Prismocitrate 18/0 and Phoxilium in our 21-bed ICU was conducted from March to July 2014., Methods and Material: Continuous venovenous hemofiltration (CVVH) was performed at fixed rate by using Prismocitrate 18/0 predilution at 1250 ml/hour, a blood flow rate of 110 ml/min and post-replacement with Phoxilium at 1250 ml/hr. CVVH was run for 72 h or until filter clotting, transportation, or achievement of the clinical target., Statistical Analysis Used: The results were displayed as the median with the interquartile range (IQR). The trend in pH, electrolytes, and base excess are shown using a standard box plot. All analyses were performed by the Statistical Package for Social Science for Windows, version 17 (SPSS, Chicago, IL, USA)., Results: Forty-five CVVH episodes were analysed. The median circuit lifetime was 44 h (interquartile range, IQR 29-55). Metabolic alkalosis, hypophosphatemia and hypomagnesemia occurred in 8.3%, 3.5% and 40.2% of the blood samples, respectively. No patient developed hypokalemia or citrate toxicity., Conclusions: This new CVVH regime is safe and easy to administer for critically ill patients., Competing Interests: There are no conflicts of interest.

Treatment selection for patients 60years of age and older with intracranial arteriovenous malformations (AVMs), requires careful consideration of the natural history and post-treatment hemorrhagic risk. We aimed to directly compare the natural history of AVMs with post-treatment hemorrhagic risk in this population. We retrospectively reviewed our AVM database of 683 patients. Patients ⩾60years at diagnosis were included. Treatment modality was divided into four groups: surgery±embolization (SE), radiosurgery±embolization (RE), embolization only (Emb), and observation (Obs). The natural history of the AVM was defined as the annual risk of hemorrhage under observation. Risk of hemorrhage after treatment was also calculated. Sixty-one patients with complete data were included. Average age was 68.4±7.5years, with 55.7% (n=34) being male. Twenty-seven (44.3%) patients presented with intracerebral hemorrhage (ICH). At last follow-up, modified Rankin Scale was higher in patients with subsequent hemorrhages (p=0.023). Overall, obliteration was 65.5%, with 100.0% in the SE group and 43.8% in the RE group (p<0.001). During an average follow-up period of 2.8±3.2years, six patients (9.8%) experienced hemorrhage, with two (12.5%) in the RE group, three (9.4%) in the Obs group and one (9.1%) in the SE group, corresponding to a natural history of 3.5% annual hemorrhage rate and a post-treatment hemorrhagic risk of 3.6%. This post-treatment hemorrhage risk was 2.4% in the SE group and 4.9% in the RE group. Presenting with ICH (p=0.042) and race (p=0.014) were associated with a higher risk of follow-up hemorrhage. Definitive treatment for AVM patients ⩾60years should be cautiously considered. Despite higher post-treatment obliteration rates, the subsequent hemorrhagic risk may exceed that of its natural history. For AVMs with a high risk for hemorrhage, surgery reduces hemorrhagic risk and achieves the highest rate of obliteration., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Management decisions for brainstem arteriovenous malformations (AVMs) are complicated by balancing the risks of treatment and natural progression to hemorrhage. The present study seeks to compare radiosurgery and conservative management outcomes in brainstem AVMs., Methods: We performed a retrospective review of patients with brainstem AVM seen at our institution from 1990 to 2013. Patients missing baseline information or those lost to follow-up were excluded. Clinical and angiographic characteristics and subsequent hemorrhagic risk were evaluated according to brainstem AVM location and treatment modality., Results: We identified 30 patients with brainstem AVM with complete data. Mean age was 41.6 ± 20.3 years, and 53.3% (n = 16) were male. Sixteen (53.3%) presented with hemorrhage. Twelve patients (40.0%) were conservatively managed, and 18 were treated. Sixteen (88.9%) of the treated patients underwent radiosurgery, 1 (5.6%) underwent surgery, and 1 (5.6%) underwent embolization only. Average follow-up period was 4.7 ± 5.7 years, and 5 patients (16.7%) experienced recurrent hemorrhage, 3 of whom were in the radiosurgery group and 2 in the conservative group, giving an annual recurrent hemorrhage risk of 3.7% and 4.8%, respectively. Lesion obliteration was achieved in 8 patients (26.7%). Baseline clinical and angiographic factors were similar between the radiosurgery and conservative group. Obliteration was achieved in 43.8% of those treated with radiosurgery (P = 0.008). Despite similar baseline modified Rankin Scale scores, more patients had improvement of modified Rankin Scale score at last follow-up in the radiosurgery group (P = 0.004). Recurrent hemorrhage during follow-up was similar between the 2 groups (P = 0.887)., Conclusions: Our results suggest that when patients with brainstem AVM are selected cautiously, radiosurgery may achieve obliteration and symptom relief without increasing subsequent hemorrhage risk., (Copyright © 2016 Elsevier Inc. All rights reserved.)

OBJECTIVE Compared with the general population, the specific natural history of arteriovenous malformations (AVMs) in pediatric patients is less well understood. Furthermore, few pediatric studies have compared posttreatment hemorrhagic risk and functional outcome across different treatment modalities. The objective of this study was to elucidate these points. METHODS The authors retrospectively reviewed all pediatric patients with AVMs evaluated at their institution between 1990 and 2013. The AVM natural history was represented by hemorrhagic risk during the observation period. For treated patients, the observation period was defined as the interval between diagnosis and treatment. Posttreatment hemorrhagic risk and functional outcomes were also assessed. RESULTS A total of 124 pediatric patients with AVMs were evaluated, and 90 patients (72.6%) were retained through follow-up. The average patient age was 13.3 ± 3.8 years, with a mean follow-up period of 9.95 years. The overall AVM obliteration rate was 59.7%. Radiosurgery had an obliteration rate of 49.0%. Thirteen patients were managed conservatively. Four patients under observation hemorrhaged during a total interval of 429.4 patient-years, translating to an annual risk of 0.9%. Posttreatment hemorrhagic risk by treatment modalities were categorized as follows: surgery ± embolization (0.0%), radiosurgery ± embolization (0.8%), embolization alone (2.8%), surgery + radiosurgery ± embolization (3.5%), and observation (0.8%). A significantly higher risk of posttreatment hemorrhage was observed for patients with hemorrhagic presentation (p = 0.043) in multivariate analysis. Seizure presentation, frontal lobe location, nonheadache presentation, and treatment modality were significantly associated with increased risk of poor functional outcomes. CONCLUSIONS In this study of pediatric patients with AVMs, the natural history of hemorrhage was relatively low at 0.9%. Resection remained the optimal management for hemorrhage control and functional outcome perseverance in these pediatric patients with AVMs. AVM obliteration is a valid treatment goal, especially for patients with ruptured presentation, to prevent further hemorrhages later in life.

Background: Giant intracranial arteriovenous malformations (AVMs) are rare cerebrovascular lesions that pose management challenges., Objective: To further clarify outcomes in patients with giant cerebral AVMs managed with conservative or interventional therapies., Methods: We performed a retrospective review of all patients diagnosed with AVMs evaluated at our institution from 1990 to 2013. Patients with a single intracranial AVM >6 cm were included. Patients were divided into 2 groups: conservative management or intervention (microsurgery, radiosurgery, or embolization). Functional outcome was assessed with the modified Rankin Scale (mRS) and compared between the 2 groups., Results: A total of 55 patients with giant AVMs were included, and 35 patients (63.6%) had clinical follow-up with a mean of 11.8 years. Spetzler-Martin grades were as follows: grade III, n = 2 (3.6%); grade IV, n = 15 (27.3%); and grade V, n = 38 (69.1%). Twenty-four patients (43.6%) were conservatively managed. The patients in the conservatively managed group had larger AVMs (P < .05) with more frequent involvement of the temporal lobe (P = .02). Five patients (26.3%) in the conservatively managed group and 5 (31.3%) in the intervention group experienced hemorrhage during follow-up, translating to an annualized risk of 2.7% and 4.1%, respectively. No significant difference in risk of first subsequent hemorrhage was observed (P = .78). Despite comparable mRS scores at presentation, we observed a trend toward better outcomes (mRS < 2) in patients undergoing conservative management (P = .06) compared with the intervention group at last follow-up., Conclusion: This study suggests that interventions for giant AVMs should be considered cautiously because hemorrhagic risk is similar regardless of management strategy and functional outcome is likely to be same or better in the conservatively managed population., Abbreviations: AVM, arteriovenous malformationmRS, modified Rankin Scale.

Objective: Few studies have focused on predictive factors of ventriculoperitoneal (VP) shunt revision in patients with idiopathic normal pressure hydrocephalus (iNPH). This study aims to determine whether comorbidities and baseline symptoms are associated with the need for shunt revision., Methods: A retrospective review of patients with iNPH treated with VP shunts by the senior author from 1993 to 2013 was conducted. Demographics and baseline symptoms were compared between patients with and without shunt revision. The need for revision, total number of revisions, and time to first revision were examined. Statistical analysis was performed using simple logistic, linear, and Poisson regression, and a multivariate analysis was performed., Results: A total of 347 patients with iNPH who received VP shunts were included. One hundred patients (28.8%) required shunt revision, with an average of 1.38 ± 0.76 revisions per patient. Mean time to revision was 19.2 ± 31.7 months. Gait and cognitive symptoms were associated with fewer revisions (incidence rate ratio, 0.45 and 0.67; P = 0.03 and 0.004, respectively). Headaches and urinary incontinence showed a greater time to revision (32.0 and 12.0 months; P = 0.014 and <0.0005, respectively). Gait instability demonstrated decreased time to revision (P < 0.0005)., Conclusions: Preoperative symptoms, such as headaches, gait instability, cognitive decline, and urinary incontinence, were significantly correlated with number of revisions and time to first revision. These factors should be considered during the initial counseling of prognosis for patients with iNPH receiving VP shunts., (Published by Elsevier Inc.)

Background: Patients diagnosed with hereditary hemorrhagic telangiectasia (HHT) are at risk of developing intracranial arteriovenous malformations (AVM). However, the clinical manifestations and natural history of HHT-related AVMs remain unclear due to the rarity of these lesions., Objective: To clarify the clinical characteristics and hemorrhagic risk in HHT-related AVMs., Methods: We performed a retrospective review of all patients diagnosed with both HHT and intracranial AVMs who were evaluated at our institution from 1990 to 2013. Patients with missing data or lost to follow-up were excluded. Baseline characteristics and subsequent hemorrhagic risk were evaluated., Results: In an AVM database of 531 patients with 542 AVMs, a total of 12 HHT patients (2.3%) with 23 AVMs were found. Mean age at diagnosis was 36.5 years, with 41.7% male. Compared to patients with sporadic AVMs, patients with HHT were less likely to present with ruptured AVM (P = .04), headaches (P = .02), and seizures (P = .02), and presented with better modified Rankin scores (P < .01). HHT-related AVMs were smaller in size (P < .01), of lower Spetzler-Martin grade (P = .01), and had less temporal lobe involvement (P = .02) compared to sporadic AVMs. Six HHT patients (50.0%) were found with multiple intracranial AVMs. One hemorrhage was found during an observation period of 149.6 patient-years and 297.5 lesion-years, translating to 1.3% per patient per year or 0.7% per AVM per year., Conclusion: HHT-related AVMs are smaller in size with lower Spetzler-Martin grade and less temporal lobe involvement than sporadic AVMs. Patients with HHT frequently present with multiple intracranial AVMs. Conservative management is generally recommended due to lesion multiplicity and relatively low hemorrhagic risk.

Objective: The risk of delayed hemorrhage occurring greater than 2 years after treatment in brain arteriovenous malformations (AVMs) rarely is reported. In this study, we compare the risk of delayed hemorrhage across different treatment modalities., Methods: We performed a retrospective chart review of treated patients with a single intracranial AVM seen at our institution from 1990 to 2013. Delayed hemorrhage was defined as hemorrhage occurring at least 2 years after last treatment. Survival analysis was used to assess risk of delayed hemorrhage by treatment modalities., Results: Our study included 420 patients. Spetzler-Martin grades were as follows: I (12.6%), II (36.2%), III (32.6%), IV (15.0%), and V (3.6%). Average follow-up time is 5.1 years. Twenty-two patients (5.2%) were found to have 28 delayed hemorrhages. Average interval between last treatment and delayed hemorrhage was 7.6 years, with the longest being 24.2 years. Proportions of delayed hemorrhages by treatment modalities were as follows: surgery ± embolization (group I, 9.1%), radiosurgery ± embolization (group II, 63.6%), embolization only (group III, 22.7%), and surgery + radiosurgery ± embolization (group IV, 4.5%). Annualized hemorrhage risk after 2 years for each treatment group was as follows: group I (0.4%), group II (1.2%), group III (3.7%), and group IV (1.7%). Survival analysis demonstrated lowest risk of delayed hemorrhage for group 1 (P < 0.01)., Conclusions: This study is the first to compare the risk of delayed hemorrhage across different treatment modalities. Surgical resection is associated with the lowest risk for delayed hemorrhage compared with other treatment modalities. Patients with partially embolized AVMs should seek timely definitive treatment to decrease the risk of delayed hemorrhage., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The initial correction rate (ICR) has been widely used as a predictor for curve progression in adolescent idiopathic scoliosis (AIS) undergoing bracing treatment. We proposed a new parameter, the initial Cobb angle reduction velocity (ARV), for prediction of curve progression. The purpose of this study was to identify whether the initial ARV was a more effective predictor than ICR for curve progression in AIS patients undergoing brace treatment, and to evaluate the ideal cut-off point of initial ARV for prediction of curve progression., Methods: This was a retrospective cohort study on AIS girls receiving standardized bracing treatment regularly followed up every 3-6 months. Standardized SRS criteria for bracing study were utilized in the case selection. The demographic data, maturity status and Cobb angle of each visit were recorded. The initial ARV and ICR were identified. Patients were divided into progressive (≥6°) and non-progressive (<6°) groups based on their final bracing outcome. Differences between two groups were identified and logistic regression analysis was applied to compare the predictive values of initial ARV and ICR for curve progression during bracing treatment., Results: Seventy-six patients were included in the non-progressive group and 19 in the progressive group. Significant differences between non-progressive and progressive groups were found in terms of initial ARV (12.8 ± 21.4°/year vs -5.4 ± 15.2°/year, P = 0.001) and ICR (12.1 ± 20.7 % vs -5.8 ± 18.0 %, P = 0.001). The logistic regression analysis revealed that age at initial visit (OR 1.742, P = 0.043) and initial ARV (OR 1.057, P = 0.002) had higher predictive values than ICR (P = 0.601) for curve progression in braced AIS girls. The ideal cut-off point of initial ARV was 10°/year (OR 8.959, P = 0.005) for the prediction of curve progression., Conclusions: The initial Cobb angle reduction velocity serves as a better predictor for curve progression than initial correction rate in braced AIS patients with follow-up interval of 3-6 months. At the second visit following bracing prescription, those AIS patients with reduction velocity in Cobb angle lower than 10°/year have significantly higher risk of curve progression.

Background: Many reports had been received on the application of antifibrinolytic medications on spinal corrective surgery and the surgical outcome evaluations of its efficacy on reducing blood loss. This study aimed to assess the efficacy of tranexamic acid (TXA) in reducing operative blood loss during posterior spinal fusion for the treatment of severe adolescent idiopathic scoliosis (AIS)., Methods: A retrospective cohort study was carried out on 90 (TXA = 55, Control = 35) AIS girls undergoing posterior spinal surgery. Patients in TXA group used TXA as an antifibrinolytic agent to reduce blood loss, while control group did not. Blood loss, haemoglobin change and amount of blood transfused was estimated from intraoperative measurement by anaesthesiologists. Demographics were compared using Student's T-test or Chi-square test where appropriate. Linear regression modelling was carried out between the use of TXA and total blood loss with controlling of confounding factors., Results: Mean age and mean maximum major curve were 15.2 and 73°, and 15.3 and 63° in TXA and control groups respectively. TXA group showed significantly less intra-operative blood loss than the control group from intraoperative measurement (1.8 L vs. 3.9 L, p < 0.01) and volume of cell saver blood transfused back to patients (0.6 L vs. 1.7 L, p < 0.01). TXA group also showed significantly shorter total time taken for surgery (437 min vs. 502 min, p < 0.01), and total blood loss per surgical segment level (0.1 L vs. 0.3 L, p < 0.01). Regression models showed that the use of TXA decreased total blood loss by 794.3 ml after adjusting for maximum major curve, age, number of segments fused, bone graft, clotting capability, and infusion of coagulation factors., Conclusions: Patients undergoing posterior spinal corrective surgery with the use of TXA showed much reduced total blood loss, reduced use of transfused blood, much less cell saver blood transfused back to the patient. The total blood loss was decreased by after using TXA after controlling for maximum major curve, age, surgical parameters, clotting capability, and infusion of coagulation factors.

Background: Environmental endocrine disruptors (EEDs) are exogenous chemicals that mimic endogenous hormones such as estrogens. Previous studies using a zebrafish transgenic reporter demonstrated that the EEDs bisphenol A and genistein preferentially activate estrogen receptors (ERs) in the larval heart compared with the liver. However, it was not known whether the transgenic zebrafish reporter was sensitive enough to detect estrogens from environmental samples, whether environmental estrogens would exhibit tissue-specific effects similar to those of BPA and genistein, or why some compounds preferentially target receptors in the heart., Methods: We tested surface water samples using a transgenic zebrafish reporter with tandem estrogen response elements driving green fluorescent protein expression (5xERE:GFP). Reporter activation was colocalized with tissue-specific expression of ER genes by RNA in situ hybridization., Results: We observed selective patterns of ER activation in transgenic fish exposed to river water samples from the Mid-Atlantic United States, with several samples preferentially activating receptors in embryonic and larval heart valves. We discovered that tissue specificity in ER activation was due to differences in the expression of ER subtypes. ERα was expressed in developing heart valves but not in the liver, whereas ERβ2 had the opposite profile. Accordingly, subtype-specific ER agonists activated the reporter in either the heart valves or the liver., Conclusion: The use of 5xERE:GFP transgenic zebrafish revealed an unexpected tissue-specific difference in the response to environmentally relevant estrogenic compounds. Exposure to estrogenic EEDs in utero was associated with adverse health effects, with the potentially unanticipated consequence of targeting developing heart valves.

Twenty-five isolates of Ornithobacterium rhinotracheale were examined by agar gel precipitation, immunoperoxidase assay, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, western blot analysis, and a polymerase chain reaction. All of the isolates were identified as serotype A. Protein profiles of whole cell extracts were similar for all the isolates, and a polypeptide with a molecular weight of 33 kD was a major component, being present in all the isolates. In the main, proteins of 33, 42, 52, and 66 kD were recognized in immunoblots with sera from chickens naturally exposed to O. rhinotracheale. A modified polymerase chain reaction assay identified O. rhinotracheale DNA from all the isolates and tracheal swabs, producing amplicons of 784 bp, and distinguished O. rhinotracheale from bacterial agents causing similar clinical signs.

An in frame gene fusion containing the coding region for mature beta-lactamase and the 3'-end of hylA encoding the haemolysin secretion signal, was constructed under the control of a lac promoter. The resulting 53 kDa hybrid protein was specifically secreted to the external medium in the presence of the haemolysin translocator proteins, HlyB and HlyD. The specific activity of the beta-lactamase portion of the secreted protein (measured by the hydrolysis of penicillin G), approximately 1 U/microgram protein, was close to that of authentic, purified TEM-beta-lactamase. This is an important example of a hybrid protein that is enzymatically active, and secreted via the haemolysin pathway. Previous studies have indicated that haemolysin is secreted directly into the medium, bypassing the periplasm, to which beta-lactamase is normally targeted. This study indicated, therefore, that normal folding of an active beta-lactamase, can occur, at least when fused to the HlyA C-terminus, without the necessity of entering the periplasm. Despite the secretion of approximately 5 micrograms/ml levels of the active beta-lactamase fusion into the medium, there was maximally only a 50% detectable increase in the LD50 for resistance to ampicillin at the individual cell level. This result suggests that, normally, resistance to ampicillin requires a high concentration of the enzyme close to killing targets, i.e. in the periplasm, in order to achieve significant levels of protection.

Indirect haemagglutination tests on sera from 757 South American camelids (alpacas, llamas and vicunas) carried out in the Andean region of Peru, revealed evidence of exposure mainly to Mycoplasma mycoides subspecies mycoides LC. The incidence of detectable antibodies to this mycoplasma in 554 alpacas was 5.0 per cent and in 141 llamas 15.6 per cent. Antibody to Mycoplasma capricolum and the F38 biotype was detected in 0.9 per cent and 0.2 per cent of alpacas, respectively. In a group of 62 vicunas only one reactor to both M m mycoides LC and M capricolum was observed. No reactors to M mycoides subspecies capri or M agalactiae were observed in the flocks examined. Antibodies to mycoplasma were also detected in nine out of 10 goat flocks tested. The incidence of antibodies to M m mycoides LC was 13.8 per cent, 3.8 per cent for M capricolum and 1.8 per cent for the F38 biotype. In a group of 110 sheep, six reactors (5.5 per cent) to M m mycoides LC and one (0.9 per cent) to F38 were observed. The implications of these results are discussed in relation to the involvement of mycoplasmas in existing disease in camelids in Peru.

Circulating antibody was detected by an indirect fluorescent antibody test (IFAT) in the serum of sheep infected experimentally with Eperythrozoon ovis. Antibodies were first detected 15 to 32 days after infection with E ovis and titres peaked at 41 days. This antibody may be associated, at least in part, with protection against infection with E ovis since the initial increase in antibody titre coincided with a fall in the primary parasitaemia. A role for antibody is suggested further by the fact that the prepatent period of infection was prolonged by one day and the parasitaemia initially remained at low levels in infected sheep protected by passively transferred hyperimmune serum. Moreover, following primary infection, acquired immunity was manifest by a lack of parasitaemia following challenge infections while increased IFA titres were observed. No evidence of opsonic activity was observed in an in vitro erythrophagocytosis test in that neither mouse macrophages nor sheep monocytes phagocytosed E ovis infected or uninfected erythrocytes sensitised with hyperimmune serum.