Equivocal Outcome Research Articles

The use of weight-of-evidence approaches to characterize developmental toxicity risk for therapeutic monoclonal antibodies in humans without in vivo studies

Regulatory guidance for global drug development relies on animal studies to evaluate safety risks for humans, including risk of reproductive toxicity. Weight-of-evidence approaches (WoE) are increasingly becoming acceptable to evaluate risk. A WoE for developmental risk of monoclonal antibodies (mAbs) was evaluated for its ability to retrospectively characterize risk and to determine the need for further in vivo testing based on the remaining uncertainty. Reproductive toxicity studies of 65 mAbs were reviewed and compared to the WoE. Developmental toxicities were absent in 52/65 (80%) mAbs. Lack of toxicity was correctly predicted in 29/52 (56%) cases. False positive and equivocal predictions were made in 9/52 (17%) and 14/52 (27%) cases. For 3/65 (5%) mAbs, the findings were equivocal. Of mAbs with developmental toxicity findings (10/65, 15%), the WoE correctly anticipated pharmacology based reproductive toxicity without any false negative predictions in 9/10 (90%) cases, and in the remaining case (1/10, 10%) an in vivo study was recommended due to equivocal WoE outcome. Therefore, this WoE approach could characterize presence and absence of developmental risk without animal studies. The current WoE could have reduced the need for developmental toxicity studies by 42% without loss of important patient information in the label.

EVALUATING SHORT-TERM OUTCOMES POST- INTRA-ARTICULAR CALCANEAL FRACTURE FIXATION VIA A SINUS TARSI APPROACH IN A NON-EXCLUSIVELY SELECTED COHORT

AimsManagement of intra-articular calcaneal fractures remains a debated topic in orthopaedics, with operative fixation often held in reserve due to concerns regarding perioperative morbidity and potential complications. The purpose of this study was to identify the characteristics of patients who developed surgical complications to inform the future stratification of patients best suited to operative treatment for intra-articular calcaneal fractures and those in whom surgery was highly likely to produce an equivocal functional outcome with potential post-operative complications.MethodsAll patients who underwent open reduction and internal fixation of calcaneal fractures utilizing the Sinus Tarsi approach between March 2014 and July 2018 were identified using theatre records. Patient imaging was used to assess pre- and post-operative fracture geometry with Computed Tomography (CT) used for pre-operative planning. Each patient's clinical presentation was established through retrospective analysis of medical records. Patients provided verbal consent to participation and patient reported outcome measures were recorded using the Maryland Foot Score.ResultsFifty-eight intra-articular calcaneal fractures (fifty-three patients including five bilateral, mean age = 46.91 years) were included. Forty-nine patients were injured as a result of a fall from a height (92.4%). Mean time from presentation to surgery was 3.23 days (range 0–21). Mean Maryland Foot score was found to be 77.6 (+/− 16.22) in forty-five patients. Five patients (9.4%) had wound complications; two superficial (3.7%) and three deep (5.6%).ConclusionIntra-articular fractures of the calcaneus should be considered for surgical intervention in order to improve long-term functional outcomes. The Sinus Tarsi approach provides the potential to decrease the operative complication rate whilst maintaining adequate fixation, however, the decision to surgically manage these fractures should be carefully balanced against the risk of post-operative complications. This increased risk of complication associated with smoking may tip the balance against benefit from surgical management.

To default or not? The aftermath of sovereign defaults and IMF programs in economic crises

AbstractEconomic crises are costly and highly disruptive, but does a sovereign default enhance or undermine economic recovery during the crisis? In this study, we approach this question by using a large dataset regarding economic crises after the Second World War. The results indicate that in terms of the real economy, domestic defaults tend to be followed by losses, especially in developing countries facing crises. Defaulting on foreign liabilities yields an equivocal economic outcome depending mostly on the level of economic development. Surprisingly, public debt seems to play no role in outcomes of defaults. We also analyse International Monetary Fund (IMF) programmes and find that they provide a more favourable crisis outcome.

The effect of pergolide mesylate on adrenocorticotrophic hormone responses to exogenous thyrotropin releasing hormone in horses

Thyrotropin releasing hormone (TRH) stimulation testing is often used to support a diagnosis of pituitary pars intermedia dysfunction (PPID) in horses although it is unclear whether or not repeat TRH stimulation testing post-treatment is a valid means of assessing response to medical therapy. Laboratory submissions from 64 suspected equine PPID cases were examined including the initial pre-treatment TRH stimulation test and a follow up test within 100 days of starting medical therapy with pergolide. In a subset of cases, further follow-up tests were examined beyond 100 days of starting treatment. Results from tests conducted between 1 July and 30 November were excluded.Significant improvements were seen in both the baseline and TRH-stimulated adrenocorticotrophic hormone (ACTH) concentrations within 100 days with no further improvements seen in the subset of cases examined thereafter. Although 88% (n = 56/64) of all cases showed a decreased response to TRH post-treatment, only 24% (n = 9/38) of horses with positive pre-treatment TRH stimulation tests normalised following treatment, with a further 34% (n = 13/38) improving into an equivocal test outcome category. Most commonly (42%; n = 16/38), horses with positive pre-treatment TRH stimulation tests remained positive following treatment, although 75% (n = 12/16) of these showed a numerically lower post-treatment response to TRH. These results will help inform practitioners of expected changes in TRH stimulation test results when assessing response of horses with PPID to medical therapy with pergolide.

Introducing variance-based global sensitivity analysis for uncertainty enabled operational and economic aircraft technology assessment

Assessing the efficacy of aircraft and technologies is a crucial step in the aeronautic product development. Due to their prospective nature, such analyses are subject to various uncertainties, which decrease their transparency and can act as a barrier for innovation. Therefore, a comprehensive and systematic inclusion of uncertainties is needed. For the use case of this paper being Hybrid Laminar Flow Control (HLFC), these comprise a number of inputs from different domains such as the design, operation, environment, or economics, leading to the underlying research question: Which parameters contribute to what extent to the output uncertainty of HLFC efficacy? To answer this, this paper introduces variance based global sensitivity analyses (GSA) in combination with a discrete event simulation framework. Considered outputs of the assessment comprise the Net Present Value (NPV) as an economic metric as well as the fuel efficiency as an operational performance indicator. A first monte-carlo simulation revealed an equivocal assessment outcome with ΔNPV values ranging from −$11M up to +$22M. Results of a subsequent GSA reveal the cruise mach speed being the dominant element (39%) in this overall uncertainty, followed by the lack of knowledge in specific fuel consumption penalty (23%) and overall drag reduction potential (9%). Furthermore, this study includes an applied comparison of different GSA methods, i.e. Fourier Amplitude Sensitivity Test and the Sobol' method. While computed sensitivity indices are fairly equal among all alternatives, the lack of quantification of higher order terms of certain methods may pose a disadvantage if interaction effects are high. The contribution of this study helps to direct further research and development efforts regarding HLFC, e.g. to focus on a robust and aerodynamically less sensitive airfoil design. More generally, the use of GSA methods and further uncertainty quantification efforts in prospective assessments can significantly improve the trust in the analysis and with that, help in terms of a commercially successful HLFC development.

Conventional dose versus dose escalated radiotherapy including high-dose-rate brachytherapy boost for patients with Gleason score 9\u201310 clinical localized prostate cancer

As several recent researches focus on the importance of Gleason 9–10, we examine the role of radiotherapy dose escalation in those patients. We analyzed 476 patients with Gleason score 9–10 prostate cancer treated with radiotherapy. Of them, 127 patients were treated with conventional-dose external beam radiotherapy (Conv RT) and 349 patients were treated with high-dose radiotherapy (HDRT; 249 patients received high-dose-rate brachytherapy boost + external beam radiotherapy [HDR boost] and 100 patients received intensity-modulated radiotherapy [IMRT]). We compared these treatment groups using multi-institutional retrospective data. The patients had a median follow-up period of 66.3 months. HDRT showed superior biochemical disease-free survival (bDFS) rate (85.2%; HDR boost 84.7% and IMRT 86.6%) to Conv RT (71.1%, p < 0.0001) at 5 years, with a hazard ratio of 0.448. There were borderline difference in prostate cancer-specific mortality (PCSM; 4.3% and 2.75%, p = 0.0581), and distant metastasis-free survival (DMFS; 94.4% and 89.6%, p = 0.0916) rates at 5-years between Conv RT and HDRT group. Dose escalated radiotherapy showed better bDFS, borderline improvement in PCSM, and equivocal outcome in DMFS in with clinically localized Gleason 9–10 prostate cancer.

Triple MAPK Inhibition Salvaged a Relapsed Post BCMA CAR-T Cell Therapy in Multiple Myeloma Patient with BRAF V600E Dominant Clone

Background:Multiple Myeloma (MM) is a progressive plasma cell neoplasm characterized by heterogeneous clonal expansion. Despite numerous targeted therapy options, failing anti-BCMA CAR-T cell therapy represents a challenging treatment course with dismal prognosis. 53% of relapsed/refractory (rr) MM patients have shown emerging clones harboring mutations within the MAPK signaling pathway including the targetable BRAF V600E in 7% of cases. Allosteric kinase inhibition of MAPK pathway with BRAF monomer selective inhibitors +/- MEK inhibitor have been frequently attempted with rrMM patients with equivocal outcome on both disease progression and survival. This could be ascribed to the feedback activation of the pathway via BRAF dimers induction. In solid tumor contexts, a recent study has revealed that the multi-kinase inhibitor regorafenib is a potent and selective inhibitor of dimeric BRAF. Moreover, the study demonstrated overcoming of this negative feedback by combining two inhibitors targeting BRAF in its monomeric and its dimeric form, respectively, with MEK inhibition leading to more efficacious and tolerable treatment (Adamopoulos C. et al. Cancer Discov. 2021). Here, we show the applicability, effectiveness, and tolerability of the aforementioned triple therapy strategy in hematological malignancy context to salvage post BCMA CAR-T cell therapy in a BRAF V600E rrMM patient.Material and Methods:CD138 + selected cells were collected from bone marrow (BM) and patient's plasmacytoma before and after CAR-T cell therapy relapse, respectively. Samples were processed using the standard GATK 4 workflows and a consensus mutation calling approach was used to call somatic mutations using a matched normal obtained from peripheral blood. PhyloWGS (Deshwar et al, Genome Biol 2015) was then used to perform intra-tumor heterogeneity modeling and phylogeny estimation.CD138 + selected cells from BM of rrMM patient were treated with encorafenib (50nM) and binimetinib (250 nM) +/- regorafinib (1mM) for 48 hours, cells were harvested, lysed and immunoblotted with BRAF V600E and pERK antibodies.In parallel, rrMM patient BM selected CD138 + cells' sensitivity to MAPK inhibitors were assessed by Travera. Cells are incubated with different inhibitors at varying concentrations and combinations for 15 hours before having their single-cell mass distributions measured. Sensitivity is then characterized by the relative statistical difference (Hellinger distance) between conditions and untreated controls.A rrMM patient was started on targeted triple therapy using the following combination: BRAF monomer-inhibitor, dabrafenib (100mg, orally twice daily), a MEK-inhibitor, trametinib (1.5mg, orally for 21/28 days daily), and a BRAF dimer inhibitor, regorafenib (40mg, orally once daily).Results:Whole Exome Sequencing (WES) showed a BRAF V600E mutation was present prior to CAR-T cell therapy and persisted through subsequent treatments. The variant allele frequency of the mutation was 41% post CAR-T cell therapy (Figure 1A).Western blot of CD138 + cells confirmed BRAF V600E mutation with a specific antibody, and showed ERK phosphorylation, which was inhibited with trametinib. Longer exposure to trametinib confirmed a feedback loop activating MAPK which was abrogated with the BRAF dimer inhibitor regorafenib (Figure 1B).Travera analysis showed CD138 + cells' sensitivity to the combination of trametinib at 5mM, and dabrafenib at 1µM. Adding regorafenib at 1µM could slightly improve the response compared to the double combination. (Figure 1C).Clinically, three months of the triple therapy administration has led to prompt reduction in subcutaneous skin lesions as well as 80% reduction in free lambda chain (Figure 1D). Furthermore, the patient exhibited good tolerance to all three medications with minimal side effects (grade 1 fatigue). The treatment regimen allowed the patient to carry out activities of daily living and resume work.Conclusion:We have shown the applicability, effectiveness, and tolerability of the triple MAPK inhibition in a hematological malignancy context to salvage post BCMA CAR-T cell therapy in a rrMM patient with BRAF V600E mutation. Also, we have revealed the power of routine WES in tracking clonal evolution, and identifying targetable mutations which allows tailoring of therapeutics for MM patients. [Display omitted] DisclosuresStevens: Travera: Current Employment. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.

Significance of Crooke's Hyaline Change in Nontumorous Corticotrophs of Patients With Cushing Disease.

BackgroundGlucocorticoid excess in Cushing disease (CD) leads to negative feedback suppression, resulting in Crooke's hyaline change (CC) of nontumorous pituitary corticotrophs. We aimed to determine the predictive value of CC of nontumorous corticotrophs in CD.MethodsThe retrospective chart review study included patients with clinical, biochemical, radiologic and outcome data and evaluable histopathology specimens from pituitary surgery for CD. The main outcome was remission of CD, defined by clinical features, biochemical testing, and corticosteroid dependency.ResultsOf 144 CD patients, 60 (50 women, mean age 43.6±14) had clinical follow-up, biochemical data and histopathology specimens that included evaluable nontumorous adenohypophysis. Specimens from 50 patients (83.3%) demonstrated CC in nontumorous corticotrophs, and 10 (16.7%) had no CC (including 3 with corticotroph hyperplasia). One patient with CC was lost to follow-up and one without CC had equivocal outcome results. During a mean (SD) follow-up period of 74.9 months (61.0), recurrent or persistent disease was documented in 18 patients (31.0%), while 40 (69.0%) were in remission. In patients with CC, the remission rate was 73.5% (95% CI, 59.7%-83.7%) (36/49), whereas it was 44.4% (95% CI, 18.9%-73.3%) (4/9) in patients with no CC. The combination of serum cortisol >138 nmol/L within a week of surgery coupled with absence of nontumorous CC greatly improved the prediction of recurrent or persistent disease.ConclusionsCC of nontumorous corticotrophs was observed in 83% of patients with CD, and most patients with CC experienced remission. Absence of CC in nontumorous corticotrophs may serve as a predictor of reduced remission in patients with CD.

1213. A TRAIL/IP-10/CRP Signature Distinguishes between Viral and Bacterial Infection in Chronic Obstructive Pulmonary Disease Patients

BackgroundChallenges in determining the etiology of acute exacerbations of chronic obstructive pulmonary disease (COPD) lead to significant overuse of antibiotics. A new host-response assay that integrates the levels of three proteins (TRAIL, IP-10, and CRP) was shown to exhibit high performance in distinguishing between bacterial and viral disease in two double-blind pediatric validation studies. Here we sought to evaluate its ability to differentiate bacterial from viral infection in adult COPD patients with suspicion of lower respiratory tract infection (LRTI).MethodsThe study population included 492 febrile adult patients prospectively recruited in “Observer”, an EU Horizon 2020 funded study (grant #684589). Patient etiology was determined by majority expert panel based on clinical, laboratory, multiplex PCR, radiological and follow-up data. We compared the expert panel diagnosis with the assay that gives three possible outcomes: viral, bacterial (including viral with bacterial coinfection) or equivocal.Results45 out 492 adult patients prospectively recruited with suspicion of LRTI had a medical history of COPD. Of these, 20 cases were assigned as suspected viral infections and 19 as suspected bacterial infections (Figure 1). Antibiotics were prescribed to 19/19 bacterial infections and 16/20 viral infections. The assay correctly classified 19/19 bacterial infections and 12/20 viral infections, with 2 viral cases classified by the assay as bacterial and 6 receiving an equivocal outcome. These data support the assay’s potential to reduce antibiotic overuse from 16/20=80% to 8/20=40% (P=0.01).FIgure 1: Flow through of COPD patients in prospective performance validation study “Observer” ConclusionA new TRAIL/IP-10/CRP signature has potential to significantly reduce antibiotic overuse for patients with suspected LRTI and a history of COPD without missing bacterial infection.DisclosuresMeital Paz, MD, MeMed Ltd. (Employee) Noa Avni, PhD, MeMed (Employee) Michal Stein, MeMed Ltd. (Employee) Liran Shani, MD, MeMed Ltd. (Employee) Tanya Gottlieb, PhD, MeMed (Employee) Kfir Oved, MD, PhD, MeMed (Employee) Eran Eden, PhD, MeMed (Employee)

1948. A Host-Response Assay Distinguishes Between Simple Influenza Patients and Influenza Patients With Bacterial Coinfection

BackgroundIdentifying bacterial coinfection in influenza patients can be difficult as the symptoms of simple influenza vs. mixed infections are often similar, leading to antibiotic overuse. A new host-response assay (ImmunoXpert™) that integrates the levels of three proteins (TRAIL, IP-10, and CRP) was shown to exhibit high performance in distinguishing between bacterial and viral disease in two double-blind validation studies. Here we sought to evaluate its ability to differentiate between simple influenza and influenza with bacterial coinfection.MethodsThe study population included 653 febrile pediatric and adult patients prospectively recruited in the “Curiosity” study. Patient etiology (simple viral vs. mixed infection) was determined by unanimous expert adjudication based on comprehensive clinical, laboratory and radiological assessment. Influenza strains (A or B) were detected using multiplex PCR applied to nasal swabs (Seeplex-RV15). We compared the expert panel diagnosis with the assay that gives three possible outcomes: viral, bacterial (including viral with bacterial coinfection) or equivocal. An equivocal outcome does not provide diagnostic information and is observed in ~10% of cases.ResultsOut of 653 patients, 51 had positive influenza detection and unanimous expert diagnosis: 44 simple viral infections and seven influenza with bacterial coinfections (Figure 1). Antibiotics were prescribed to all seven cases of influenza with bacterial coinfection and to 20/44 cases adjudicated as simple viral infections, indicating an overuse rate of 45%. The assay correctly classified 40 of the 44 simple viral cases (out of the remaining four, two were assigned viral with bacterial coinfection, and two received equivocal outcomes) as well as five of the seven viral with bacterial coinfection cases (the remaining two received equivocal outcomes) supporting the assay’s potential to reduce antibiotic overuse 5-fold (from 45% to 4/44 = 9%, P < 0.001).ConclusionThe host–response assay can differentiate between simple influenza and influenza patients with bacterial coinfection, with potential to reduce antibiotic overuse. Utility studies are warranted to demonstrate that the assay can safely assist physicians in correct management of influenza patients. Disclosures M. Paz, MeMed Diagnostics: Employee, Salary. K. Oved, MeMed Diagnostics: Board Member, Employee and Shareholder, Salary. T. Gottlieb, MeMed Diagnostics: Employee, Salary. A. Cohen, MeMed Diagnostics: Employee, Salary. R. Navon, MeMed Diagnostics: Employee, Salary. N. Mastboim, MeMed Diagnostics: Employee, Salary. E. Bamberger, MeMed Diagnostics: Employee, Salary. T. Friedman, MeMed Diagnostics: Employee, Salary. L. Etshtein, MeMed Diagnostics: Employee, Salary. O. Boico, MeMed Diagnostics: Employee, Salary. I. Potasman, MeMed Diagnostics: Holding stock options, Stock options. E. Eden, MeMed Diagnostics: Board Member, Employee and Shareholder, Salary. L. Shani, MeMed Diagnostics: Employee, Salary.

Comparison of Image-Guided Intensity-Modulated Radiotherapy and Low-dose Rate Brachytherapy with or without External Beam Radiotherapy in Patients with Localized Prostate Cancer

To compare the outcome of low-dose rate brachytherapy (LDR-BT) and image-guided intensity-modulated radiotherapy (IG-IMRT) for localized prostate cancer, we examined 488 LDR-BT and 269 IG-IMRT patients. IG-IMRT treated older and advanced disease with more hormonal therapy than LDR-BT, which excluded T3b–T4 tumor and initial PSA > 50 ng/ml. The actuarial five-year biochemical failure-free survival rate was 88.7% and 96.7% (p = 0.0003) in IG-IMRT and LDR-BT, respectively; it was 88.2% (85.1% for IG-IMRT and 94.9% for LDR-BT, p = 0.0578) for the high-risk group, 95.2% (91.6% and 97.0%, p = 0.3361) for the intermediate IG-IMRT and 96.8% (95.7% and 97%, p = 0.8625) for the low-risk group. Inverse probability of treatment weighting (IPTW) involving propensity scores was used to reduce background selection bias. IPTW showed a statistically significant difference between LDR-BT and IG-IMRT in high risk (p = 0.0009) and high risk excluding T3-4/initial PSA > 50 ng/ml group (p = 0.0073). IG-IMRT showed more gastrointestinal toxicity (p = 0.0023) and less genitourinary toxicity (p < 0.0001) than LDR-BT. LDR-BT and IG-IMRT showed equivocal outcome in low- and intermediate-risk groups. For selected high-risk patients, LDR-BT showed more potential to improve PSA control rate than IG-IMRT.

Outcome of HER2 Testing by FISH applying ASCO/CAP 2007 and 2013 guideline in IHC equivocal group of breast cancer: Experience at tertiary cancer care centre.

Background and Objectives:HER2 testing guideline of ASCO/CAP for interpretation and reporting has recently been revised. The study is aimed to measure the impact of 2013 CAP guideline on equivocal HER2 test outcome (immunohistochemistry [IHC] 2+) when tested by fluorescent in situ hybridization (FISH). The study also aims at finding the frequency of polysomy and monosomy of chromosome 17.Materials and Methods:Specimens were collected in Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India. IHC was performed in every case, and FISH was performed in IHC2+ cases.Results:In final analysis includes 557 subjects on the basis of CAP guideline 2007 and CAP guideline 2013. One hundred ninety-two subjects (34.4%) were HER2 amplified according to CAP scoring 2007, and 246 subjects (44%) according to 2013 CAP scoring.Conclusions:FISH results were evaluated (IHC2 + interpreted according to CAP 2007 guideline) with both 2007 and 2013 ASCO/CAP scoring criteria, we identified significantly more HER2 positive cases as compared to cases evaluated using the 2007 criteria (P < 0.05). We also found that in breast carcinoma, HER2 status in the presence of polysomy 17 may vary with the scoring criteria used. Evaluation of FISH result using 2013 ASCO/CAP criteria means that more patients with breast cancer may be appropriate for targeted treatment with trastuzumab, potentially improving their outcome.

Metronomic Chemotherapy: Seems Prowess to Battle against Cancer in Current Scenario.

Metronomic chemotherapy is an emerging method of chemotherapy. Metronomic 'lowdose' chemotherapy regimen induces tumour dormancy and reduces cancer resistance against anticancer drugs. It tends to improve overall success rate of cancer chemotherapy than conventional cyclical regimen. The aim of this systemic review was to provide comprehensive data of metronomic chemotherapy trials, regimens used and it's outcome in cancer therapeutics. Fifty chemotherapy trial data were searched sequentially from web. The main sources were official website of Clinical trial forum, USA and Clinical Trial Registry India (CTRI). Evidence on efficacy and safety of such metronomic chemotherapy trials was gathered from various data published in Medline, New England Journal of Medicine (NEJM), Lancet Oncology and other journals with high credentials. As a result of our search, out of 50 trials including breast -15(30%), colon-, 5(10%) ovarian -5(10%), prostate-5(10%) and others including haematologic, soft tissue and nervous system malignancies -20 (50%). Twenty seven trials showed favourable, 20 trials showed equivocal outcome and 3 trials reported unfavourable outcome. Overall comparison showed definitive statistical significance for using metronomic regimen (p-0.05). It can be concluded that metronomic chemotherapy regimen seems convincing beneficial to induce tumour remission and survival at a higher than conventional regimen. More metanalyses are needed to frame common metronomic chemotherapeutic regimen.

Posterior Shoulder Instability in Throwing Athletes: A Case-Matched Comparison of Throwers and Non-Throwers

To evaluate the results of arthroscopic capsulolabral repair for the treatment of posterior shoulder instability in a throwing athlete cohort when compared with non-throwers. Forty-eight overhead-throwing athletes undergoing arthroscopic posterior capsulolabral reconstruction were case matched with 48 non-throwing athletes. These cohorts were followed as they underwent posterior capsulolabral reconstruction by measuring shoulder pain, function, return to sport, and operative failures. Operative details such as intra-articular pathology and repair construct were also recorded. At a mean follow-up of 37 months (range, 12 to 97 months) postoperatively, no statistical differences were noted between throwers and non-throwers regarding American Shoulder and Elbow Surgeons scores, stability, strength, or range of motion. Sixty percent of throwing athletes were able to return to their preinjury level of competitive throwing. Throwers with a discrete labral tear intraoperatively had a 10-fold increased likelihood of returning to sport (odds ratio, 9.6; P= .012). Similarly, throwers who had suture anchor constructs showed a 10-fold increased likelihood of returning to play compared with anchor-less repairs (odds ratio, 9.6; P=.012). Non-throwers showed no variability by labral findings or fixation techniques. Pitchers had equivocal outcome scores when compared with other throwers but had poorer return-to-play rates (50% v 60% full return). Arthroscopic capsulolabral plication for unidirectional posterior shoulder instability is an effective treatment for overhead-throwing athletes. Intraoperatively, achieving an adequate capsular plication and stabilizing the repair with suture anchors will give this athletic population the best odds of returning to competitive sports. Level III, retrospective comparative study.

Uncertainty of Measurement for ELISA in a Serological Testing Laboratory

Background: Analytical results estimating Uncertainty of Measurement (MU) signifies the confidence level of the concerned assay. Enzyme-linked immunosorbent assay (ELISA) is an extensively used important tool for infectious disease sero-diagnosis, nevertheless, MU for ELISA result is not reported since procedure of MU estimation is hardly available. International Organization for Standardization (ISO) provides the Guide to the Expression of Uncertainty in Measurement (GUM) describing set of guidelines, however no detailed procedures or instructions for evaluating specific measurement processes is described. This article aims step by step procedure for MU estimation in a serology laboratory by describing the potential sources of uncertainty during each step of ELISA. Methods: HIV sample was tested by commercial ELISA following routine procedure. Uncertainty was estimated by specification of measurand, identification of uncertainty sources, quantification of values attributed to the sources of uncertainty and calculation of the combined standard uncertainty following GUM by converting all the standard uncertainties of ELISA into dimensionless relative standard uncertainties. The combined standard uncertainty was calculated using the propagation principle Results: Uncertainty arising from systematic error (RSD 0.10966) and routine analytical imprecision (RSD 0.04938) were considered as the sources of uncertainty contributing to the total MU of this routine qualitative diagnostic method. Analysis of the data revealed that results obtained for the relative expanded uncertainty Urel was 24% with 95% confidence level (k=2). Conclusion: Quantification of uncertainty by combining systematic error and analytical imprecision seems a feasible method of MU for ELISA. The estimated MU reflects the extent of variation for the cut-off absorbance for equivocal outcome of the qualitative interpretation.

Impact of interventions designed to reduce medication administration errors in hospitals: a systematic review.

There is a need to identify effective interventions to minimize the threat posed by medication administration errors (MAEs). Our objective was to review and critically appraise interventions designed to reduce MAEs in the hospital setting. Ten electronic databases were searched between 1985 and November 2013. Randomized controlled trials (RCTs) and controlled trials (CTs) reporting rates of MAEs or related adverse drug events between an intervention group and a comparator group were included. Data from each study were independently extracted and assessed for potential risk of bias by two authors. Risk ratios (RRs, with 95% confidence intervals [CIs]) were used to examine the effect of an intervention. Six RCTs and seven CTs were included. Types of interventions clustered around four main themes: medication use technology (n=4); nurse education and training (n=3); changing practice in anesthesia (n=2); and ward system changes (n=4). Reductions in MAE rates were reported by five studies; these included automated drug dispensing (RR 0.72, 95% CI 0.53-1.00), computerized physician order entry (RR 0.51, 95 % 0.40-0.66), barcode-assisted medication administration with electronic administration records (RR 0.71, 95 % CI 0.53-0.95), nursing education/training using simulation (RR 0.17, 95 % CI 0.08-0.38), and clinical pharmacist-led training (RR 0.76, 95 % CI 0.67-0.87). Increased or equivocal outcome rates were found for the remaining studies. Weaknesses in the internal or external validity were apparent for most included studies. Theses and conference proceedings were excluded and data produced outside commercial publishing were not searched. There is emerging evidence of the impact of specific interventions to reduce MAEs in hospitals, which warrant further investigation using rigorous and standardized study designs. Theory-driven efforts to understand the underlying causes of MAEs may lead to more effective interventions in the future.

Ex vivo reconstruction of the donor renal artery in renal transplantation: a case-control study.

Transplantation of renal allografts with anatomic variability or injured vasculature poses a challenge to the transplanting surgeon but can be salvaged for transplantation with ex vivo bench reconstruction of the vasculature. We investigated whether renal allograft function is impaired in these reconstructed allografts; compared to the donor-matched, un-reconstructed allograft. Reconstructed allografts were transplanted into 60 patients at our institution between 1986 and 2012. A control group was selected from the matched pair of the recipient in deceased donor transplantation. We found no significant difference in the overall graft and patient survival rates (P = 1.0, P = 0.178). Serum creatinine levels were not significantly higher in the study group at 1, 3 and 12 months postoperatively. There were two cases of vascular thrombosis in the study group that were not related to the ex vivo reconstruction. A significantly greater proportion of reconstructed patients were investigated with a colour duplex ultrasound postoperatively (0.007). Although we have demonstrated a higher index of suspicion of transplant failure in patients with a reconstructed allograft, this practice has proven to be a safe and useful technique with equivocal outcome when compared to normal grafts; increasing the organ pool available for transplantation.

Repetitive transcranial magnetic stimulation for hallucination in schizophrenia spectrum disorders: A meta-analysis.

Objective:This study assessed the efficacy and tolerability of repetitive transcranial magnetic stimulation for treatment of auditory hallucination of patients with schizophrenia spectrum disorders.Data Sources:Online literature retrieval was conducted using PubMed, ISI Web of Science, EMBASE, Medline and Cochrane Central Register of Controlled Trials databases from January 1985 to May 2012. Key words were “transcranial magnetic stimulation”, “TMS”, “repetitive transcranial magnetic stimulation”, and “hallucination”.Study Selection:Selected studies were randomized controlled trials assessing therapeutic efficacy of repetitive transcranial magnetic stimulation for hallucination in patients with schizophrenia spectrum disorders. Experimental intervention was low-frequency repetitive transcranial magnetic stimulation in left temporoparietal cortex for treatment of auditory hallucination in schizophrenia spectrum disorders. Control groups received sham stimulation.Main Outcome Measures:The primary outcome was total scores of Auditory Hallucinations Rating Scale, Auditory Hallucination Subscale of Psychotic Symptom Rating Scale, Positive and Negative Symptom Scale-Auditory Hallucination item, and Hallucination Change Scale. Secondary outcomes included response rate, global mental state, adverse effects and cognitive function.Results:Seventeen studies addressing repetitive transcranial magnetic stimulation for treatment of schizophrenia spectrum disorders were screened, with controls receiving sham stimulation. All data were completely effective, involving 398 patients. Overall mean weighted effect size for repetitive transcranial magnetic stimulation versus sham stimulation was statistically significant (MD = –0.42, 95%CI: –0.64 to –0.20, P = 0.000 2). Patients receiving repetitive transcranial magnetic stimulation responded more frequently than sham stimulation (OR = 2.94, 95%CI: 1.39 to 6.24, P = 0.005). No significant differences were found between active repetitive transcranial magnetic stimulation and sham stimulation for positive or negative symptoms. Compared with sham stimulation, active repetitive transcranial magnetic stimulation had equivocal outcome in cognitive function and commonly caused headache and facial muscle twitching.Conclusion:Repetitive transcranial magnetic stimulation is a safe and effective treatment for auditory hallucination in schizophrenia spectrum disorders.

St John’s Wort (Hypericum perforatum) versus Sertraline and Placebo in Major Depressive Disorder: Continuation Data from a 26-Week RCT

Hypericum perforatum (St John's wort: SJW) has been extensively studied as an antidepressant in short-term trials, however little research has been conducted on longer-term efficacy.Our objective was to analyze the continuation data from a 26-week randomized, double-blind, controlled study of SJW (LI-160) vs. sertraline and placebo in major depressive disorder. 124 participant "responders" continued treatment after week 8, until week 26. They continued randomly assigned SJW (900-1 500 mg), sertraline (50-100 mg) or matching placebo.At week 26, on the primary outcome, Hamilton depression rating scale (HAM-D) completer scores were: SJW (6.6±4.5), sertraline (7.1±5.4) and placebo (5.7±5.4) with a significant effect for time (p=0.036). Comparisons between all treatments were however non-significant (p=0.61). This effect was mirrored on the other outcomes: the BDI, CGI-severity, CGI-improvement, and on intention-to-treat analyses.While the continuation data revealed an equivocal outcome between treatments at week 26, both SJW and sertraline were still therapeutically effective, with a pronounced "placebo-effect" impeding a significant result at week 26.

Stabilizing Group Treatment for Complex Posttraumatic Stress Disorder Related to Child Abuse Based on Psychoeducation and Cognitive Behavioural Therapy: A Multisite Randomized Controlled Trial

Background: Evidence-based treatments for complex posttraumatic stress disorder (PTSD) related to childhood abuse are scarce. This is the first randomized controlled trial to test the efficacy of psycho-educational and cognitive behavioural stabilizing group treatment in terms of both PTSD and complex PTSD symptom severity. Methods: Seventy-one patients with complex PTSD and severe comorbidity (e.g. 74% axis II comorbidity) were randomly assigned to either a 20-week group treatment in addition to treatment as usual or to treatment as usual only. Primary outcome measures were the Davidson Trauma Scale (DTS) for PTSD and the Structured Interview for Disorders of Extreme Stress (SIDES) for complex PTSD symptoms. Statistical analysis was conducted in the intention-to-treat (ITT) and in the completer sample. Subjects were considered responders when scoring at 20 weeks at least 1 standard deviation below pretest findings. Results: The 16% attrition was relatively low. After 20 weeks, the experimental condition (large effect sizes) and control condition (medium effect sizes) both showed significant decreases on the DTS and SIDES, but differences between the conditions were not significant. The secondary responder analysis (ITT) revealed significantly more responders on the DTS (45 vs. 21%), but not on the SIDES (61 vs. 42%). Conclusions: Adding psycho-educational and cognitive behavioural stabilizing group treatment for complex PTSD related to child abuse to treatment as usual showed an equivocal outcome. Patients in both conditions improved substantially during stabilizing treatment, and while significant superiority on change scores was absent, responder analysis suggested clinical meaningfulness of adding group treatment.