Intra-operative extracorporeal irradiation of tumour-invaded craniotomy bone flap in meningioma: a case series.

BACKGROUND: Extracorporeal irradiation of tumorous calvaria (EITC) can be performed to restore function and form of the skull after resection of bone-invasive meningioma. We sought to examine the rate of tumour recurrence and other selected outcomes in patients undergoing meningioma resection and EITC. METHODS: Retrospective single-centre study of adult patients undergoing meningioma resection and EITC between January 2015 and November 2022 at a tertiary neurosurgical centre. Patient demographics, surgery data, tumour data, use of adjuvant therapy, surgical complications, and tumour recurrences were collected. RESULTS: Eighteen patients with 11 (61%) CNS WHO grade 1, 6 (33%) grade 2, and 1 (6%) grade 3 meningiomas were included. Median follow-up was 42 months (range 3-88). Five (28%) patients had a recurrence, but none were associated with the bone flap. Two (11%) wound infections requiring explant surgery occurred. Six (33%) patients required a further operation. Two operations were for recurrences, one was for infection, one was a washout and wound exploration but no evidence of infection was found, one patient requested the removal of a small titanium implant, and one patient required a ventriculoperitoneal shunt for a persistent CSF collection. There were no cases of bone flap resorption and cosmetic outcome was not routinely recorded. CONCLUSION: EITC is feasible and fast to perform with good outcomes and cost-effectiveness compared to other reconstructive methods. We observed similar recurrence rates and lower infection rates requiring explant compared to the largest series of cranioplasty in meningioma. Cosmetic outcome is universally under-reported and should be reported in future studies.

Epithelial Carcinomas Arising within Phyllodes Tumours of the Breast: A Review of Their Pathological Characteristics.

Epithelial proliferation is a common feature of phyllodes tumours (PTs), but epithelial malignancy is rare. This review seeks to further our understanding of epithelial malignancy within PTs by analysing their histopathological characteristics in previously reported cases and providing an overview of studies on their pathological features. PubMed and DeepDyve were searched for case reports, case series, and literature reviews of in situ and invasive carcinoma within PTs. Only cases where the carcinoma was within the PT were included. Cases of synchronous carcinoma in the ipsilateral or contralateral breast were excluded. Ninety-eight cases of in situ or invasive carcinoma within a PT were identified. Across the grades of PTs, there was a similar proportion of invasive carcinomas compared to in situ lesions. Malignant PT correlates with a higher likelihood of epithelial malignancy, and molecular studies support a possible causal pathophysiological relationship. This higher likelihood may suggest interactions between malignant stroma and the transforming epithelium that could potentially play a significant role in the phenomenon, which remains to be elucidated. Encasement within a PT likely improves the prognosis of breast carcinoma due to earlier detection. The presence of carcinoma within a malignant PT has uncertain prognostic implications. Thorough sampling of all PTs is recommended for appropriate prognostication and management.

Burden of Uncontrolled Severe Asthma With and Without Elevated Type-2 Inflammatory Biomarkers.

BACKGROUND: Many patients with asthma have type-2 airway inflammation, identified by the presence of biomarkers, including history of allergy, high blood eosinophil (EOS) count, and high fractional exhaled nitric oxide levels. OBJECTIVE: To assess disease burden in relation to type-2 inflammatory biomarker status (history of allergy, blood EOS count, and fractional exhaled nitric oxide level) in patients with uncontrolled and controlled severe asthma in the NOVEL observational longiTudinal studY (NOVELTY) (NCT02760329). METHODS: Asthma diagnosis and severity were physician-reported. Control was defined using Asthma Control Test score (uncontrolled <20, controlled ≥20) and/or 1 or more severe physician-reported exacerbation in the previous year. Biomarker distribution (history of allergy, blood EOS count, and fractional exhaled nitric oxide level), symptom burden (Asthma Control Test score, modified Medical Research Council dyspnea scale), health status (St George's Respiratory Questionnaire score), exacerbations, and health care resource utilization were assessed. RESULTS: Of 647 patients with severe asthma, 446 had uncontrolled and 123 had controlled asthma. Among those with uncontrolled asthma, 196 (44%) had 2 or more positive biomarkers, 187 (42%) had 1 positive biomarker, 325 (73%) had low blood EOS, and 63 (14%) were triple-negative. Disease burden was similarly high across uncontrolled subgroups, irrespective of biomarker status, with poor symptom control (Asthma Control Test score 14.9-16.6), impaired health status (St George's Respiratory Questionnaire total score 46.7-49.4), clinically important breathlessness (modified Medical Research Council grade ≥2 in 47.3%-57.1%), and 1 or more severe exacerbation (70.6%-76.2%). CONCLUSIONS: Type-2 inflammatory biomarkers did not differentiate disease burden in patients with severe asthma. Patients with low type-2 inflammatory biomarker levels have few biologic therapy options; their needs should be addressed.

Symptom Burden, Health Status, and Productivity in Patients with Uncontrolled and Controlled Severe Asthma in NOVELTY.

Background: Few studies have quantified symptom burden, health status, and productivity in patients with uncontrolled and controlled severe asthma. Up-to-date, real-world, global evidence is needed. Objective: To quantify symptom burden, health status, and productivity in patients with uncontrolled and controlled severe asthma using baseline data from the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329). Methods: NOVELTY included patients aged ≥18 years (or ≥12 years in some countries) from primary care and specialist centres in 19 countries, with a physician-assigned diagnosis of asthma, asthma+chronic obstructive pulmonary disease (COPD), or COPD. Disease severity was physician-assessed. Uncontrolled severe asthma was defined by an Asthma Control Test (ACT) score <20 and/or severe physician-reported exacerbations in the previous year; controlled severe asthma required an ACT score ≥20 and no severe exacerbations. Assessment of symptom burden included Respiratory Symptoms Questionnaire (RSQ) and ACT score. Assessment of health status included St George's Respiratory Questionnaire (SGRQ), EuroQoL 5 Dimensions 5 Levels Health Questionnaire (EQ-5D-5L) index value, and EQ-5D-5L Visual Analog Score (EQ-VAS). Assessment of productivity loss included absenteeism, presenteeism, overall work impairment, and activity impairment. Results: Of 1652 patients with severe asthma, asthma was uncontrolled in 1078 (65.3%; mean age 52.6 years, 65.8% female) and controlled in 315 (19.1%; mean age 55.2 years, 56.5% female). With uncontrolled versus controlled severe asthma, symptom burden was higher (mean RSQ score 7.7 vs 2.5), health status more impaired (mean SGRQ total score 47.5 vs 22.4; mean EQ-5D-5L index value 0.68 vs 0.90; mean EQ-VAS score 64.1 vs 78.1), and productivity lower (presenteeism 29.3% vs 10.5%). Conclusion: Our findings highlight the symptom burden of uncontrolled severe asthma compared with controlled severe asthma and its impact on patient health status and productivity, and support the need for interventions to improve control of severe asthma.

Key Moments in the History of Liposuction by Dermatologists.

Dermatologists have been pioneers in the development and refinement of liposuction using local anesthesia. Although other specialties routinely use general anesthesia for liposuction, the safety profile of liposuction using local anesthesia is impressive. This article traces the history and development of liposuction by dermatologists in the United States. J Drugs Dermatol. 2022;21(9):997-1000. doi:10.36849/JDD.6952.

Comparative Analysis of Lumbar Spine Vertebral Morphology Between Maori and New Zealand Europeans: A Computed Tomography Study.

BACKGROUND: Most existing studies of lumbar anatomy do not consider ethnic influence and recruit mostly white participants. Recent studies have considered other populations; however, none have assessed Maori, the indigenous people of New Zealand (NZ). A computed tomography study of vertebral body (VB) and canal dimensions was performed for lumbar vertebrae of Maori and NZ European patients to evaluate for ethnic variation. METHODS: Lumbar vertebrae from 196 patients were measured using computed tomography. After interrater and intrarater reliability analyses, a single trained examiner measured VB heights, VB lengths, segmental angle, pedicle height and width, and vertebral canal length (VCL) and vertebral canal width for each level. Canal:body ratio was calculated. Demographic data recorded included age, sex, and ethnicity. RESULTS: VCL remained relatively constant through the lumbar spine; canal width increased to a maximum of 28.2 mm at L5. Canal:body ratios and pedicle height decreased while pedicle width increased to a maximum of 16.1 mm at L5. There were few differences between Maori and NZ Europeans except at the L5 level, where VCL and canal:body ratio were larger in NZ Europeans (P < 0.05), and pedicle height, width, and VB pediculolaminar length were larger in Maori (P < 0.05). Females had generally smaller measurements and age was a positive predictor of measured values (P < 0.05). CONCLUSIONS: This study is the first to characterize lumbar anatomy in a Maori cohort. Adequately powered results demonstrated few differences between Maori and NZ Europeans. Isolated differences observed at L5 may be due to sacropelvic differences, which represent an area for further investigation. LEVEL OF EVIDENCE: 3. CLINICAL RELEVANCE: Diagnosis, surgical planning, ethnic differences.

Retrospective evaluation of prognostic factors in metastatic spine disease: serum albumin and primary tumour type are key.

BACKGROUND: Treatment decisions for metastatic spine disease are complex and depend on prognosis. Four prognostic systems in use are the Oswestry Risk Index, modified Bauer score (MBS), van der Linden score and New England Spinal Metastasis Score (NESMS). We aimed to determine the performance of these scoring systems in a New Zealand cohort of patients and develop a prognostic score specific to this demographic. METHODS: A retrospective review of a patient cohort from 2009 to 2016 was undertaken. Scores and individual scoring items were evaluated with univariate and multivariate analyses. Significant items were used to design a simple, population-specific objective scoring system, which was then tested. RESULTS: A total of 106 patients receiving either surgery and radiotherapy (65) or radiotherapy alone (41) were included. Mean post-treatment survival time was 13.7 months. All scoring systems were significantly correlated with survival and had similar concordances. The MBS had the largest coefficient of determination (Cox and Snell's R2 = 0.18), followed by the NESMS (R2 = 0.14). On multivariate analysis, the lung cancer (MBS) and serum albumin (NESMS) items were significant. A modified Oswestry Risk Index primary tumour item and NESMS serum albumin outperformed the MBS (R2 = 0.20), providing the basis for a prognostic scoring tool specific to our demographic. CONCLUSION: Based on serum albumin and primary tumour type, we propose the 'Metastatic Spine Risk Index' as a simple and objective tool, specific to our population for predicting survival, which can be used in conjunction with other clinical information when considering treatment options.

AAV Targeting of Glial Cell Types in the Central and Peripheral Nervous System and Relevance to Human Gene Therapy.

Different glial cell types are found throughout the central (CNS) and peripheral nervous system (PNS), where they have important functions. These cell types are also involved in nervous system pathology, playing roles in neurodegenerative disease and following trauma in the brain and spinal cord (astrocytes, microglia, oligodendrocytes), nerve degeneration and development of pain in peripheral nerves (Schwann cells, satellite cells), retinal diseases (Müller glia) and gut dysbiosis (enteric glia). These cell type have all been proposed as potential targets for treating these conditions. One approach to target these cell types is the use of gene therapy to modify gene expression. Adeno-associated virus (AAV) vectors have been shown to be safe and effective in targeting cells in the nervous system and have been used in a number of clinical trials. To date, a number of studies have tested the use of different AAV serotypes and cell-specific promoters to increase glial cell tropism and expression. However, true glial-cell specific targeting for a particular glial cell type remains elusive. This review provides an overview of research into developing glial specific gene therapy and discusses some of the issues that still need to be addressed to make glial cell gene therapy a clinical reality.

Comparison of higher order wavefront aberrations with four aberrometers.

Purpose: To evaluate the agreement of selected higher order aberration measurements between aberrometers based on three different wavefront technologies. Methods: Twenty-three eyes of 23 participants were compared between Zywave, OPD-Scan III, and iDesign aberrometers, for total ocular aberrations. Participants were between 19 and 69 years of age, and exclusion criteria were previous ocular surgery or trauma, contact lens wear within the preceding 2 weeks, and ocular or systemic disease. Corneal aberrations were compared between the OPD-Scan III and GALILEI™ G2 aberrometers. Zernike coefficients of vertical and oblique trefoil, vertical and horizontal coma, and spherical aberration were analyzed in R software. Results: In all, 276 scans were captured in total, with a male-to-female ratio of 11:12. Total ocular vertical coma [mean difference (MD) = 0.026 µm, P < 0.005], vertical trefoil (MD = 0.033 µm, P < 0.05), and spherical aberration (MD = 0.022 µm, P < 0.05) differed significantly between the iDesign and OPD-Scan III. Differences in total vertical (MD = 0.072 µm, P < 0.05) and oblique trefoil (MD = 0.058 µm, P < 0.05) were demonstrated between the Zywave and OPD-Scan III, and spherical aberration (MD = 0.030 µm, P < 0.005) between iDesign and Zywave. iDesign corneal horizontal coma (MD = 0.025 µm, P < 0.05) and spherical aberration (MD = 0.043 µm, P < 0.005) measurements were significantly different between the GALILEI™ G2 and the OPD-Scan III. Conclusion: Zywave, iDesign, and OPD-Scan III, and GALILEITM G2 and OPD-Scan III may be used interchangeably for their total ocular and corneal wavefront functions, respectively; however, care must be taken if using these devices for guiding ablation or monitoring corneal disease.

Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset.

The release of circulating tumor cells (CTCs) into vasculature is an early event in the metastatic process. The analysis of CTCs in patients has recently received widespread attention because of its clinical implications, particularly for precision medicine. Accumulated evidence documents a large heterogeneity in CTCs across patients. Currently, the most accepted view is that tumor cells with an intermediate phenotype between epithelial and mesenchymal have the highest plasticity. Indeed, the existence of a meta-stable or partial epithelial⁻mesenchymal transition (EMT) cell state, with both epithelial and mesenchymal features, can be easily reconciled with the concept of a highly plastic stem-like state. A close connection between EMT and cancer stem cells (CSC) traits, with enhanced metastatic competence and drug resistance, has also been described. Accordingly, a subset of CTCs consisting of CSC, present a stemness profile, are able to survive chemotherapy, and generate metastases after xenotransplantation in immunodeficient mice. In the present review, we discuss the current evidence connecting CTCs, EMT, and stemness. An improved understanding of the CTC/EMT/CSC connections may uncover novel therapeutic targets, irrespective of the tumor type, since most cancers seem to harbor a pool of CSCs, and disclose important mechanisms underlying tumorigenicity.

Randomised, phase 1, dose-finding study of MEDI4166, a PCSK9 antibody and GLP-1 analogue fusion molecule, in overweight or obese patients with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Cardiovascular disease is the leading cause of morbidity and mortality in people with type 2 diabetes. MEDI4166 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and glucagon-like peptide-1 (GLP-1) analogue fusion molecule designed to treat patients with type 2 diabetes who are at risk for cardiovascular disease. In this completed, first-in-human study, we evaluated the safety and efficacy of single or multiple doses of MEDI4166 in participants with type 2 diabetes. METHODS: In this phase 1 study that was conducted across 11 clinics in the USA, eligible adults had type 2 diabetes, a BMI of ≥25 kg/m2 to ≤42 kg/m2, and LDL-cholesterol levels ≥1.81 mmol/l. Participants were randomised 3:1 to receive MEDI4166 or placebo using an interactive voice/web response system, which blinded all participants, investigators and study site personnel to the study drug administered. In 'Part A' of the study, five cohorts of participants received a single s.c. injection of MEDI4166 at 10 mg, 30 mg, 100 mg, 200 mg or 400 mg, or placebo. 'Part B' of the study consisted of three cohorts of participants who received an s.c. dose of MEDI4166 once weekly for 5 weeks at 50 mg, 200 mg or 400 mg, or placebo. The primary endpoint in Part A was safety. The co-primary endpoints in Part B were change in LDL-cholesterol levels and area under the plasma glucose concentration-time curve (AUC0-4h) post-mixed-meal tolerance test (MMTT) from baseline to day 36. The pharmacokinetics and immunogenicity of MEDI4166 were also evaluated. RESULTS: MEDI4166 or placebo was administered to n = 30 or n = 10 participants, respectively, in Part A of the study, and n = 48 or n = 15 participants, respectively, in Part B. The incidence of treatment-emergent adverse events (TEAEs) were comparable between MEDI4166 and placebo in both Part A (60% vs 50%) and Part B (79% vs 87%) of the study. Common TEAEs with MEDI4166 included injection-site reactions, diarrhoea and headache; there was no evidence for dose-related increases in TEAEs. In Part B of the study, at all tested doses of MEDI4166, there was a significant decrease in LDL-cholesterol levels vs placebo (least squares mean [95% CI]; MEDI4166 50 mg, -1.25 [-1.66, -0.84]; MEDI4166 200 mg, -1.97 [-2.26, -1.68]; MEDI4166 400 mg, -1.96 [-2.23, -1.70]; placebo, -0.03 [-0.35, 0.28]; all p < 0.0001). However, there were no clinically relevant reductions or significant differences between MEDI4166 vs placebo in glucose AUC0-4h post-MMTT (least squares mean [95% CI]; MEDI4166 50 mg, -10.86 [-17.69, -4.02]; MEDI4166 200 mg, -4.23 [-8.73, 0.28]; MEDI4166 400 mg, -2.59 [-7.14, 1.95]; placebo, -4.84 [-9.95, 0.28]; all p > 0.05). MEDI4166 was associated with a pharmacokinetic profile supportive of weekly dosing and an overall treatment-induced anti-drug antibody-positive rate of 22%. CONCLUSIONS/INTERPRETATION: MEDI4166 was associated with an acceptable tolerability profile and significantly decreased LDL-cholesterol levels in a dose-dependent manner in overweight or obese patients with type 2 diabetes. However, there were no significant reductions in postprandial glucose levels at any dose of MEDI4166. TRIAL REGISTRATION: ClinicalTrials.gov NCT02524782 FUNDING: This study was funded by MedImmune LLC, Gaithersburg, MD, USA.

Healthy physical coactivity in parent-child dyads of children with overweight.

Parent and child physical activity levels are correlated, but are they interdependent? A dyadic version of the theory of planned behavior (TPB) was developed to investigate interdependence in the motivation and intention of parents and their children with overweight to engage in healthy physical coactivity (HPCA). Baseline measures of the TPB constructs (subjective norms, attitude, perceived behavior control, and intention) for both dyad members were used to predict parent-reports of their actual HPCA at 12 weeks using the actor-partner interdependence model. The sample included 65 mother-child dyads and 48 father-child dyads from 66 predominantly Caucasian families. In mother-child dyads, a positive attitude toward HPCA predicted each person's own intention to engage in HPCA (both actor effects). In addition, mother's perceived behavior control over HPCA predicted the child's intention to engage in HPCA (a partner effect). Mother's attitude toward HPCA also predicted mother-reported HPCA. In father-child dyads, perceived behavior control predicted each person's own intention to engage in HPCA (both actor effects). The child's intention was also predicted by the child's subjective norms (an actor effect) and the father's perceived behavior control (a partner effect). Only the child's perceived behavior control predicted father-reported HPCA. There is interdependence in the motivation to engage in HPCA because both parents' perceived behavior control predicted their child's intention. However, interventions targeting mother's attitude toward HPCA with her child and the child's perceived behavior control in relation to the father would be most likely to increase HPCA in the parent-child dyads of children with overweight. (PsycINFO Database Record

Integration of protein phosphorylation, acetylation, and methylation data sets to outline lung cancer signaling networks.

Protein posttranslational modifications (PTMs) have typically been studied independently, yet many proteins are modified by more than one PTM type, and cell signaling pathways somehow integrate this information. We coupled immunoprecipitation using PTM-specific antibodies with tandem mass tag (TMT) mass spectrometry to simultaneously examine phosphorylation, methylation, and acetylation in 45 lung cancer cell lines compared to normal lung tissue and to cell lines treated with anticancer drugs. This simultaneous, large-scale, integrative analysis of these PTMs using a cluster-filtered network (CFN) approach revealed that cell signaling pathways were outlined by clustering patterns in PTMs. We used the t-distributed stochastic neighbor embedding (t-SNE) method to identify PTM clusters and then integrated each with known protein-protein interactions (PPIs) to elucidate functional cell signaling pathways. The CFN identified known and previously unknown cell signaling pathways in lung cancer cells that were not present in normal lung epithelial tissue. In various proteins modified by more than one type of PTM, the incidence of those PTMs exhibited inverse relationships, suggesting that molecular exclusive "OR" gates determine a large number of signal transduction events. We also showed that the acetyltransferase EP300 appears to be a hub in the network of pathways involving different PTMs. In addition, the data shed light on the mechanism of action of geldanamycin, an HSP90 inhibitor. Together, the findings reveal that cell signaling pathways mediated by acetylation, methylation, and phosphorylation regulate the cytoskeleton, membrane traffic, and RNA binding protein-mediated control of gene expression.

Sources of perceived responsiveness in family relationships.

Perceived responsiveness has become one of the most important constructs in the relationship sciences. It is central to the development of a secure attachment style, the experience of social support, an internal locus of control, and the sense of control in close relationships. Conversely, an unresponsive environment is associated with learned helplessness and depression. Viewed through the lens of the social relations model (SRM), perceived responsiveness in family relationships could have multiple sources: the perceiver; the target or partner; the perceiver-target relationship; and the family group. This study used the SRM to determine the relative importance of these sources of perceived responsiveness in the relationships of 207 two-parent two-child families. Characteristics of the perceiver and the target each accounted for about 25% of the systematic variance in perceived responsiveness, whereas the perceiver-target relationship accounted for approximately 48%. At the individual level of analysis, reciprocity of perceived responsiveness was pervasive in the family relationships of the two children. Regardless of age, young people who generally perceived others as responsive were generally perceived by others as responsive. At the dyadic level of analysis, reciprocity was present in two dyads: mother-father and older child-younger child. Reliable target variances support the view that perceived responsiveness is not just "inside the head" of the perceiver, and reciprocity correlations suggest potentially useful systemic interventions. (PsycINFO Database Record

Assessment of Saxagliptin Efficacy: Meta-Analysis of 14 Phase 2 and 3 Clinical Trials.

INTRODUCTION: This meta-analysis of data from 14 phase 2 and 3, double-blind, randomized, controlled 12- and 24-week studies (N = 4632) summarizes saxagliptin efficacy in patients with type 2 diabetes (T2D) across treatment regimens. METHODS: Patients received saxagliptin 5 mg/d or control as either monotherapy (n = 1196 vs placebo), add-on therapy (n = 2139 vs placebo and n = 514 vs uptitrated sulfonylurea), or initial combination therapy (n = 619 vs control monotherapy). Patients with renal impairment received saxagliptin 2.5 mg/d or placebo (n = 164). RESULTS: Mean baseline glycated hemoglobin (A1C) ranged from 8.07% to 9.43% for the saxagliptin and control groups across treatment regimens. A1C reduction from baseline was greater with saxagliptin versus control for all studies combined (mean treatment difference [95% CI]: -0.55% [-0.63%, -0.47%]) and when used as monotherapy (-0.52% [-0.63, -0.40%]), add-on (-0.55% [-0.69%, -0.40%] vs placebo; -0.72% [-0.88%, -0.56%] vs uptitrated sulfonylurea), initial combination therapy (-0.54% [-0.73%, -0.35%] vs control monotherapy), and in patients with renal impairment (-0.42% [-0.75%, -0.09%]). Similar reductions in A1C versus control were noted for patients <65 years (-0.55% [-0.67%, -0.43%]) and ≥65 years (-0.54% [-0.69%, -0.38%]) and for men (-0.54% [-0.69%, -0.40%]) and women (-0.55% [-0.64%, -0.47%]) across treatment regimens. More patients achieved A1C <7% (39% vs 23%) and A1C ≤6.5% (24% vs 14%) with saxagliptin than with placebo or active-control treatment. Saxagliptin versus control was associated with a reduction in glucagon area under the curve (AUC) from baseline and increases in insulin AUC, C-peptide AUC, and the homeostasis model assessment of ß-cell function. CONCLUSION: Results of this meta-analysis demonstrate the consistency of saxagliptin efficacy in different subgroups of patients with T2D across treatment regimens. FUNDING: AstraZeneca.

Effects of Glimepiride versus Saxagliptin on ß-Cell Function and Hypoglycemia: A Post Hoc Analysis in Older Patients with Type 2 Diabetes Inadequately Controlled with Metformin.

PURPOSE: The management of hyperglycemia is challenging in older patients with type 2 diabetes owing to excess fragility and risk for adverse outcomes should hypoglycemia episodes occur. We evaluated baseline ß-cell function as a potential risk factor for the development of hypoglycemia when saxagliptin or glimepiride was added in patients aged ≥65 years whose type 2 diabetes was poorly controlled on stable metformin monotherapy. METHODS: A post hoc analysis of data from the GENERATION (Efficacy and Tolerability of Saxagliptin Compared with Glimepiride in Elderly Patients with Type 2 Diabetes: A Randomized, Controlled Study) trial, which enrolled 720 patients aged ≥65 years, was conducted. ß-Cell function was assessed using homeostasis model assessment-2%ß (HOMA-2%ß). FINDINGS: The percentage of patients experiencing any hypoglycemia event (ie, symptomatic event or event of plasma glucose concentration <54 mg/dL regardless of symptoms) was lower with saxagliptin compared with glimepiride (5.8% vs 34.8%). Regardless of treatment, patients with lower (median HOMA-2%ß ≤39.1% [≤median]) versus higher (HOMA-2%ß above median value [>median]) baseline ß-cell function had a higher hypoglycemia event rate (1.27 vs 0.82 events/patient-year; adjusted incidence rate ratio [IRR] = 1.800; 95% CI, 1.501-2.159). In patients receiving glimepiride, the hypoglycemia event rate was higher in patients with baseline HOMA-2%ß ≤median versus >median (2.29 vs 1.60 events/patient-year; adjusted IRR = 1.737; 95% CI, 1.439-2.097); corresponding saxagliptin hypoglycemia event rates were too low to draw meaningful conclusions (0.16 vs 0.09 events/patient-year; adjusted IRR = 2.457; 95% CI, 1.148-5.256). The association between lower ß-cell function at baseline and increased prevalence of hypoglycemia was particularly strong in patients aged ≥75 years (adjusted IRR = 2.409; 95% CI, 1.686-3.442; P < 0.001), although it was also significant in patients aged 65 to <75 years old (adjusted IRR, 1.654; 95% CI, 1.339-2.043; P < 0.001). IMPLICATIONS: In patients with lower ß-cell function, the addition of a sulfonylurea to a metformin regimen was associated with an increased risk for hypoglycemia compared with that in patients with higher ß-cell function; low hypoglycemia event rates with the addition of saxagliptin limited equivalent assessments. These findings in older patients are especially relevant because morbidity associated with hypoglycemia is higher in this age group. ClinicalTrials.gov identifier: NCT01006603 (ClinicalTrials.gov).

Osmolarity and spectrophotometric property of brilliant blue green define the degree of toxicity on retinal pigment epithelial cells exposed to surgical endoilluminator.

OBJECTIVE: To evaluate the effect of varying concentrations of brilliant blue green (BBG) and their different biochemical characteristics on retinal pigment epithelial (RPE) cells under xenon light source illumination at varying distances to identify safe parameters for intraoperative use. METHODS: Human retinal RPE cells (ARPE-19) were exposed to two concentrations (0.25 and 0.50 mg/mL) of BBG and illuminated with a xenon surgical illuminator at varying distances (10 and 25 mm), intensity levels, and time intervals (1, 5, and 15 minutes). Additionally, the effect of osmolarity was examined by diluting BBG in different concentrations of glucose. Cytotoxicity of BBG and osmolarity effects on cell viability were evaluated using a WST-1 assay. Light absorption and emission characteristic of BBG in different solvents were measured using a plate reader at different wavelengths. Lastly, the activity of caspase-3 was also studied. RESULTS: Cell viability of ARPE-19 cells was 77.4%±12.7%, 78.7%±17.0%, and 65.0%±19.7% at 1, 5, and 15 minutes to exposure of high illumination xenon light at 10 mm (P<0.05) compared to controls. At both distances of illumination (10 and 25 mm), similar cell viabilities were seen between 1 and 5 minutes of exposure. However, there was a decline in viability when the illumination was carried out to 15 minutes in all groups (P<0.05). There was no significant reduction in cell viability in presence or absence of xenon light in different osmolar solutions concentrations of glucose (P>0.05). Maximal light absorption of BBG was noted between 540 and 680 nm. Activated caspase-3 level was not significant in both the concentrations of BBG (P>0.05). CONCLUSION: Our findings suggest that BBG at 0.25 mg/mL during vitreoretinal surgery is safe and not toxic to RPE cells up to 5 minutes under focal high illumination (10 mm) and up to 15 minutes under medium diffuse illumination (25 mm). BBG was safe to be mixed with isotonic glucose solution at the concentration range of 2.5%-10%, regardless of the illumination status.