Building on the success of anti-vascular endothelial growth factor therapy: a vision for the next decade

This article aims to identify key opportunities for improvement in the diagnosis and treatment of retinal disease, and describe recent innovations that will potentially facilitate improved outcomes with existing intravitreal vascular endothelial growth factor (VEGF) therapies and lay the groundwork for new treatment approaches. The review begins with a summary of the key discoveries that led to the development of anti-VEGF therapies and briefly reviews their impact on clinical practice. Opportunities for improvements in diagnosis, real-world outcomes with existing therapies, long-acting therapeutics and personalised health care are discussed, as well as the need to identify new targets for therapeutic intervention. Low-cost, remote patient screening and monitoring using artificial intelligence (AI)-based technologies can help improve diagnosis rates and enable remote disease monitoring with minimal patient burden. AI-based tools can be applied to generate patient-level prognostic data and predict individual treatment needs, reducing the time needed to optimise a patient’s treatment regimen. Long-acting therapeutics can help improve visual outcomes by reducing the treatment burden. When paired with AI-generated prognoses, long-acting therapeutics enable the possibility of vision loss prevention. Dual-acting drugs may help improve efficacy and/or durability beyond what is possible with anti-VEGF agents alone. Recent developments and ongoing innovations will help build upon the success of anti-VEGF therapies to further reduce vision loss owing to retinal disease while lowering the overall burden of care.Subject terms: Retinal diseases, Quality of life     

Longitudinal blood pressure patterns and cardiovascular disease risk

Abstract

Observational and interventional studies have unequivocally demonstrated that “present”, i.e. single-occasion, blood pressure is one of the key determinants of cardiovascular disease risk. Over the past two decades, however, numerous publications have suggested that longitudinal blood pressure data and assessment of long-term blood pressure exposure provide incremental prognostic value over present blood pressure. These studies have used several different indices to quantify the overall exposure to blood pressure, such as time-averaged blood pressure, cumulative blood pressure, blood pressure trajectory patterns, and age of hypertension onset. This review summarises existing research on the association between these indices and hard cardiovascular outcomes, outlines the strengths and weaknesses of these indices, and provides an overview of how longitudinal blood pressure changes can be measured and used to improve cardiovascular disease risk prediction.

• KEY MESSAGES

• Numerous recent publications have examined the relation between cardiovascular disease and long-term blood pressure (BP) exposure, quantified using indices such as time-averaged BP, cumulative BP, BP trajectory patterns, and age of hypertension onset.

• This review summarises existing research on the association between these indices and hard cardiovascular outcomes, outlines the strengths and weaknesses of these indices, and provides an overview of how longitudinal BP changes can be measured and used to improve cardiovascular disease risk prediction.

• Although longitudinal BP indices seem to predict cardiovascular outcomes better than present BP, there are considerable differences in the clinical feasibility of these indices along with a limited number of prospective data.

     

Prolonged mechanical ventilation after cardiac surgery: substudy of the Transfusion Requirements in Cardiac Surgery III trial

Purpose

Prolonged mechanical ventilation (MV) is a major complication following cardiac surgery. We conducted a secondary analysis of the Transfusion Requirements in Cardiac Surgery (TRICTS) III trial to describe MV duration, identify factors associated with prolonged MV, and examine associations of prolonged MV with mortality and complications.

Methods

Four thousand, eight hundred and nine participants undergoing cardiac surgery at 71 hospitals worldwide were included. Prolonged MV was defined based on the Society of Thoracic Surgeons definition as MV lasting 24 hr or longer. Adjusted associations of patient and surgical factors with prolonged MV were examined using multivariable logistic regression. Associations of prolonged MV with complications were assessed using odds ratios, and adjusted associations between prolonged MV and mortality were evaluated using multinomial regression. Associations of shorter durations of MV with survival and complications were explored.

Results

Prolonged MV occurred in 15% (725/4,809) of participants. Prolonged MV was associated with surgical factors indicative of complexity, such as previous cardiac surgery, cardiopulmonary bypass duration, and separation attempts; and patient factors such as critical preoperative state, left ventricular impairment, renal failure, and pulmonary hypertension. Prolonged MV was associated with perioperative but not long-term complications. After risk adjustment, prolonged MV was associated with perioperative mortality; its association with long-term mortality among survivors was weaker. Shorter durations of MV were not associated with increased risk of mortality or complications.

Conclusion

In this substudy of the TRICS III trial, prolonged MV was common after cardiac surgery and was associated with patient and surgical risk factors. Although prolonged MV showed strong associations with perioperative complications and mortality, it was not associated with long-term complications and had weaker association with long-term mortality among survivors.

Study registration

www.ClinicalTrials.gov (NCT02042898); registered 23 January 2014. This is a substudy of the Transfusion Requirements in Cardiac Surgery (TRICS) III trial.

     

Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

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A Diagnostic Algorithm for Posterior Fossa Tumors in Children: A Validation Study

BACKGROUND AND PURPOSE:Primary posterior fossa tumors comprise a large group of neoplasias with variable aggressiveness and short and long-term outcomes. This study aimed to validate the clinical usefulness of a radiologic decision flow chart based on previously published neuroradiologic knowledge for the diagnosis of posterior fossa tumors in children.MATERIALS AND METHODS:A retrospective study was conducted (from January 2013 to October 2019) at 2 pediatric referral centers, Children''s Hospital of Philadelphia, United States, and Great Ormond Street Hospital, United Kingdom. Inclusion criteria were younger than 18 years of age and histologically and molecularly confirmed posterior fossa tumors. Subjects with no available preoperative MR imaging and tumors located primarily in the brain stem were excluded. Imaging characteristics of the tumors were evaluated following a predesigned, step-by-step flow chart. Agreement between readers was tested with the Cohen κ, and each diagnosis was analyzed for accuracy.RESULTS:A total of 148 cases were included, with a median age of 3.4 years (interquartile range, 2.1–6.1 years), and a male/female ratio of 1.24. The predesigned flow chart facilitated identification of pilocytic astrocytoma, ependymoma, and medulloblastoma sonic hedgehog tumors with high sensitivity and specificity. On the basis of the results, the flow chart was adjusted so that it would also be able to better discriminate atypical teratoid/rhabdoid tumors and medulloblastoma groups 3 or 4 (sensitivity = 75%–79%; specificity = 92%–99%). Moreover, our adjusted flow chart was useful in ruling out ependymoma, pilocytic astrocytomas, and medulloblastoma sonic hedgehog tumors.CONCLUSIONS:The modified flow chart offers a structured tool to aid in the adjunct diagnosis of pediatric posterior fossa tumors. Our results also establish a useful starting point for prospective clinical studies and for the development of automated algorithms, which may provide precise and adequate diagnostic tools for these tumors in clinical practice.

In the past 10 years, there has been an exponential increase in knowledge of the molecular characteristics of pediatric brain tumors, which was only partially incorporated in the 2016 World Health Organization Classification of Tumors of the Central Nervous System.¹ The main update in the 2016 Classification was the introduction of the molecular profile of a tumor as an important factor for predicting different biologic behaviors of entities which, on histology, look very similar or even indistinguishable.² A typical example is the 4 main groups of medulloblastoma: wingless (WNT), sonic hedgehog (SHH) with or without the p53 mutation, group 3, and group 4. Although they may appear similar on microscopy, these categories have distinct molecular profiles, epidemiology, prognosis, and embryologic origin.³Subsequent to the publication of the 2016 World Health Organization Classification, further studies have identified even more molecular subgroups of medulloblastoma with possible prognostic implications⁴ and also at least 3 new molecular subgroups of atypical teratoid/rhabdoid tumor (AT/RT)⁵ and several subgroups of ependymoma.⁶ MR imaging shows promise as a technique for differentiating histologic tumors and their molecular subgroups. This capability relies on not only various imaging characteristics but also the location and spatial extension of the tumor, evident on MR imaging, which can be traced to the embryologic origin of the neoplastic cells.^5,7-10One approach to the challenge of identifying imaging characteristics of different tumors in children is to use artificial intelligence. Yet despite this exciting innovation, correctly identifying the location of the mass and its possible use as an element for differential diagnosis still requires the expertise of an experienced radiologist. Previously, D''Arco et al¹¹ proposed a flow chart (Fig 1) for the differential diagnosis of posterior fossa tumors in children based on epidemiologic, imaging signal, and location characteristics of the neoplasm. The aims of the current study were the following: 1) to validate, in a retrospective, large cohort of posterior fossa tumors from 2 separate pediatric tertiary centers, the diagnostic accuracy of that flow chart, which visually represents the neuroadiologist''s mental process in making a diagnosis of posterior fossa tumors in children, 2) to describe particular types of posterior fossa lesions that are not correctly diagnosed by the initial flow chart, and 3) to provide an improved, clinically accessible flow chart based on the results.Open in a separate windowFIG 1.Predesigned radiologic flow chart created according to the literature before diagnostic accuracy analysis. The asterisk indicates brain stem tumors excluded from the analysis. Double asterisks indicate relative to gray matter. Modified with permission from D''Arco et al.¹¹     

Evaluation of DISORDER: Retrospective Image Motion Correction for Volumetric Brain MRI in a Pediatric Setting

BACKGROUND AND PURPOSE:Head motion causes image degradation in brain MR imaging examinations, negatively impacting image quality, especially in pediatric populations. Here, we used a retrospective motion correction technique in children and assessed image quality improvement for 3D MR imaging acquisitions.MATERIALS AND METHODS:We prospectively acquired brain MR imaging at 3T using 3D sequences, T1-weighted MPRAGE, T2-weighted TSE, and FLAIR in 32 unsedated children, including 7 with epilepsy (age range, 2–18 years). We implemented a novel motion correction technique through a modification of k-space data acquisition: Distributed and Incoherent Sample Orders for Reconstruction Deblurring by using Encoding Redundancy (DISORDER). For each participant and technique, we obtained 3 reconstructions as acquired (Aq), after DISORDER motion correction (Di), and Di with additional outlier rejection (DiOut). We analyzed 288 images quantitatively, measuring 2 objective no-reference image quality metrics: gradient entropy (GE) and MPRAGE white matter (WM) homogeneity. As a qualitative metric, we presented blinded and randomized images to 2 expert neuroradiologists who scored them for clinical readability.RESULTS:Both image quality metrics improved after motion correction for all modalities, and improvement correlated with the amount of intrascan motion. Neuroradiologists also considered the motion corrected images as of higher quality (Wilcoxon z = −3.164 for MPRAGE; z = −2.066 for TSE; z = −2.645 for FLAIR; all P < .05).CONCLUSIONS:Retrospective image motion correction with DISORDER increased image quality both from an objective and qualitative perspective. In 75% of sessions, at least 1 sequence was improved by this approach, indicating the benefit of this technique in unsedated children for both clinical and research environments.

Head motion is a common cause of image degradation in brain MR imaging. Motion artifacts negatively impact MR image quality and therefore radiologists’ capacity to read the images, ultimately affecting patient clinical care.¹ Motion artifacts are more common in noncompliant patients,² but even in compliant adults, intrascan movement is reported in at least 10% of cases.³ For children who require high-resolution MR images, obtaining optimal image quality can be challenging, owing to the requirement to stay still over long durations needed for acquisition.⁴ Sedation can be an option, but it carries higher risks, costs, and preparation and recovery time.⁵In conditions such as intractable focal epilepsy, identification of an epileptogenic lesion is clinically important to guide surgical treatment. However, these lesions can be visually subtle, particularly in children in whom subtle cortical dysplasias are more common.⁶ Dedicated epilepsy MR imaging protocols use high-resolution 3D sequences to allow better cortical definition and free reformatting of orientation but involve acquisition times in the order of minutes, so data collection becomes more sensitive to motion.⁷For children in particular, multiple strategies are available for minimizing motion during MR examinations. Collaboration with play specialists using mock scanners and training or projecting a cartoon are good approaches to reduce anxiety.^8,9 These tools are not always available in clinical radiology and, even with these strategies, motion can still be an issue.¹⁰ Different scanning approaches to correct for intrascan motion have been proposed. Broadly, prospective methods track head motion in real time and modify the acquisition directions accordingly.¹¹ These approaches are applicable to a wide range of sequences but require optical systems with external tracking markers, sometimes uncomfortable or impractical, and extra setup can ultimately result in longer examinations. Furthermore, these approaches may also not be robust to continuous motion.^11-13 Retrospective techniques have also been proposed, in some cases relying on imaging navigators that are not compatible with all standard sequences or contrasts.¹²Here, we use a more general retrospective motion correction technique: Distributed and Incoherent Sample Orders for Reconstruction Deblurring by using Encoding Redundancy (DISORDER). In this method, k-space samples are reordered to enable retrospective motion correction during image reconstruction.¹⁴ Our hypothesis is that DISORDER improves clinical MR imaging quality and readability. To assess its use for clinical sequences, we acquired a dedicated epilepsy MR imaging protocol in 32 children across a wide age range. We used both objective image quality metrics and expert neuroradiologist ratings to evaluate the outcome after motion correction.     

Impact on Health-Related Quality of Life of Induction Chemotherapy Compared With Concurrent Cisplatin and Radiation Therapy in Patients With Head and Neck Cancer

AimsOrgan preservation, an important goal in the treatment of head and neck squamous cell carcinoma (HNSCC), may include induction chemotherapy and cisplatin with radiation therapy (CRT). To our knowledge, no reports have directly compared the impact of induction chemotherapy with that of CRT on health-related quality of life (HRQOL).Materials and methodsIn a phase II trial, we assessed the HRQOL of patients treated with induction chemotherapy followed by CRT. Eligible patients had stage III–IV HNSCC. HRQOL questionnaires were administered at baseline, the end of induction (EOI), the end of CRT (EOCRT) and after CRT. Functional Assessment of Cancer Therapy (FACT version 4) assessed HRQOL. We carried out a comparison of changes in HRQOL from baseline to EOI and from EOI to EOCRT. This trial is registered with ClinicalTrials.gov (NCT01566435).ResultsThirty patients were enrolled in the study. Most HRQOL questionnaires were completed (88%). The mean total FACT scores did not differ from baseline to EOI (general: 83.8 versus 79.1, P = 0.08; head and neck: 109.7 versus 105.8, P = 0.33; Total Outcome Index: 69.7 versus 62.3, P = 0.03; respectively, using P ≤ 0.01 to adjust for multiple simultaneous tests of differences). However, total FACT scores significantly worsened from EOI to EOCRT (79.1 versus 62.3, P = 0.01; 105.8 versus 74.2, P < 0.01; 62.3 versus 34.2, P = 0.01; respectively). Within domains, the head and neck cancer subscale score did not differ from baseline to EOI (median 28.5 versus 27.0, P = 0.69), but significantly worsened from EOI to EOCRT (27.0 versus 9.5, P < 0.01). Swallowing, oral pain and voice quality improved from baseline to EOI, but worsened from EOI to EOCRT. Physical and functional scores worsened from baseline to EOI and from EOI to EOCRT. The emotional well-being score improved from baseline to EOI but worsened from EOI to EOCRT.ConclusionsOverall, HRQOL did not significantly change from baseline to EOI but dramatically worsened from EOI to EOCRT.     

Reliability and validity of the UTBAS-TR (The Unhelpful Thoughts and Beliefs Scale-the Turkish version) in the Turkish population

Abstract

Purpose: This paper decribes the development of the Turkish adaptation of UTBAS (UTBAS-TR) and reports the results concerning its applicability and psychometric structure.

Method: The sample consisted of 81 males and 19 females diagnosed with developmental stuttering in two centres. Test-retest reliability score was obtained by correlating results of repeated aplications of the scale within a one-week interval and a paired t-test was calculated to see the differences in the total and UTBAS I, II and III scores. The internal consistency was assessed using the Cronbach’s alpha. Construct validity was also assessed by examining inter-scale correlations and with the correlations of the UTBAS-TR with two other scales (State-Trait Anxiety Inventory (STAI) and Beck Anxiety Inventory (BAI)).

Result: The internal consistency of the UTBAS-TR and the test and retest reliability score was stati?stically significant. The correlation between UTBAS-TR total score and the UTBAS-TR I, II and III correlations were high. A significant correlation was observed between UTBAS-TR total score with State Anxiety Inventory. However, the correlations between UTBAS-TR-Total Score and Trait Anxiety Inventory and Beck Anxiety Inventory were low.

Conclusion: The UTBAS-TR proved to be suitable for use with the Turkish population.     

Association between periodontitis and medication-related osteonecrosis of the jaw: A systematic review and meta-analysis

Consensus has yet to be reached about the prevention and treatment of medication-related osteonecrosis of the jaw (MRONJ), which is a treatment sequela of several antiresorptive therapies and other pharmaceutical interventions. Several epidemiologic studies have identified periodontal disease (PD) as a risk factor for this outcome. Thus, the objective of this systematic review and meta-analysis was to investigate this association and its magnitude. A systematic search in MEDLINE via PubMed, Scopus and ISI Web of Science, and a meta-analysis were undertaken. Observational studies that gathered information regarding prefixed definitions for both outcomes were selected, and the relevant information was then extracted, and their risk of bias was evaluated using the Newcastle-Ottawa Scale. The protocol of the study was registered on PROSPERO (CRD42019125646). The initial search yielded 757 eligible records, of which 12 were deemed adequate for inclusion (5 cohort studies and 7 case-control studies). On a random-effects meta-analysis, the risk of PD in MRONJ-affected sites compared with at-risk non-affected patients was significantly greater, with a risk ratio of 2.75 (95% CI: 1.67-4.52). Nonetheless, from a pooled analysis of three standardized periodontal measures (ie plaque index, clinical attachment loss and probing depth) no significant results were obtained. MRONJ appears to be associated with an increase in prevalence of PD. The direction of this association, and the factors influencing it must be investigated using further prospective data, and likewise, the possibility for using periodontal therapy as a prevention strategy must be looked into. Periodontal screening needs to be made an indispensable requisite for clinicians in order to establish a correct multidisciplinary approach in MRONJ.