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When properly understood in the context of entrepreneurship, entanglement explains the complex ingredients in the tangled relations required for entrepreneurial success. However, in examining entrepreneurial success, many scholars overlook a critical consideration—are the right resources (people and materials) in the right place at the right time? How do entanglement and convergence come about? This occurs when a microsystem is entangled with many fine-grained structures with different degrees of freedom, converging to generate emergence. These fine-grained structures are the heterogeneous agents with correlated histories (co-founders, financiers, suppliers, competitors, customers, employees, etc.) that are entangled with the entrepreneurs. This article explains the complex causes in the emergent order arising from several entangled dynamics among the heterogeneous agents and resources. The challenge is understanding what complex ingredients and combinations are necessary for a new emergent order that gives rise to such possibilities. Finally, such emergence arising from entanglement is discussed to explain collaboration and coevolution effects, and suggestions for future research that utilises the intended theorisations of practice are offered.

Encapsulated angioinvasive follicular thyroid carcinoma (EAFTC) is associated with an increased risk of distant metastasis and reduced survival compared to minimally invasive follicular thyroid carcinoma (MIFTC). There is controversy regarding the extent of surgery and adjuvant radioactive iodine therapy for angioinvasive follicular thyroid carcinoma when stratified by number of foci of angioinvasion.All follicular thyroid carcinoma cases from 1990-2018 were identified from a thyroid cancer database. Primary outcomes were distant metastasis-free survival (DMFS) and disease-specific survival (DSS) with factors of interest being age, gender, tumour size, treatment, foci of angioinvasion and histological subtype.A total of 292 cases were identified; 139 MIFTC, 141 EAFTC and 12 widely invasive follicular thyroid carcinoma (WIFTC). Over a follow-up period of 6.25 years, DMFS was significantly reduced (p 0.001) with 14.2% (EAFTC) and 50% of WIFTC developing metastasis. The risk of metastasis in EAFTC with ≥ 4 foci of angioinvasion was 31.7% (HR = 5.89, p = 0.004), 6.3% for EAFTC with 4 foci of angioinvasion (HR = 1.74, p = 0.47), compared to 3.6% MIFTC. Age ≥ 50 years (HR = 4.24, p = 0.005) and tumour size (HR = 1.27, p = 0.014) were significantly associated with increased risk of distant metastasis. DSS was reduced significantly (p 0.001), with 7.8% EAFTC patients dying of disease. For EAFTC patients, DSS was 96.8% for 4 foci and 82.6% for ≥ 4 foci of angioinvasion (p = 0.003).EAFTC is at increased risk of distant metastasis related to the extent of angioinvasion. Tumours with 4 foci of angioinvasion should be considered for a total thyroidectomy, particularly in older patients.

Diffuse sclerosing variant (DSV) of papillary thyroid carcinomais a rare form of thyroid cancer that demonstrates more aggressive histopathology than classical papillary thyroid carcinoma (c-PTC); however, if this leads to worse survival is debated. Many DSVs are driven by fusion events which are of recent clinical importance due to the advent of targeted RET inhibitors. A systematic search and meta-analysis of the literature was performed to compare outcomes of disease-specific mortality (DSM), metastatic and recurrent disease and the incidence of fusion events between DSV and c-PTC to July 2022. The Newcastle–Ottawa Quality Assessment studies was used to assess quality. An odds ratio (OR) was utilised to measure outcomes with 95% CIs. The Preferred Reporting Items for Systematic Reviews and Meta-analysis guideline was followed. Seventeen studies were included with 874 DSV patients compared to 76,013 c-PTC patients. DSV patients had worse DSM (OR=2.50, 95% CI 1.39–4.51) and presented with a higher rate of metastatic lymph nodes (OR = 5.85, 95% CI 2.73–12.53) and more distant metastases (OR = 3.83, 95% CI 2.17–6.77). DSV patients had higher odds of recurrent disease (OR = 3.23, 95% CI 2.00–5.23) and overall distant metastasis (OR = 2.70, 95% CI 1.74–4.17). Rates of RET fusion alterations for DSV ranged from 25 to 83%. DSV has a worse prognosis than c-PTC with higher rates of recurrent disease and distant metastasis. The high prevalence of RET fusions offers the potential to improve outcomes for patients with DSV.

This paper proposes a reinterpretation of the Chinese worldview onequilibrium/nonequilibrium and yin-yang. Important terminologies and concepts thatconstitute Yijing have correlative aspects with irreversible thermodynamics and quantumreality- instability, nonlinearity, nonequilibrium and temporality. Ilya Prigogine is a Nobellaureate noted for his contribution to dissipative structures and their role in thermodynamicsystems far from equilibrium, complexity and irreversibility. His expressions, as argued inthis paper, resonate with the principles in Yijing. Thus, this paper attempts to re-stateexisting interpretations of Yijing’s ideas with reference to science. Understanding Yijing’sterms and concepts must be contextualised to account for its pervasiveness of temporalityand the change process. Otherwise, these cardinal concepts may be misconstrued as ahodgepodge of Eastern traditions with no relevance to modern science. This paperconcentrates on the fundamental role of indeterminism in nonlinear systems on classicaland quantum levels using Yijing’s conceptual framework. It concludes that the dominant ideas in Yijing and ancient Chinese philosophy resonate with the current scientific belief – the end of certainty. Instability, far-from-equilibrium, irreversibility, probability, bifurcation, and self-organisation are intrinsic properties of nature appearing at all levels, from particle, protein folding, and DNA double helix to cosmological scales. Information is the basis of all changes, and the agency of change is the human (‘ren’) with a consciousness existing in the probability space between heaven (‘tian’) and earth (‘di’). Finally, this paper outlines a modelling approach with the self-organising human in the centre between heaven and earth, representing living systems as discrete dynamical systems presented with binary choices (yin-yang). The interplay of yin and yang lines in a hexagram is thought to reflect the changing dynamics of a given situation, and the interpretation of the hexagram is based on the relationships between the yin and yang lines based on informational availability. In this way, the concepts of yin-yang and information causality are central to Yijing's understanding of change and are clarified in this paper.

Summary: Background: Primary hyperparathyroidism is a prevalent disease with proven benefits for appropriately selected patients who undergo parathyroidectomy. The ability to accurately predict expected single adenoma gland weight as the cause based on preoperative biochemical tests could improve cure rates in a minimally invasive approach. Objective: To assess the correlation between parathyroid weight and preoperative parathyroid hormone and calcium levels in patients with primary hyperparathyroidism with a solitary adenoma and determine if these could be used to predict expected parathyroid weight. Methods: Patients with primary hyperparathyroidism who underwent curative parathyroidectomy from 2013 to 2018 was retrospectively analysed. Results: There is a strong positive correlation r = 0.602 between preoperative PTH levels with respect to parathyroid weight (p

Human Complement Receptor 1 (HuCR1) is a potent membrane-bound regulator of complement both in vitro and in vivo, acting via interaction with its ligands C3b and C4b. Soluble versions of HuCR1 have been described such as TP10, the recombinant full-length extracellular domain, and more recently CSL040, a truncated version lacking the C-terminal long homologous repeat domain D (LHR-D). However, the role of N-linked glycosylation in determining its pharmacokinetic (PK) and pharmacodynamic (PD) properties is only partly understood. We demonstrated a relationship between the asialo-N-glycan levels of CSL040 and its PK/PD properties in rats and non-human primates (NHPs), using recombinant CSL040 preparations with varying asialo-N-glycan levels. The clearance mechanism likely involves the asialoglycoprotein receptor (ASGR), as clearance of CSL040 with a high proportion of asialo-N-glycans was attenuated in vivo by co-administration of rats with asialofetuin, which saturates the ASGR. Biodistribution studies also showed CSL040 localization to the liver following systemic administration. Our studies uncovered differential PD effects by CSL040 on complement pathways, with extended inhibition in both rats and NHPs of the alternative pathway compared with the classical and lectin pathways that were not correlated with its PK profile. Further studies showed that this effect was dose dependent and observed with both CSL040 and the full-length extracellular domain of HuCR1. Taken together, our data suggests that sialylation optimization is an important consideration for developing HuCR1-based therapeutic candidates such as CSL040 with improved PK properties and shows that CSL040 has superior PK/PD responses compared with full-length soluble HuCR1.

Alzheimer’s disease (AD) is a major cause of dementia debilitating the global ageing population. Current understanding of the AD pathophysiology implicates the aggregation of amyloid beta (Aβ) as causative to neurodegeneration, with tauopathies and neuroinflammation considered as other major culprits. Curiously, vascular endothelial barrier dysfunction is strongly associated with Aβ deposition and 80-90% AD subjects also experience cerebral amyloid angiopathy. Here we show amyloid proteins-induced endothelial leakiness (APEL) in human microvascular endothelial monolayers as well as in mouse cerebral vasculature. Using signaling pathway assays and discrete molecular dynamics, we revealed that the angiopathy first arose from a disruption to vascular endothelial (VE)-cadherin junctions exposed to the nanoparticulates of Aβ oligomers and seeds, preceding the earlier implicated proinflammatory and pro-oxidative stressors to endothelial leakiness. These findings are analogous to nanomaterials-induced endothelial leakiness (NanoEL), a major phenomenon in nanomedicine depicting the paracellular transport of anionic inorganic nanoparticles in the vasculature. As APEL also occurred with the anionic seeds of pathogenic alpha synuclein and functional FapC bacterial amyloid, this study projects a general new paradigm for elucidating the vascular permeation, systemic spread, and cross-seeding of amyloid proteins that underlie the pathogeneses of AD, Parkinson’s, as well as a range of amyloid diseases.

What arouses entrepreneurial action? The role of entrepreneurial opportunities in stimulating entrepreneurial action under uncertainty is a subject of intense scholarly debate. This article engages in a crucial theoretical exploration to extend the boundaries of opportunity by reframing it as an artifact. Reframing the opportunity as an artifact (crystallized information) shifts the dialogue and perspectives. Through information visualization and mental modeling approaches, information is aggregated, integrated, and configured to generate an experience that triggers actions. The interaction, transformation, and representation of information are intended to reduce uncertainty and guide entrepreneurial enactment. This article presents an integrated information processing model showing how information excites, instigates, and motivates enactment. This contextualization aims to develop a descriptively accurate and prescriptively useful concept of opportunity as an artifact. Theoretically, analytically, and conceptually, the focus on information as the fundamental unit of analysis shifts the discussion by featuring inward to move the scholarly debate on opportunity forward. This re-pivoting can avoid the calls for abandonment and debunking of the opportunity construct.

In exploring entrepreneurial action as a response to opportunities, this paper uses signalling theory to provide new insights as the entrepreneur moves from perception to recognition to enactment. We adopt a dynamic approach to how entrepreneurs perceive opportunities and form initial opportunity beliefs, recognizing that, over time, beliefs change. The perceived potentialities from the signals arising from opportunities also change. Strength of the initial opportunity beliefs, morph-ability of opportunities, frequency of opportunity appearances, multiple interpretations of opportunity, latency of opportunity, observability (intensity, visibility, strength and clarity), distortions of opportunity and false opportunity are topics that are not sufficiently addressed in research on entrepreneurial opportunities. We argue that the signalling effects open new avenues of inquiry related to the central role of opportunity in the entrepreneurial process. Instead of seeing opportunity from either the discovery or creation approaches, opportunity should be viewed as an artifact with embedded perceived potentialities. Implications are drawn for the developmental context.

This paper reviews the concept of entrepreneurial actions arising from the opportunities using signalling theory as the building blocks to discuss the process from perception, recognition to enactment. By adopting a dynamic approach to study how entrepreneurs see opportunities, particularly the initial opportunities beliefs, over time, beliefs change. The perceived potentialities from the signals arising from opportunities also change. Strength of the initial opportunity beliefs, morph-ability of opportunities, frequency of opportunity appearances, multiple interpretations of opportunity, latency of opportunity, observability (intensity, visibility, strength and clarity), distortions of opportunity and false opportunity are topics that are scarcely addressed in entrepreneurial opportunities studies. We argue that the signalling effects open new veins of inquiry related to opportunity and entrepreneurial actions. Instead of seeing opportunity from either the discovery or creation approaches, opportunity should be viewed as opportunity-as-artefact with embedded perceived potentialities.

Background Intraoperative nerve monitoring (IONM) has increasingly been used in thyroid surgery by general, endocrine and head and neck surgeons. The purpose of this paper was to explore the prevalence and reasons for the usage of IONM in endocrine surgery in Australia and New Zealand. Methods A survey was sent to general surgeons registered with the Royal Australasian College of Surgeons involved in endocrine surgery and members of the Australian and New Zealand Endocrine Surgeons. Users were divided into surgeon type, area of work, hospital type and volume of surgery. These data were analysed with univariate and multivariate logistic regression models. Results Significant differences in IONM usage levels were observed between endocrine and general surgeons, area of work and volume of surgery performed. Endocrine surgeons are significantly more likely to use IONM than general surgeons. Surgeons who work in tertiary hospitals are more likely to use IONM as compared to those working in district hospitals. Surgeons who perform less than 100 thyroidectomies were more likely to be users of IONM. Conclusion IONM is not routinely used in thyroid surgery in Australia and New Zealand. The main reasons for the use of IONM given in our study by routine users were to establish familiarity of equipment and medicolegal reasons. Selective users chose as the most common reasons, a documented pre-existing unilateral nerve paresis or a hostile surgical field. Non-users stated that there was conflicting evidence that it improves outcomes and increased costs.

IntroductionLung cancer is the leading cause of cancer mortality, comprising the largest national cancer disease burden in Australia and New Zealand. Regional reports identify substantial evidence-practice gaps, unwarranted variation from best practice, and variation in processes and outcomes of care between treating centres. The Australia and New Zealand Lung Cancer Registry (ANZLCR) will be developed as a Clinical Quality Registry to monitor the safety, quality and effectiveness of lung cancer care in Australia and New Zealand.Methods and analysisPatient participants will include all adults >18 years of age with a new diagnosis of non-small-cell lung cancer (NSCLC), SCLC, thymoma or mesothelioma. The ANZLCR will register confirmed diagnoses using opt-out consent. Data will address key patient, disease, management processes and outcomes reported as clinical quality indicators. Electronic data collection facilitated by local data collectors and local, state and federal data linkage will enhance completeness and accuracy. Data will be stored and maintained in a secure web-based data platform overseen by registry management. Central governance with binational representation from consumers, patients and carers, governance, administration, health department, health policy bodies, university research and healthcare workers will provide project oversight.Ethics and disseminationThe ANZLCR has received national ethics approval under the National Mutual Acceptance scheme. Data will be routinely reported to participating sites describing performance against measures of agreed best practice and nationally to stakeholders including federal, state and territory departments of health. Local, regional and (bi)national benchmarks, augmented with online dashboard indicator reporting will enable local targeting of quality improvement efforts.

This paper presents the development of a closed loop, sensorless field oriented control (FOC) of a low inductance and low power permanent magnet synchronous motor (PMSM) in a low acceleration application. The FOC speed control algorithm is implemented utilizing the InstaSPIN - Motion ™ C2000™ LaunchPad™ DSP, DRV8301 BoosterPack™ inverter, and Code Composer Studio. The software settings are presented considering the low inductance nature of the PMSM motor along with controller gain settings. The experimental results confirmed a sinusoidal phase current without any distortion and a quadrature current ripple of approximately 5 %. Low acceleration was achieved through software decimation. The speed output was stable, following the command signal.

Introduction Parathyroid computed tomography using multiple phases (four-dimensional computed tomography (4DCT) for parathyroid localization was first described in 2006. Since its inception, there has been variable uptake of this technique due to inconsistency of results between institutions and perceived higher radiation dose than technetium-99 sestamibi scans (MIBI). 4DCT has been the primary imaging modality for parathyroid localization at our institution since 2013. Methods A retrospective study of surgically managed patients with primary hyperparathyroidism who had preoperative localization with 4DCT from 2013-2018 was performed. Results A total of 353 patients were included for analysis. The positive predictive value (PPV) of our three-phase 4DCT protocol was 93.3%, sensitivity (localized) 85.2% with a 5.8% false-positive rate and 13.9% false-negative (non-localizing) rate when reported by a head and neck radiologist (HNR). Calculated effective dose varied from 4.5 to 8.9mSV. On multivariable logistic regression, reporting by an experienced HNR (P 200 mg (P = 0.002) were significant for higher accuracy, lower false positives and false negatives. Conclusion A first-line three-phase 4DCT protocol for primary hyperparathyroidism is an accurate technique providing precise anatomical localization of abnormal parathyroid glands, particularly when performed by a specialist HNR. In our practise, it provides the best rate of detection and superior anatomical localization needed for minimally invasive parathyroid surgery, compared to other commonly used localization techniques. It also avoids the need for four gland exploration in the majority of patients with primary hyperparathyroidism.

Adrenocortical carcinoma is a rare but aggressive form of endocrine neoplasm that confers a poor prognosis. To date, the only Australian data published is from New South Wales. This paper describes our experience in Western Australia with a focus on surgical approach and outcomes.A retrospective study of patients treated for adrenocortical carcinoma in Western Australia over 14 years was performed.Over the 14-year period, a total of 33 patients underwent surgery for adrenocortical carcinoma. Resection outcomes were superior in an open en bloc approach with an 85% R0 margin (P = 0.007). Local recurrence rates were lowest in an open en bloc approach (11%) compared to laparoscopic (75%). Multivariate analysis showed that an en bloc resection is highly correlated with an R0 resection (P 0.05) and significantly associated with lower (odds ratio = 0.06) local recurrence (P = 0.009). Higher volume surgeons (5 cases) had lower operative times and blood loss. Compliance with mitotane was significantly improved with close monitoring of levels. The European Network for the Study of Adrenal Tumours (ENSAT) stage at presentation was most predictive of long-term survival with 100% of stage I patients alive compared to 53% of stage II, 25% of stage III and 17% of stage IV patients at the end of the follow-up period.An open en bloc approach with a low threshold for multi-visceral resection performed by high volume surgeons have improved outcomes in local recurrence, operative times and blood loss.

G-CSF is a hemopoietic growth factor that has a role in steady state granulopoiesis, as well as in mature neutrophil activation and function. G-CSF– and G-CSF receptor–deficient mice are profoundly protected in several models of rheumatoid arthritis, and Ab blockade of G-CSF also protects against disease. To further investigate the actions of blocking G-CSF/G-CSF receptor signaling in inflammatory disease, and as a prelude to human studies of the same approach, we developed a neutralizing mAb to the murine G-CSF receptor, which potently antagonizes binding of murine G-CSF and thereby inhibits STAT3 phosphorylation and G-CSF receptor signaling. Anti–G-CSF receptor rapidly halted the progression of established disease in collagen Ab-induced arthritis in mice. Neutrophil accumulation in joints was inhibited, without rendering animals neutropenic, suggesting an effect of G-CSF receptor blockade on neutrophil homing to inflammatory sites. Consistent with this, neutrophils in the blood and arthritic joints of anti–G-CSF receptor–treated mice showed alterations in cell adhesion receptors, with reduced CXCR2 and increased CD62L expression. Furthermore, blocking neutrophil trafficking with anti–G-CSF receptor suppressed local production of proinflammatory cytokines (IL-1β, IL-6) and chemokines (KC, MCP-1) known to drive tissue damage. Differential gene expression analysis of joint neutrophils showed a switch away from an inflammatory phenotype following anti–G-CSF receptor therapy in collagen Ab-induced arthritis. Importantly, G-CSF receptor blockade did not adversely affect viral clearance during influenza infection in mice. To our knowledge, we describe for the first time the effect of G-CSF receptor blockade in a therapeutic model of inflammatory joint disease and provide support for pursuing this therapeutic approach in treating neutrophil-associated inflammatory diseases.

Human complement receptor 1 (HuCR1) is a pivotal regulator of complement activity, acting on all three complement pathways as a membrane-bound receptor of C3b/C4b, C3/C5 convertase decay accelerator, and cofactor for factor I-mediated cleavage of C3b and C4b. In this study, we sought to identify a minimal soluble fragment of HuCR1, which retains the complement regulatory activity of the wildtype protein. To this end, we generated recombinant, soluble, and truncated versions of HuCR1 and compared their ability to inhibit complement activation in vitro using multiple assays. A soluble form of HuCR1, truncated at amino acid 1392 and designated CSL040, was found to be a more potent inhibitor than all other truncation variants tested. CSL040 retained its affinity to both C3b and C4b as well as its cleavage and decay acceleration activity and was found to be stable under a range of buffer conditions. Pharmacokinetic studies in mice demonstrated that the level of sialylation is a major determinant of CSL040 clearance in vivo. CSL040 also showed an improved pharmacokinetic profile compared with the full extracellular domain of HuCR1. The in vivo effects of CSL040 on acute complement-mediated kidney damage were tested in an attenuated passive antiglomerular basement membrane antibody-induced glomerulonephritis model. In this model, CSL040 at 20 and 60 mg/kg significantly attenuated kidney damage at 24 h, with significant reductions in cellular infiltrates and urine albumin, consistent with protection from kidney damage. CSL040 thus represents a potential therapeutic candidate for the treatment of complement-mediated disorders.

The direct introduction of crude oil samples diluted in organic solvents to be analyzed by inductively coupled plasma-atomic emission spectroscopy (ICP-OES) and inductively coupled plasma mass spectrometry (ICP-MS) is an attractive way to perform elemental analysis, particularly in high sample volume facilities, where turnaround time is critical. Here, it is presented results obtained by performing direct injection of a broad set of petroleum crude oils diluted in o-xylene and analyzed by ICP-OES/MS. By utilizing proper sample preparation and instrument tuning parameters, we set out to assess data accuracy, standard deviation, and recovery, particularly in the region of mg kg–1 to μg kg–1. A multielement Conostan standard (10 elements at 2 mg kg–1 in crude oil) as well as NIST 1634c CRM were selected for this purpose. In general, the data from both instruments were comparable regarding precision, relative standard deviation, and recoveries for metals evaluated at a concentration range of interest. The pot...

Data aggregation is an integral part of Advanced Metering Infrastructure (AMI) deployment that is implemented by the concentrator. Data aggregation reduces the number of transmissions, thereby reducing communication costs and increasing the bandwidth utilization of AMI. However, the concentrator poses a great risk of being tampered with, leading to erroneous bills and possible consumer disputes. In this paper, we propose an end-to-end integrity protocol using elliptic curve based chameleon hashing to provide data integrity and authenticity. The concentrator generates and sends a chameleon hash value of the aggregated readings to the Meter Data Management System (MDMS) for verification, while the smart meter with the trapdoor key computes and sends a commitment value to the MDMS so that the resulting chameleon hash value calculated by the MDMS is equivalent to the previous hash value sent by the concentrator. By comparing the two hash values, the MDMS can validate the integrity and authenticity of the data sent by the concentrator. Compared with the discrete logarithm implementation, the ECC implementation reduces the computational cost of MDMS, concentrator and smart meter by approximately 36.8%, 80%, and 99% respectively. We also demonstrate the security soundness of our protocol through informal security analysis.

Trace elemental analysis using microwave-induced plasma (MP) generated by nitrogen gas was employed as an atomization and excitation source for emission spectrometric (microwave plasma atomic emission spectroscopy, MP-AES) analysis for crude oil samples. Nitrogen gas produced from air through a gas generator, and in combination with an external gas control module (EGCM) used to introduce air into the plasma, leads to a stable robust microwave-induced plasma, enough to perform the analysis of crude oil samples with different API values, sulfur (0.5–5 wt %) and nitrogen (500 −2500 mg/kg) by direct dilution in a o-xylene diluent. Excellent detection limits and spike recoveries at low and high concentration levels were determined for Ni, V, Fe, Ca, and Na in crude oil matrix. The recoveries obtained from the analysis of the three quality control (QC) test materials were within ±10% of the actual/certified values. Comparable results for Ni and V as well as the V/(V + Ni) ratio in crude oils between nitrogen pl...

Activation of Fc receptors and complement by immune complexes is a common important pathogenic trigger in many autoimmune diseases and so blockade of these innate immune pathways may be an attractive target for treatment of immune complex-mediated pathomechanisms. High-dose IVIG is used to treat autoimmune and inflammatory diseases, and several studies demonstrate that the therapeutic effects of IVIG can be recapitulated with the Fc portion. Further, recent data indicate that recombinant multimerized Fc molecules exhibit potent anti-inflammatory properties. In this study, we investigated the biochemical and biological properties of an rFc hexamer (termed Fc-μTP-L309C) generated by fusion of the IgM μ-tailpiece to the C terminus of human IgG1 Fc. Fc-μTP-L309C bound FcγRs with high avidity and inhibited FcγR-mediated effector functions (Ab-dependent cell-mediated cytotoxicity, phagocytosis, respiratory burst) in vitro. In addition, Fc-μTP-L309C prevented full activation of the classical complement pathway by blocking C2 cleavage, avoiding generation of inflammatory downstream products (C5a or sC5b-9). In vivo, Fc-μTP-L309C suppressed inflammatory arthritis in mice when given therapeutically at approximately a 10-fold lower dose than IVIG, which was associated with reduced inflammatory cytokine production and complement activation. Likewise, administration of Fc-μTP-L309C restored platelet counts in a mouse model of immune thrombocytopenia. Our data demonstrate a potent anti-inflammatory effect of Fc-μTP-L309C in vitro and in vivo, likely mediated by blockade of FcγRs and its unique inhibition of complement activation.

Diabodies are noncovalent dimers of single-chain antibody fragments that retain the avidity of intact IgG but have more favorable blood clearance than intact IgG. Radiometals offer a wide range of half-lives and emissions for matching imaging and therapy requirements and provide facile labeling of chelate-antibody conjugates. However, because of their high retention and metabolism in the kidney, the use of radiometal-labeled diabodies can be problematic for both imaging and therapy. Methods: Having previously shown that 111In-DOTA-polyethylene glycol (PEG)3400-anti–carcinoembryonic antigen diabody has less than half the kidney uptake and retention of non-PEGylated diabody and that the two have similarly high tumor uptake and retention, we synthesized a similar derivative for an anti–tumor-associated glycoprotein 72 diabody. We also reduced the molecular size of the polydispersed PEG3400 to monodispersed PEG27 and PEG12 (nominal masses of 1,321 and 617, respectively). We performed biodistributions of their DOTA conjugates radiolabeled with 125I, 111In, or 64Cu in tumor-bearing athymic mice. Results: The addition of PEG3400 to the diabody reduced kidney uptake to a level (≈10 percentage injected dose/g) comparable to that obtained with radiometal-labeled intact IgG. The PEG27 and PEG12 diabody conjugates also demonstrated low kidney uptake without reduction of tumor uptake or tumor-to-blood ratios. When radiolabeled with 64Cu, the DOTA-PEG12 and -PEG27 diabody conjugates gave high-contrast PET images of colon cancer xenografts in athymic mice. Conclusion: PEGylated diabodies may be a valuable platform for delivery of radionuclides and other agents to tumors.

Clinical empathy, a critical skill for the doctor-patient relationship, is infrequently taught in graduate medical education. No study has tested if clinical empathy can be taught effectively.To assess whether medicine residents can learn clinical empathy techniques from theater professors.A controlled trial of a clinical empathy curriculum taught and assessed by 4 theater professors.Virginia Commonwealth University, Richmond, Virginia, a large urban university and health system.Twenty Internal Medicine residents: 14 in the intervention group, 6 in the control group.Six hours of classroom instruction and workshop time with professors of theater.Scores derived from an instrument with 6 subscores designed to measure empathy in real-time patient encounters. Baseline comparisons were made using two-sample T tests. A mixed-effects analysis of variance model was applied to test for significance between the control and intervention groups.The intervention group demonstrated significant improvement (por = .011) across all 6 subscores between pre-intervention and post-intervention observations. Compared to the control group, the intervention group had better posttest scores in 5 of 6 subscores (por = .01).The study was neither randomized nor blinded.Collaborative efforts between the departments of theater and medicine are effective in teaching clinical empathy techniques.

Summary Although vaccines have been highly successful in preventing and treating many infectious diseases (including smallpox, polio and diphtheria) diseases prevalent in the developing world such as malaria and HIV, that suppress the host immune system, require new, multiple strategies that will be defined by our growing understanding of specific immune activation. The definition of adjuvants, previously thought of as any substance that enhanced the immunogenicity of antigen, could now include soluble mediators and antigenic carriers that interact with surface molecules present on DC (e.g. LPS, Flt3L, heat shock protein) particulate antigens which are taken up by mechanisms available to APC but not other cell types (e.g. immunostimulatory complexes, latex, polystyrene particles) and viral/ bacterial vectors that infect antigen presenting cells (e.g. vaccinia, lentivirus, adenovirus). These approaches, summarized herein, have shown potential in vaccinating against disease in animal models, and in some cases in humans. Of these, particle-antigen conjugates provide rapid formulation of the vaccine, easy storage and wide application, with both carrier and adjuvant functions that activate DC. Combined vaccines of the future could use adjuvants such as virus-like particles and particles targeted towards a predominant cellular type or immune response, with target cell activation enhanced by growth factors or maturation signals prior to, or during immunization. Collectively, these new additions to adjuvant technology provide opportunities for more specific immune regulation than previously available.

Ocular lymphoid tumours represent a spectrum of lymphoproliferative disease and can be subdivided into benign or reactive lymphoid hyperplasia, indeterminate or atypical lymphoid proliferations and malignant lymphoma. Treatment options include a wait and watch approach, systemic steroids, local radiotherapy or systemic chemotherapy. We describe a case of bilateral atypical lymphoid hyperplasia treated successfully with combination immunotherapy and radiotherapy. A 60-year-old lady presented with proptosis and left supra-orbital mass and was diagnosed to have bilateral atypical lymphoid hyperplasia. She had extensive extraocular facial infiltrates but no other sites of involvement on staging investigations. She was treated with eight doses of rituximab 375 mg/m² at weekly intervals with a good partial response, followed by consolidative radiotherapy. Rituximab may be an effective treatment adjunct/alternative for patients with atypical lymphoid hyperplasia of the orbit, particularly where widespread lesions preclude the use of initial radiotherapy.

In recent years a significant number of Singapore companies have invested in the PRC, and a large number are set to follow in their path. The purpose of this research is to ascertain the Critical Success Factors (CSF) that have, in the opinion of senior executives, determined success in this market. Thus a guideline is produced to help executives of potential new entrants by indicating to them where their attention should be focused. The data is gathered in two modes: survey and interview. Initially a sample of twenty-six companies was surveyed and asked a battery of questions to establish the relevant factors. These CSFs were analyzed for different industries under the headings of entry mechanisms, human resource factors, Government incentives, infrastructure and political factors. Two companies were then interviewed in depth in order to flesh out the survey data.

Previous studies compared uptake by dendritic cells (DC) of 20, 40, 100, 200, 500, 1000, and 2000 nm beads in vivo. When beads were used as antigen carriers, bead size influenced antibody responses and induction of IFN-gamma-producing CD4 and CD8 T cells. Beads of 40-50 nm were taken up preferentially by DC and induced particularly strong immunity. Herein, we examine immunity induced by minute differences in nanobead size, specifically within a narrow viral-sized range (20, 40, 49, 67, 93, 101, and 123 nm), to see if bead carrier size influenced the induction of type 1 or type 2 cells as demonstrated by the production of IFN-gamma or IL-4. In vivo uptake by DC was assessed for selected sizes in this range. Responses to whole ovalbumin (OVA) or the OVA-derived CD8 T cell peptide epitope (SIINFEKL) were tested. After one immunization with beads-OVA, IFN-gamma responses to both OVA and SIINFEKL were significantly better with 40 and 49 nm beads than other sizes, while, in contrast, IL-4 responses to OVA were higher after immunization with OVA conjugated to larger beads (93, 101, and 123 nm). Thus IFN-gamma induction from CD8 T cells was limited to 40-49 nm beads, while CD4 T cell activation and IL-4 were induced by 93-123 nm beads-OVA. After two immunizations, there were comparable high levels of IFN-gamma produced with 40 and 49 beads and IL-4 reactivity was still higher for larger beads (93, 101, 123 nm). Production of IgG1 was seen across the full range of bead sizes, increasing after two immunizations. Since protection against respiratory syncytial virus (RSV) depends on strong IFN responses, while IL-4 responses are reported to cause asthma-like symptoms, immunization with RSV antigens on the 49 nm carrier beads could provide the basis for a suitable vaccine. When the 49 nm beads were conjugated to RSV proteins G88 (surface) or M2.1 (internal capsid), one immunization with G88 induced high levels of IFN-gamma and low levels of IL-4. IL-4 increased with two immunizations. Beads-M2.1 induced only moderate levels of IFN-gamma and low titer antibody after two immunizations. Mice vaccinated once with G88-conjugated 49 nm beads and challenged intranasally with RSV strain A2 subtype showed reduced viral titers and recovered from weight loss more rapidly than mice immunized with M2.1-conjugated 49 nm beads or naive control mice. These results show that precise selection of nanobead size for vaccination can influence the type 1/type 2 cytokine balance after one immunization, and this will be useful in the development of effective vaccines against common human pathogens such as RSV.

The ability and efficiency of various techniques to purifyadult stem cells from a heterogeneous cell population is animportant determinant for the successful characterizationand application of stem cells. Strategies employed to isolateor purify such cells are numerous,and these include sortingof cells according to specific cell surface markers usingeither fluorescence [ 1] (the current gold standard in purify-ing stem cells) or immunomagnetic technology [ 2],exploit-ing the differential plating efficiencies of stem cells on cul-ture plastic [3], and column-separation techniques [4].Adding to this, a strategy reported by Hung et al. [5] uses“double-decker culture plates” with “3- µm” pores to sepa-rate stem cells from a heterogeneous population.Hung et al. described plating Percoll gradient separatedbone marrow stem cells on double-decker culture plates(Transwell,Corning,NY) where the top plate was fabricatedwith 3- µm pores. Size-sieved (SS) postcultured cells on theupper plate were described to be fibroblastic in morphologyand large in size,while the lowere plate (LP) cells were smalland polygonal. A series of assays characterizing the differen-tiation potential, proliferation, and a selected group of sur-face markers was reported,but only on the SS cells. Hung etal. suggested that the 3-µm pores separated the stem cellsfrom the heterogeneous cell population. The true advantageand attractiveness of the proposed strategy would be its costeffectiveness, straightforward and user-friendly protocol.However, it would be more convincing to the scientificcommunities of stem cell and tissue engineering if the LPcells were also characterized and shown not to possess thesame differentiation potential and characteristics. Thiswould be important before one can arrive at the conclusionthat successful “sieving” of stem cells had occurred. The“stem-ness”of the separated cell population subsets (SS,LP)would directly correlate with the efficacy of the proposedstrategy. The greater the efficacy, the more localized stem-ness would be on SS cells and the less on LP cells. Conse-quently, this would mean that the SS to LP data justify andreflect the efficacy of the procedure. Reporting SS cells ashaving stem cell characteristics may not be adequate becausewithout sieve separation, the multipotency of bone mar-row–derived stem cells have already been reported [6–10],thus leading us to expect some degree of stem cell character-istics with the SS cells anyway. Confirming the stem-ness ofa stem cell population must precede its characterization.Without such confirmation,any conclusions arising from thecharacteristics of the purported stem cell population wouldbe incomplete, and the derived clinical applications wouldhave profound repercussion throughout the field. Ideally,research should assess stem-ness in terms of cellular self-renewal ability–the differentiation of in vitro and in vivo sin-gle-cell clones into cell types of the tissue of origin and atleast one other different tissue cell type [11].In addition, the characterization of LP cells would alsoprovide some insights to stem cell biology. The presupposi-tion of the proposed strategy is that stem cells in suspensionwould be larger than 3 µm and would thus remain in the upper

Granulocyte colony-stimulating factor (G-CSF) is a haemopoietic cytokine first identified for its role in steady state granulopoiesis but is now also recognised as a proinflammatory mediator of mature neutrophil activation and function. G-CSF binds to the G-CSF receptor (G-CSFR), which is present on neutrophils and haemopoietic progenitors. G-CSF-deficient mice are protected from disease in several models of rheumatoid arthritis, and blockade of G-CSF is also protective in those models. To further investigate the actions of blocking G-CSF/G-CSFR signalling in inflammatory disease, we developed a neutralising monoclonal antibody to mouse G-CSFR which prevents the binding of G-CSF and inhibits G-CSFR signalling. In the anti-collagen antibody induced arthritis model, anti-G-CSFR treatment rapidly halted the progression of established disease. This therapeutic effect was observed at low dose and was associated with transient suppression of peripheral blood neutrophilia. Anti-G-CSFR treatment significantly inhibited neutrophil accumulation in the joints without rendering animals neutropenic, suggesting an effect of G-CSFR blockade on neutrophil homing to inflammatory sites. Consistent with this, neutrophils in the blood and arthritic joints of anti-G-CSFR treated mice showed alterations in homing receptors, with reduced CXCR2 and increased CD62L expression. Microarray analysis of neutrophils from joints and peripheral blood showed a common up-regulation of 6 genes and down-regulation of 22 genes following anti-G-CSFR treatment. Blocking neutrophil traffic to joints with anti-G-CSFR suppressed local production of proinflammatory cytokines (IL-1b and IL-6) and chemokines (KC and MCP-1) known to drive tissue damage. These data show for the first time the effect of blockade of G-CSFR in a therapeutic model of inflammation and provide further support for utilising this approach in the treatment of inflammatory diseases such as rheumatoid arthritis.