Neurology Training and Medical Education in Resource-Limited Settings: Building and Growing the First Neurology Residency Program in East Africa.

The burden of neurological disease disproportionately affects low- and middle-income countries, where the lowest number of neurologists are located. Building local training opportunities in resource-limited settings is a foundational step to enhancing the neurological workforce and improving access to neurological care in these regions. In this article, we describe the development and growth of the first neurology residency program in East Africa, which was established in 2006 at Zewditu Memorial Hospital and the Tikur Anbessa Specialized Hospital, Addis Ababa University, Ethiopia. We highlight the impact of the program on clinical care, research, collaborations between neurologists across Ethiopia, and ways to build educational opportunities and mentorship while faced with limited resources. The main challenges in starting the residency program included lack of faculty with neurological expertise, lack of a precedent for subspecialty training in our setting, as well as limited resources and space. The formation of sustainable international collaborations with clinicians at established institutions in high-income countries and neurological societies has been a major source of support in developing the initial infrastructure, curriculum and educational content, knowledge assessments, and mentored research projects. Local partnerships with related medical specialties, including internal medicine, critical care, neurological surgery, and psychiatry, were also instrumental in creating training opportunities. As the program continues to evolve, many challenges remain, including limited diagnostics, lack of access to advanced treatment modalities, lack of fellowship training opportunities in various neurological subspecialties, and insufficient training and experience in scientific writing. Despite these challenges, the residency program has persevered and its creation resulted in many positive changes: since its inception in 2006, we graduated 80 neurologists and the number of practicing neurologists in Ethiopia has increased from 5 to 78, our institution has evolved into a national referral center for neurology, graduates have published 61 articles in the past 3 years and contributed to international neurology research, and alumni of the program have grown the Association of Ethiopian Neurologists. Future directions include development of fellowship opportunities, creation of international rotations, and implementation of teleneurology to further strengthen neurological care across Ethiopia.

Ten Years of Improving Glycemic Control in Pediatric Diabetes Care: Data From the Norwegian Childhood Diabetes Registry.

OBJECTIVE: To evaluate, from 2013 to 2022, how HbA1c, the incidence of acute complications, and use of diabetes technology changed at the national level in Norway and how glycemic control was associated with use of diabetes technology, carbohydrate counting, or participation in a quality improvement project. RESEARCH DESIGN AND METHODS: This longitudinal observational study was based on 27,214 annual registrations of 6,775 children from the Norwegian Childhood Diabetes Registry from 2013 to 2022. Individuals aged >18 years, those with diabetes other than type 1, and those without HbA1c measurements were excluded. The outcome measure was HbA1c. The predictor variables in the adjusted linear mixed-effects model were 1) the use of diabetes technology, 2) the use of carbohydrate counting for meal bolusing, and 3) whether the patient's diabetes team participated in a quality improvement project. RESULTS: Mean HbA1c decreased from 8.2% (2013) to 7.2% (2021), and the proportion of youth reaching an HbA1c <7.0% increased from 13% (2013) to 43% (2022). Insulin pump use increased from 65% (2013) to 91% (2022). Continuous glucose monitoring (CGM) use increased from 34% (first recorded in 2016) to 97% (2022). Insulin pump, CGM, and carbohydrate counting were associated with lower HbA1c and higher achievement of glycemic targets. Girls had a higher mean HbA1c than boys. Mean HbA1c levels were lower in clinics that participated in a quality improvement project for the following 4 years after the project. CONCLUSIONS: Diabetes technology, carbohydrate counting, and systematic quality improvement in pediatric departments led to improved glycemic control.

The use of environmental data in descriptive and predictive models of vector-borne disease in North America.

Vector-borne disease incidence and burden are on the rise. Weather events and climate patterns are known to influence vector populations and disease distribution and incidence. Changes in weather trends and climatic factors can shift seasonal vector activity and host behavior, thus altering pathogen distribution and introducing diseases to new geographic regions. With the upward trend in global temperature, changes in the incidence and distribution of disease vectors possibly linked to climate change have been documented. Forecasting and modeling efforts are valuable for incorporating climate into predicting changes in vector and vector-borne disease distribution. These predictions serve to optimize disease outbreak preparedness and response. The purpose of this scoping review was to describe the use of climate data in vector-borne disease prediction in North America between 2000 and 2022. The most investigated diseases were West Nile virus infection, Lyme disease, and dengue. The uneven geographical distribution of publications could suggest regional differences in the availability of surveillance data required for vector-borne disease predictions and forecasts across the United States, Canada, and Mexico. Studies incorporated environmental data from ground-based sources, satellite data, previously existing data, and field-collected data. While environmental data such as meteorological and topographic factors were well-represented, further research is warranted to ascertain if relationships with less common variables, such as oceanographic characteristics and drought, hold among various vector populations and throughout wider geographical areas. This review provides a catalogue of recently used climatic data that can inform future assessments of the value of such data in vector-borne disease models.

HIV False-Positive Test in the Setting of CD4 Lymphocytopenia.

In 2016, we implemented a non-targeted Emergency Department (ED)-based HIV screening program at our academic medical center following revised CDC guidelines utilizing the Abbott Alinity 4th generation HIV-1/2 antigen (Ag)/antibody (Ab) immunoassay (Abbott Laboratories, Abbott Park, IL). Following the CDC algorithm, after reactive fourth-generation testing, HIV-1/2 Ab testing is conducted. Patients undergoing acute seroconversion (acutes) may express p24 Ag but have a negative confirmatory Ab test. Acutes have the same laboratory signature during the ED encounter as those that are false positive (False +), and the two patient groups are denoted as "equivocals" until viral load testing specifies a definitive HIV status. Among False + patients (Ab/Ag positive, Ab negative, viral load undetectable), there have been limited studies on those also demonstrating a reduction in CD4+ count, an uncommon phenomenon known as "idiopathic CD4 lymphocytopenia." We review a patient with a reactive fourth-generation HIV Ab/p24 Ag test on two separate occasions. Despite lymphopenia with a reduced CD4 count, his symptoms resolved, and an RNA PCR test did not detect any presence of HIV (False +). This patient was unique as False + patient with p24 Ag reactive, as well as a coincidental low CD4 count in the absence of HIV infection. A low CD4 count is often a sign of significant HIV infection.

Using Data Science for Mechanistic Insights and Selectivity Predictions in a Non-Natural Biocatalytic Reaction.

The study of non-natural biocatalytic transformations relies heavily on empirical methods, such as directed evolution, for identifying improved variants. Although exceptionally effective, this approach provides limited insight into the molecular mechanisms behind the transformations and necessitates multiple protein engineering campaigns for new reactants. To address this limitation, we disclose a strategy to explore the biocatalytic reaction space and garner insight into the molecular mechanisms driving enzymatic transformations. Specifically, we explored the selectivity of an "ene"-reductase, GluER-T36A, to create a data-driven toolset that explores reaction space and rationalizes the observed and predicted selectivities of substrate/mutant combinations. The resultant statistical models related structural features of the enzyme and substrate to selectivity and were used to effectively predict selectivity in reactions with out-of-sample substrates and mutants. Our approach provided a deeper understanding of enantioinduction by GluER-T36A and holds the potential to enhance the virtual screening of enzyme mutants.

Relation of Health-Related Quality of Life with Glycemic Control and Use of Diabetes Technology in Children and Adolescents with Type 1 Diabetes: Results from a National Population Based Study.

Objective: The primary aim was to analyse the association between diabetes-specific health-related quality of life (HRQOL) and HbA1c in children and adolescents with type 1 diabetes. The secondary aims were to evaluate the associations between diabetes-specific HRQOL and age, sex, diabetes duration, and the use of diabetes technology in diabetes treatment. Research Design and Methods. Children with type 1 diabetes (10-17 years, N = 1,019) and parents (children <10 years, N = 371; 10-17 years, N = 1,070) completed the DISABKIDS diabetes-specific questionnaire (DDM-10) as part of the 2017 data collection for the Norwegian Childhood Diabetes Registry. The DDM-10 consists of two subscales-'impact' and 'treatment'-with six and four items, respectively. In the linear regression models, the items and subscales were outcome variables, while HbA1c, age, sex, diabetes duration, insulin pump use, and continuous glucose monitoring (CGM) system use were predictor variables. Results: Lower HbA1c measurements and male sex were associated with higher HRQOL scores on both DDM-10 scales in the age group 10-17 years, but not in children under 10 years. Parents gave lower HRQOL scores than children in the 10-17 age group. Insulin pump and CGM use were not significantly associated with HRQOL on the impact and treatment scale. Conclusions: Low HbA1c and male sex are significantly associated with high HRQOL in children aged 10-17 with type 1 diabetes, but the use of diabetes technology is not positively associated with HRQOL. Differences in child- and parent-reported scores imply that parents might both over- and underestimate their child's HRQOL.

REGULATION OF ANTIOXIDANT ENZYMES IN PATIENTS AFTER PERIODONTAL TREATMENT WITH NATURAL AGENTS.

OBJECTIVE: The aim: The study of the possibilities of oxidase-antioxidant system indicators regulation at patients with periodontitis under the influence of complex treatment. PATIENTS AND METHODS: Materials and methods: 36 healthy and 125 patients with chronic and exacerbated periodontitis of primary (22 and 21), I (21) and II (20) degrees were examined.Indicators of lipid peroxidation and antioxidant protection (levels of diene conjugates and malonic dialdehyde, catalase activity and transferrin iron saturation, ceruloplasmin activity) in the blood serum were studied before, 6 and 12 months after the appointed treatment. Initial periodontal therapy and a paste developed by us (spirulina microalgae powders and silica enterosorbent taken in equal amounts and 0.05% chlorhexidine bigluconate) for applications and instillations were exogenously used in the complex treatment. Spirulina tablets were prescribed per os as well. RESULTS: Results: All patients exhibit elevated levels of diene conjugates and malonic dialdehyde, decreased catalase activity and transferrin iron saturation as well as an increased ceruloplasmin activity, especially pronounced at stages I and II (p1≤0.01-0.001). Treatment contributed to long-term and reliable (p2<0.05 - 0.001) regulation of the studied parameters: reduction of diene conjugates and malonic dialdehyde, ceruloplasmin activity and increased catalase activity and transferrin iron saturation. All indicators differed slightly from the norm during the year (p1>0.05), and complete normalization of most of them lasted six months. At the same time clinical stabilization of periodontitis was reached. CONCLUSION: Conclusions: Indicators of the oxidase-antioxidant system in patients with periodontitis are significantly altered and indicate their participation in the pathogenesis of the disease. Complex treatment was able to almost completely normalize them within six months, but a year later the difference between the obtained indicators with data in healthy people was insignificant (except for ceruloplasmin). Clinical stabilization was achieved in all patients.

Electrodiagnostic referrals and neuromuscular disease pattern in East Africa: Experience from a tertiary hospital in Ethiopia.

Objective: We present a retrospective cross-sectional review of the electrodiagnostic (EDX) referral and diagnostic patterns in patients with suspected neuromuscular conditions at a tertiary hospital in Ethiopia. Methods: Between 2016 and 2019, 313 patients were evaluated at the EDX lab in Tikur Anbessa Specialised Hospital, Addis Ababa, Ethiopia. In our patients, nerve conduction study and when appropriate needle electromyography was done. Demographic and clinical data were extracted from a digital registry. Results: Polyneuropathy (19.8%), carpal tunnel syndrome (12.1%), and lumbosacral radiculopathy (9.9 %) were the top three reasons for EDX referral in Ethiopia. Among them, polyneuropathy was the most frequent electrodiagnosis, where diffuse axonal and demyelinating subtypes accounted for 54% and 18.8%, respectively. Guillain-Barre syndrome was suspected in 18 patients and 15 had EDX confirmed motor axon polyneuropathy while three patients had demyelinating variant. Although a quarter (26.2%) of the referrals had a normal EDX, abnormal test results were significantly associated with weakness (95% CI: 3.29-7.04, p < 0.001), bound to wheelchair (95% CI: 1.86-2.87, p = 0.01) and having a specific diagnosis at time of referral (95% CI: 2.53-4.68, p = 0.007). Conclusions: Diffuse and entrapment neuropathies were the main reasons for electrodiagnosis test referrals in Ethiopia. Also, motor axonal variant was the most common type of inflammatory polyneuropathy diagnosed with EDX. Significance: Proper patient evaluation and documentation significantly improves the diagnostic yield and cost-effectiveness of EDX testing in a resource-poor countries like Ethiopia. This might be achieved through educating medical students, residents, and other care providers on the basics of EDX and its indications for correct use in the clinical care.

A Multicentre Retrospective Study of Fulvestrant Use and Efficacy in Advanced/Metastatic Breast Cancer.

AIMS: Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres. MATERIALS AND METHODS: Medical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored. RESULTS: Data from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21-95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0-1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0-5) prior lines of endocrine therapy and median 0 (range 0-6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1-88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0-88). CONCLUSIONS: This is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients.

The associations of CD4 count, CD4/CD8 ratio, and HIV viral load with survival from non-small cell lung cancer in persons living with HIV.

HIV status may influence survival from non-small cell lung cancer (NSCLC). Among NSCLC patients in the Bronx, NY, we assessed (1) associations of CD4 count, CD4/CD8 ratio and HIV viral load (VL) with survival and (2) prognostic factors among persons living with HIV (PLWH). We compared survival from NSCLC diagnosis (2004-2017) between HIV-negative persons (HIV-, n=2,881) and PLWH (n=88) accounting for clinical and sociodemographic factors. HIV-survival was also compared with PLWH, dichotomized by CD4 (<200 vs. ≥200cells/µL), CD4/CD8 (median, <0.43 vs. ≥0.43) and VL (<75 vs. ≥75copies/mL) at NSCLC diagnosis. Among PLWH, we assessed the relationships of CD4, CD4/CD8, and VL with survival, adjusting for age, sex, and cancer stage. PLWH with CD4< 200cells/µL had lower survival than HIV- [hazard ratio, 95% confidence interval [HR(95%CI)]=1.86(0.98-3.55)]. Survival was similar between PLWH with CD4≥ 200cells/µL and HIV- [HR(95%CI) = 0.90(0.61-1.33)]. Results were similar when categorizing PLWH by CD4/CD8 [vs. HIV-: low CD4/CD8: HR(95%CI) = 1.74(1.07-3.89); high CD4/CD8: HR(95%CI) = 0.63(0.37-1.07)] and VL [vs. HIV-: <75copies/mL: HR(95%CI) = 0.74(0.46-1.21), ≥75copies/mL: HR(95%CI) = 1.41(0.88-2.27)]. Among PLWH, CD4< 200cells/µL was associated with worse survival [vs. CD4≥ 200cells/µL: HR(95%CI) = 2.37(1.14-4.92)]. CD4, CD4/CD8, and VL may be prognostic markers for PLWH with NSCLC, suggesting immune status may be important in NSCLC survival among PLWH.

Retinal venular oxygen saturation is associated with non-proliferative diabetic retinopathy in young patients with type 1 diabetes.

PURPOSE: To determine the contribution of retinal vessel density (VD), central retinal vessel diameter and retinal oxygen (O2 ) saturation independently of other known risk factors in the development of non-proliferative diabetic retinopathy (NPDR). METHODS: Macular optical coherence tomography angiography (OCTA), central retinal artery/vein equivalent diameter (CRAE/CRVE) measurements and retinal oximetry were performed in a cross-sectional study of 166 eyes from 166 individuals with type 1 diabetes (T1D) aged 14-30 years. Multiple logistic regression analysis was used to investigate whether O2 saturation, retinal vessel diameters and vessel density in the deep capillary plexus (VD-DCP) were associated with NPDR, when adjusting for known risk factors. The individuals were allocated to one group without and one group with NPDR. RESULTS: Multiple logistic regression analysis showed that age (OR = 1.25, 95% CI: 1.04-1.49) and AV-difference in O2 saturation (OR = 0.85, 95% CI 0.77-0.93) were significantly associated with NPDR. CONCLUSION: Our findings suggest that age and lower AV-O2 saturation difference contribute to explaining the grade of NPDR independently of other well-known risk factors. Reduced delivery of O2 to the retinal tissue is associated with the development of NPDR in young patients with T1D and should be given appropriate weight in the risk stratification at early stages of the disease.

Does Current Diabetes Technology Improve Metabolic Control? A Cross-Sectional Study on the Use of Insulin Pumps and Continuous Glucose Monitoring Devices in a Nationwide Pediatric Population.

OBJECTIVE: To examine the use of multiple daily injections (MDI), insulin pumps, self-measured blood glucose (SMBG), and continuous glucose monitoring (CGM) systems, and their association with glycated hemoglobin (HbA1c), diabetic ketoacidosis (DKA), and severe hypoglycemia. METHODS: In a pediatric population-based nationwide cross-sectional study, we analyzed data from 2623 participants up to 18 years of age with type 1 diabetes, using 2017 annual data from the Norwegian Childhood Diabetes Registry. HbA1c was adjusted for age, gender, and diabetes duration. Using a linear mixed-effects model, we assessed HbA1c and the incidence of DKA and severe hypoglycemia according to the use of MDI, insulin pumps, SMBG, and CGM. RESULTS: We observed that 74.7% of participants were using an insulin pump and 52.6% were using a CGM system. Mean HbA1c was 7.8% (62 mmol/mol). The HbA1c of pump users was 0.14 percentage points (pp) higher than that of MDI users. Fewer pump users than MDI users achieved an HbA1c of < 7.5% (38.3 vs. 41.6%). CGM users had a 0.18 pp lower HbA1c than SMBG users, with 40.5 and 38.0%, respectively, achieving an HbA1c of < 7.5%. The incidence of severe hypoglycemia or hospitalization due to DKA was not different in pump and CGM users compared with nonusers. Compared with other insulin pumps, patch pump use was associated with a significantly lower odds ratio for DKA. CONCLUSIONS: Despite the broad use of diabetes technology, as many as 61% of our pediatric cohort did not reach the HbA1c target recommended by the International Society for Pediatric and Adolescent Diabetes (ISPAD). Lower HbA1c was associated with CGM use but not with insulin pump use. Acute complications were not less frequent in the groups using insulin pumps or CGM compared with those using MDI and SMBG. Further research is required to explore the lower incidence of DKA among patch pump users. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04201171.

A Cross-Cultural Study on Attachment and Adjustment Difficulties in Adolescence: The Mediating Role of Self-Control in Italy, Spain, China, and Poland.

From a socio-ecological perspective, individuals are influenced by the interplay of individual, relational, and societal factors operating as a broader system. Thereby, to support youth adjustment during the critical adolescence period, the interplay between these factors should be investigated. This study aimed to investigate cross-cultural differences in adolescents' maternal and paternal attachment, adolescents' adjustment difficulties and self-control, and in their association. N = 1000 adolescents (mean (M) age = 16.94, SD = 0.48; 45.90% males) from China, Italy, Spain, and Poland participated by completing self-report measures. Results showed cross-country similarities and differences among the considered variables and their associative pattern. Moreover, conditional process analysis evaluating the association between maternal vs. paternal attachment and adjustment difficulties, mediated by self-control, and moderated by country, was performed. Maternal attachment directly, and indirectly through greater self-control, influenced adjustment difficulties in all four countries. This association was stronger among Spaniards. Paternal attachment influenced directly, and indirectly through self-control, on adolescents' adjustment difficulties only in Italy, Spain, and Poland, and was stronger among Polish adolescents. For Chinese adolescents, paternal attachment solely associated with adjustment difficulties when mediated by self-control. Thus, results highlighted both similarities and differences across countries in the interplay between maternal vs. paternal attachment and self-control on adolescents' adjustment difficulties. Implications are discussed.

Bacterial Genetic Approach to the Study of Reactive Oxygen Species Production in Galleria mellonella During Salmonella Infection.

Over the last decade, an increasing number of reports presented Galleria mellonella larvae as an important model to study host-pathogen interactions. Coherently, increasing information became available about molecular mechanisms used by this host to cope with microbial infections but few of them dealt with oxidative stress. In this work, we addressed the role of reactive oxygen species (ROS) produced by the immune system of G. mellonella to resist against Salmonella enterica, an intracellular pathogen responsible for a wide range of infections. We confirmed that Salmonella was pathogen for G. mellonella and showed that it had to reach a minimal bacterial load within the hemolymph to kill the larvae. ROS production by G. mellonella was revealed by the virulence defects of Salmonella mutants lacking catalases/peroxiredoxins or cytoplasmic superoxide dismutases, both strains being highly sensitive to these oxidants. Finally, we used bacterial transcriptional fusions to demonstrate that hydrogen peroxide (H2O2) was produced in the hemolymph of Galleria during infection and sensed by S. enterica. In line with this observation, the H2O2-dependent regulator OxyR was found to be required for bacterial virulence in the larvae. These results led us to conclude that ROS production is an important mechanism used by G. mellonella to counteract bacterial infections and validate this host as a relevant model to study host-pathogen interactions.

Associations between Macular OCT Angiography and Nonproliferative Diabetic Retinopathy in Young Patients with Type 1 Diabetes Mellitus.

METHODS: OCTA of both eyes was performed in a cross-sectional study of 14 to 30-year-old individuals with at least 10-year duration of T1D and controls recruited from the Norwegian Atherosclerosis and Childhood Diabetes (ACD) study. Vessel density (VD) and foveal avascular zone (FAZ) area in the superficial and deep capillary plexus (SCP and DCP), total retinal volume (TRV), and central macular thickness (CMT) were calculated using automated software. Univariate and multivariate ordered logistic regression (OLR) models were used accordingly. RESULTS: We included 168 control eyes and 315 T1D eyes. Lower VD in DCP (OR 0.65, 95% CI 0.51-0.83), longer diabetes duration (OR 1.51, 95% CI 1.22-1.87), and higher waist circumference (OR 1.08, 95% CI 1.02-1.14) were significantly associated with progression of NPDR. VD in SCP and DCP were significantly lower in T1D patients without diabetic retinopathy than in controls. CONCLUSIONS: Sparser VD in DCP is significantly associated with severity of NPDR, supporting that OCTA might detect the earliest signs of NPDR before it is visible by ophthalmoscopy.

GmNAC81 Inversely Modulates Leaf Senescence and Drought Tolerance.

Glycine max NAC81 (GmNAC81) is a downstream effector of the DCD/NRP-mediated cell death signaling, which interacts with GmNAC30 to fully induce the caspase 1-like vacuolar processing enzyme (VPE) expression, the executioner of the cell death program. GmNAC81 has been previously shown to positively modulate leaf senescence via the NRP/GmNAC81/VPE signaling module. Here, we examined the transcriptome induced by GmNAC81 overexpression and leaf senescence and showed that GmNAC81 further modulates leaf senescence by regulating an extensive repertoire of functionally characterized senescence-associated genes (SAGs). Because the NRP/GmNAC81/VPE signaling circuit also relays stress-induced cell death signals, we examined the effect of GmNAC81 overexpression in drought responses. Enhanced GmNAC81 expression in the transgenic lines increased sensitivity to water deprivation. Under progressive drought, the GmNAC81-overexpressing lines displayed severe leaf wilting, a larger and faster decline in leaf Ψw, relative water content (RWC), photosynthesis rate, stomatal conductance, and transpiration rate, in addition to higher Ci/Ca and lower Fm/Fv ratios compared to the BR16 control line. Collectively, these results indicate that the photosynthetic activity and apparatus were more affected by drought in the transgenic lines. Consistent with hypersensitivity to drought, chlorophyll loss, and lipid peroxidation were higher in the GmNAC81-overexpressing lines than in BR16 under dehydration. In addition to inducing VPE expression, GmNAC81 overexpression uncovered the regulation of typical drought-responsive genes. In particular, key regulators and effectors of ABA signaling were suppressed by GmNAC81 overexpression. These results suggest that GmNAC81 may negatively control drought tolerance not only via VPE activation but also via suppression of ABA signaling.

ASC-Mediated Inflammation and Pyroptosis Attenuates Brucella abortus Pathogenesis Following the Recognition of gDNA.

Brucella abortus is a zoonotic pathogen that causes brucellosis. Because of Brucella's unique LPS layer and intracellular localization predominately within macrophages, it can often evade immune detection. However, pattern recognition receptors are capable of sensing Brucella pathogen-associated molecular patterns (PAMPS). For example, NOD-like receptors (NLRs) can form a multi-protein inflammasome complex to attenuate Brucella pathogenesis. The inflammasome activates IL-1ß and IL-18 to drive immune cell recruitment. Alternatively, inflammasome activation also initiates inflammatory cell death, termed pyroptosis, which augments bacteria clearance. In this report, we assess canonical and non-canonical inflammasome activation following B. abortus infection. We conducted in vivo studies using Asc-/- mice and observed decreased mouse survival, immune cell recruitment, and increased bacteria load. We also conducted studies with Caspase-11-/- mice and did not observe any significant impact on B. abortus pathogenesis. Through mechanistic studies using Asc-/- macrophages, our data suggests that the protective role of ASC may result from the induction of pyroptosis through a gasdermin D-dependent mechanism in macrophages. Additionally, we show that the recognition of Brucella is facilitated by sensing the PAMP gDNA rather than the less immunogenic LPS. Together, these results refine our understanding of the role that inflammasome activation and pyroptosis plays during brucellosis.

Venular oxygen saturation is increased in young patients with type 1 diabetes and mild nonproliferative diabetic retinopathy.

PURPOSE: To clarify how early in the development of diabetic retinopathy (DR) can oxygen (O2 ) saturation changes be detected. METHODS: Retinal oximetry was performed in a cross-sectional study, involving 14- to 30-year-old individuals: 185 with type 1 diabetes (T1D) and 94 controls. The subjects were divided into four groups according to the grade of DR. One-way ANOVA and post hoc tests were used to test for differences in the mean O2 saturations between the groups. RESULTS: Fifty-eight (31 %) of the T1D patients had nonproliferative DR. There was no significant difference in O2 saturations between controls and T1D patients with no DR. Arteriolar and venular O2 saturations in T1D patients were significantly higher in moderate/severe DR than in no DR (p = 0.009 and p > 0.001), while venular O2 saturation was significantly higher in mild DR than in no DR (p = 0.013). CONCLUSION: Increase in venular O2 saturation could not be detected before mild retinopathy had developed, and the retinal O2 saturation increase was measurable on the venular side first. Our results suggest that the increase in O2 saturation is likely a consequence of DR.

Annexin V+ Microvesicles in Children and Adolescents with Type 1 Diabetes: A Prospective Cohort Study.

BACKGROUND: Type 1 diabetes is a chronic disease including hyperglycemia and accelerated atherosclerosis, with high risk of micro- and macrovascular complications. Circulating microvesicles (cMVs) are procoagulant cell fragments shed during activation/apoptosis and discussed to be markers of vascular dysfunction and hypercoagulability. Limited knowledge exists on hypercoagulability in young diabetics. We aimed to investigate cMVs over a five-year period in children/adolescents with type 1 diabetes compared with controls and any associations with glycemic control and cardiovascular risk factors. We hypothesized increased shedding of cMVs in type 1 diabetes in response to vascular activation. METHODS: The cohort included type 1 diabetics (n = 40) and healthy controls (n = 40), mean age 14 years (range 11) at inclusion, randomly selected from the Norwegian Atherosclerosis and Childhood Diabetes (ACD) study. Citrated plasma was prepared and stored at -80°C until cMV analysis by flow cytometry. RESULTS: Comparable levels of Annexin V (AV+) cMVs were observed at inclusion. At five-year follow-up, total AV+ cMVs were significantly lower in subjects with type 1 diabetes compared with controls; however, no significant differences were observed after adjusting for covariates. In the type 1 diabetes group, the total AV+, tissue factor-expressing AV+/CD142+, neutrophil-derived AV+/CD15+ and AV+/CD45+/CD15+, and endothelial-derived AV+/CD309+ and CD309+/CD34+ cMVs were inversely correlated with HbA1c (r = -0.437, r = -0.515, r = -0.575, r = -0.529, r = -0.416, and r = -0.445, respectively; all p ≤ 0.01), however, only at inclusion. No significant correlations with cardiovascular risk factors were observed. CONCLUSIONS: Children/adolescents with type 1 diabetes show similar levels of AV+ cMVs as healthy controls and limited associations with glucose control. This indicates that our young diabetics on intensive insulin treatment have preserved vascular homeostasis and absence of procoagulant cMVs.

A nurse-led paediatric oncology fast-track clinic proves a successful ambulatory intervention for patients.

AIM: To assess the impact of a pilot nurse-led paediatric oncology fast-track clinic (OFTC) for complications and side effects following chemotherapy within a paediatric tertiary hospital. METHODS: Prospective clinical data from the first 100 patients seen in the OFTC were compared with retrospective data of oncology patient presentations to the emergency department (ED) (over a 1-year period, n = 196) who would have been eligible for review in the OFTC. Parent and patient satisfaction of clinical care were also assessed via surveys pre- and post-OFTC implementation. RESULTS: Analysis which achieved statistical difference was a reduction in the number of blood tubes taken in OFTC (average 1.9 for those discharged from clinic, 2.9 for those admitted from clinic) in comparison to those seen in the ED (average 3.2) (p = 0.0027). The average number of interventions per patient seen in the ED were 2.1 (standard deviation 1.64) compared with 1.7 (standard deviation 1.55) interventions per patient seen in the OFTC, and who were not admitted following review. This result approached statistical significance with p = 0.0963. Other results which did not meet statistical significance included a reduction in treatment times, hospital admissions and medical oncology reviews. CONCLUSION: Our pilot study implementing an OFTC for the triage and assessment of chemotherapy-related complications has proven successful from an operational and consumer perspective. The clinic improved care by ensuring expedited review, more streamlined interventions, and less overall hospital admissions. The improvements in efficiency were also mirrored by increased parent and patient satisfaction.