Optimizing the Anti-VEGF Treatment Strategy for Neovascular Age-Related Macular Degeneration: From Clinical Trials to Real-Life Requirements.

NlmCategory="UNASSIGNED">This Perspective discusses the pertinence of variable dosing regimens with anti-vascular endothelial growth factor (VEGF) for neovascular age-related macular degeneration (nAMD) with regard to real-life requirements. After the initial pivotal trials of anti-VEGF therapy, the variable dosing regimens pro re nata (PRN), Treat-and-Extend, and Observe-and-Plan, a recently introduced regimen, aimed to optimize the anti-VEGF treatment strategy for nAMD. The PRN regimen showed good visual results but requires monthly monitoring visits and can therefore be difficult to implement. Moreover, application of the PRN regimen revealed inferior results in real-life circumstances due to problems with resource allocation. The Treat-and-Extend regimen uses an interval based approach and has become widely accepted for its ease of preplanning and the reduced number of office visits required. The parallel development of the Observe-and-Plan regimen demonstrated that the future need for retreatment (interval) could be reliably predicted. Studies investigating the observe-and-plan regimen also showed that this could be used in individualized fixed treatment plans, allowing for dramatically reduced clinical burden and good outcomes, thus meeting the real life requirements. This progressive development of variable dosing regimens is a response to the real-life circumstances of limited human, technical, and financial resources. This includes an individualized treatment approach, optimization of the number of retreatments, a minimal number of monitoring visits, and ease of planning ahead. The Observe-and-Plan regimen achieves this goal with good functional results. Translational Relevance: This perspective reviews the process from the pivotal clinical trials to the development of treatment regimens which are adjusted to real life requirements. The article discusses this translational process which- although not the classical interpretation of translation from fundamental to clinical research, but a subsequent process after the pivotal clinical trials - represents an important translational step from the clinical proof of efficacy to optimization in terms of patients' and clinics' needs. The related scientific procedure includes the exploration of the concept, evaluation of security, and finally proof of efficacy.

Interrater variability of EEG interpretation in comatose cardiac arrest patients.

OBJECTIVE: EEG is widely used to predict outcome in comatose cardiac arrest patients, but its value has been limited by lack of a uniform classification. We used the EEG terminology proposed by the American Clinical Neurophysiology Society (ACNS) to assess interrater variability in a cohort of cardiac arrest patients included in the Target Temperature Management trial. The main objective was to evaluate if malignant EEG-patterns could reliably be identified. METHODS: Full-length EEGs from 103 comatose cardiac arrest patients were interpreted by four EEG-specialists with different nationalities who were blinded for patient outcome. Percent agreement and kappa (κ) for the categories in the ACNS EEG terminology and for prespecified malignant EEG-patterns were calculated. RESULTS: There was substantial interrater agreement (κ 0.71) for highly malignant patterns and moderate agreement (κ 0.42) for malignant patterns. Substantial agreement was found for malignant periodic or rhythmic patterns (κ 0.72) while agreement for identifying an unreactive EEG was fair (κ 0.26). CONCLUSIONS: The ACNS EEG terminology can be used to identify highly malignant EEG-patterns in post cardiac arrest patients in an international context with high reliability. SIGNIFICANCE: The establishment of strict criteria with high transferability between interpreters will increase the usefulness of routine EEG to assess neurological prognosis after cardiac arrest.

Indirect comparison meta-analysis of two enoxaparin regimens in patients undergoing major orthopaedic surgery. Impact on the interpretation of thromboprophylactic effects of new anticoagulant drugs.

Two enoxaparin dosage regimens are used as comparators to evaluate new anticoagulants for thromboprophylaxis in patients undergoing major orthopaedic surgery, but so far no satisfactory direct comparison between them has been published. Our objective was to compare the efficacy and safety of enoxaparin 3,000 anti-Xa IU twice daily and enoxaparin 4,000 anti-Xa IU once daily in this clinical setting by indirect comparison meta-analysis, using Bucher's method. We selected randomised controlled trials comparing another anticoagulant, placebo (or no treatment) with either enoxaparin regimen for venous thromboembolism prophylaxis after hip or knee replacement or hip fracture surgery, provided that the second regimen was assessed elsewhere versus the same comparator. Two authors independently evaluated study eligibility, extracted the data, and assessed the risk of bias. The primary efficacy outcome was the incidence of venous thomboembolism. The main safety outcome was the incidence of major bleeding. Overall, 44 randomised comparisons in 56,423 patients were selected, 35 being double-blind (54,117 patients). Compared with enoxaparin 4,000 anti-Xa IU once daily, enoxaparin 3,000 anti-Xa IU twice daily was associated with a reduced risk of venous thromboembolism (relative risk [RR]: 0.53, 95% confidence interval [CI]: 0.40 to 0.69), but an increased risk of major bleeding (RR: 2.01, 95% CI: 1.23 to 3.29). In conclusion, when interpreting the benefit-risk ratio of new anticoagulant drugs versus enoxaparin for thromboprophylaxis after major orthopaedic surgery, the apparently greater efficacy but higher bleeding risk of the twice-daily 3,000 anti-Xa IU enoxaparin regimen compared to the once-daily 4,000 anti-Xa IU regimen should be taken into account.

Standardized EEG interpretation accurately predicts prognosis after cardiac arrest.

OBJECTIVE: To identify reliable predictors of outcome in comatose patients after cardiac arrest using a single routine EEG and standardized interpretation according to the terminology proposed by the American Clinical Neurophysiology Society. METHODS: In this cohort study, 4 EEG specialists, blinded to outcome, evaluated prospectively recorded EEGs in the Target Temperature Management trial (TTM trial) that randomized patients to 33°C vs 36°C. Routine EEG was performed in patients still comatose after rewarming. EEGs were classified into highly malignant (suppression, suppression with periodic discharges, burst-suppression), malignant (periodic or rhythmic patterns, pathological or nonreactive background), and benign EEG (absence of malignant features). Poor outcome was defined as best Cerebral Performance Category score 3-5 until 180 days. RESULTS: Eight TTM sites randomized 202 patients. EEGs were recorded in 103 patients at a median 77 hours after cardiac arrest; 37% had a highly malignant EEG and all had a poor outcome (specificity 100%, sensitivity 50%). Any malignant EEG feature had a low specificity to predict poor prognosis (48%) but if 2 malignant EEG features were present specificity increased to 96% (p < 0.001). Specificity and sensitivity were not significantly affected by targeted temperature or sedation. A benign EEG was found in 1% of the patients with a poor outcome. CONCLUSIONS: Highly malignant EEG after rewarming reliably predicted poor outcome in half of patients without false predictions. An isolated finding of a single malignant feature did not predict poor outcome whereas a benign EEG was highly predictive of a good outcome.

The interpretation of symptoms of starvation/severe dietary restraint in eating disorder patients

The aims of the study were to test the hypotheses that some symptoms of starvation/severe dietary restraint are interpreted by patients with eating disorders in terms or control. Sixty-nine women satisfying the Diagnostic and Statistical Manual of Mental Disorders - IV edition (DSM-IV) criteria for a clinical eating disorder and 107 controls participated in the Study. All the participants completed an ambiguous scenarios paradigm, the Eating Disorder Lamination Questionnaire (EDE-Q) and the Beck Depression Inventory (BDI). Significantly more eating disorder patients than non clinical participants interpreted the starvation/dietary restraint symptoms of hunger, heightened satiety, and dizziness in terms of control. The data give further Support to the recent cognitive-behavioural theory of eating disorders suggesting that eating disorder patients interpret some starvation/dietary restraint symptoms in terms of control.

Borg's rating of perceived exertion scales: do the verbal anchors mean the same for different clinical groups?

Objective: To examine the interpretation of the verbal anchors used in the Borg rating of perceived exertion (RPE) scales in different clinical groups and a healthy control group. Design: Prospective experimental study. Setting: Rehabilitation center. Participants: Nineteen subjects with brain injury, 16 with chronic low back pain (CLBP), and 20 healthy controls. Interventions: Not applicable. Main Outcome Measures: Subjects used a visual analog scale (VAS) to rate their interpretation of the verbal anchors from the Borg RPE 6-20 and the newer 10-point category ratio scale. Results: All groups placed the verbal anchors in the order that they occur on the scales. There were significant within-group differences (P > .05) between VAS scores for 4 verbal anchors in the control group, 8 in the CLBP group, and 2 in the brain injury group. There was no significant difference in rating of each verbal anchor between the groups (P > .05). Conclusions: All subjects rated the verbal anchors in the order they occur on the scales, but there was less agreement in rating of each verbal anchor among subjects in the brain injury group. Clinicians should consider the possibility of small discrepancies in the meaning of the verbal anchors to subjects, particularly those recovering from brain injury, when they evaluate exercise perceptions.

Threat interpretation in anxious children and their mothers: comparison with nonclinical children and the effects of treatment

Interpretation biases towards threat play a prominent role in cognitive theories of anxiety, and have been identified amongst highly anxious adults and children. Little is known, however, about the development of these cognitive biases although family processes have been implicated. The current study investigated the nature of threat interpretation of anxious children and their mothers through (i) comparison of a clinic and non-clinic population, (ii) analysis of individual differences; and (ill) pre- and post-treatment comparisons. Participants were 27 children with a primary anxiety disorder and 33 children from a non-clinic population and their mothers. Children and mothers completed self-report measures of anxiety and indicated their most likely interpretation of ambiguous scenarios. Clinic and non-clinical groups differed significantly on measures of threat interpretation. Furthermore, mothers' and children's threat interpretation correlated significantly. Following treatment for child anxiety, both children and their mothers reported a reduction in threat interpretation. (c) 2005 Elsevier Ltd. All rights reserved.

Thalassaemia: its diagnosis and interpretation in past skeletal populations

The diagnosis of thalassaemia in archaeological populations has long been hindered by a lack of pathogonomic features, and the non-specific nature of cribra orbitalia and porotic hyperostosis. In fact, clinical research has highlighted more specific diagnostic criteria for thalassaemia major and intermedia based on changes to the thorax (‘rib-within-a-rib’ and costal osteomas). A recent re-examination of 364 child skeletons from Romano-British Poundbury Camp, Dorset revealed children with general ‘wasting’ of the bones and three children who demonstrated a variety of severe lesions (e.g. zygomatic bone and rib hypertrophy, porotic hyperostosis, rib lesions, osteopenia and pitted diaphyseal shafts) that are inconsistent with dietary deficiency alone, and more consistent with a diagnosis of genetic anaemia. Two of these children displayed rib lesions typical of those seen in modern cases of thalassaemia. The children of Poundbury Camp represent the first cases of genetic anaemia identified in a British archaeological population. As thalassaemia is a condition strongly linked to Mediterranean communities, the presence of this condition in a child from England, found within a mausoleum, suggests that they were born to wealthy immigrant parents living in this small Roman settlement in Dorset. This paper explores the diagnostic criteria for genetic anaemia in the archaeological literature and what its presence in ancient populations can contribute to our knowledge of past human migration.

Biased interpretation in perfectionism and its modification

Perfectionism is a transdiagnostic construct associated with a range of diagnoses, including depression, eating disorders and obsessive compulsive disorder. Treatments that directly target perfectionist cognitions have been shown to successfully reduce associated pathologies. However, the way in which they do this is not clear. We set out to assess the role of one candidate mechanism of action, namely the cognitive process of interpretation of ambiguity. In one experiment we looked for associations between biased interpretation and perfectionism. In a second, we manipulated interpretations, thereby providing a strong test of their aetiological significance. Results from the first experiment confirmed the presence of biased interpretation in perfectionism and demonstrated that these are highly specific to perfection relevant information, rather than reflecting general negativity. The second experiment succeeded in manipulating these perfection relevant interpretations and demonstrated that one consequence of doing so is a change in perfectionist behaviour. Together, these data experimentally demonstrate that biased interpretation of perfection relevant ambiguity contributes to the maintenance of perfectionism, but that it is also possible to reverse this. Clinical implications include the identification of one likely mechanism of therapeutic change within existing treatments, as well as identification of an appropriate evidence based focus for future treatment development. Targeting underlying functional mechanisms, such as biased interpretation, has the potential to offer transdiagnostic benefits.

Interpretation bias in preschool children at risk for anxiety: a prospective study

A story-stem paradigm was used to assess interpretation bias in preschool children. Data were available for 131 children. Interpretation bias, behavioural inhibition (BI) and anxiety were assessed when children were aged between 3 years 2 months and 4 years 5 months. Anxiety was subsequently assessed 12-months, 2-years and 5-years later. A significant difference in interpretation bias was found between participants who met criteria for an anxiety diagnosis at baseline, with clinically anxious participants more likely to complete the ambiguous story-stems in a threat-related way. Threat interpretations significantly predicted anxiety symptoms at 12-month follow-up, after controlling for baseline symptoms, but did not predict anxiety symptoms or diagnoses at either 2-year or 5- year follow-up. There was little evidence for a relationship between BI and interpretation bias. Overall, the pattern of results was not consistent with the hypothesis that interpretation bias plays a role in the development of anxiety. Instead, some evidence for a role in the maintenance of anxiety over relatively short periods of time was found. The use of a story-stem methodology to assess interpretation bias in young children is discussed along with the theoretical and clinical implications of the findings.

Threat interpretation bias in anxious children and their mothers

The role of parents in the development of anxiety disorders in children is of increasing research and clinical interest. This study investigated interpretation biases of anxious children and their mothers using the ambiguous stimuli task developed by Hadwin, Frost, French, and Richards (1997). Three groups of children (aged 7 to 12 years) and their mothers were recruited; 23 non-clinical controls, 18 children with an anxiety disorder and 15 children with an externalising disorder. Following diagnostic assessments of the children, children and their mothers independently completed the homophone task and self-report measures of anxiety. Mothers of anxious children had significantly higher self-reported anxiety than mothers of non-clinical children. As hypothesised, children in the anxious group had higher threat interpretation scores than the non-clinical group. The hypothesis that mothers of anxious children would make more threat interpretations was not supported. Paired correlations showed no significant association between threat interpretations made by children and their mothers. There was a significant positive correlation between maternal threat interpretation and child anxiety. The results suggest that there is a complex association between mother's anxiety and cognitions and those of their children, which requires further examination in controlled observational and experimental studies, including treatment trials.

Clinical implications of cognitive bias modification for interpretative biases in social anxiety: an integrative literature review

Cognitive theories of social anxiety indicate that negative cognitive biases play a key role in causing and maintaining social anxiety. On the basis of these cognitive theories, laboratory-based research has shown that individuals with social anxiety exhibit negative interpretation biases of ambiguous social situations. Cognitive Bias Modification for interpretative biases (CBM-I) has emerged from this basic science research to modify negative interpretative biases in social anxiety and reduce emotional vulnerability and social anxiety symptoms. However, it is not yet clear if modifying interpretation biases via CBM will have any enduring effect on social anxiety symptoms or improve social functioning. The aim of this paper is to review the relevant literature on interpretation biases in social anxiety and discuss important implications of CBM-I method for clinical practice and research.

Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies

Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype (similar to 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.

Clinical and Microbiologic Evaluation of Chronic Leg Ulcers: A Cross-sectional Study

OBJECTIVE: This study aimed at evaluating the flora and bacterial load of chronic leg ulcers (CLUs) according to the clinical judgment of colonization or infection.DESIGN: This was an analytical and cross-sectional study.SETTING: This study was conducted in an outpatient wound care unit in the Dermatology Department of the Botucatu School of Medicine-UNESP, Brazil.PARTICIPANTS: The participants were patients with CLUs who did not use systemic antibiotics.METHODS: The ulcers were clinically divided into 3 groups: ulcers with good granulation tissue (GGT), critical colonization (CC), and infection. Secretion was collected from a 1-cm(2) area using a swab and seeded by the semiquantitative method.OUTCOME MEASURES: The main outcome measures were genus and species of the bacteria found in the cultures and result of the semiquantitative culture correlating with the clinical diagnosis of GGT, CC, and infection.MAIN RESULTS: Seventy-seven ulcers were evaluated: 27 with GGT, 29 with CC, and 21 with infection. Gram-negative bacteria were most often found in all groups (81%): Pseudomonas aeruginosa, in granulation and colonized ulcers, and Proteus mirabilis, in infected ulcers. Ulcers from the infected group showed higher bacterial load.CONCLUSIONS: The flora of CLUs was predominantly constituted by gram-negative bacteria, and P aeruginosa was the most prevalent. The bacterial load of infected ulcers was higher as compared with the others, although some ulcers with GGT also presented a high load. The interpretation of microbiologic tests based on the swab techniques and even on semiquantitative analysis requires close clinical correlation.

Reparative phase events on periodontal disease progression: interpretation and considerations

Periodontal disease progress by destructive acute phases intercalated by reparative chronic phases. The aim of this study was to investigate the clinical and histological evidence of the periodontal disease reparative phase by analyzing bone wall conditions inside periodontal pockets and histologic images of periodontal pockets, identified in relevant publications. 81 patients with periodontitis, were randomly assigned into this study. Clinical and radiographic parameters were established to diagnose periodontal disease providing a sample of 133 diseased areas, which were treated by modified Widman flap. Documentation by digital photography were recorded in the surgery. Relevant publications showing histological images of periodontal pockets, were identified in Medline, PubMed and Google data base, were scanned and digitalized. All images obtained were evaluated and the presences of the reparative evidence in the zone around the underlying destroyed alveolar bone were critically analyzed. All periodontal bone defects, showed cortical bone reparations at different levels inside periodontal bone defects. All histologic images of periodontal pockets identified in relevant publications showed repaired gingival-attached connective tissue localized above underlying destroyed alveolar bone. All the evidences analyzed in this study suggested that periodontal disease is predominantly chronic, quiescent, showing reparative phases in different levels.