Functional and morphological changes in diabetic macular edema over the course of anti‐vascular endothelial growth factor treatment

Purpose:  To evaluate macular morphology and function in diabetic macular edema (DME) over the course of intravitreal anti‐vascular endothelial growth factor (VEGF) treatment with Ranibizumab. Methods:  A consecutive series of 39 study eyes with centre‐involving DME were included in this study. In all subjects, best‐corrected visual acuity (BCVA) according ETDRS protocol, fluorescein angiography (FA), microperimetric macular sensitivity (MP) and Spectral Domain optical coherence tomography (SD‐OCT) cross‐sectional scans were obtained before treatment and after 3 monthly applied intravitreal Ranibizumab injections. Six different morphological qualities [IS/OS layer integrity, outer nuclear layer (ONL) cysts, ONL cyst size, inner nuclear layer (INL) cysts, blocking phenomenon and subretinal fluid] were graded of each cross‐sectional OCT scan before and over the course of treatment by two experienced graders. Correlation analyses between functional and morphological parameters were obtained. Results:  Mean BCVA increased from 26 ± 14 to 33 ± 13 letters after 3 consecutive monthly applied Ranibizumab injections (p < 0.001). Central retinal thickness (CRT) decreased from 504 ± 144 to 387 ± 122 μm (p < 0.001). Over the course of treatment, IS/OS continuity improved (index: 0.56 ± 0.52 to 0.43 ± 0.49, Z = ?1.415, p = 0.157), ONL cyst prevalence and size decreased significantly (index: 0.61 ± 0.44 to 0.56 ± 0.35, Z = ?3.41, p = 0.001 and 1.75 ± 0.88 to 1.17 ± 1.05, Z = ?4.02, p < 0.001), INL cyst prevalence decreased (index: 0.35 ± 0.52 to 0.28 ± 0.52, Z = ?1.60, p = 0.109), blocking phenomenon did not change significantly (index: 00.12 ± 0.16 to 0.13 ± 0.15, Z = ?0.45, p = 0.656) and subretinal fluid almost disappeared (index: 0.10 ± 0.24 vs. 0.00 ± 0.01, Z = ?2.56, p = 0.011). Correlation analyses revealed highest significant correlations between ONL cyst prevalence and their size and CRT as well as BCVA and MP before treatment and over the course of treatment. Conclusions:  ONL cysts and their size as morphological parameters correlate with retinal function measured with BCVA and microperimetry before and over the course of anti‐VEGF therapy with Ranibizumab in patients with DME.     

Amorphization and modified release of ibuprofen by post-synthetic and solvent-free loading into tailored silica aerogels

Promising active pharmaceutical ingredients (APIs) often exhibit poor aqueous solubility and thus a low bioavailability that substantially limits their pharmaceutical application. Hence, efficient formulations are required for an effective translation into highly efficient drug products. One strategy is the preservation of an amorphous state of the API within a carrier matrix, which leads to enhanced dissolution. In this work, mesoporous silica aerogels (SA) were utilized as a carrier matrix for the amorphization of the poorly water-soluble model drug ibuprofen. Loading of tailored SA was performed post-synthetically and solvent-free, either by co-milling or via the melting method. Thorough analyses of these processes demonstrated the influence of macrostructural changes during the drying and grinding process on the microstructural properties of the SA. Furthermore, interfacial SA-drug interaction properties were selectively tuned by attaching terminal hydrophilic amino- or hydrophobic methyl groups to the surface of the gel. We demonstrate that not only the chemical surface properties of the SA, but also formulation-related parameters, such as the carrier-to-drug ratio, as well as process-related parameters, such as the drug loading method, decisively influence the ibuprofen adsorption efficiency. In addition, the drug-loaded SA formulations exhibited a remarkable physical stability over a period of 6 months. Furthermore, the release behavior is shown to change considerably with different surface properties of the SA matrix. Hence, the reported results demonstrate that utilizing specifically processed and modified SA offers a compelling technique for enhancement of the bioavailability of poorly-water soluble APIs and a versatile adjustment of their release profile.     

Fundus lesions in malignant hypertension. III. Arterial blood pressure, biochemical, and fundus changes

Malignant (accelerated) renovascular arterial hypertension was produced in 57 adult rhesus monkeys by clamping the renal artery (one-kidney model in 25 animals and two-kidney model in 32). The animals were investigated before renal artery clamping and serially thereafter by recording systolic arterial blood pressure (BP), biochemical changes, and changes in the fundus of the eye; the latter was evaluated by ophthalmoscopy, stereoscopic color fundus photography, and fluorescein fundus angiography. All of the animals developed arterial hypertension. The data on BP, biochemical, and fundus findings were analyzed and correlated. The findings of this study clearly showed that the various fundus lesions seen in these hypertensive animals fall into three distinct categories: (1) hypertensive retinopathy, (2) hypertensive choroidopathy, and (3) hypertensive optic neuropathy. The appearance of the retinopathy was significantly earlier than that of the choroidopathy or optic neuropathy (P less than 0.01), but the difference between the times of appearance of the choroidopathy and neuropathy was not significant. There was no significance in the order in which the three types of fundus changes reached their maximum severity. There was no significant difference between the mean BPs when the retinopathy, choroidopathy, or optic neuropathy first appeared, nor between the BPs at the time of their appearance and at the time when they were most marked. In monkeys of the one-kidney model, the rise in BP developed significantly (P = 0.01) faster and the fundus lesions appeared significantly (P = 0.00001) earlier than in those with the two-kidney model.     

Preventive services use among women seen by gynecologists, general medical physicians, or both

OBJECTIVE: To estimate how preventive services and counseling differ for women seen by general medical physicians and gynecologists, and whether seeing both types of physicians had a greater impact on delivery of gender-specific and gender-neutral preventive care than by either type of physician alone. METHODS: Using data from the 2000 National Health Interview Survey, we studied the association of provider type with Pap tests, tobacco use screening, and exercise and diet counseling among women 18-64 years (n=7,317), and these services along with clinical breast examinations, mammograms, and colon cancer screening among women aged 50-64 years (n=1,551). We modeled care using multivariable logistic regression and used propensity score techniques to limit selection bias from choice of provider. RESULTS: In the study sample, 15% were seen by general medical physicians, 62% by gynecologists, and 23% by both. Overall rates of gender-specific services (Pap test, clinical breast examination, mammography) were high (88-95%), whereas gender-neutral services were low (23-53%). Patients of gynecologists only were more likely to have Pap tests (adjusted relative risk [RR] 1.26, 95% confidence interval [CI] 1.24-1.27), tobacco use screening (adjusted RR 1.08, 95% CI 1.02-1.14), mammography (adjusted RR 1.25, 95% CI 1.20-1.28), and clinical breast examination (adjusted RR 1.25, 95% CI 1.19-1.29). In general, combined gynecologist and general care did not increase the likelihood of preventive care. Propensity score analyses confirmed these results. CONCLUSION: Patients of gynecologists receive more preventive services compared with patients of general medical physicians, although rates of gender-neutral services were low regardless of provider type. These findings validate gynecologists' roles as providers of basic preventive care services but demonstrate that considerable room exists to improve delivery of preventive care to women.     

The effect of learning to drum on behavior and brain function in autistic adolescents

This current study aimed to investigate the impact of drum training on behavior and brain function in autistic adolescents with no prior drumming experience. Thirty-six autistic adolescents were recruited and randomly assigned to one of two groups. The drum group received individual drum tuition (two lessons per week over an 8-wk period), while the control group did not. All participants attended a testing session before and after the 8-wk period. Each session included a drumming assessment, an MRI scan, and a parent completing questionnaires relating to the participants’ behavioral difficulties. Results showed that improvements in drumming performance were associated with a significant reduction in hyperactivity and inattention difficulties in drummers compared to controls. The fMRI results demonstrated increased functional connectivity in brain areas responsible for inhibitory control, action outcomes monitoring, and self-regulation. In particular, seed-to-voxel analyses revealed an increased functional connectivity in the right inferior frontal gyrus and the right dorsolateral prefrontal cortex. A multivariate pattern analysis demonstrated significant changes in the medial frontal cortex, the left and right paracingulate cortex, the subcallosal cortex, the left frontal pole, the caudate, and the left nucleus accumbens. In conclusion, this study investigates the impact of a drum-based intervention on neural and behavioral outcomes in autistic adolescents. We hope that these findings will inform further research and trials into the potential use of drum-based interventions in benefitting clinical populations with inhibition-related disorders and emotional and behavioral difficulties.

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder characterized by deficits in social communication and social interactions as well as a range of restricted, repetitive interests, activities, and behaviors (1). Over recent decades, incidence estimates for ASD have increased (2), with a prevalence of 1 in 59 children in the United States (3) and over 600,000 people in the United Kingdom, which is equivalent to a population prevalence of ∼1% (4, 5). In this context of increased autism prevalence, there is an existing need to develop interventions that offer new insights and perspectives and help address the specifically high demand for services for autistic adolescents and young adults (6). [The term “autistic” is used throughout this paper because of a large percentage of the UK autism community’s preference for the identity-first construction (e.g., “autistic person”) over the person-first phrase (e.g., “person with autism”) (7).] Indeed, autistic young people often face discontinuity in care provision in the transitionary period from child and adolescent services to adult services, just when their care needs are most pressing, making their transition into adulthood particularly difficult (8). In particular, mismatches across services, such as differences in eligibility criteria or age cutoffs, mean that many autistic young adults fall through the care gap after exiting high school (8). Autistic individuals are particularly vulnerable during this period because they often face high unemployment rates, increased levels of comorbid psychiatric diagnoses such as anxiety and depression, and, more broadly, greater reliance on assistance from others when it comes to carrying out adulthood-related daily activities (9–11).A growing body of research suggests that key social domains of the ASD symptomatology may be related to atypical executive functioning (12, 13). Inhibitory control, one of the core executive functions (EFs), corresponds to the ability to delay the onset of behavioral responses, or withhold behaviors that are prepotent but contextually inappropriate (14, 15). It works in concert with other EFs, such as cognitive flexibility and working memory, to exert top-down control on behavioral responses, enable self-regulation, and help navigate social relationships, therefore supporting transition into adulthood and independent living (16, 17). More specifically, it is thought that atypical inhibitory control in autism may underlie significant strengths but may also exacerbate key features of the ASD symptomatology, such as struggling with change and uncertainty, or having difficulty interpreting social cues (18–21). Impaired performance on inhibitory control tasks is frequent in autistic individuals (12, 13, 22, 23). In particular, it has been associated with severe restricted and repetitive behaviors (19, 24, 25), as well as a deficit in proactive response slowing [the ability to slow the initiation of a behavioral response in preparation for stopping during conditions of uncertainty (19)]. At the neuroimaging level, prior studies have revealed atypical recruitment of frontal regions in autistic adolescents (20), and impaired functional connectivity (FC) of the inferior frontal junction, key regions for inhibitory control, in autistic children (26).Autistic individuals often report being preoccupied with certain topics (27) and struggling with anxiety and anger management (28, 29). In a study by Van Hees et al. (30), higher-education autistic students described feeling overwhelmed by the demands placed on them while facing significant difficulties with planning, information processing, time management, organizational skills, and sensory overload. These difficulties may reflect impaired attention and inhibition abilities, complementary processes that allow individuals to pursue the achievement of a particular goal while remaining flexibly responsive to environmental demands (21, 31). A research study on a population-based twin sample of 17,000 children (9 y to 12 y old) concluded that the vast majority of children with ASD traits also exhibit cooccurring attention deficit and hyperactivity disorder (ADHD) traits (32). More specifically, the authors demonstrated that 82% of the boys and 95% of the girls with high ASD traits on all three ASD domains (social impairments, communication impairments, and restricted repetitive behaviors and interests) exhibited difficulties on at least one of the three ADHD domains (attentional difficulties, hyperactivity, and impulsivity). Additionally, they reported that repetitive and restricted behaviors in ASD correlated with ADHD domains, particularly with impulsivity and attentional difficulties. This is in line with a previous twin study in adults, which reported the highest phenotypic and genetic overlap between ADHD traits and “nonsocial” autistic-like traits such as attention switching difficulties (33).Music has long been known to promote cognitive and emotional wellbeing in both clinical and healthy populations (34, 35). Rhythm-based musical training, in particular, has been shown to enhance higher-order cognition and motor control (31). There is growing evidence that activities designed to improve beat synchronization skills may provide an effective approach to developing neurological processes that underpin self-regulation and EF skills (36). Indeed, EF deficits have been linked with poor rhythm perception in children (37) and poor sensorimotor synchronization in young adults (38). Using the Integrated Visual and Auditory Plus Continuous Performance Test (39), Slater et al. (31) highlighted that drumming practice is associated with better scores in inhibitory control and selective attention in adult percussionists compared to nonmusicians.More specifically, learning to drum requires error monitoring and temporal accuracy and therefore both attentional and inhibitory control (31, 40). In a recent study, Lowry et al. (40) used a mixed-methods analysis to investigate behavioral changes in children with emotional and behavioral difficulties, after learning to drum. Following drum training, the participants displayed enhanced attentional focus and reduced hyperactivity and peer problems (40). These results concur with Draper et al.’s (41) recent findings showing that drumming improves motor control and attentional focus and reduces emotional and peer problems in autistic children. It is important to note that motor control is particularly relevant in the context of ASD. Indeed, recent studies have consistently demonstrated motor impairments across the autism spectrum (42, 43), including gross and fine motor difficulties (44, 45) and delays with motor planning (46). Sokhadze et al. (47) showed that ∼80% of autistic individuals also present with clumsiness or motor dyspraxia, which can manifest as having difficulty with motor coordination as well as concentration, planning, and organization. These difficulties may impact the individual’s ability to carry out daily activities, which, in turn, can lead to rejection from peers and social isolation (48). Similarly, motor impairments in balance, motor accuracy, and object manipulation scores have been reported to be predictive of social dysfunction in young autistic boys (49). In this context, learning to drum could be regarded as particularly beneficial because it involves not only musicality but also the development of multimodal skills such as body coordination, sensorimotor integration, and cardiovascular exercise processes (50). Additionally, it is appealing and accessible to everyone regardless of age, gender, ethnicity, or musical background (51, 52).In our proof-of-concept study, Amad et al. (53) showed that the brain is capable of neuroplastic modifications through drum-based practice in neurotypical adolescents. In particular, changes in FC were observed post drum training in brain regions known to exhibit atypical functioning in autism, such as areas associated with motor skills and the mirror neuron system.In the present study, we investigated the impact of drum training on brain function in 36 autistic adolescents who were split into two age- and gender-matched groups: a drum group (n = 19), who were evaluated before and after learning to drum, and a control group (n = 17), who were also evaluated longitudinally but with no intervention. We explored behavioral outcomes related to drum practice in this clinical population and examined their association with changes in FC between the two groups (i.e., drum group vs. control group) over time (i.e., before vs. after drum training).We hypothesized that drumming performance would improve in the drum group over time, while no improvement would be observed in the control group. Furthermore, we hypothesized that changes in hyperactivity, attentional difficulties, problem behaviors, and repetitive and restricted behaviors would be observed in the drum group. We also hypothesized that cooccurring changes in FC in brain areas responsible for attentional focus and inhibitory control would be identified following drum training.