Patient-Reported Outcomes After Complex Adult Spinal Deformity Surgery: 5-Year Results of the Scoli-Risk-1 Study

Adult spinal deformity; Patient reported outcomes; Spinal deformity surgeryDeformidad espinal en el adulto; Resultados informados por el paciente; Cirugía de deformidad espinalDeformitat espinal de l'adult; Resultats informats pel pacient; Cirurgia de deformitat espinalStudy Design: Prospective cohort. Objective: To prospectively evaluate PROs up to 5-years after complex ASD surgery. Methods: The Scoli-RISK-1 study enrolled 272 ASD patients undergoing surgery from 15 centers. Inclusion criteria was Cobb angle of >80°, corrective osteotomy for congenital or revision deformity, and/or 3-column osteotomy. The following PROs were measured prospectively at intervals up to 5-years postoperative: ODI, SF36-PCS/MCS, SRS-22, NRS back/leg. Among patients with 5-year follow-up, comparisons were made from both baseline and 2-years postoperative to 5-years postoperative. PROs were analyzed using mixed models for repeated measures. Results: Seventy-seven patients (28.3%) had 5-year follow-up data. Comparing baseline to 5-year data among these 77 patients, significant improvement was seen in all PROs: ODI (45.2 vs. 29.3, P 0.05) and proportion achieving MCID did not differ significantly in patients with major surgery-related complications compared to those without. Conclusions: After complex ASD surgery, significant improvement in PROs were seen at 5-years postoperative in ODI, SF36-PCS/MCS, SRS-22r, and NRS-back/leg pain. No significant changes in PROs occurred during the 2 to 5-year postoperative period. Those with major surgery-related complications had similar PROs and proportion of patients achieving MCID as those without these complications.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by AO Spine through the AO Spine Knowledge Forum Deformity, the Scoliosis Research Society (SRS), and Norton Healthcare. AO Spine Knowledge Forum Deformity is a focused group of international deformity experts. AO Spine is a clinical division of the AO Foundation, which is an independent medically-guided not-for-profit organization. Study support was provided directly through the AO Spine Research Department and the AO Innovation Translation Center, Clinical Evidence

The KCNJ11 E23K Polymorphism and Progression of Glycaemia in Southern Chinese: A Long-Term Prospective Study

Context: The KCNJ11 E23K variant is associated with type 2 diabetes mellitus (T2DM) in cross-sectional studies, but conflicting findings have been reported from prospective studies. Objective: This study aimed to evaluate whether the E23K variant could predict glycaemic progression in a Southern Chinese population. Methods/Principal Findings: We performed a long-term prospective study on 1912 subjects from the Hong Kong Cardiovascular Risk Factors Prevalence Study (CRISPS). The KCNJ11 E23K variant was associated with the progression to prediabetes after a median interval of 12 years on multinomial logistic regression analysis, even after adjustment for traditional risk factors (OR 1.29, P age, sex, BMI and fasting plasma glucose [FPG] adjusted = 0.02). Based on Cox proportional hazard regression analysis, the E23K variant also predicted incident prediabetes (HR 1.18, P age, sex, BMI and FPG adjusted = 0.021). However, E23K was not associated with the progression to T2DM in either multinomial or Cox regression analysis, and the association of E23K with glycaemic progression to either prediabetes or T2DM was significant only in unadjusted Cox regression analysis (P = 0.039). In a meta-analysis of eight prospective studies including our own, involving 15680 subjects, the E23K variant was associated with incident T2DM (fixed effect: OR 1.10, P = 4×10 -3; random effect: OR 1.11, P = 0.035). Conclusions: Our study has provided supporting evidence for the role of the E23K variant in glycaemic progression in Chinese, with its effect being more evident in the early stage of T2DM, as the subjects progressed from normal glucose tolerance to prediabetes. © 2011 Cheung et al.published_or_final_versio

Eosinophils Are Important for Protection, Immunoregulation and Pathology during Infection with Nematode Microfilariae

Eosinophil responses typify both allergic and parasitic helminth disease. In helminthic disease, the role of eosinophils can be both protective in immune responses and destructive in pathological responses. To investigate whether eosinophils are involved in both protection and pathology during filarial nematode infection, we explored the role of eosinophils and their granule proteins, eosinophil peroxidase (EPO) and major basic protein-1 (MBP-1), during infection with Brugia malayi microfilariae. Using eosinophil-deficient mice (PHIL), we further clarify the role of eosinophils in clearance of microfilariae during primary, but not challenge infection in vivo. Deletion of EPO or MBP-1 alone was insufficient to abrogate parasite clearance suggesting that either these molecules are redundant or eosinophils act indirectly in parasite clearance via augmentation of other protective responses. Absence of eosinophils increased mast cell recruitment, but not other cell types, into the broncho-alveolar lavage fluid during challenge infection. In addition absence of eosinophils or EPO alone, augmented parasite-induced IgE responses, as measured by ELISA, demonstrating that eosinophils are involved in regulation of IgE. Whole body plethysmography indicated that nematode-induced changes in airway physiology were reduced in challenge infection in the absence of eosinophils and also during primary infection in the absence of EPO alone. However lack of eosinophils or MBP-1 actually increased goblet cell mucus production. We did not find any major differences in cytokine responses in the absence of eosinophils, EPO or MBP-1. These results reveal that eosinophils actively participate in regulation of IgE and goblet cell mucus production via granule secretion during nematode-induced pathology and highlight their importance both as effector cells, as damage-inducing cells and as supervisory cells that shape both innate and adaptive immunity

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Big Bang Models in String Theory

These proceedings are based on lectures delivered at the "RTN Winter School on Strings, Supergravity and Gauge Theories", CERN, January 16 - January 20, 2006. The school was mainly aimed at Ph.D. students and young postdocs. The lectures start with a brief introduction to spacetime singularities and the string theory resolution of certain static singularities. Then they discuss attempts to resolve cosmological singularities in string theory, mainly focusing on two specific examples: the Milne orbifold and the matrix big bang.Comment: 44 pages, 18 figures; v2: misprints in section 4.2 fixed (corrects published version), reference adde

Identification of Human Papillomavirus Type 58 Lineages and the Distribution Worldwide

Background. Human papillomavirus type 58 (HPV-58) accounts for a much higher proportion of cervical cancers in East Asia than other types. A classification system of HPV-58, which is essential for molecular epidemiological study, is lacking. Methods and results. This study analyzed the sequences of 401 isolates collected from 15 countries and cities. The 268 unique concatenated E6-E7-E2-E5-L1-LCR sequences that comprised 57% of the whole HPV-58 genome showed 4 distinct clusters. L1 and LCR produced tree topologies that best resembled the concatenated sequences and thus are the most appropriate surrogate regions for lineage classification. Moreover, short fragments from L1 (nucleotides 6014–6539) and LCR (nucleotides 7257–7429 and 7540–52) were found to contain sequence signatures informative for lineage identification. Lineage A was the most prevalent lineage across all regions. Lineage C was more frequent in Africa than elsewhere, whereas lineage D was more prevalent in Africa than in Asia. Among lineage A variants, sublineage A2 dominated in Africa, the Americas, and Europe, but not in Asia. Sublineage A1, which represents the prototype that originated from a patient with cancer, was rare worldwide except in Asia. Conclusions. HPV-58 can be classified into 4 lineages that show some degree of ethnogeographic predilection in distribution. The evolutionary, epidemiological, and pathological characteristics of these lineages warrant further study

Multi-Modality Therapeutics with Potent Anti-Tumor Effects: Photochemical Internalization Enhances Delivery of the Fusion Toxin scFvMEL/rGel

BACKGROUND: There is a need for drug delivery systems (DDS) that can enhance cytosolic delivery of anti-cancer drugs trapped in the endo-lysosomal compartments. Exposure of cells to specific photosensitizers followed by light exposure (photochemical internalization, PCI) results in transfer of agents from the endocytic compartment into the cytosol. METHODOLOGY AND PRINCIPAL FINDINGS: The recombinant single-chain fusion construct scFvMEL/rGel is composed of an antibody targeting the progenitor marker HMW-MAA/NG2/MGP/gp240 and the highly effective toxin gelonin (rGel). Here we demonstrate enhanced tumor cell selectivity, cytosolic delivery and anti-tumor activity by applying PCI of scFvMEL/rGel. PCI performed by light activation of cells co-incubated with scFvMEL/rGel and the endo-lysosomal targeting photosensitizers AlPcS(2a) or TPPS(2a) resulted in enhanced cytotoxic effects against antigen-positive cell lines, while no differences in cytotoxicity between the scFvMEL/rGel and rGel were observed in antigen-negative cells. Mice bearing well-developed melanoma (A-375) xenografts (50-100 mm(3)) were treated with PCI of scFvMEL/rGel. By 30 days after injection, approximately 100% of mice in the control groups had tumors>800 mm(3). In contrast, by day 40, 50% of mice in the PCI of scFvMEL/rGel combination group had tumors<800 mm(3) with no increase in tumor size up to 110 days. PCI of scFvMEL/rGel resulted in a synergistic effect (p<0.05) and complete regression (CR) in 33% of tumor-bearing mice (n = 12). CONCLUSIONS/SIGNIFICANCE: This is a unique demonstration that a non-invasive multi-modality approach combining a recombinant, targeted therapeutic such as scFvMEL/rGel and PCI act in concert to provide potent in vivo efficacy without sacrificing selectivity or enhancing toxicity. The present DDS warrants further evaluation of its clinical potential

Reflections: OD or Not OD that is the Question! A Constructivist's Thoughts on the Changing Nature of Change

The landscape of organization development (OD) has changed significantly over the last several decades. This article provides a broad commentary on these changes. In particular, it offers a critique of 'current OD' in terms of the marginalization of materiality in discourse-based OD techniques and the neglect of problem-centred, diagnostic approaches in favour of solution-driven, emergent approaches. The future of OD is also explored in relation to the scope for meaningful 'bottom-up OD' (i.e. employee-instigated change) and 'outside-in OD' (i.e. involving a range of non-organizational stakeholders). © 2013 Taylor & Francis

Current management of intracerebral haemorrhage in China: a national, multi-centre, hospital register study

<p>Abstract</p> <p>Background</p> <p>We aimed to examine current practice of the management and secondary prevention of intracerebral haemorrhage (ICH) in China where the disease is more common than in Western populations.</p> <p>Methods</p> <p>Data on baseline characteristics, management in-hospital and post-stroke, and outcome of ICH patients are from the ChinaQUEST (QUality Evaluation of Stroke Care and Treatment) study, a multi-centre, prospective, 62 hospital registry in China during 2006-07.</p> <p>Results</p> <p>Nearly all ICH patients (n = 1572) received an intravenous haemodiluting agent such as mannitol (96%) or a neuroprotectant (72%), and there was high use of intravenous traditional Chinese medicine (TCM) (42%). Neurosurgery was undertaken in 137 (9%) patients; being overweight, having a low Glasgow Coma Scale (GCS) score on admission, and Total Anterior Circulation Syndrome (TACS) clinical pattern on admission, were the only baseline factors associated with this intervention in multivariate analyses. Neurosurgery was associated with nearly three times higher risk of death/disability at 3 months post-stroke (odd ratio [OR] 2.60, p < 0.001). Continuation of antihypertensives in-hospital and at 3 and 12 months post-stroke was reported in 732/935 (78%), 775/935 (83%), and 752/935 (80%) living patients with hypertension, respectively.</p> <p>Conclusions</p> <p>The management of ICH in China is characterised by high rates of use of intravenous haemodiluting agents, neuroprotectants, and TCM, and of antihypertensives for secondary prevention. The controversial efficacy of these therapies, coupled with the current lack of treatments of proven benefit, is a call for action for more outcomes based research in ICH.</p