Limitations Of Available Evidence Research Articles

Prevention and Management of Osteoradionecrosis in Patients With Head and Neck Cancer Treated With Radiation Therapy: ISOO-MASCC-ASCO Guideline.

To provide evidence-based recommendations for prevention and management of osteoradionecrosis (ORN) of the jaw secondary to head and neck radiation therapy in patients with cancer. The International Society of Oral Oncology-Multinational Association for Supportive Care in Cancer (ISOO-MASCC) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library databases were searched for randomized controlled trials and observational studies, published between January 1, 2009, and December 1, 2023. The guideline also incorporated systematic reviews conducted by ISOO-MASCC, which included studies published from January 1, 1990, through December 31, 2008. A total of 1,539 publications were initially identified. There were 487 duplicate publications, resulting in 1,052 studies screened by abstract, 104 screened by full text, and 80 included for systematic review evaluation. Due to limitations of available evidence, the guideline relied on informal consensus for some recommendations. Recommendations that were deemed evidence-based with strong evidence by the Expert Panel were those pertaining to best practices in prevention of ORN and surgical management. No recommendation was possible for the utilization of leukocyte- and platelet-rich fibrin or photobiomodulation for prevention of ORN. The use of hyperbaric oxygen in prevention and management of ORN remains largely unjustified, with limited evidence to support its practice.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

The impact of thyroid autoimmunity on pregnancy outcomes in women with unexplained infertility undergoing intrauterine insemination: a retrospective single-center cohort study and meta-analysis.

Infertility affects 8-12% of couples worldwide, with 15-30% classified as unexplained infertility (UI). Thyroid autoimmunity (TAI), the most common autoimmune disorder in women of reproductive age, may impact fertility and pregnancy outcomes. However, the underlying mechanism is unclear. This study focuses on intrauterine insemination (IUI) and its potential association with TAI in UI patients. It is the first meta-analysis following a comprehensive literature review to improve result accuracy and reliability. Retrospective cohort study analyzing 225 women with unexplained infertility, encompassing 542 cycles of IUI treatment. Participants were categorized into TAI+ group (N=47, N= 120 cycles) and TAI- group (N=178, N= 422 cycles). Additionally, a systematic review and meta-analyses following PRISMA guidelines were conducted, incorporating this study and two others up to June 2023, totaling 3428 IUI cycles. Analysis revealed no significant difference in independent variables affecting reproductive outcomes. However, comparison based on TAI status showed significantly lower clinical pregnancy rates (OR: 0.43, P= 0.028, 95%CI: 0.20-0.93) and live birth rate (OR: 0.20, P= 0.014, 95%CI: 0.05 ~ 0.71) were significantly lower than TAI- group. There was no significant difference in pregnancy rate between the two groups (OR: 0.61, P= 0.135, 95%CI: 0.32-1.17). However, the meta-analysis combining these findings across studies did not show statistically significant differences in clinical pregnancy rates (OR:0.77, P=0.18, 95%CI: 0.53-1.13) or live birth rates (OR: 0.68, P=0.64, 95%CI: 0.13-3.47) between the TAI+ and TAI- groups. Our retrospective cohort study found an association between TAI and reduced reproductive outcomes in women undergoing IUI for unexplained infertility. However, the meta-analysis incorporating other studies did not yield statistically significant associations. Caution is required in interpreting the relationship between thyroid autoimmunity and reproductive outcomes. Future studies should consider a broader population and a more rigorous study design to validate these findings. Clinicians dealing with women with unexplained infertility and TAI should be aware of the complexity of this field and the limitations of available evidence.

Real-World Evidence to Inform Regulatory Decision Making: A Scoping Review.

Real-world evidence (RWE) is increasingly considered in regulatory decision making. When, and to which extent, RWE is considered relevant by regulators likely depends on many factors. This review aimed to identify factors that make RWE necessary or desirable to inform regulatory decision making. A scoping review was conducted using literature databases (PubMed, Embase, Emcare, Web of Science, and Cochrane Library) and websites of regulatory agencies, health technology assessment agencies, research institutes, and professional organizations involved with RWE. Articles were included if: (1) they discussed factors or contexts that impact whether RWE could be necessary or desirable in regulatory decision making; (2) focused on pharmacological or biological interventions in humans; and (3) considered decision making in Europe or North America, or without a focus on a specific region. We included 118 articles in the scoping review. Two major themes and six subthemes were identified. The first theme concerns questions addressable with RWE, with subthemes epidemiology and benefit-risk assessment. The second theme concerns contextual factors, with subthemes feasibility, ethical considerations, limitations of available evidence, and disease and treatment-specific aspects. Collectively, these themes encompassed 43 factors influencing the need for RWE in regulatory decisions. Although single factors may not make RWE fully necessary, their cumulative influence could make RWE essential and pivotal in regulatory decision making. This overview contributes to ongoing discussions emphasizing the nuanced interplay of factors influencing the necessity or desirability of RWE to inform regulatory decision making.

Incidence and Surgical Outcomes of Intracranial Arachnoid Cysts: A Systematic Review Comparing Endoscopic Fenestration, Open Craniotomy and Cystoperitoneal Shunt Approaches

ABSTRACT Background: Arachnoid cysts (ACs) are non-neoplastic collections of cerebrospinal fluid, often posing challenges in diagnosis and management due to their rarity and varied clinical presentations. This systematic review aims to investigate the frequency of ACs, analyse optimal intervention approaches and evaluate neurological complications postoperatively. Materials and Methods: A systematic search of Science Direct, PubMed and Cochrane databases was conducted using controlled vocabulary terms and keywords. Inclusion criteria encompassed studies focusing on adults with symptomatic ACs requiring surgical intervention. Data extraction involved factors influencing subdural haemorrhage, surgical techniques, drainage types and imaging approaches. Adherence to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines ensured methodological rigor and transparency. Results: The review identified multiple surgical approaches, including microsurgical fenestration, endoscopic fenestration and cystoperitoneal shunt, tailored to different cyst locations. Studies showed cystoperitoneal bypass as effective for supratentorial cysts, endoscopic fenestration for midline cysts and cystoperitoneal shunt for infratentorial cysts. Notably, endoscopic fenestration exhibited a 90% success rate, while cystoventricular drainage emerged as an alternative option. However, limitations in comparative studies and variations in follow-up durations hindered comprehensive analyses. Conclusion: Cystocysternostomy, preferably minimally invasive, showed promising outcomes in managing ACs. Wide endoscopic fenestration was recommended without causing damage to adjacent structures. Surgical adaptation for uncontrolled bleeding during procedures was suggested. Intracranial shunts were preferred due to lower infection risks. Postoperative care involving anticonvulsants and conservative antibiotic therapy exhibited low complication rates. Despite limitations in available evidence, this review highlights potential effective interventions for managing ACs, emphasising the need for further comprehensive studies.

Redressing Historical Bias: Exploring the Path to an Accurate Representation of the Past

The study examines the role of historical bias and the ways in which it can be addressed to achieve a more accurate representation of the past. The study aims to identify the factors that contribute to historical bias, the impact it has on our understanding of history, and the strategies that can be employed to overcome it. The study employs a mixed-methods approach that includes a comprehensive review of relevant literature, interviews with scholars and historians, and analysis of historical narratives. The study finds that historical bias is perpetuated by a variety of factors, including political and cultural agendas, the limitations of available evidence, and the perspectives and biases of historians themselves. The study also identifies several strategies that can be used to address historical bias, including the adoption of a more diverse and inclusive approach to historical research, the incorporation of multiple perspectives and sources, and the acknowledgement of historical injustices and their impact on marginalized groups. The study concludes that a commitment to redressing historical bias is necessary to achieve a more accurate and inclusive representation of the past, which can in turn contribute to a more just and equitable society.

Specialist Perspectives on the Imaging Selection of Large Vessel Occlusion in the Late Window.

The proper imaging modality for use in the selection of patients for endovascular thrombectomy (EVT) presenting in the late window remains controversial, despite current guidelines advocating the use of advanced imaging in this population. We sought to understand if clinicians with different specialty training differ in their approach to patient selection for EVT in the late time window. We conducted an international survey of stroke and neurointerventional clinicians between January and May 2022 with questions focusing on imaging and treatment decisions of large vessel occlusion (LVO) patients presenting in the late window. Interventional neurologists, interventional neuroradiologists, and endovascular neurosurgeons were defined as interventionists whereas all other specialties were defined as non-interventionists. The non-interventionist group was defined by all other specialties of the respondents: stroke neurologist, neuroradiologist, emergency medicine physician, trainee (fellows and residents) and others. Of 3000 invited to participate, 1506 (1027 non-interventionists, 478 interventionists, 1declined to specify) physicians completed the study. Interventionist respondents were more likely to proceed directly to EVT (39.5% vs. 19.5%; p < 0.0001) compared to non-interventionist respondents in patients with favorable ASPECTS (Alberta Stroke Program Early CT Score). Despite no difference in access to advanced imaging, interventionists were more likely to prefer CT/CTA alone (34.8% vs. 21.0%) and less likely to prefer CT/CTA/CTP (39.1% vs. 52.4%) for patient selection (p < 0.0001). When faced with uncertainty, non-interventionists were more likely to follow clinical guidelines (45.1% vs. 30.2%) while interventionists were more likely to follow their assessment of evidence (38.7% vs. 27.0%) (p < 0.0001). Interventionists were less likely to use advanced imaging techniques in selecting LVO patients presenting in the late window and more likely to base their decisions on their assessment of evidence rather than published guidelines. These results reflect gaps between interventionists and non-interventionists reliance on clinical guidelines, the limits of available evidence, and clinician belief in the utility of advanced imaging.

Primordial and primary prevention of peri-implant diseases: A systematic review and meta-analysis.

This systematic review and meta-analysis aims to assess the efficacy of risk factor control to prevent the occurrence of peri-implant diseases (PIDs) in adult patients awaiting dental implant rehabilitation (primordial prevention) or in patients with dental implants surrounded by healthy peri-implant tissues (primary prevention). A literature search was performed without any time limit on different databases up to August 2022. Interventional and observational studies with at least 6months of follow-up were considered. The occurrence of peri-implant mucositis and/or peri-implantitis was the primary outcome. Pooled data analyses were performed using random effect models according to the type of risk factor and outcome. Overall, 48 studies were selected. None assessed the efficacy of primordial preventive interventions for PIDs. Indirect evidence on the primary prevention of PID indicated that diabetic patients with dental implants and good glycaemic control have a significantly lower risk of peri-implantitis (odds ratio [OR]=0.16; 95% confidence interval [CI]: 0.03-0.96; I2 : 0%), and lower marginal bone level (MBL) changes (OR=-0.36 mm; 95% CI: -0.65 to -0.07; I2 : 95%) compared to diabetic patients with poor glycaemic control. Patients attending supportive periodontal/peri-implant care (SPC) regularly have a lower risk of overall PIDs (OR=0.42; 95% CI: 0.24-0.75; I2 : 57%) and peri-implantitis compared to irregular attendees. The risk of dental implant failure (OR=3.76; 95% CI: 1.50-9.45; I2 : 0%) appears to be greater under irregular or no SPC than regular SPC. Implants sites with augmented peri-implant keratinized mucosa (PIKM) show lower peri-implant inflammation (SMD=-1.18; 95% CI: -1.85 to -0.51; I2 : 69%) and lower MBL changes (MD=-0.25; 95% CI: -0.45 to -0.05; I2 : 62%) compared to dental implants with PIKM deficiency. Studies on smoking cessation and oral hygiene behaviors were inconclusive. Within the limitations of available evidence, the present findings indicate that in patients with diabetes, glycaemic control should be promoted to avoid peri-implantitis development. The primary prevention of peri-implantitis should involve regular SPC. PIKM augmentation procedures, where a PIKM deficiency exists, may favour the control of peri-implant inflammation and the stability of MBL. Further studies are needed to assess the impact of smoking cessation and oral hygiene behaviours, as well as the implementation of standardized primordial and primary prevention protocols for PIDs.

Does Voluntary Medical Male Circumcision Reduce HIV Risk in Men Who Have Sex with Men?

To review the evidence on the effect of voluntary medical male circumcision (VMMC) on reducing HIV risk among men who have sex with men (MSM) and assess the limitations of available evidence. Individual studies have shown conflicting results, but recent meta-analyses have consistently suggested that VMMC was associated with 7 to 23% reductions in HIV prevalence or incidence in MSM, particularly among a subgroup of men who predominantly practice insertive role in anal sex. Mathematical models have also suggested a moderate population-level impact of VMMC intervention. All original studies have been observational and are subject to confounding and bias. Randomized clinical trials (RCTs) are needed to provide strong evidence of assessing the efficacy of VMMC on HIV risk among MSM. VMMC is a promising HIV risk reduction tool for MSM. RCTs are needed to evaluate the efficacy of VMMC intervention.

Measuring the Impact of Food Immunotherapy on Health-Related Quality of Life in Clinical Trials.

Food allergy is a common, and often lifelong, disorder with considerable negative impact on the quality of life of those affected and their families. While several promising immunotherapies for food allergy have either been approved or are in late-phase clinical trials based on demonstrated effectiveness at inducing desensitization, evidence of benefit in terms of improving patient-centered outcomes is inconsistent. Historically, health-related quality of life has not been prioritized as an endpoint in food immunotherapy trials and, even when included, findings have been undermined by methodological limitations of the measurement instruments used and issues with data interpretation. This review highlights the importance of measuring health-related quality of life as an endpoint in food immunotherapy trials and discusses the strengths and limitations of available evidence in this regard, with a focus on the appropriate use of assessment instruments and interpretation of findings. There remains much to learn regarding the impact of food immunotherapies on patient wellbeing, both during treatment and over the longer term. Our aim is to assist clinicians, researchers, policy makers and consumers in their interpretation of the existing literature, and to promote greater scientific rigor in the design and selection of outcome measurement frameworks for future studies evaluating the efficacy of immunotherapy treatments for food allergy.

EE94 Health Economic Evidence for Adjuvant Chemotherapy in Stage II and III Colorectal Cancer: A Systematic Review

To appraise the health economic evidence for adjuvant chemotherapy (AC) strategies in stage II and III colorectal cancer (CRC) and to identify the limitations of available evidence that might inform further research.

A weighty issue: The implications of an ultrasound prediction of a large baby in pregnancy

Introduction: The assessment of fetal growth in Aotearoa New Zealand is governed by a largely medical model of care which highly values the purported objectivity of sonographic assessment. Ultrasound scans are an increasingly normalised part of pregnancy care, and expectant parents may advocate strongly for access to them. It could be questioned whether the increasing number of scans is aligned with clinical need. This paper presents a literature review that explores the implications of an ultrasound diagnosis of a large baby during pregnancy. Method: Databases searched were CINAHL, PubMed, Proquest, and Google Scholar. Search terms used were “macrosomia”, “large for dates” and “large for gestational age”. This search was first undertaken in May 2019, and then repeated in November 2020. Findings: Sonographic assessment of fetal size can be inaccurate and the existence of a predicted fetal weight on scan increases the likelihood of birth interventions, regardless of the baby’s actual size. While there are potentially negative outcomes associated with a larger baby, it is unclear whether birth interventions will significantly reduce the occurrence of these outcomes. There is limited research that focuses on the parents’ experience of having a predicted large baby, offering contradictory insights, which suggests the influence of conflicting meanings applied to large babies and ignoring the experiences of women whose babies were predicted to be large but were born “normal” sized. Discussion: Midwives are encouraged to openly discuss with women the limitations in available evidence in this area. Midwives can consider the context of the woman and whānau (wider family), and how they may assess risk uniquely. Finally, midwives can honour the woman and whānau as the decision-makers in their own experience. There are further opportunities for research to provide a counter-narrative to medicalising discourses about large babies, grounded in a midwifery belief in normal birth. Conclusion: Midwives and women are drawn into a risk-centric paradigm that pathologises large babies for questionable benefit. To support informed decision-making within the midwifery partnership, midwives need to critically evaluate existing research and communicate its limitations and risk-centric orientation.

Immunogenicity of biologic therapies in psoriasis: Myths, facts and a suggested approach.

With biologic drugs dominating the therapeutic space for severe immune-mediated inflammatory disease, it is critical for clinicians to be familiar with the concept of drug immunogenicity, with the potential for our patients to develop antidrug antibodies (ADA) of clinical relevance. Whilst there are clear differences between different therapeutic biologics in terms of reported ADA rates, there is no accepted dermatology guideline or grouping of drugs by risk of clinically relevant ADA, nor a consensus on approach to ADA management. This is partly because making valid comparisons of immunogenicity across drugs is fundamentally flawed: the differing types of ADA assay, trial design and included patient population - as well as the molecular structure of the biologic molecules themselves - are all highly influential on reported ADA prevalence and impact on clinical response. Therefore, the first part of this article aims to give an overview of ADA that also clarifies common misconceptions on the subject, whilst the second part of this article outlines Phase III immunogenicity data on commonly used biologics for psoriasis, the most common dermatological indication. Based on this, and acknowledging current limitations in available evidence, we propose a working categorization of biologics together with a broad approach to management: Group 1 - biologics with higher risk of clinically relevant ADA; Group 2 - biologics with lower risk of clinically relevant ADA; and Group 3 - biologics with no established risk of clinically relevant ADA. However, these groupings represent a working concept only; more research is required, using comparable ADA assays and consistent reporting of related outcomes. Finally, there is an urgent need for better characterization of individuals at particular risk of developing ADA to inform future clinical decision-making.

Late (> 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

Many preterm infants who survive go on to develop bronchopulmonary dysplasia, probably as the result of persistent inflammation in the lungs. Corticosteroids have powerful anti-inflammatory effects and have been used to treat individuals with established bronchopulmonary dysplasia. However, it is unclear whether any beneficial effects outweigh the adverse effects of these drugs. To examine the relative benefits and adverse effects of late systemic postnatal corticosteroid treatment (> 7 days) for preterm infants with evolving or established bronchopulmonary dysplasia. For the 2017 update, we used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1); MEDLINE via PubMed (January 2013 to 21 February 2017); Embase (January 2013 to 21 February 2017); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; January 2013 to 21 February 2017). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We selected for inclusion in this review randomised controlled trials (RCTs) comparing systemic postnatal corticosteroid treatment versus placebo or nothing initiated more than seven days after birth for preterm infants with evolving or established bronchopulmonary dysplasia. We used the GRADE approach to assess the quality of evidence.We extracted and analysed data regarding clinical outcomes including mortality, bronchopulmonary dysplasia, death or bronchopulmonary dysplasia, failure to extubate, complications during primary hospitalisation, and long-term health outcomes. Twenty-one RCTs enrolling a total of 1424 participants were eligible for this review. All were RCTs, but methods used for random allocation were not always clear. Allocation concealment, blinding of the intervention, and blinding of outcome assessments most often were satisfactory. Late steroid treatment was associated with a reduction in neonatal mortality (at 28 days) but no reduction in mortality at 36 weeks, at discharge, or at latest reported age. Benefits of delayed steroid treatment included reductions in failure to extubate by 3, 7, or 28 days; bronchopulmonary dysplasia both at 28 days of life and at 36 weeks' postmenstrual age; need for late rescue treatment with dexamethasone; discharge on home oxygen; and death or bronchopulmonary dysplasia both at 28 days of life and at 36 weeks' postmenstrual age. Data revealed a trend towards increased risk of infection and gastrointestinal bleeding but no increase in risk of necrotising enterocolitis. Short-term adverse affects included hyperglycaemia, glycosuria, and hypertension. Investigators reported an increase in severe retinopathy of prematurity but no significant increase in blindness. Trial results showed a trend towards reduction in severe intraventricular haemorrhage, but only five studies enrolling 247 infants reported this outcome. Trends towards an increase in cerebral palsy or abnormal neurological examination findings were partly offset by a trend in the opposite direction involving death before late follow-up. The combined rate of death or cerebral palsy was not significantly different between steroid and control groups. Major neurosensory disability and the combined rate of death or major neurosensory disability were not significantly different between steroid and control groups. There were no substantial differences between groups for other outcomes in later childhood, including respiratory health or function, blood pressure, or growth, although there were fewer participants with a clinically important reduction in forced expired volume in one second (FEV1) on respiratory function testing in the dexamethasone group.GRADE findings were high for all major outcomes considered, but review authors degraded the quality of evidence by one level because we found evidence of publication bias (bronchopulmonary dysplasia at 36 weeks). Benefits of late corticosteroid therapy may not outweigh actual or potential adverse effects. This review of postnatal systemic corticosteroid treatment for bronchopulmonary dysplasia initiated after seven days of age suggests that late therapy may reduce neonatal mortality without significantly increasing the risk of adverse long-term neurodevelopmental outcomes. However, the methodological quality of studies determining long-term outcomes is limited in some cases (some studies assessed surviving children only before school age, when some important neurological outcomes cannot be determined with certainty), and no studies were sufficiently powered to detect increased rates of important adverse long-term neurosensory outcomes. Evidence showing both benefits and harms of treatment and limitations of available evidence suggests that it may be prudent to reserve the use of late corticosteroids for infants who cannot be weaned from mechanical ventilation, and to minimise both dose and duration for any course of treatment.

Effects of Orthodox religious fasting on human health: a systematic review.

Different studies have pointed towards a positive effect of religious fasting on human health. Orthodox fasting (OF) regime could be characterized as a periodical vegetarian diet, demonstrating several common characteristics with the typical Mediterranean diet. The present systematic review aimed to synthesize available results regarding the potential impact of OF on human health. Key biomedical databases were searched to identify studies examining the effects of OF on humans. Following implementation of specific criteria, ten studies were included in the analysis and their results were systematically reported and critically appraised in this review. According to the available limited results, OF periods are characterized by a restriction in total energy and fat intake, an increase in carbohydrate and fiber consumption, while in terms of protein intake, results are contradictive. The overall effect of OF on lipids profile seems to be optimal, with the reduction of total cholesterol and LDL-C levels, being a consistent finding across studies (up to 17.8 and 31.4%, respectively). However, the effect on HDL-C is still unclear. Conclusions regarding the impact on body weight and glucose homeostasis cannot be drawn, given that relevant data are limited with conflicting results. Any potential negative aspects of OF, mainly attributed to reduced dietary intake of vitamin D and B12 and minerals (mainly calcium), require further investigation. Given the limitations of available evidence, more studies are required before reaching definite conclusions about the effects of OF on human health.

Annals for Educators - 21 February 2017

Annals for Educators - 21 February 2017

Metacognition-oriented Social Skills Training (MOSST): Theoretical Framework, Working Methodology and Treatment Description for Patients with Schizophrenia

Metacognition-oriented Social Skills Training (MOSST): Theoretical Framework, Working Methodology and Treatment Description for Patients with Schizophrenia. The presence of social deficits in schizophrenia has been widely described in literature as well as the negative impact of these deficits on psychosocial functioning. As a result, social skills training (SST) has emerged as a well-validated intervention that is recommended in several treatment guidelines for schizophrenia. However, different studies have found that the effects and generalizability of current SST programmes are limited regarding the potential benefits on daily psychosocial functioning of these patients. This paper aims to describe a newly developed intervention model that integrates metacognitive remediation into SST for patients affected by schizophrenia: metacognition-oriented social skills training (MOSST). Theoretical model of MOSST is based on recent findings suggesting the central role of metacognitive deficits to successful psychosocial functioning in schizophrenia. Thereby, MOSST focuses not only on train interpersonal skills but also on improving the understanding of one’s own mental states and those of the others as well as the connection between mental states and effective social behaviour. In order to facilitate the treatment description, a case report of an adult diagnosed by schizophrenia who successfully completed the programme is presented. Finally, clinical implications and limitations of available evidence on MOSST are discussed, and future research directions with this programme are pointed out.

Politicisation of Science in the Process of Dealing with Manufactured Risk

Politicisation of Science in the Process of Dealing with Manufactured Risk An Interdisciplinary Case Study A key feature of modern society is the emergence of new characteristics of risks, which have been conceptualized by U. Beck as ‘manufactured risk’.1 Whereas in the past, risks principally consisted of natural hazards, which were limited in both time and space, manufactured risks are man-made, have a global effect, are potentially catastrophic, and can only be assessed speculatively. The global dimension of these risks has rendered apparent the latent divergence in the conceptions of risks that exist among different nations and regulatory regimes, thus resulting in tensions at and between national, regional, and international levels. One of the entities where these conflicts are most visible is the World Trade Organisation’s (WTO) dispute settlement body, which has recently been faced with several cases relating to manufactured risk.2 In these situations, and partially due to the WTO’s need to legitimize its going beyond national sovereignty, science has gained paramount importance in providing for a neutral and objective international normative yardstick for decision-making.3 Indeed, such function of science is exemplified in the WTO Agreement on the Application of Sanitary and Phytosanitary Measures (SPS Agreement), which indicates that, in order to leave to Member States their discretion to set the levels of protection, the WTO only ‘disciplines’ the existing risk assessments, thus ensuring that the risk regulations are appropriately based on science. In this respect, a clear-cut distinction is made between risk assessment, which provides for objectivity and authority, and risk management, which is expected to appropriately respond with policy decisions.4 The undisputed reliance on science, in case of manufactured risk, is problematic concerning two central aspects. Firstly, ‘risk’ is stil mainly conceptualised according to the traditional theory, which states that risk can be managed by rationally evaluating the probability of its occurrence and measuring it against the extent of the harm that might be caused by a disaster.5 However, due to the speculative characteristic of manufactured risk, no historical data exist regarding the probability, the form, or even the existence of these risks. As these aspects can only be evaluated retrospectively, a mere positivistic6 description of what manufactured risk consists of is drastically jeopardised. Secondly, the way science is being used as an ‘internationallyardstick’ fails to acknowledge and problematize the ways science may be politicised, thus potentially leading to a misuse of scientific knowledge when dealing with manufactured risk. Consequently, this paper will investigate some potential effects of the current use of science with regard to manufactured risk. To start with, the WTO’s approach towards science and its limiting definition of risk, appears not only incomplete vis-a-vis emerging forms of risk, but also ignores the practical inability of science to be used as a decisive tool in dispute settlement. Subsequently, the demeanour of displaying scientific knowledge as complete, unequivocal, and authoritative as well as disregarding the existence of various forms of uncertainty results in a de facto impediment of Member States’ freedom to “determine their own appropriate level of sanitary protection”.7 Therefore, this paper will empirically analyse how scientific knowledge is being politicised in the process of dealing with manufactured risks. For this purpose, the interdisciplinary analysis of a case concerning the selected genetically modified organism (GMO), Bt-176,8 will be presented. This specific GMO was banned in Germany, Austria, and Luxembourg, accepted by the European Communities (EC, now: European Union),9 and assessed in the WTO Dispute Settlement on the Measures Affecting the Approval and Marketing of Biotech Products (EC-Biotech).10 On this basis, the authors will, in the first part, propose a conceptual framework significant in evaluating how the relevant authorities at the national, EU, and WTO levels approach scientific knowledge when dealing with manufactured risks. In the following section, the paper will analyse the various facets on which the scientific evidence presented by Member States and the EC agencies conflict. Finally, the way the WTO Panel ‘disciplined’ the risk assessments, according to applicable law, will be investigated. Based on the analysis of the EC- Biotech case, diverging manners by which science is being politicised will be identified. In particular, the paper will investigate how different types of uncertainty are being ignored or disregarded, thus ultimately leading to the limitation of available evidence on which Member States can base their safeguard measures. In conclusion, the argument substantiated in this paper is that, due to the characteristics of manufactured risk and the inherent politicisation of science, under no circumstances should science be used as the most important normative yardstick in the WTO decisionmaking process. Additionally, this paper claims that in order to appropriately deal with manufactured risk and its speculative characteristic, scientific risk assessment should not only attempt to positively assess the risk, but as well attribute a major importance to all identified forms of uncertainty.

Pharmacologic Interventions for Infantile Hemangioma: A Meta-analysis.

Infantile hemangiomas (IH) may be associated with significant functional impact. The objective of this study was to meta-analyze studies of pharmacologic interventions for children with IH. Data sources were Medline and other databases from 1982 to June 2015. Two reviewers assessed studies using predetermined inclusion criteria. One reviewer extracted data with review by a second. We included 18 studies in a network meta-analysis assessing relative expected rates of IH clearance associated with β-blockers and steroids. Oral propranolol had the largest mean estimate of expected clearance (95%; 95% Bayesian credible interval [BCI]: 88%-99%) relative to oral corticosteroids (43%, 95% BCI: 21%-66%) and control (6%, 95% BCI: 1%-11%). Strength of evidence (SOE) was high for propranolol's effects on reducing lesion size compared with observation/placebo. Corticosteroids demonstrated moderate effectiveness at reducing size/volume (moderate SOE for improvement in IH). SOE was low for effects of topical timolol versus placebo. Methodologic limitations of available evidence may compromise SOE. Validity of meta-analytic estimates relies on the assumption of exchangeability among studies, conditional on effects of the intervention. Results rely on assumed lack of reporting bias. Propranolol is effective at reducing IH size compared with placebo, observation, and other treatments including steroids in most studies. Corticosteroids demonstrate moderate effectiveness at reducing IH size/volume. The meta-analysis estimates provide a relative ranking of anticipated rates of lesion clearance among treatments. Families and clinicians making treatment decisions should also factor in elements such as lesion size, location, number, and type, and patient and family preferences.

Beyond Monoamines-Novel Targets for Treatment-Resistant Depression: A Comprehensive Review.

Major depressive disorder (MDD) is a leading cause of disability worldwide. Current first line therapies target modulation of the monoamine system. A large variety of agents are currently available that effectively alter monoamine levels; however, approximately one third of MDD patients remain treatment refractory after adequate trials of multiple monoamine based therapies. Therefore, patients with treatment-resistant depression (TRD) may require modulation of pathways outside of the classic monoamine system. The purpose of this review was thus to discuss novel targets for TRD, to describe their potential mechanisms of action, the available clinical evidence for these targets, the limitations of available evidence as well as future research directions. Several alternate pathways involved in the patho-etiology of TRD have been uncovered including the following: inflammatory pathways, the oxidative stress pathway, the hypothalamic-pituitary-adrenal (HPA) axis, the metabolic and bioenergetics system, neurotrophic pathways, the glutamate system, the opioid system and the cholinergic system. For each of these systems, several targets have been assessed in preclinical and clinical models. Preclinical models strongly implicate these pathways in the patho-etiology of MDD. Clinical trials for TRD have been conducted for several novel targets; however, most of the trials discussed are small and several are uncontrolled. Therefore, further clinical trials are required to assess the true efficacy of these targets for TRD. As well, several promising novel agents have been clinically tested in MDD populations, but have yet to be assessed specifically for TRD. Thus, their applicability to TRD remains unknown.

Adjuvant chemotherapy for soft tissue sarcoma.

Adjuvant chemotherapy is not standard treatment in soft tissue sarcoma (STS). However, when the risk of relapse is high, it is an option for shared decision making with the patient in conditions of uncertainty. This is because available evidence is conflicting, even if several randomized clinical trials have been performed for 4 decades and also have been pooled into meta-analyses. Indeed, available meta-analyses point to a benefit in the 5% to 10% range in terms of survival and distant relapse rate. Some local benefit also was suggested by some trials. Placing chemotherapy in the preoperative setting may help gain a local advantage in terms of the quality of surgical margins or decreased sequelae. This may be done within a personalized approach according to the clinical presentation. Attempts to personalize treatment on the basis of the variegated pathology and molecular biology of STS subgroups are ongoing as well, according to what is done in the medical treatment of advanced STS. Thus, decision making for adjuvant and neoadjuvant indications deserves personalization in clinical research and in clinical practice, taking profit from all multidisciplinary clinical skills available at a sarcoma reference center, though with a degree of subjectivity because of the limitations of available evidence.