A system approach to improving guideline-directed therapy for cardio-renal-metabolic conditions: The "beyond diabetes" initiative.

Objective: Despite demonstrating improvements in cardiovascular disease, kidney disease, and survival outcomes, guideline-directed antihyperglycemic medications such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like-peptide-1 receptor agonists (GLP1-RA), are underutilized. Many obstacles constrain their use including lack of systematic provider and patient education, concern for medication side effects, and patient affordability. Methods: We designed a multimodality, systems-based approach to address these challenges with the goal of increasing medication utilization across the largest healthcare system in New York State. This multispecialty collaborative included provider and patient education, an electronic health record-enabled platform to identify eligible patients, and access to pharmacists for medication guidance and addressing insurance coverage barriers. Surveys were administered following grand rounds lectures and knowledge-based questionnaires were given before and after case-based sessions for housestaff, with results analyzed using a two-sided Student's t-test. Rates of first prescriptions of SGLT2i/GLP1-RA in combined and individual analyses were compared between the pre- and post-education periods (6 months prior to 3/31/2021 and 6 months post 8/19/2021), and the change in prescriptions per 100 eligible-visits was assessed using the incidence density approach. Results: Among grand rounds participants, 69.3% of respondents said they would make changes to their clinical practice. Knowledge increased by 14.7% (p-value <0.001) among housestaff following case-based sessions. An increase in SGLT2i/GLP1-RA prescribing was noted for eligible patients among internal medicine, cardiology, nephrology, and endocrinology providers, from 11.9 per 100 eligible visits in the pre-education period to 14.8 in the post-education period (absolute increase 2.9 [24.4%], incidence risk ratio 1.24 [95% CI 1.18-1.31]; p-value <0.001). Increases in prescribing rates were also seen among individual medical specialties. Conclusions: Our "Beyond Diabetes" initiative showed an improvement in provider knowledge-base and was associated with a modest, but statistically significant increase in the use of SGLT2i and GLP1-RA throughout our healthcare system.

Optical coherence tomography angiography analysis of changes in the foveal avascular zone in eyes with diabetic macular edema treated with intravitreal anti-vascular endothelial growth factor.

BACKGROUND: To analyze the changes in foveal avascular zone (FAZ) area, perimeter, and circularity in the superficial (SCP) and deep (DCP) capillary plexuses in eyes with diabetic macular edema (DME) treated with intravitreal anti-VEGF using optical coherence tomography angiography (OCTA). METHODS: This prospective observational study included 56 eyes from 32 patients with DME that received intravitreal anti-VEGF. OCTA images were obtained at baseline and 1, 3, and 6 months of follow-up. The outcome measures were FAZ area, perimeter, and circularity in both the SCP and DCP, as well as central subfield thickness (CST) and best-corrected visual acuity (BCVA). RESULTS: The mean number of intravitreal anti-VEGF injections received during the observation period was 4.60 ± 0.82 (range: 3-6). The FAZ area, perimeter, and circularity were statistically unchanged at all observation points in both the SCP (p = 0.772, p = 0.405, p = 0.157, respectively) and the DCP (p = 0.620, p = 0.769, p = 0.481, respectively). Despite having no change in the FAZ parameters, there was still a statistically significant decrease in CST (p < 0.001) as well as a statistically significant increase in BCVA (p = 0.004) during the observation period. CONCLUSIONS: The FAZ area, perimeter, and circularity in the SCP and DCP as measured by OCTA remained stable during the first 6 months of intravitreal anti-VEGF therapy in eyes with DME. While there were no significant changes in the FAZ, treatment with intravitreal anti-VEGF still resulted in decreased CST and improved BCVA.

New Measures, Old Conclusions: Obesity Does Not Worsen Outcomes after Elective Abdominal Aortic Aneurysm Repair.

BACKGROUND: The "obesity paradox," whereby the body mass index (BMI) mortality curve is "U-shaped," is a well-studied phenomenon in vascular surgery. However, there has been an overreliance on BMI as the measure of obesity, which has shown to poorly correlate with clinical outcomes. Robust measures such as waist-hip ratio (WHR) have been suggested as a more accurate marker reflecting central obesity. OBJECTIVES: The objectives of this study were to evaluate the correlation between BMI and WHR on postoperative morbidity and mortality after elective abdominal aortic aneurysm (AAA) repair. METHODS: Data were collected from the Leeds Vascular Institute between January 2006 and December 2016. The primary outcome was mortality and secondary outcomes included length of stay (LOS) and all-cause readmission. Binary logistic regression, linear regression, and correlation analysis were used to identify associations between BMI and WHR in relation to outcome measures. RESULTS: After exclusions, 432 elective AAA repairs (281 open surgical repair [OSR] and 151 endovascular aneurysm repairs [EVARs]) were identified to be eligible for the study. The combined 30-day and 4-year mortality was 1.2 and 20.1%, respectively. The 30-day readmission rate was 3.9% and the average LOS was 7.33 (standard deviation 18.5) days. BMI data was recorded for 275 patients (63.7%) and WHR for 355 patients (82.2%). Logistic regression analysis highlighted no association between BMI and WHR with mortality, readmission, or LOS following OSR or EVAR. CONCLUSION: The results of this study suggest patients should not be denied treatment for AAA based on obesity alone.

Bacillus Calmette-Guerin (BCG): the adroit vaccine.

BACKGROUND: The Bacillus Calmette-Guerin (BCG) vaccine has been in use for 99 years, and is regarded as one of the oldest human vaccines known today. It is recommended primarily due to its effect in preventing the most severe forms of tuberculosis, including disseminated tuberculosis and meningeal tuberculosis in children; however, its efficacy in preventing pulmonary tuberculosis and TB reactivation in adults has been questioned. Several studies however have found that asides from its role in tuberculosis prevention, the BCG vaccine also has protective effects against a host of other viral infections in humans, an effect which has been termed: heterologous, non-specific or off-target. OBJECTIVES: As we approach 100 years since the discovery of the BCG vaccine, we review the evidence of the non-specific protection offered by the vaccine against viral infections, discuss the possible mechanisms of action of these effects, highlight the implications these effects could have on vaccinology and summarize the recent epidemiological correlation between the vaccine and the on-going COVID-19 pandemic. RESULTS: Several epidemiological studies have established that BCG does reduce all-cause mortality in infants, and also the time of vaccination influences this effect significantly. This effect has been attributed to the protective effect of the vaccine in preventing unrelated viral infections during the neonatal period. Some of such viral infections that have been investigated include: herpes simplex virus (HSV), human Papilloma virus (HPV), yellow fever virus (YFV), respiratory syncytial virus (RSV) and influenza virus type A (H1N1). These effects are thought to be mediated via induction of innate immune memory as well as heterologous lymphocytic activation. While epidemiological studies have suggested a correlation, the potential protection of the BCG vaccine against COVID-19 transmission and mortality rates is currently unclear. Ongoing clinical trials and further research may shed more light on the subject in the future. CONCLUSION: BCG is a multifaceted vaccine, with many numerous potential applications to vaccination strategies being employed for current and future viral infections. There however is a need for further studies into the immunologic mechanisms behind these non-specific effects, for these potentials to become reality, as we usher in the beginning of the second century since the vaccine's discovery.

Spectrophotometric Analysis of Coronal Tooth Discoloration Induced by Tricalcium Silicate Cements in the Presence of Blood.

INTRODUCTION: New tricalcium silicate cements have been shown to induce less coronal discoloration. The purpose of this in vitro study was to evaluate the degree of color change induced by various silicate materials in the presence and absence of blood. METHODS: One hundred human extracted anterior single-canal teeth were sectioned to standardized root lengths, accessed, and instrumented. Eight random experimental groups and 2 control groups were created wherein specimens were filled with experimental materials below the buccal cementoenamel junction as follows: EndoSequence RRM putty (Brasseler USA, Savannah, GA), EndoSequence RRM fast set putty (Brasseler USA), Biodentine (Septodont, Saint-Maur-des-Fossés, France), and white mineral trioxide aggregate (Dentsply Sirona, York, PA) either with the presence or absence of blood. Blood-only and saline-only samples were used for the positive and negative controls. After incubation in 100% humidity at 37°C, color changes were evaluated with a spectrophotometer (Ocean Optics, Dunedin, FL) on days 0, 30, 60, and 180 after material placement. Data were transformed into Commission International de I'Eclairage's L∗a∗b color values, and corresponding ΔE values were calculated. The 1-way analysis of variance test was performed for statistical analysis. RESULTS: Discoloration was observed in all specimens in the presence of blood. There was no statistical significance when comparing different materials in contact with blood. Intragroup observation at various time points, Biodentine, and EndoSequence RRM fast set putty showed significant difference between the presence and absence of blood at 180 days (P < .05). CONCLUSIONS: Contamination with blood of tricalcium silicate materials has the potential to cause coronal tooth discoloration.

AUTOMATIC BRAIN ORGAN SEGMENTATION WITH 3D FULLY CONVOLUTIONAL NEURAL NETWORK FOR RADIATION THERAPY TREATMENT PLANNING.

3D organ contouring is an essential step in radiation therapy treatment planning for organ dose estimation as well as for optimizing plans to reduce organs-at-risk doses. Manual contouring is time-consuming and its inter-clinician variability adversely affects the outcomes study. Such organs also vary dramatically on sizes - up to two orders of magnitude difference in volumes. In this paper, we present BrainSegNet, a novel 3D fully convolutional neural network (FCNN) based approach for automatic segmentation of brain organs. BrainSegNet takes a multiple resolution paths approach and uses a weighted loss function to solve the major challenge of the large variability in organ sizes. We evaluated our approach with a dataset of 46 Brain CT image volumes with corresponding expert organ contours as reference. Compared with those of LiviaNet and V-Net, BrainSegNet has a superior performance in segmenting tiny or thin organs, such as chiasm, optic nerves, and cochlea, and outperforms these methods in segmenting large organs as well. BrainSegNet can reduce the manual contouring time of a volume from an hour to less than two minutes, and holds high potential to improve the efficiency of radiation therapy workflow.

Expanded Scope of Bacillus Calmette-Guerin (BCG) Vaccine Applicability in Disease Prophylaxis, Diagnostics, and Immunotherapeutics.

Following the discovery of the Bacillus Calmette-Guerin (BCG) vaccine, its efficacy against Mycobacterium tuberculosis was soon established, with several countries adopting universal BCG vaccination schemes for their populations. Soon, however, studies aimed to further establish the efficacy of the vaccine in different populations discovered that the vaccine has a larger effect in reducing mortality rate than could be explained by its effect on tuberculosis alone, which sparked suggestions that the BCG vaccine could have effects on other unrelated or non-mycobacterial pathogens causing diseases in humans. These effects were termed heterologous, non-specific or off-target effects and have been shown to be due to both innate and adaptive immune system responses. Experiments carried out in a bid to further understand these effects led to many more discoveries about the applicability of the BCG vaccine for the prevention, diagnosis, and treatment of certain disease conditions. As we approach the second century since the discovery of the vaccine, we believe it is timely to review these interesting applications of the BCG vaccine, such as in the prevention of diabetes, atherosclerosis, and leukemia; the diagnosis of Kawasaki disease; and the treatment of multiple sclerosis, non-muscle invading bladder cancer, and stage III melanoma. Furthermore, complications associated with the administration of the BCG vaccine to certain groups of patients, including those with severe combined immunodeficiency and HIV, have been well described in literature, and we conclude by describing the mechanisms behind these complications and discuss their implications on vaccination strategies, especially in low-resource settings.

Aberrant Frontostriatal Connectivity in Negative Symptoms of Schizophrenia.

Negative symptoms represent a distinct component of psychopathology in schizophrenia (SCZ) and are a stable construct over time. Although impaired frontostriatal connectivity has been frequently described in SCZ, its link with negative symptoms has not been carefully studied. We tested the hypothesis that frontostriatal connectivity at rest may be associated with the severity of negative symptoms in SCZ. Resting state functional connectivity (rsFC) data from 95 mostly medicated patients with SCZ and 139 healthy controls (HCs) were acquired. Negative symptoms were assessed using the Brief Negative Symptom Scale. The study analyzed voxel-wise rsFC between 9 frontal "seed regions" and the entire striatum, with the intention to reduce potential biases introduced by predefining any single frontal or striatal region. SCZ showed significantly reduced rsFC between the striatum and the right medial and lateral orbitofrontal cortex (OFC), lateral prefrontal cortex, and rostral anterior cingulate cortex compared with HCs. Further, rsFC between the striatum and the right medial OFC was significantly associated with negative symptom severity. The involved striatal regions were primarily at the ventral putamen. Our results support reduced frontostriatal functional connectivity in SCZ and implicate striatal connectivity with the right medial OFC in negative symptoms. This task-independent resting functional magnetic resonance imaging study showed that medial OFC-striatum functional connectivity is reduced in SCZ and associated with severity of negative symptoms. This finding supports a significant association between frontostriatal connectivity and negative symptoms and thus may provide a potential circuitry-level biomarker to study the neurobiological mechanisms of negative symptoms.

Antagonistic pleiotropy for carbon use is rare in new mutations.

Pleiotropic effects of mutations underlie diverse biological phenomena such as ageing and specialization. In particular, antagonistic pleiotropy ("AP": when a mutation has opposite fitness effects in different environments) generates tradeoffs, which may constrain adaptation. Models of adaptation typically assume that AP is common - especially among large-effect mutations - and that pleiotropic effect sizes are positively correlated. Empirical tests of these assumptions have focused on de novo beneficial mutations arising under strong selection. However, most mutations are actually deleterious or neutral, and may contribute to standing genetic variation that can subsequently drive adaptation. We quantified the incidence, nature, and effect size of pleiotropy for carbon utilization across 80 single mutations in Escherichia coli that arose under mutation accumulation (i.e., weak selection). Although ∼46% of the mutations were pleiotropic, only 11% showed AP; among beneficial mutations, only ∼4% showed AP. In some environments, AP was more common in large-effect mutations; and AP effect sizes across environments were often negatively correlated. Thus, AP for carbon use is generally rare (especially among beneficial mutations); is not consistently enriched in large-effect mutations; and often involves weakly deleterious antagonistic effects. Our unbiased quantification of mutational effects therefore suggests that antagonistic pleiotropy may be unlikely to cause maladaptive tradeoffs.

Listeria monocytogenes in Food-Processing Facilities, Food Contamination, and Human Listeriosis: The Brazilian Scenario.

Listeria monocytogenes is a foodborne pathogen that contaminates food-processing environments and persists within biofilms on equipment, utensils, floors, and drains, ultimately reaching final products by cross-contamination. This pathogen grows even under high salt conditions or refrigeration temperatures, remaining viable in various food products until the end of their shelf life. While the estimated incidence of listeriosis is lower than other enteric illnesses, infections caused by L. monocytogenes are more likely to lead to hospitalizations and fatalities. Despite the description of L. monocytogenes occurrence in Brazilian food-processing facilities and foods, there is a lack of consistent data regarding listeriosis cases and outbreaks directly associated with food consumption. Listeriosis requires rapid treatment with antibiotics and most drugs suitable for Gram-positive bacteria are effective against L. monocytogenes. Only a minority of clinical antibiotic-resistant L. monocytogenes strains have been described so far; whereas many strains recovered from food-processing facilities and foods exhibited resistance to antimicrobials not suitable against listeriosis. L. monocytogenes control in food industries is a challenge, demanding proper cleaning and application of sanitization procedures to eliminate this foodborne pathogen from the food-processing environment and ensure food safety. This review focuses on presenting the L. monocytogenes distribution in food-processing environment, food contamination, and control in the food industry, as well as the consequences of listeriosis to human health, providing a comparison of the current Brazilian situation with the international scenario.

The Continuous Challenge of Characterizing the Foodborne Pathogen Listeria monocytogenes.

Listeria monocytogenes is an important foodborne pathogen commonly isolated from food processing environments and food products. This organism can multiply at refrigeration temperatures, form biofilms on different materials and under various conditions, resist a range of environmental stresses, and contaminate food products by cross-contamination. L. monocytogenes is recognized as the causative agent of listeriosis, a serious disease that affects mainly individuals from high-risk groups, such as pregnant women, newborns, the elderly, and immunocompromised individuals. Listeriosis can be considered a disease that has emerged along with changing eating habits and large-scale industrial food processing. This disease causes losses of billions of dollars every year with recalls of contaminated foods and patient medical treatment expenses. In addition to the immune status of the host and the infecting dose, the virulence potential of each strain is crucial for the development of disease symptoms. While many isolates are naturally virulent, other isolates are avirulent and unable to cause disease; this may vary according to the presence of molecular determinants associated with virulence. In the last decade, the characterization of genetic profiles through the use of molecular methods has helped track and demonstrate the genetic diversity among L. monocytogenes isolates obtained from various sources. The purposes of this review were to summarize the main methods used for isolation, identification, and typing of L. monocytogenes and also describe its most relevant virulence characteristics.

The effect of leg compression garments on the mechanical characteristics and performance of single-leg hopping in healthy male volunteers.

BACKGROUND: Compression garments (CG) are commonly used by athletes to improve motor performance and recovery during or following exercise. Numerous studies have investigated the effect of CG on physiological and physical parameters with variable results as to their efficacy. A possible effect of commercially available CG may be to induce a change in leg mechanical characteristics during repetitive tasks to fatigue. This investigation determined the effect of CG on performance and vertical stiffness during single-leg-hopping to exhaustion. METHODS: Thirty-eight healthy, male participants, mean (SD) 22.1 (2.8) years of age performed single-leg hopping at 2.2 Hz to volitional exhaustion with a CG, without CG and with a sham. Differences in total duration of hopping (1-way repeated ANOVA) and dependant variables for the start and end periods (2-way repeated ANOVA) including duration of flight (tf), loading (tl) and contact (tc) phases, vertical height displacement during flight (zf) and loading (zl) phases, normalised peak vertical ground reaction force (FzN) and normalised vertical stiffness (k N), were determined. Bonferroni correction was performed to reduce the risk of type 1 error. RESULTS: There was no significant difference (p = 0.73) in the total duration of hopping between conditions (CG (mean (SD)) 89.6 (36.3) s; without CG 88.5 (27.5) s; sham 91.3 (27.7) s). There were no significant differences between conditions for spatiotemporal or kinetic characteristics (p > 0.05). From the start to the end periods there was no significant difference in tl (p = 0.15), significant decrease in tf (p < 0.001), zf and zl (p < 0.001) and increase in tc (p < 0.001). There was also a significant increase in k N from start to end periods (p < 0.01) ranging from 9.6 to 14.2%. CONCLUSIONS: This study demonstrates that commercially available CG did not induce a change in spatiotemporal or vertical stiffness during a fatiguing task. The finding that vertical stiffness increased towards the end of the task, while hopping frequency and duration of loading were maintained, may indicate that there was an alteration to the motor control strategy as fatigue approached. TRIAL REGISTRATION: Current Controlled Trials ACTRN12615000240549. Registered 17 March 2015.

The use of prosody during syntactic processing in children and adolescents with autism spectrum disorders.

In this study, we employed an eye-gaze paradigm to explore whether children (ages 8-12) and adolescents (ages 12-18) with autism spectrum disorders (ASDs) are able to use prosodic cues to determine the syntactic structure of an utterance. Persons with ASD were compared to typically developing (TD) peers matched on age, IQ, gender, and receptive language abilities. The stimuli were syntactically ambiguous but had a prosodic break that indicated the appropriate interpretation (feel the frog … with the feather vs. feel … the frog with the feather). We found that all groups were equally sensitive to the initial prosodic cues that were presented. Children and teens with ASD used prosody to interpret the ambiguous phrase as rapidly and efficiently as their TD peers. However, when a different cue was presented in subsequent trials, the younger ASD group was more likely to respond in a manner consistent with the initial prosodic cue rather than the new one. Eye-tracking data indicated that both younger groups (ASD and TD) had trouble shifting their interpretation as the prosodic cue changed, but the younger TD group was able to overcome this interference and produce an action consistent with the prosodic cue.

Brief Report: A Pilot Summer Robotics Camp to Reduce Social Anxiety and Improve Social/Vocational Skills in Adolescents with ASD.

This pilot study evaluated a novel intervention designed to reduce social anxiety and improve social/vocational skills for adolescents with autism spectrum disorder (ASD). The intervention utilized a shared interest in robotics among participants to facilitate natural social interaction between individuals with ASD and typically developing (TD) peers. Eight individuals with ASD and eight TD peers ages 12-17 participated in a weeklong robotics camp, during which they learned robotic facts, actively programmed an interactive robot, and learned "career" skills. The ASD group showed a significant decrease in social anxiety and both groups showed an increase in robotics knowledge, although neither group showed a significant increase in social skills. These initial findings suggest that this approach is promising and warrants further study.

Neural correlates of language and non-language visuospatial processing in adolescents with reading disability.

Despite anecdotal evidence of relative visuospatial processing strengths in individuals with reading disability (RD), only a few studies have assessed the presence or the extent of these putative strengths. The current study examined the cognitive and neural bases of visuospatial processing abilities in adolescents with RD relative to typically developing (TD) peers. Using both cognitive tasks and functional magnetic resonance imaging (fMRI) we contrasted printed word recognition with non-language visuospatial processing tasks. Behaviorally, lower reading skill was related to a visuospatial processing advantage (shorter latencies and equivalent accuracy) on a geometric figure processing task, similar to findings shown in two published studies. FMRI analyses revealed key group by task interactions in patterns of cortical and subcortical activation, particularly in frontostriatal networks, and in the distributions of right and left hemisphere activation on the two tasks. The results are discussed in terms of a possible neural tradeoff in visuospatial processing in RD.

Measurement tools and target symptoms/skills used to assess treatment response for individuals with autism spectrum disorder.

This study examined the measurement tools and target symptoms/skills used to assess treatment response during Autism Spectrum Disorder (ASD) intervention trials from 2001 through 2010. Data from 195 prospective trials were analyzed. There were 289 unique measurement tools, of which 61.6 % were used only once, and 20.8 % were investigator-designed. Only three tools were used in more than 2 % of the studies, and none were used in more than 7 % of studies. Studies investigated an average of 11.4 tool-symptom combinations per trial, with as many as 45 in one study. These results represent a lack of consistency in outcome measurements in ASD intervention trials. These findings highlight the need to set guidelines for appropriate outcome measurement in the ASD field.

Clinical and microbiologic characteristics of invasive Streptococcus pyogenes infections in north and south India.

The lack of epidemiologic data on invasive Streptococcus pyogenes infections in many developing countries is concerning, as S. pyogenes infections are commonly endemic in these areas. Here we present the results of the first prospective surveillance study of invasive Streptococcus pyogenes infections in India. Fifty-four patients with invasive S. pyogenes infections were prospectively enrolled at two study sites, one in the north and one in the south of India. Sterile-site isolates were collected, and clinical information was documented using a standardized questionnaire. Available acute-phase sera were tested for their ability to inhibit superantigens produced by the patient's own isolate using a cell-based neutralizing assay. The most common clinical presentations were bacteremia without focus (30%), pneumonia (28%), and cellulitis (17%). Only two cases of streptococcal toxic shock syndrome and no cases of necrotizing fasciitis were identified. Characterization of the isolates revealed great heterogeneity, with 32 different emm subtypes and 29 different superantigen gene profiles being represented among the 49 sterile-site isolates. Analyses of acute-phase sera showed that only 20% of the cases in the north cohort had superantigen-neutralizing activity in their sera, whereas 50% of the cases from the south site had neutralizing activity. The results demonstrate that there are important differences in both clinical presentation and strain characteristics between invasive S. pyogenes infections in India and invasive S. pyogenes infections in Western countries. The findings underscore the importance of epidemiologic studies on streptococcal infections in India and have direct implications for current vaccine developments.

Acoustic Differences In The Imitation Of Prosodic Patterns In Children With Autism Spectrum Disorders.

In research, it has been difficult to characterize the prosodic production differences that have been observed clinically in Autism Spectrum Disorders (ASD). Moreover, the nature of these differences has been particularly hard to identify. This study examined one possible contributor to these perceived differences: motor planning. We examined the ability of children and adolescents with ASD to imitate prosodic patterns in comparison to a group with learning disabilities (LD) and a typically-developing (TD) comparison group. Overall, we found that both the ASD and LD groups were significantly worse at perceiving and imitating prosodic patterns than the TD comparison group. Similar to previous studies using non-imitative speech, participants with ASD showed a significantly longer duration of utterances than the two comparison groups when attempting to imitate an intonation pattern. The implications of differences in duration of utterances are discussed. This study also highlights the importance of using clinical comparison groups in studies of language performance in individuals with ASD.