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PC3 cells stably expressing different levels of MSLN

Agonistic CD40 monoclonal antibodies (mAb) have demonstrated some clinical activity, but with dose-limiting toxicity. To reduce systemic toxicity, we developed a bispecific molecule that was maximally active in the presence of a tumor antigen and had limited activity in the absence of the tumor antigen. LB-1 is a bispecific molecule containing single-chain Fv domains targeting mouse CD40 and the tumor antigen mesothelin. LB-1 exhibited enhanced activity upon binding to cell-surface mesothelin but was less potent in the absence of mesothelin binding. In a mouse model implanted with syngeneic 4T1 tumors expressing cell-surface mesothelin, LB-1 demonstrated comparable antitumor activity as an agonistic CD40 mAb but did not cause elevation of serum cytokines and liver enzymes, as was observed in anti-CD40–treated mice. The results from our study of LB-1 were used to develop a human cross-reactive bispecific molecule (ABBV-428) that targeted human CD40 and mesothelin. ABBV-428 demonstrated enhanced activation of antigen-presenting cells and T cells upon binding to cell-surface mesothelin, and inhibition of cultured or implanted PC3 tumor cell growth after immune activation. Although expression of cell-surface mesothelin is necessary, the bispecific molecules induced immune-mediated antitumor activity against both mesothelin+ and mesothelin− tumor cells. ABBV-428 represents a class of bispecific molecules with conditional activity dependent on the binding of a tumor-specific antigen, and such activity could potentially maximize antitumor potency while limiting systemic toxicity in clinical studies.

Binding affinity of LB-1

Table S1: ABT-165 binding affinity; Table S2: ABT-165 in vitro potency; Table S3: Effect of VEGF on anti-DLL4 cellular potency of ABT-165; Table S4: Summary of in vivo efficacy; Table S5: Key safety findings of ABT-487 and ABT-165; Figure S1: Serum concentration-time profiles of ABT-165 in cynomolgus monkeys; Figure S2: Effect of antibody or antibody fragment valency on anti-DLL4 cellular potency; Figure S3: Effect of VEGF on the activity of DLL4 mAb and ABT-165 to downregulate DLL4 protein; Figure S4: Plasma levels of total soluble DLL4 and VEGF in cynomolgus monkeys after ABT-165 treatment.

This file describes the binding assay details of surface plasmon resonance technology, ligand and receptor binding competition assays, western blot detection of DLL4 protein down-regulation, and the methods to measure total circulating soluble DLL4 and VEGF in cynomolgus monkey plasma.

Antiangiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved antiangiogenic drugs primarily inhibit the VEGF pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor-initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF. In vivo, ABT-165 induced significant tumor growth inhibition compared with either parental antibody treatment alone, due, in part, to the disruption of functional tumor vasculature. In combination with chemotherapy agents, ABT-165 also induced greater antitumor response and outperformed anti-VEGF treatment. ABT-165 displayed nonlinear pharmacokinetic profiles in cynomolgus monkeys, with an apparent terminal half-life > 5 days at a target saturation dose. In a GLP monkey toxicity study, ABT-165 was well-tolerated at doses up to 200 mg/kg with non-adverse treatment–related histopathology findings limited to the liver and thymus. In summary, ABT-165 represents a novel antiangiogenic strategy that potently inhibits both DLL4 and VEGF, demonstrating favorable in vivo efficacy, pharmacokinetic, and safety profiles in preclinical models. Given these preclinical attributes, ABT-165 has progressed to a phase I study. Mol Cancer Ther; 17(5); 1039–50. ©2018 AACR.

Whilst a growing number of women in the United Kingdom (UK) are making a success of a career in medicine as a whole, a considerable gender imbalance persists in neurosurgery. The extent of this disparity and the factors that perpetuate it are difficult to assess. Furthermore, over the 70 years since the first female neurosurgeon in the UK commenced her postgraduate training, it is difficult to gauge the progress that has been made. In this article we present a snapshot of women who have played, and who are playing, a key role in UK neurosurgery, highlighting their diverse career paths. We also present the current training distribution and subspecialties of women in UK neurosurgery. We use these data to reflect upon the possible barriers to completion of neurosurgical training, obtaining a substantive consultant position, and reaching positions of academic and clinical leadership. We discuss potential interventions that may overcome these. Highlighting the role women play in UK neurosurgery's past, present and future should inspire more female neurosurgeons to become leaders in the coming years.

Prolonged inflammation and impaired re-epithelization are major contributing factors to chronic non-healing diabetic wounds; diabetes is also characterized by xerosis. Advanced glycation end products (AGEs), and the activation of toll-like receptors (TLRs), can trigger inflammatory responses. Aquaporin-3 (AQP3) plays essential roles in keratinocyte function and skin wound re-epithelialization/re-generation and hydration. Suberanilohydroxamic acid (SAHA), a histone deacetylase inhibitor, mimics the increased acetylation observed in diabetes. We investigated the effects of TLR2/TLR4 activators and AGEs on keratinocyte AQP3 expression in the presence and absence of SAHA. Primary mouse keratinocytes were treated with or without TLR2 agonist Pam3Cys-Ser-(Lys)4 (PAM), TLR4 agonist lipopolysaccharide (LPS), or AGEs, with or without SAHA. We found that (1) PAM and LPS significantly upregulated AQP3 protein basally (without SAHA) and PAM downregulated AQP3 protein with SAHA; and (2) AGEs (100 µg/mL) increased AQP3 protein expression basally and decreased AQP3 levels with SAHA. PAM and AGEs produced similar changes in AQP3 expression, suggesting a common pathway or potential crosstalk between TLR2 and AGEs signaling. Our findings suggest that TLR2 activation and AGEs may be beneficial for wound healing and skin hydration under normal conditions via AQP3 upregulation, but that these pathways are likely deleterious in diabetes chronically through decreased AQP3 expression.

Background Limited data describe cognitive deficits in patients with Cushing syndrome (CS). The impact of mild autonomous cortisol secretion (MACS) on cognition is unknown. Objective To determine the impact of MACS on cognitive function. Methods Single-center cross-sectional study of adults with MACS and age and sex-matched volunteers. MACS was defined as cortisol >1.8 mcg/dL following the dexamethasone suppression test (DST) in patients with an adrenal incidentaloma and no features of CS. We measured cognitive function through the NIH toolbox cognition battery (7 standardized tests of attention, episodic and working memory, language, executive function, and processing speed). T-scores corrected for age, sex, education, and race were used for analysis. All patients completed the SF-36 questionnaire. The frailty index was calculated as previously reported (Singh S. JCEM 2020). Results Participants included 50 patients with MACS (median age 61, range 54-68) and 50 volunteers (median age 60 years, range 54-68), with 60% women in both groups. In patients with MACS, median post-DST morning cortisol was 3.6 (range, 2.4-6.2), and median corticotropin was 8.5 (range, 5.9-13) pg/mL (normal 6-60). Patients with MACS had a higher median frailty index (median of 0.26 vs. 0. 05 in volunteers, p Conclusion Compared to volunteers, patients with MACS demonstrate cognitive impairment, particularly in the executive domain, which closely mimics changes observed with aging. These deficits do not correlate with the degree of cortisol excess. Presentation: No date and time listed

The impact of stress in persons with multiple sclerosis (MS) is an area of ongoing inquiry. A limited number of published systematic reviews have reported an association between stress and MS onset. In addition to reviewing more recently published evidence, this review expands upon existing systematic reviews by considering the timing of stress exposure (childhood or adulthood).A review of human-subjects literature published in English after 2010 was conducted between April 2020 and May 2020. In total, 6 databases were searched using the terms 'allostatic load', 'multiple sclerosis (MS)', 'chronic stress', and 'stress', and 13 relevant studies were analyzed. Each article was read by at least two of the authors to confirm its relevance. Studies were categorized based on the timing of stress exposure (childhood or adulthood). Study designs included longitudinal cohort, cross-sectional cohort, cross-sectional case-control, and longitudinal case-control studies. The NIH study quality assessment tools and Strengthening The Reporting of OBservational studies in Epidemiology (STROBE) checklist were used to assess study quality. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews were followed.Manuscripts reviewed included 8 studies on MS onset, 2 studies on MS relapse, and 3 studies on MS onset and relapse. In total, 5 studies examined childhood stress, 7 studies examined adulthood stress, and 1 study examined both childhood and adulthood stress in 2 respective cohorts. Studies of varying design consistently reported an association between MS relapse and stress, regardless of the timing of stress exposure. However, the link between stress and MS onset was conflicting for both childhood and adult stress exposures.This systematic review is the first to report the strong association between stress and MS relapse, and, contradictory to past reports, an inconsistent relationship between stress and MS onset. Notably, the timing of stress (childhood or adulthood) seems to have little effect on the occurrence of either MS onset or relapse, though no study examined both childhood and adult stress within the same participant. Most studies were conducted in small, homogeneous samples using self-reported stress measures, which ultimately limits the generalizability of the findings. Overall, the state of the science remains tentative for all areas examined in this review, necessitating future research.

Shelterin is a six-protein complex that coats chromosome ends to ensure their proper protection and maintenance. Similar to the human shelterin, fission yeast shelterin is composed of telomeric double- and single-stranded DNA-binding proteins, Taz1 and Pot1, respectively, bridged by Rap1, Poz1 and Tpz1. The assembly of the proteinaceous Tpz1-Poz1-Rap1 complex occurs cooperatively and disruption of this shelterin bridge leads to unregulated telomere elongation. However, how this biophysical property of bridge assembly is integrated into shelterin function is not known. Here, utilizing synthetic bridges with a range of binding properties, we find that synthetic shelterin bridge lacking cooperativity requires a linker pair that matches the native bridge in complex lifespan but has dramatically higher affinity. We find that cooperative assembly confers kinetic properties on the shelterin bridge allowing disassembly to function as a molecular timer, regulating the duration of the telomere open state, and consequently telomere lengthening to achieve a defined species-specific length range.

Agonistic CD40 monoclonal antibodies (mAb) have demonstrated some clinical activity, but with dose-limiting toxicity. To reduce systemic toxicity, we developed a bispecific molecule that was maximally active in the presence of a tumor antigen and had limited activity in the absence of the tumor antigen. LB-1 is a bispecific molecule containing single-chain Fv domains targeting mouse CD40 and the tumor antigen mesothelin. LB-1 exhibited enhanced activity upon binding to cell-surface mesothelin but was less potent in the absence of mesothelin binding. In a mouse model implanted with syngeneic 4T1 tumors expressing cell-surface mesothelin, LB-1 demonstrated comparable antitumor activity as an agonistic CD40 mAb but did not cause elevation of serum cytokines and liver enzymes, as was observed in anti-CD40–treated mice. The results from our study of LB-1 were used to develop a human cross-reactive bispecific molecule (ABBV-428) that targeted human CD40 and mesothelin. ABBV-428 demonstrated enhanced activation of antigen-presenting cells and T cells upon binding to cell-surface mesothelin, and inhibition of cultured or implanted PC3 tumor cell growth after immune activation. Although expression of cell-surface mesothelin is necessary, the bispecific molecules induced immune-mediated antitumor activity against both mesothelin+ and mesothelin− tumor cells. ABBV-428 represents a class of bispecific molecules with conditional activity dependent on the binding of a tumor-specific antigen, and such activity could potentially maximize antitumor potency while limiting systemic toxicity in clinical studies.

Background The COVID-19 pandemic has resulted in significant changes to healthcare systems which impact the delivery of surgical training. This study aimed to investigate the qualitative impact of COVID-19 on surgical training in the United Kingdom (UK) & Republic of Ireland (ROI) Methods This national, collaborative, cross-sectional study involving 13 surgical trainee associations distributed a pan-surgical specialty questionnaire on the impact of COVID-19 on surgical training over 4 weeks in May 2020. Various aspects of training were assessed. Results 810 completed responses were analysed (males = 401, females = 390) from all deaneries and training grades. The perceived negative overall impact of the pandemic on surgical training experience was significant. (Weighted average = 8.66). 41% of respondents (n = 301) were redeployed with 74% redeployed for >4 weeks. Complete loss of training was reported in elective operating (69.5%), outpatient activity (67.3%) and endoscopy (69.5%). A reduction of >50% was reported in emergency operating (48%) and completion of work-based assessments (WBAs) (46%). 3.3% (n = 17) of respondents reported plans to leave medicine altogether. Cancellations in study leave and regional teaching programmes without rescheduling were reported in 72% and 60% of the cohort respectively. Elective operative exposure and WBAs completion were the primary reported factors affecting potential trainee progression. Only 9% of trainees reported that they would definitely meet all required competencies. Conclusion COVID-19 has had a negative impact on surgical training across all grades and specialties, with implications for trainee progression, recruitment and retention of the surgical workforce. Further investigation of the long-term impact at a national level is required.

Antiangiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved antiangiogenic drugs primarily inhibit the VEGF pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor-initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF. In vivo, ABT-165 induced significant tumor growth inhibition compared with either parental antibody treatment alone, due, in part, to the disruption of functional tumor vasculature. In combination with chemotherapy agents, ABT-165 also induced greater antitumor response and outperformed anti-VEGF treatment. ABT-165 displayed nonlinear pharmacokinetic profiles in cynomolgus monkeys, with an apparent terminal half-life > 5 days at a target saturation dose. In a GLP monkey toxicity study, ABT-165 was well-tolerated at doses up to 200 mg/kg with non-adverse treatment–related histopathology findings limited to the liver and thymus. In summary, ABT-165 represents a novel antiangiogenic strategy that potently inhibits both DLL4 and VEGF, demonstrating favorable in vivo efficacy, pharmacokinetic, and safety profiles in preclinical models. Given these preclinical attributes, ABT-165 has progressed to a phase I study. Mol Cancer Ther; 17(5); 1039–50. ©2018 AACR.

Objectives Publication productivity metrics can help evaluate academic faculty for hiring, promotion, grants, and awards; however, limited benchmarking data exist, which makes intra- and interdepartmental comparisons difficult. Therefore, we sought to evaluate the scholarly activity of physician faculty at academic radiation oncology (RO) departments and establish factors associated with increased academic productivity. Methods and materials Citation database searches were performed for all physician-faculty in US residency-affiliated academic RO departments. Demographics, National Institutes of Health (NIH) funding, and bibliometrics (number of publications, Hirsch-[h]-index, and m-index [Hirsch index divided by the number of years since first publication]) were collected and stratified by academic rank. Senior academic rank was defined as full professor, professor, and/or chair. Junior academic rank was defined as all others. Logistic regression was performed to determine the association of academic rank and other factors with h- and m-indices. Results A total of 1191 academic RO physician faculty from 75 institutions were included in the analysis. The mean (standard deviation) number of publications and h- and m-indices were 48.2 (71.2), 14.5 (15), and 0.86 (0.83), respectively. The median (interquartile range) number of publications and h- and m-indices were 20 (6-61), 9 (4-20), and 0.69 (0.38-1.10), respectively. Recursive partitioning analysis revealed a statistically significant numeric h-index threshold of 21 between junior and senior faculty (LogWorth 114; receiver operating characteristic, 0.828). Senior faculty status, receipt of NIH funding, and a larger department size were associated with increased h- and m-indices. Conclusions Current academic RO departments have relatively high objective metrics of scholastic productivity compared with prior benchmarking analyses of RO departments and compared with published metrics from other academic medicine subspecialties. An h-index of 21 or greater was associated with senior faculty status. Additionally, receipt of NIH funding and greater departmental size were associated with a higher h-index. These data may be of interest to faculty preparing for promotion or award applications as well as institutional leadership evaluating their departments.

Gynecologic cancers are the unregulated growth of neoplastic cells that arise in the cervix, ovaries, fallopian tubes, uterus, vagina, and vulva. Although gynecologic cancers are characterized by different signs and symptoms, studies have shown that they share common risk factors, such as smoking, obesity, age, exposure to certain chemicals, infection with human immunodeficiency virus (HIV), and infection with human papilloma virus (HPV). Despite recent advancements in the preventative, diagnostic, and therapeutic interventions for gynecologic cancers, many patients still die as a result of metastasis and recurrence. Since mounting evidence indicates that the epithelial-mesenchymal transition (EMT) process plays an essential role in metastatic relapse of cancer, understanding the molecular aberrations responsible for the EMT and its underlying signaling should be given high priority in order to reduce cancer morbidity and mortality.

Laparoscopic cholecystectomy is commonly performed, and several factors increase the risk of open conversion, prolonging operating time and hospital stay. Preoperative stratification would improve consent, scheduling and identify appropriate training cases. The aim of this study was to develop a validated risk score for conversion for use in clinical practice.Preoperative patient and disease-related variables were identified from a prospective cholecystectomy database (CholeS) of 8820 patients, divided into main and validation sets. Preoperative predictors of conversion were identified by multivariable binary logistic regression. A risk score was developed and validated using a forward stepwise approach.Some 297 procedures (3.4%) were converted. The risk score was derived from six significant predictors: age (p = 0.005), sex (p 0.001), indication for surgery (p 0.001), ASA (p 0.001), thick-walled gallbladder (p = 0.040) and CBD diameter (p = 0.004). Testing the score on the validation set yielded an AUROC = 0.766 (p 0.001), and a score6 identified patients at high risk of conversion (7.1% vs. 1.2%).This validated risk score allows preoperative identification of patients at six-fold increased risk of conversion to open cholecystectomy.

Perinatal growth restriction is associated with heightened sympathetic tone and hypertension. We have previously shown that naturally occurring neonatal growth restriction (GR) programs hypertension in male but not female mice. We therefore hypothesized that intact ovarian function or post-ovariectomy estrogen administration protects GR female mice from hypertension. Utilizing a non-interventional model that categorizes mice with weanling weights below the 10th percentile as GR, control and GR adult mice were studied at three distinct time points: baseline, post-ovariectomy (OVX), and post-OVX with oral estrogen replacement. OVX elicited hypertension in GR mice that was significantly exacerbated by psychomotor arousal (systolic blood pressure at light to dark transition: control 122+/−2; GR 119+/−2; control-OVX 116+/−3; GR-OVX 126+/−3 mmHg). Estrogen partially normalized the rising blood pressure surge seen in GR-OVX mice (23+/−7% reduction). GR mice had left ventricular hypertrophy, and GR-OVX mice in particular had exaggerated bradycardic responses to sympathetic blockade. For GR mice, a baseline increase in baroreceptor reflex sensitivity and high frequency spectral power support a vagal compensatory mechanism, and that compensation was lost following OVX. For GR mice, the OVX-induced parasympathetic withdrawal was partially restored by estrogen (40+/−25% increase in high frequency spectral power, P

Poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281) has gained both United States Food and Drug Administration (USFDA) and the European Commission (EC) approval for use inBRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized. In this review, we detail many of the biomarkers that have been investigated for their ability to predict both PARP inhibitor sensitivity and resistance in preclinical studies as well as the results of several clinical trials that have tested the safety and efficacy of different PARP inhibitor agents inBRCAand non-BRCA-mutated cancers.

INTRODUCTION: Language mapping during awake craniotomy is commonly used to guide tumour resection, but there is little description of its outcome. We present a series of 22 patients who underwent awake craniotomies with language mapping for glioma resection between 2007 and 2015. METHOD: Patients who had awake craniotomies with language mapping at a single centre were identified and included in this retrospective study. Details of patient demographics, tumour characteristics, treatment, speech and language assessments (SALT) and outcomes were recorded and analysed. 10 of these patients were also noted to have undergone pre-operative functional MRI (fMRI) with motor and language mapping. RESULTS: The majority were primary gliomas (16), of which 8 were WHO Grade 1-2. 5 out of the 6 recurrent cases were Grade 3-4. 9 were astrocytomas, and the rest were oligodendrogliomas (3), mixed astrocytoma/oligodendroglioma (6), and glioblastomas (4). Pre-operative SALT assessment identified language disorders in 11 patients. Intra-operative language mapping with direct cortical stimulation (DCS) was negative in 7 patients, and extent of tumour resection was guided by positive mapping in 14 patients. Post-operatively, 12 patients' speech remained unchanged, 8 developed worsening speech, and 2 had improved speech. Patients with a pre-operative fMRI were noted to have mildly lower rate of post-operative speech or neurological deficits compared to those who did not (20% vs 33% respectively). CONCLUSION: From our experience and this series, language mapping during awake craniotomies is a helpful tool for safer surgery without increasing complication rate. The addition of pre-operative fMRI may further reduce post-operative speech deficits.

INTRODUCTION: Invasion is a cardinal feature of glioblastomas - diffusely invasive tumours have worse prognosis than less invasive gliomas. Diffusion tensor imaging (DTI) provides a non-invasive method of studying the invasive margin. Studies measuring diffusion changes across the tumour margin, a measure of changes of cellularity, suggest it may be a marker of invasiveness. In this study we have assessed isotropic diffusion changes across the DTI defined tumour margin. METHOD: 47 patients with glioblastomas were studied before 5-ALA guided resection of these tumours before starting chemoradiotherapy. Imaging included anatomical imaging and DTI - which was processed into isotropic (p) and anisotropic (q) components. The area with the largest separation of the p and q was selected as the most invasive region and a line drawn across the border of p (the margin between invasive tumour and normal brain). The transition was quantified by the border transition gradient measured from the slope of point either side of the margin as well as whether the p values were more than12% above normal brain at the margin. These values were compared with time to progression (TTP). RESULTS: There was no correlation between the border transition gradient across the margin and TTP (r= 0.3, P = 0.85). There was an increased TTP where the p values were below threshold at the margin, but this was not significant (424 days vs. 326 days; P = 0.74). CONCLUSION: Transitional measurements across the DTI defined invasive margin do not provide information on the invasive nature of tumours and the time to progression.

INTRODUCTION: Low grade gliomas (LGG) are slow growing tumours, with the potential of transforming into aggressive high grade gliomas. Treatment of LGG must balance risk of malignant transformation against morbidity of early aggressive treatment. We evaluated the variation in management of low grade gliomas in the UK. METHOD: A survey was sent to all adult UK neurosurgery units, addressing surgical technology, treatment choice and surveillance. 23 units participated (82% participation rate). RESULTS: All LGG patients are discussed in an MDT meeting at initial presentation. 11 units manage patients in neurosurgical oncology clinics, and 6 units had dedicated LGG clinics. Others manage patients in general neurosurgical (3), combined (2) and oncology (1) clinics. The majority of centres use intra-operative ultrasound (20) and functional MRI (19) for motor and language mapping. 11 units use intra-operative EMG. Post-operative surveillance imaging intervals range from 3 to 12 months. Most units have multimodal MRI to detect tumour transformation, but do not always use them. Only 5 units use volumetric changes and 5 use PET imaging. Two clinical scenarios were also given: for a peripheral LGG, all units would consider resection followed by surveillance. Variable responses were given for an insular LGG: 9 would manage only with active surveillance, 6 would consider resection followed by surveillance. The rest choose to biopsy, followed by surveillance (4) or radiotherapy (4). CONCLUSION: This study demonstrates variable management of LGG across the UK, particularly surveillance intervals and of tumours in eloquent areas. More research to stratify transformation risk can help guide optimal treatment.

Background: Social media applications are promising adjuncts to online weight management interventions through facilitating education, engagement, and peer support. However, the precise impact of social media on weight management is unclear. Objective: The objective of this study was to systematically describe the use and impact of social media in online weight management interventions. Methods: PubMed, PsycINFO, EMBASE, Web of Science, and Scopus were searched for English-language studies published through March 25, 2013. Additional studies were identified by searching bibliographies of electronically retrieved articles. Randomized controlled trials of online weight management interventions that included a social media component for individuals of all ages were selected. Studies were evaluated using 2 systematic scales to assess risk of bias and study quality. Results: Of 517 citations identified, 20 studies met eligibility criteria. All study participants were adults. Because the included studies varied greatly in study design and reported outcomes, meta-analysis of interventions was not attempted. Although message boards and chat rooms were the most common social media component included, their effect on weight outcomes was not reported in most studies. Only one study measured the isolated effect of social media. It found greater engagement of participants, but no difference in weight-related outcomes. In all, 65% of studies were of high quality; 15% of studies were at low risk of bias. Conclusions: Despite the widespread use of social media, few studies have quantified the effect of social media in online weight management interventions; thus, its impact is still unknown. Although social media may play a role in retaining and engaging participants, studies that are designed to measure its effect are needed to understand whether and how social media may meaningfully improve weight management. [J Med Internet Res 2013;15(11):e262]

This paper explores what differentiates success from failure in post-acquisition integration. It seeks to overcome some of the limitations of previous research by adopting a more holistic and dynamic examination of the process and by focusing on aspects that can be readily applied in practice. Four cases of mergers and acquisitions (MA in each case, there was one successful M&A and one failure. It is inducted that what differentiates the successful cases from the failures is their different approaches to two common tensions in post-acquisition integration, namely, their approaches to integration strategy and people issues. A two-level framework is proposed in which post-integration is managed simultaneously and dynamically at the strategic and people levels. These inductive findings, if verified by a more broadly based empirical examination, will extend M&A theory by providing a more integrated and dynamic approach to post-acquisition integration, in which strategic and people perspectives are jointly taken into account and interact with each other, thereby creating value for both acquiring and acquired firms.

Migrating business applications to cloud can be costly, labor-intensive, and error-prone due to the complexity of business applications, the constraints of the clouds, and the limitations of existing migration techniques provided by migration service vendors. However, the emerging software-as-a-service offering model of migration services makes it possible to combine multiple migration services for a single migration task. In this paper, we propose a novel migration service composition approach to achieve a cost-effective migration solution. In particular, we first formalize the migration service composition problem into an optimization model. Then, we present an algorithm to determine the optimal composition solution for a given migration task. Finally, using synthetic trace driven simulations, we validate the effectiveness and efficiency of the proposed optimization model and algorithm.

Bipolar disorder; migraines and epilepsy are three prevalent conditions, of which little is understood about their pathophysiological processes. Co-morbidities often present between two of these conditions, but it is uncommon for all three to co-exist in a patient. Here, we present a middle-aged gentleman, seen in the outpatient department of a district general hospital in England, who suffers from severe effects of all three disorders, with no other medical history. Clinical difficulties have arisen in the diagnosis and treatment of his bipolar disorder. Management of his depressive episodes with simple selective serotonin reuptake inhibitors and mood stabilisers were either ineffective, or precipitated complicating adverse effects. Persistent use of citalopram is likely to have triggered bipolar disorder, whilst quetiapine induced seizures. The clinical problems presented question the possibility that bipolar disorder; migraines and epilepsy may fall on the same spectrum of disorders. This could contribute towards the complexities in treating his conditions. Further insight into their link and interactions would facilitate diagnoses of these conditions, as well as improve treatment strategies when they are presented co-morbidly.

Significant medical workforce shortages, particularly in rural and remote locations, have prompted a range of responses in Australia at both state and Commonwealth levels. One such response was a pilot project to test the suitability of the Physician Assistant (PA) role in the Australian context. Five US-trained and accredited PAs were employed by Queensland Health and deployed in urban, rural and remote settings across Queensland. A concurrent mixed-method evaluation was conducted by Urbis, an independent research firm. The evaluation found that the PAs provided quality, safe clinical care under the supervision of local medical officers. The majority of nurses and doctors who worked with the PAs believed that the PAs made a positive contribution to the health care team by increasing capacity to meet patient needs; reducing on-call requirements for doctors; liaising with other clinical team members; streamlining procedures for efficient patient throughput; and providing continuity during periods of doctor changeover. The Pilot demonstrated that a delegated PA role can provide safe, quality health care by augmenting an established healthcare team. The PA role has the potential to benefit the community by increasing the capacity of the health care system, and to improve recruitment and retention by providing an additional professional pathway. The small size of the Pilot limits the ability to generalise regarding the future efficacy of the PA role in Australia. Further research is required to test training and deployment of PAs in a wider range of Australian clinical settings, including general practice and rural health clinics.