True Efficacy Research Articles

The efficacy of liposomal bupivacaine compared with traditional peri-articular injection for pain control following total knee arthroplasty: an updated meta-analysis of randomized controlled trials

BackgroundThe efficacy of postoperative pain management is an important factor that influences the final outcome of total knee arthroplasty (TKA). Whether liposomal bupivacaine offers better efficacy compared with traditional peri-articular injection after TKA remains inconclusive. We conduct this study to compare the true efficacy of liposomal bupivacaine (LB) with traditional peri-articular injection (TPAI) following TKA.Materials and methodsRandomized controlled trials (RCTs) from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science were searched. Thirteen RCTs involving 1373 patients were finally included in our meta-analysis (LB = 691, TPAI = 682). The continuous and dichotomous outcome were collected in a standard form, and the data were analysed by using Review Manager 5.3 software. Finally, the results were presented in the forest plots.ResultThe pooled data demonstrated that the postoperative visual analogue score (VAS) in the LB group was not significantly different compared with that in the TPAI group at every time period after TKA. The liposomal bupivacaine group had significantly lower consumption of morphine equivalents 24 to 72 h postoperatively and reduced incidence of nausea and vomiting after TKA compared with the TPAI group. Finally, the length of hospital stay in the two groups was not significantly different.ConclusionLiposomal bupivacaine did not yield different results on the visual analogue scale compared with traditional peri-articular injection after total knee arthroplasty. However, liposomal bupivacaine was preferred in terms of lower consumption of morphine equivalents 24–72 h postoperatively and lower incidence of nausea and vomiting after total knee arthroplasty.

Efficacy of laser treatment for onychomycotic nails: a systematic review and meta-analysis of prospective clinical trials.

Laser therapy for onychomycosis is emerging but its efficacy remains unestablished. To examine current evidence on efficacy of laser treatment of onychomycosis. A systematic review and one-arm meta-analysis, including all prospective clinical trials, identified on PubMed, Cochrane Library, and EMBASE databases. Trials with participants as unit of analysis (UOA), n = 13, were analyzed separately from trials with nails as UOA, n = 7. Summary proportions and 95% confidence intervals (95% CI) were calculated. Outcomes were mycological cure, clinical improvement, or complete cure. Twenty-two prospective trials (four randomized controlled trials and 18 uncontrolled trials) with a total of 755 participants were analyzed. Summary proportions with 95% CI for participants as UOA were mycological cure 70.4%, 95% CI 52.2-83.8%; clinical improvement 67.2%, 95% CI 43.2-84.7%; and complete cure 7.2%, 95% CI 1.9-23.5%. High statistical heterogeneity was detected (mycological cure I2 = 88%, P < 0.01; clinical improvement I2 = 69%, P < 0.01; complete cure I2= 60%, P = 0.11). The current level of evidence is limited and with high heterogeneity, making it difficult to assess the true efficacy of laser treatment for onychomycosis. Larger randomized controlled trials with well-defined methodology are warranted.

Vitamin D as an Adjunctive Treatment to Standard Drugs in Pulmonary Tuberculosis Patients: An Evidence-Based Case Report.

Background Vitamin D has a prominent role in the body's innate immunity as it is important in the maintenance of macrophages and monocytes and its function in defending against infections. In-vitro studies have established vitamin D's potential role in tuberculosis (TB) infection, in that it restricts Mycobacterium tuberculosis growth, thus implying the potential benefit of vitamin D as an adjunctive treatment for TB. However, clinical trials and reviews have contradicting findings regarding the true clinical efficacy of adjunctive vitamin D, particularly in reducing the sputum conversion rate (SCR). Objective This study aims to update the current evidence regarding vitamin D supplementation as an adjunctive treatment in achieving the smear sputum conversion rate (SCR) among pulmonary TB patients. Method A comprehensive search was conducted in October 2018 in PubMed-NCBI, MEDLINE-OVID, SCOPUS-Elsevier, and Cochrane. The selection of studies was done as per the predetermined inclusion and exclusion criteria of this EBCR and resulted in the inclusion of 11 eligible studies (8 RCTs and 3 systematic reviews). The selected studies were then critically appraised for their validity, importance, and applicability according to the CEBM (Centre for Evidence-Based Medicine) appraisal tools. Results Overall, most of the trials showed no statistically significant changes in terms of the proportion of TB patients with a negative sputum smear conversion in the group treated with an adjunctive therapy vs. the group treated with standard antituberculosis therapy alone. Only one trial showed significant results, which was conducted in a population of TB patients with vitamin D deficiency. Furthermore, overall the reviews showed no significant change in the 8-week sputum smear conversion after treatment within the group given vitamin D in comparison to those who were not. Conclusion Vitamin D as adjunctive therapy in TB patients shows no clinical improvement in terms of sputum conversion to antituberculosis management.

Efficacy of commercially available biological agents for the topical treatment of cervical intraepithelial neoplasia: a systematic review

BackgroundCervical cancer is a major public health issue in the world, especially in developing countries. It can be prevented through vaccination against HPV (primary prevention) and through screening and treatment of cervical intraepithelial neoplasia (CIN) (secondary prevention). Surgical methods for treatment of CIN are linked to complications such as bleeding and adverse pregnancy outcomes. Furthermore, these methods are not generally available in resource-poor settings. Therefore, topical agents for local application on the cervix have been used since decades to overpass complications and limitations of the surgical methods.AimsReview of the literature on the efficacy of commercially available biological agents used for topical treatment of cervical intraepithelial neoplasia (CIN).MethodsA systematic search through PubMed and the Cochrane database was performed up to December 2017, using the medical subheadings (MesH) for topical agent, treatment, and cervical intraepithelial neoplasia. Appropriate inclusion/exclusion criteria have been used for the selection of eligible clinical studies. Clinical studies containing a minimum of 20 women, aged 18–50 with a diagnosis of CIN 1–3, and at least a 4 weeks follow-up after the end of the topical treatment were included.ResultsThe initial electronic database search resulted in a total of 849 articles. After screening titles and abstracts, 62 articles were selected as potential studies. Of these, six articles were included in the review after reading the full text: two were on 5-FluoroUracil, two on trans retinoic acid, one on Imiquimod, and one on Cidofovir. The reported regression/remission rates for CIN differed among studies. In CIN2 patients, the overall remission rate ranged between 43 and 93% for the active agents.ConclusionAmong the topical agents studied, 5-FluoroUracil showed good remission rates above 80%. Varying results seen in this review is due to the differences in quality of the design between studies. Large-scale and less biaised studies are needed to elucidate the true efficacy and safety of topical agents in the treatment of CIN.

Pain and Functional Outcomes After Sacroiliac Joint Injection with Anesthetic and Corticosteroid at Six Months, Stratified by Anesthetic Response and Physical Exam Maneuvers

To evaluate sacroiliac joint (SIJ) injection outcomes with local anesthetic and corticosteroid. Prospective cohort. Single academic medical center. Thirty-four patients referred for SIJ injection with a clinical diagnosis of SIJ pain underwent injections with 1:1 mixture of 2% lidocaine and triamcinolone 40 mg/mL. Pain provocation physical exam (PE) maneuvers were recorded immediately before and after injection. Outcome measures at two to four weeks and six months included pain numeric rating scale (NRS) and Oswestry Disability Index (ODI). For the analysis of outcomes by the overall group (not stratified by PE and/or anesthetic block), a 58.8% (95% confidence interval [CI] = +/-16.5%) ≥2 NRS reduction, a 32.4% (95% CI = +/-15.7%) ≥50% NRS reduction, and a 38.2% (95% CI = +/-16.3%) ≥30% ODI reduction were observed at two to four weeks, with similar improvements at six months. Outcomes stratified based on pre-injection PE did not reveal significant differences at either time point. The stratification based on the presence of 100% postinjection anesthetic response demonstrated a significant difference at two to four weeks for ≥50% NRS improvement. The true positive/true negative group (TP/TN) stratification demonstrated a significant difference for ≥50% NRS improvement at two to four weeks, whereas six-month outcomes for TP/TN demonstrated significant differences for ≥50% NRS and ≥30% ODI improvement. An increased injection response was observed with stratification of patients more likely to have true SIJ pain (i.e., TP), with TP/TN stratification demonstrating a 75% (95% CI = +/-30.0%) ≥2 NRS improvement and a 62.5% (95% CI = +/-33.5%) improvement of ≥50% NRS and ≥30% ODI for the TP group at two to four weeks, with similar results at six months. SIJ steroid injection based on referral clinical diagnosis is unlikely to demonstrate true injection efficacy, and more specific selection criteria are warranted.

Evaluation of the effects of autohemotransfusion in arthritic rats induced by two doses of complete Freund´s adjuvant

The aim the study was to evaluate the effects of autohemotransfusion in adjuvant-induced arthritis model by injections of high and low doses of Complete Freund´s Adjuvant (CFA). Male Holtzman rats (200-230g) were distributed in six groups: control (C); control treated by autohemotransfusion (CT); CFA induced arthritis 0.5% w/v (AIA); CFA induced arthritis 0.5% w/v treated with autohemotransfusion (AIAT); CFA induced arthritis 0.1% w/v (AS) and CFA induced arthritis 0.1% w/v treated with autohemotransfusion (AST). The number of leukocytes, the weight of different organs and the paw volume were analyzed. The autohemotransfusion without erythrocytes promoted a reduction in the number of leukocytes in AIAT and AST when compared to AIA (p &lt; 0.001). In the AST group an increase of the thymus weight (p &lt; 0.05) was observed when compared to C, AIA and AIAT. The autohemotransfusion did not prevent the occurrence of paw edema in arthritic animals of AIAT and AST groups (p&gt;0.05). The autohemotransfusion used in this work presented positive effects on AIA as they promoted a reduction in the number of leukocytes and an increase in thymus weight and body growth. However, other types of autohemotransfusion must be tested to determine the true efficacy of this alternative method of treatment.

Shockwave Therapy in the Treatment of Peyronie's Disease.

Peyronie's disease is an acquired condition of the connective tissue of the penis that affects 0.5-20.3% of the male population and is marked by fibrotic plaques in the tunica albuginea. It can result in penile curvature/deviation, painful erections, and sexual dysfunction. Several treatment modalities have been proposed, with studies from the past decade investigating extracorporeal shockwave therapy's (ESWT) potential efficacy in Peyronie's management. To investigate the effects of ESWT on Peyronie's disease parameters such as penile curvature, plaque size, erectile function, and penile pain. We reviewed the literature examining the effects of ESWT on Peyronie's disease. The main outcome measures after receiving extracoporeal shockwave therapy included changes in degree of penile curvature, penile plaque size, International Index of Erectile Function-5 questionnaire score, and visual analogue scale score. Randomized controlled trials examining the efficacy of ESWT in Peyronie's disease do not show a statistically significant benefit in curvature reduction, plaque size, or erectile function, although a recent meta-analysis demonstrates a benefit in plaque size reduction. A statistically significant reduction in penile pain has been observed across multiple studies. Extracorporeal shockwave therapy may be beneficial in the management of Peyronie's disease for refractory penile pain and plaque size reduction. However, penile pain typically resolves spontaneously over time, and shockwave therapy can pose a substantial financial burden to patients. A multi-institutional randomized controlled trial with standardization of methods and strict inclusion criteria regarding disease duration would prove beneficial in determining the true efficacy of shockwave therapy in Peyronie's disease. Krieger JR, Rizk PJ, Kohn TP, etal. Shockwave Therapy in the Treatment of Peyronie's Disease. Sex Med Rev 2019;7:499-507.

Re-evaluation of Significance and the Implications of Placebo Effect in Antidepressant Therapy.

Placebo was conceived as an epistemological tool to control for incidental factors that could influence investigated outcomes (1, 2). As a phenomenon, placebo has been conceptualized in many different ways, both theoretically and practically, although a generally accepted definition is still to be devised (3). In clinical research setting it is, however, helpful to distinguish placebo response from placebo effect. Placebo response is considered to be the composite change observed in individuals after administration of placebo, consisting of different aspects, such as natural course of the disease and methodological artifacts, as well as the placebo effect itself (4, 5). Placebo effect would therefore be the change observed in individuals after controlling for natural course of the disorder, methodological aspects, and the effect linked to treatment-specific features (i.e., antidepressant verum) (1). In other words, placebo responses may or may not include placebo effect as genuine psychobiosocial effect that is usually attributed to various features of treatment situation and contexts (5). Recent findings consistently show a modest average effect (a mean effect size of d = 0.30) of antidepressants above placebo in short-term treatment of adult depression (6, 7). This could be interpreted as strong evidence of a modest effect. Whether this effect on outcome measures, that are rather limited and subjective, is clinically meaningful remains an open question (8). Issues of true long-term efficacy, safety and cost-effectiveness of antidepressant drugs still loom over the horizon (8–11). Still, these recent findings pose interesting questions, since similarly consistent findings have been published showing a large and highly variable placebo effect in studies aiming to prove true efficacy of antidepressants (12, 13). In other words, participants in antidepressant studies that are receiving, at least from a theoretical point, a supposedly inherently neutral intervention (one that should be lacking known, relevant, and specific features), show substantial and consistent improvement across different study designs and contexts.

Heart Transplant Induction Therapy in Canada: A National Survey

Purpose Indications and usage of induction therapy in heart transplantation is controversial. As a result, induction therapy is inconsistently used in heart transplant programs. We aimed to capture a point-prevalence view of opinions and utilization of induction therapy among adult Canadian heart transplant programs. Methods An electronic survey questionnaire was distributed to all heart transplant centers in Canada in August 2018. The survey consisted of 13 questions on site-specific induction therapy protocols, induction agent selection, dosing, and complications. Results All nine heart transplant centers in Canada completed the survey. Five centers (56%) use induction therapy on all patients and all centers use induction therapy on more than 50% of patients. Antithymocyte globulin (ATG) is the preferred drug in five centers (56%) whilst basiliximab (BAS) is the preferred drug in three centers (33%) . Only one center used a single agent (ATG) exclusively. For patients who were at higher risk of infection, BAS was preferred in eight (89%) centers. For patients who were at higher risk of kidney failure, ATG was preferred in 5 (56%) centers. Four centers (44%) used a reduced dose protocol more than 50% of the time when using ATG. Centers perceived that the relative increased risk of complications from induction therapy in descending order were: infection (21.4%), dehiscence (7.7%), acute respiratory distress syndrome (2.4%), and delirium (1.8%). Conclusion Induction therapy use is inconsistent across Canadian centers and may be more dependent on local practice patterns rather than on true efficacy or utility. Despite potential benefits, there were specific perceived concerns regarding the therapy. This clinical equipoise presents an opportunity for further prospective study.

Body surface area-based versus concentration-based intraperitoneal perioperative chemotherapy in a rat model of colorectal peritoneal surface malignancy: pharmacologic guidance towards standardization.

Worldwide, cytoreductive surgery (CRS) and hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) are used in current clinical practice for colorectal peritoneal surface malignancy (PSM) treatment. Although, there is an acknowledged standardization regarding the CRS, we are still lacking a much-needed standardization amongst the various intraperitoneal (IP) chemotherapy protocols, including the HIPEC dosing regimen. We should rely on pharmacologic evidence building towards such a standardization. The current IP chemotherapy dosing regimens can be divided into body surface area (BSA)-based and concentration-based protocols. A preclinical animal study was designed to evaluate pharmacologic advantage (PA), efficacy and survival. WAG/Rij rats were IP injected with the rat colonic carcinoma cell line CC-531. Animals were randomized into three groups: CRS alone or CRS combined with oxaliplatin-based HIPEC (either BSA- or concentration-based). There was no difference in PA between the two groups (p=0.283). Platinum concentration in the tumor nodule was significantly higher in the concentration-based group (p<0.001). Median survival did not differ between the treatment groups (p<0.250). This preclinical study, in contrast to previous thinking, clearly demonstrates that the PA does not provide any information about the true efficacy of the drug and emphasizes the importance of the tumor nodule as pharmacologic endpoint.

Analgesic strategies for day-case knee surgery.

Analgesic strategies for day-case knee surgery.

Abstract TP479: Early Differential Expression of Chemotactic Genes in Peripheral Blood May Predict Poststroke Blood Brain Barrier Disruption

PhD Complications of endovascular thrombectomy limit its current utility to a subset of patients. Expanding the utility of mechanical thrombectomy is possible with the addition of blood biomarkers that could be used to identify patients who are at risk for complications related to reperfusion injury such as blood brain barrier (BBB) disruption and malignant edema. The objective of this pilot study was to identify an early pattern of gene expression in the peripheral immune system which could be used to predict post-stroke BBB disruption. Peripheral whole blood samples were obtained from acute ischemic stroke patients at emergency department admission, and BBB disruption was assessed via level of hyperintense reperfusion injury marker (HARM) on MRI at 24-hour follow-up. Microarray was used to transcriptionally profile admission blood samples, and a machine-learning technique known as genetic algorithm k-nearest neighbors (GA/kNN) was used to identify a pattern of gene expression which could optimally discriminate between patients who presented with mild HARM (n=8) and severe HARM (n=8) at follow-up imaging. GA/kNN identified ten genes ( LAIR2, IL8, CXCL5, RBP7, CCDC149, LY96, HPSE, DDIT4, E2F3, and ADAM15 ) whose coordinate expression levels could discriminate between groups with 94% accuracy (88% sensitivity, 100% specificity). Furthermore, functional annotation enrichment analysis suggested that top genes identified by GA/kNN were enriched for genes involved in chemotaxis, suggesting that the early differential expression of genes associated with cellular migration may be predictive of post-stroke BBB disruption. The pattern of gene expression identified in this study shows strong potential for helping to guide selection of patients for mechanical thrombectomy, and warrants further evaluation to determine its true clinical efficacy.

Treatment of morphea with hydroxychloroquine: A retrospective review of 84 patients at Mayo Clinic, 1996-2013

Few studies support treating morphea (localized scleroderma) with hydroxychloroquine. To assess the efficacy of hydroxychloroquine treatment of morphea. We conducted a retrospective study of 84 patients who had morphea and were treated with hydroxychloroquine monotherapy for at least 6months at our institution from 1996 through 2013. The median times to initial and maximal responses were assessed. Of the 84 patients (median age at diagnosis, 29.5years), 65 (77.4%) were female, 36 (42.9%) had a complete response to hydroxychloroquine, 32 (38.1%) had a partial response greater than 50%, 10 (11.9%) had a partial response less than or equal to 50%, and 6 (7.1%) had no response. The median time to initial response was 4months, and the median time to maximal response was 12months. Ten patients (11.9%) experienced adverse effects from hydroxychloroquine; the most common adverse effect was nausea (6patients). Retrospective study. Hydroxychloroquine is a valuable treatment for morphea because of its high response rateand low rate of adverse effects; however, prospective studies are needed to determine its true efficacy.

Robotic versus laparoscopic surgery for rectal cancer: an overview of systematic reviews with quality assessment of current evidence.

The clinical benefits of robotic surgery for patients with rectal cancer have been reported and many systematic reviews have been published. However, they have investigated a variety of outcomes and differ remarkably in quality. In this overview, we summarize the findings of these reviews and evaluate their quality. The PubMed, Scopus, and Cochrane Central Register of Controlled Trials databases were comprehensively searched to identify systematic reviews and meta-analyses that compared robotic and laparoscopic surgery. We assessed the quality of the reviews using the AMSTAR-2 tool. The literature search identified 17 eligible reviews, all of which reported that the incidence of conversion to open surgery was lower for robotic surgery than for laparoscopic surgery. Most of the reviews reported no difference in the other outcomes between robotic surgery and laparoscopic surgery. However, the quality of the reviews was judged to be low or critically low. Critically low quality evidence suggests that robotic surgery for rectal cancer decreases the likelihood of conversion to open surgery, but other clinical benefits remain unclear. High-quality systematic reviews in which selection of high-quality studies is combined with adequate methodology are needed to clarify the true efficacy of robotic surgery for rectal cancer.

A diagnostic software algorithm for morphological detection of lobular and ductal carcinoma on ultrasound

Breast cancer remains the most common form of cancer amongst women. This has led to the need to enable early detection by using the latest technology in high frequency ultrasound.The increased interest in ultrasound as a diagnostic tool for breast cancer detection has led to rapid developments in the application thereof.Sonography is a popular tool for physicians, radiologists, sonographers and clinical enthusiasts, however true efficacy, in practice, is limited.This study aims to improve diagnostic proficiency by means of calculated algorithms applied to ultrasound images. Through application thereof, inter-rater variability can be reduced.The first tier of the study would be retrospective quantitative study, with cross sectional study design.The second tier would be a prospective case controlled study.The study will be conducted at private radiology practice in the Pretoria area which serves as dedicated womens’ wellness centre.A small mock study sample was tested during the development of the research protocol.The sample population included 12 random selected suspicious mass lesions reported with ultrasound. A senior application specialist of the company MIPAR assisted in the basic recipe/ algorithm which could be used for image segmentation of a tumour within an ultrasound image.The values of the various intensity means were processed as a data set, as seen below in Table 2.It is evident from the mock study sample that ILC has an intensity range of (24-58) in comparison to IDC which is (54-89). This initial evaluation is sufficient evidence for the study to be used prospectively 2019-2020.This study will examine and analyse the validity and utility of the use of retrospective analysis of ultrasound images by means of segmentation software. This will be used in the development of a prospective algorithm tool similar to CAD, but with improved efficacy by means of targeted lesion segmentation and classification through calculated measurements and standardized algorithms (Table 1). Breast cancer remains the most common form of cancer amongst women. This has led to the need to enable early detection by using the latest technology in high frequency ultrasound. The increased interest in ultrasound as a diagnostic tool for breast cancer detection has led to rapid developments in the application thereof. Sonography is a popular tool for physicians, radiologists, sonographers and clinical enthusiasts, however true efficacy, in practice, is limited. This study aims to improve diagnostic proficiency by means of calculated algorithms applied to ultrasound images. Through application thereof, inter-rater variability can be reduced. The first tier of the study would be retrospective quantitative study, with cross sectional study design. The second tier would be a prospective case controlled study. The study will be conducted at private radiology practice in the Pretoria area which serves as dedicated womens’ wellness centre. A small mock study sample was tested during the development of the research protocol. The sample population included 12 random selected suspicious mass lesions reported with ultrasound. A senior application specialist of the company MIPAR assisted in the basic recipe/ algorithm which could be used for image segmentation of a tumour within an ultrasound image. The values of the various intensity means were processed as a data set, as seen below in Table 2. It is evident from the mock study sample that ILC has an intensity range of (24-58) in comparison to IDC which is (54-89). This initial evaluation is sufficient evidence for the study to be used prospectively 2019-2020. This study will examine and analyse the validity and utility of the use of retrospective analysis of ultrasound images by means of segmentation software. This will be used in the development of a prospective algorithm tool similar to CAD, but with improved efficacy by means of targeted lesion segmentation and classification through calculated measurements and standardized algorithms (Table 1). Table 1.Table 1Dataset findings for mock study sampleAlgorithm 1 N = intensity mean (pixel)DatasetILC - TILC - STLC 136.3966105.7651LC 234.133282.4882LC 358.106987.4093LC 445.8658104.4974LC 534.118195.8381LC 624.700198.8514Algorithm 2Dataset 2IDC – TIDC - STDC 154.6937111.7207DC 271.8258118.6943DC 387.8457102.7707DC 461.362895.9202DC 560.802880.1279DC 689.7359114.0227 Open table in a new tab

Synthesis and evaluation of 99mTc-analogues of [123/131I]mIBG prepared via [99mTc][Tc(CO)3(H2O)3]+ synthon for targeting norepinephrine transporter

Introductionmeta-[123/131I]Iodobenzylguanidine (mIBG) is a clinical agent used for imaging neuroendocrine tumors, where uptake in tumor is via active transport mechanism through norepinephrine transporters (NET). Our group in past have evaluated a 99mTc-analogue of the above tracer, based on 99mTc-4 + 1 labeling approach, which exhibited significant affinity for NET but suffered from reduced specific uptake in comparison to reference standard no-carrier-added (n.c.a.) [125I]mIBG. The present work attempts to synthesize two new 99mTc-analogues of the radio-iodinated derivative following [99mTc]Tc(CO)31+ approach with an aim to improve the above specific uptake content. MethodsTwo different precursors, xylylenediamine and 1,3-bis(chloromethyl)benzene, were synthetically modified to yield meta-functionalized benzylguanidine derivatives bearing iminodiacetate (IDA) and aminoethylglycine (AEG) tridentate chelating moieties, respectively. These ligands were labeled with technetium-99m via [99mTc][Tc(CO)3(H2O)3]+ synthon to form desired radioactive complexes 9 and 10. The radiolabeling yields of the complexes obtained were >90% as confirmed by radio-HPLC. The HPLC purified complexes were used for in vitro and in vivo evaluation to understand the true biological efficacy. Structural characterization of the radiolabeled complexes was carried after synthesizing and characterizing their Re-analogues. ResultsCell uptake studies with the radiolabeled complexes in SK-N-SH neuroblastoma cell lines revealed reduced uptake in the cells (<1% of incubated radioactivity/106 cells) in comparison to n.c.a. [125I]mIBG (~12%). However, limited specificity (~60%) was observed for the complexes as ascertained through desmethylimipramine (DMI) inhibition. Biodistribution studies in normal Wistar rats exhibited desired non-target clearance pharmacokinetics for the complexes but in vivo NET efficacy in myocardium for the neutral complex 10 could not be established. ConclusionsTridentate [99mTc]Tc(CO)31+ chelation approach severely affects biological behavior of the present small bioactive molecule under study to a significant extent in comparison to monodentate ligation in 99mTc-4 + 1 strategy.

Influence of aseptic surge tank venting on equipment sterilization

Abstract Aseptic surge tank (AST) systems are applied to aseptic production in order to store sterile product until aseptic filling, maintaining the commercial sterility condition achieved from previous production steps. To avoid microbial recontamination of the product, a sterility condition must be achieved in the aseptic tank system through the application of a heating, venting, and sterilization cycle. This cycle must follow specific validation protocols to ensure operational integrity - FDA 21 CFR Part 113.40g (ii). The demand for larger capacity systems and the implication of this volume increase on sterilization efficiency require a review of results obtained from current validation protocols. The purpose of this work was to evaluate aseptic surge tank’s venting cycles, studying internal pressure and temperature distribution to better understand this operation and its efficiency. Tests carried out at an industrial setting showed that the venting cycle was insufficient, with 13%-23% of air remaining inside the tank. Consequently, the subsequent sterilization process was not conducted under saturated steam condition. This different condition may change the kinetics for thermal destruction of microorganism spores from a moist heat state to a drier state in which its thermal resistance is higher. This finding raises a question regarding the true efficacy of the sterilization process and validation protocols currently used by the industry. The apparent success of current sterilization processes could be due to the application of excessive temperature and longer times. New operational and validation criteria will result in improvements in product integrity protection and operational cost reductions.

Measuring Small-molecule Inhibition of Protein Interactions in Live Cells Using FLIM-FRET.

This protocol was designed to quantitatively measure small-molecule displacement of proteins in live mammalian cells using fluorescence lifetime imaging microscopy-Förster resonance energy transfer (FLIM-FRET). Tumour cell survival is often dependent on anti-apoptotic proteins, which bind to and inhibit pro-apoptotic proteins, thus preventing apoptosis. Small-molecule inhibitors that selectively target these proteins (termed BH3-mimetics) are therefore a promising avenue for the treatment of several cancers. Previous techniques used to study the efficacy of these drugs often use truncated versions of both pro- and anti-apoptotic proteins, as they are membrane bound and hydrophobic in nature. As a result, the true efficacy of these drugs to displace full-length pro-apoptotic proteins in their native environment within a cell is poorly understood. This protocol describes FLIM-FRET methods to directly measure the displacement (or lack of displacement) of full-length Bcl-2 family proteins in live mammalian cells.

Variance prior specification for a basket trial design using Bayesian hierarchical modeling.

In the era of targeted therapies, clinical trials in oncology are rapidly evolving, wherein patients from multiple diseases are now enrolled and treated according to their genomic mutation(s). In such trials, known as basket trials, the different disease cohorts form the different baskets for inference. Several approaches have been proposed in the literature to efficiently use information from all baskets while simultaneously screening to find individual baskets where the drug works. Most proposed methods are developed in a Bayesian paradigm that requires specifying a prior distribution for a variance parameter, which controls the degree to which information is shared across baskets. A common approach used to capture the correlated binary endpoints across baskets is Bayesian hierarchical modeling. We evaluate a Bayesian adaptive design in the context of a non-randomized basket trial and investigate three popular prior specifications: an inverse-gamma prior on the basket-level variance, a uniform prior and half-t prior on the basket-level standard deviation. From our simulation study, we can see that the inverse-gamma prior is highly sensitive to the input hyperparameters. When the prior mean value of the variance parameter is set to be near zero , this can lead to unacceptably high false-positive rates in some scenarios. Thus, use of this prior requires a fully comprehensive sensitivity analysis before implementation. Alternatively, we see that a prior that places sufficient mass in the tail, such as the uniform or half-t prior, displays desirable and robust operating characteristics over a wide range of prior specifications, with the caveat that the upper bound of the uniform prior and the scale parameter of the half-t prior must be larger than 1. Based on the simulation results, we recommend that those involved in designing basket trials that implement hierarchical modeling avoid using a prior distribution that places a majority of the density mass near zero for the variance parameter. Priors with this property force the model to share information regardless of the true efficacy configuration of the baskets. Many commonly used inverse-gamma prior specifications have this undesirable property. We recommend to instead consider the more robust uniform prior or half-t prior on the standard deviation.

Hybrid Entity Mismatches and the International Trend of Matching Tax Outcomes: A Critical Approach

The international tax debate as regards hybrid entities has certainly changed after the OECD BEPS Project. Since then, the trend has been focused exclusively on matching transactions involving hybrids and reverse hybrid entities and double non-taxation, however without questioning whether these two elements are necessarily interconnected or whether they should serve each other in the design of domestic anti-hybrid provisions. This is particularly evident as regards the notion of ‘hybrid (entity) mismatch arrangements’ the design of which is based on the assumption that income should be taxed somewhere – no matter where – and as regards the complex set of domestic solutions proposed (‘linking rules’) the true efficacy of which is nevertheless still unknown. In this vein, this article adopts a critical approach both as regards the diagnosis of the problems and as regards the solutions proposed. As to the diagnosis, the author argues that the artificial attempt to match transactions involving hybrid entities and double non-taxation not only disregards the fundamental issue as regards hybrid entity mismatches (i.e. the disparate tax characterization of the same entity by two different states), but also carries with it the risk of creating presumptions of abusive practices in all those cases in which a hybrid entity structure is simply not taxed at all. As to the remedies, the author argues against the complexity, excessive reliance on foreign laws and potential economic double taxation issues that the implementation of linking rules might cause from a tax policy perspective. From a practical perspective, the author questions the proper interaction between linking rules and other anti-base erosion provisions, such as interest limitations and CFC rules. This article ultimately concludes that a re-orientation in the international debate regarding hybrids and reverse hybrid entities is crucial in order to open the door for more fundamental – and perhaps also more coordinated – solutions.