Epigenetics to clinicopathological features: a bibliometric analysis of H3 G34-mutant diffuse hemispheric glioma literature.

PURPOSE: Pediatric-type diffuse high-grade gliomas are the leading cause of cancer-related morbidity and mortality in children. More than 30% of diffuse hemispheric gliomas (DHG) in adolescents harbor histone H3 G34 mutations and are recognized by the World Health Organization as a distinct tumor entity. By reporting bibliometric characteristics of the most cited publications on H3 G34-mutant DHG (H3 G34 DHG), we provide an overview of emerging literature and speculate where future research efforts may lead. METHODS: One hundred fourteen publications discussing H3 G34 DHG were identified, categorized as basic science (BSc), clinical (CL), or review (R), and ranked by citation number. Various bibliometric parameters were summarized, and a comparison between article types was performed. RESULTS: Articles within this study represent principal investigators from 15 countries and were published across 63 journals between 2012 and 2024, with 36.84% of articles originating in the United States. Overall median values were as follows: citation count, 20 (range, 0-2591), number of authors, 9 (range, 2-78), and year of publication, 2020 (range, 2012-2024). Among the top ten most cited articles, BSc articles accounted for all ten reports. Compared to CL and R articles, BSc articles were published in journals with higher impact factors. CONCLUSION: We establish variability in bibliometric parameters for the most cited publications on H3 G34 DHG. Our findings demonstrate a paucity of high-impact and highly cited CL reports and acknowledge an unmet need to intersect basic mechanism with clinical data to inform novel therapeutic approaches.

Evaluating the effects of minimum unit pricing in Scotland on the prevalence of harmful drinking: a controlled interrupted time series analysis.

OBJECTIVES: In May 2018, the Scottish Government introduced a minimum unit price (MUP) for alcohol of £0.50 (1 UK unit = 8 g ethanol) to reduce alcohol consumption, particularly among people drinking at harmful levels. This study aimed to evaluate MUP's impact on the prevalence of harmful drinking among adults in Scotland. STUDY DESIGN: This was a controlled interrupted monthly time series analysis of repeat cross-sectional data collected via 1-week drinking diaries from adult drinkers in Scotland (N = 38,674) and Northern England (N = 71,687) between January 2009 and February 2020. METHODS: The primary outcome was the proportion of drinkers consuming at harmful levels (>50 [men] or >35 [women] units in diary week). The secondary outcomes included the proportion of drinkers consuming at hazardous (≥14-50 [men] or ≥14-35 [women] units) and moderate (<14 units) levels and measures of beverage preferences and drinking patterns. Analyses also examined the prevalence of harmful drinking in key subgroups. RESULTS: There was no significant change in the proportion of drinkers consuming at harmful levels (ß = +0.6 percentage points; 95% confidence interval [CI] = -1.1, +2.3) or moderate levels (ß = +1.4 percentage points; 95% confidence interval = -1.1, +3.8) after the introduction of MUP. The proportion consuming at hazardous levels fell significantly by 3.5 percentage points (95% CI = -5.4, -1.7). There were no significant changes in other secondary outcomes or in the subgroup analyses after correction for multiple testing. CONCLUSIONS: Introducing MUP in Scotland was not associated with reductions in the proportion of drinkers consuming at harmful levels but did reduce the prevalence of hazardous drinking. This adds to previous evidence that MUP reduced overall alcohol consumption in Scotland and consumption among those drinking above moderate levels.

A Far-Red Molecular Rotor Fluorogenic Trehalose Probe for Live Mycobacteria Detection and Drug-Susceptibility Testing.

Increasing the speed, specificity, sensitivity, and accessibility of mycobacteria detection tools are important challenges for tuberculosis (TB) research and diagnosis. In this regard, previously reported fluorogenic trehalose analogues have shown potential, but their green-emitting dyes may limit sensitivity and applications in complex settings. Here, we describe a trehalose-based fluorogenic probe featuring a molecular rotor turn-on fluorophore with bright far-red emission (RMR-Tre). RMR-Tre, which exploits the unique biosynthetic enzymes and environment of the mycobacterial outer membrane to achieve fluorescence activation, enables fast, no-wash, low-background fluorescence detection of live mycobacteria. Aided by the red-shifted molecular rotor fluorophore, RMR-Tre exhibited up to a 100-fold enhancement in M. tuberculosis labeling compared to existing fluorogenic trehalose probes. We show that RMR-Tre reports on M. tuberculosis drug resistance in a facile assay, demonstrating its potential as a TB diagnostic tool.

Differential impacts of economic and demographic variables on substance use patterns during the COVID-19 pandemic.

Background: The COVID-19 pandemic and subsequent economic crisis has provided a unique opportunity to investigate the effects of economic shifts on substance use. Existing literature on this relationship is limited and conflicting, warranting further exploration.Objective: This study aimed to identify relationships between socioeconomic status (SES), demographic variables, and substance use patterns before and after government-mandated business closures due to COVID-19.Methods: Participants were recruited based on self-reported substance use through Amazon's Mechanical Turk (MTurk). Qualifying participants (N = 315, 43% female, mean age = 35.35) reported their substance use and SES for two-week periods before and after pandemic-related business closures. Regression models analyzed relationships between substance use and study variables.Results: Regression models found that, during COVID-19 closures, greater financial strain predicted decreased benzodiazepine (ß = -1.12) and tobacco (ß = 1.59) use. Additionally, certain predictor variables (e.g., participants' age [ß = 1.22], race [ß = -4.43], psychiatric disorders including ADHD [ß = -2.73] and anxiety [ß = 1.53], and concomitant substance use [ß = 3.38]) predicted changes in substance use patterns; however, the directionality of these associations varied across substances.Conclusion: Specific substance use patterns were significantly and differentially impacted by economic strain, psychiatric diagnoses, and concomitant substance use. These results can help direct harm reduction efforts toward populations at greatest risk of harmful substance use following the pandemic.

Covid-19 Epidemic Impact on Clinical Training in Irish GP Training.

Aim To describe the effect of the Covid pandemic on the general practice workplace based learning of GP training in Ireland. Methods A prospective national survey of GP trainees who were in their GP practice placements on three separate occasions throughout the winter pandemic of 2020/2021 Results The average response rate to the three surveys was 19.4%. As the pandemic worsened, the number of face to face consultations dropped so that 51% (n=41) of trainees were seeing less than 5 patients face to face by the third survey. Conversely, the number of telephone/video consultations rose so that by the third survey 54% (n=44) of trainees were conducting more than 16 consultations per day remotely. Examinations and GP presentations expected to be daily occurrences diminished as the pandemic grew more severe, such that by the third survey 24-25% of trainees had not conducted a respiratory examination or dealt with new/unexpected hypertension in the previous month. Conclusion This study demonstrates abrupt change to the normal course of their training which was experienced by Irish GP trainees as a result of Covid, with examples from clinical practice. Adaptions of the training programme helped mitigate against the effects of the pandemic.

Bridging the age gap in breast cancer: impact of omission of breast cancer surgery in older women with oestrogen receptor-positive early breast cancer on quality-of-life outcomes.

BACKGROUND: Primary endocrine therapy may be an alternative treatment for less fit women with oestrogen receptor (ER)-positive breast cancer. This study compared quality-of-life (QoL) outcomes in older women treated with surgery or primary endocrine therapy. METHODS: This was a multicentre, prospective, observational cohort study of surgery or primary endocrine therapy in women aged over 70 years with operable breast cancer. QoL was assessed using European Organisation for Research and Treatment of cancer QoL questionnaires QLQ-C30, -BR23, and -ELD14, and the EuroQol Five Dimensions 5L score at baseline, 6 weeks, and 6, 12, 18, and 24 months. Propensity score matching was used to adjust for baseline variation in health, fitness, and tumour stage. RESULTS: The study recruited 3416 women (median age 77 (range 69-102) years) from 56 breast units. Of these, 2979 (87.2 per cent) had ER-positive breast cancer; 2354 women had surgery and 500 received primary endocrine therapy (125 were excluded from analysis due to inadequate data or non-standard therapy). Median follow-up was 52 months. The primary endocrine therapy group was older and less fit. Baseline QoL differed between the groups; the mean(s.d.) QLQ-C30 global health status score was 66.2(21.1) in patients who received primary endocrine therapy versus 77.1(17.8) among those who had surgery plus endocrine therapy. In the unmatched analysis, changes in QoL between 6 weeks and baseline were noted in several domains, but by 24 months most scores had returned to baseline levels. In the matched analysis, major surgery (mastectomy or axillary clearance) had a more pronounced adverse impact than primary endocrine therapy in several domains. CONCLUSION: Adverse effects on QoL are seen in the first few months after surgery, but by 24 months these have largely resolved. Women considering surgery should be informed of these effects.

Systematic review and meta-analysis of randomized controlled trials of psychological interventions to improve glycaemic control in children and adults with type 1 diabetes.

AIM: We conducted a systematic review aggregate and network meta-analysis of psychological interventions for people with type 1 diabetes to assess their effectiveness in improving glycaemic levels. METHODS: We searched the following databases from 1 January 2003 to 1 July 2018: MEDLINE, CINAHL, PsycINFO, Embase, Cochrane Controlled Trials, Web of Science, clinicaltrials.gov, Dissertation Abstract International. We included randomized controlled trials (RCT) of psychological interventions for children and adults with type 1 diabetes reported in any language. We extracted data on publications, participant characteristics at baseline, intervention and control group, and data for the primary outcome, change in glycaemic control [HbA1c (mmol/mol/%)]. Study authors were contacted for missing data. The review was registered with international prospective register of systematic reviews registration (PROSPERO) CRD42016033619. RESULTS: Twenty-four adult RCTs and 23 of children with type 1 diabetes were included in the systematic review. In aggregate meta-analysis there was no overall effect of psychological intervention compared with control on HbA1c [adults, nine RCTs, n = 1102, pooled mean difference -0.12, 95% confidence intervals (CI) -0.27 to 0.03, I2 = 29.0%, P = 0.19; children, 20 RCTs, n = 2567, -0.09, 95% CI -0.22 to 0.04, I2 =54.0% P=0.002]. Network meta-analysis suggested that probability and rank-ordering of effectiveness is highest for attention control groups (b = -0.47, 95% CI -0.80 to -0.12) followed by cognitive behavioural therapy (CBT) (-0.26, 95% CI -0.45 to -0.06) compared with usual care for adults. CONCLUSIONS: Overall psychological interventions for children and adults with type 1 diabetes do not improve glycaemic control. For adults, CBT-based interventions have the potential to be effective.

Managing vasomotor symptoms effectively without hormones.

Vasomotor symptoms (hot flushes and/or night sweats) affect approximately 80% of women over the menopause transition and can affect quality of life, productivity, and relationships. Vasomotor symptoms are the main reason for seeking treatment during the menopausal transition. Although menopausal hormone therapy (MHT) is effective for symptom management, the majority of symptomatic women do not take MHT. In this article, we review the evidence for non-hormonal treatments for vasomotor symptoms, including pharmacological and non-pharmacological approaches, and provide a clinical algorithm for managing symptomatic women.

Multiple deprivation and geographic distance to community physical activity events - achieving equitable access to parkrun in England.

OBJECTIVES: To evaluate geographic access to free weekly outdoor physical activity events ('parkrun') in England, with a particular focus on deprived communities, and to identify optimal locations for future events to further maximise access. STUDY DESIGN: This study is a cross-sectional ecological analysis of the socio-economic disparities in geographic access to parkrun events in England in late 2018. METHODS: We combined geolocation data on all English Lower Layer Super Output Areas and parkrun events to calculate geodesic distances to the nearest event for more than 32,000 communities in England. We use this measure of geographic access to summarise the relationship between access and socio-economic deprivation, measured using the index of multiple deprivation. We then used geographic coordinates of public green spaces in England to conduct a simple location-allocation analysis to identify 200 locations for future event locations that would maximise access. RESULTS: In England, 69% of the population live within 5 km of one of the 465 parkrun events. There is a small negative correlation between distance and deprivation, indicating that access is slightly better in more socio-economically deprived areas. Setting up an additional 200 events in optimal locations would improve access: the average distance to the nearest parkrun event would improve by 1.22 km, from 4.65 km to 3.43 km, and approximately 82% of the English population would live within 5 km of a parkrun event. CONCLUSION: Over two-thirds of the English population live within 5 km of a parkrun event, and contrary to our expectation, we find that geographic access is slightly better for those living in more deprived communities. Creating additional events may improve geographic access, but effective strategies will still be needed to increase engagement in new and existing events by those living in socio-economically deprived areas.

Histopathology of Anterior Urethral Strictures: Toward a Better Understanding of Stricture Pathophysiology.

PURPOSE: Histopathology can provide insights into disease mechanisms but to date it has been poorly described for urethral stricture. The purpose of this study was to comprehensively describe histopathological findings of stricture specimens obtained at the time of anterior urethroplasty. MATERIALS AND METHODS: All pathological specimens of men who underwent anterior urethroplasty of urethral stricture disease from 2010 to 2017 at a single institution were rereviewed by a single blinded pathologist directed to rule out lichen sclerosus and then describe inflammatory cell type and severity when present. Cohorts comprising strictures with no inflammation, minimal to mild inflammation or moderate to severe inflammation were developed and stricture, patient and surgical outcome characteristics were compared. RESULTS: Histopathology slides from 100 anterior urethroplasty cases were reviewed. Two or more lichen sclerosus characteristics were present in 21% of specimens and 44% of specimens showed chronic inflammation, which was minimal in 20%, mild in 39%, moderate in 39% and severe in 2%. Lymphocytes in 86% of specimens and plasma cells in 12% were the predominant cell types. Patients with inflammatory stricture reported worse overall health. Inflammation was largely absent from isolated bulbomembranous strictures (9%) and more common in lichen sclerosus strictures (100%). The 11% overall failure rate was not affected by the presence (7%) or absence (14%) of inflammation. CONCLUSIONS: Chronic inflammation is prevalent in a significant percent of urethral stricture disease specimens. Associations with worse overall health suggest systemic mediators. Absent inflammation in bulbomembranous strictures suggests a unique pathophysiology in this region. The presence of inflammation did not affect surgical outcomes at mid-term followup.

Type IV Cell-Mediated Hypersensitivity Reaction Caused by Titanium Implant Following Double Calcaneal Osteotomy and First Metatarsal-Cuneiform Arthrodesis: A Case Report and Review of the Literature.

Because of their inert character and desired biocompatibility, titanium implants have been universally accepted as safer alternatives to the conventional stainless steel orthopedic implants; however, recent emergence of type IV hypersensitivity reactions to titanium have included eczema, contact dermatitis, a prolonged febrile state, sterile osteonecrosis, and impaired fracture and wound healing. This report presents a patient with postoperative incision dehiscence and devascularization of surfaces in contact with titanium hardware after undergoing a double calcaneal osteotomy and a first metatarsal-cuneiform arthrodesis using titanium alloy implants. Titanium hypersensitivity was confirmed in this case through standard allergy patch testing by a board-certified immunologist. Complete healing occurred after diagnosis of the titanium allergy and hardware explant. To our knowledge, this is one of a few known allergies to titanium implants after foot and ankle surgery.

Proteomic analysis of serum and sputum analytes distinguishes controlled and poorly controlled asthmatics.

BACKGROUND: A major goal of asthma therapy is to achieve disease control, with maintenance of lung function, reduced need for rescue medication, and prevention of exacerbation. Despite current standard of care, up to 70% of patients with asthma remain poorly controlled. Analysis of serum and sputum biomarkers could offer insights into parameters associated with poor asthma control. OBJECTIVE: To identify signatures as determinants of asthma disease control, we performed proteomics using Olink proximity extension analysis. METHODS: Up to 3 longitudinal serum samples were collected from 23 controlled and 25 poorly controlled asthmatics. Nine of the controlled and 8 of the poorly controlled subjects also provided 2 longitudinal sputum samples. The study included an additional cohort of 9 subjects whose serum was collected within 48 hours of asthma exacerbation. Two separate pre-defined Proseek Multiplex panels (INF and CVDIII) were run to quantify 181 separate protein analytes in serum and sputum. RESULTS: Panels consisting of 9 markers in serum (CCL19, CCL25, CDCP1, CCL11, FGF21, FGF23, Flt3L, IL-10Rß, IL-6) and 16 markers in sputum (tPA, KLK6, RETN, ADA, MMP9, Chit1, GRN, PGLYRP1, MPO, HGF, PRTN3, DNER, PI3, Chi3L1, AZU1, and OPG) distinguished controlled and poorly controlled asthmatics. The sputum analytes were consistent with a pattern of neutrophil activation associated with poor asthma control. The serum analyte profile of the exacerbation cohort resembled that of the controlled group rather than that of the poorly controlled asthmatics, possibly reflecting a therapeutic response to systemic corticosteroids. CONCLUSIONS AND CLINICAL RELEVANCE: Proteomic profiles in serum and sputum distinguished controlled and poorly controlled asthmatics, and were maintained over time. Findings support a link between sputum neutrophil markers and loss of asthma control.

Urethral lichen sclerosus under the microscope: a survey of academic pathologists.

INTRODUCTION: Given the poor understanding of the pathophysiology of genital lichen sclerosus (GLS) and a lack of accepted definitive diagnostic criteria, we proposed to survey pathologists regarding their understanding of GLS. We hypothesized that significant disagreement about GLS will exist. MATERIALS AND METHODS: All urologists participating in the Trauma and Urologic Reconstruction Network of Surgeons identified genitourinary (GUP) and dermatopathologists (DP) at their respective institutions who were then invited to participate in an online survey regarding their experience with diagnosing GLS, GLS pathophysiology and its relationship to urethral stricture disease. RESULTS: There were 23 (12 DP, 11 GUP) pathologists that completed the survey. The most agreed upon criteria for diagnosis were dermal collagen homogenization (85.7%), loss of the normal rete pattern (33.3%) and atrophic epidermis (28.5%). No pathologists believed GLS had an infectious etiology (19% maybe, 42% unknown) and 19% believed GLS to be an autoimmune disorder (42% maybe, 38% unknown); 19% believed LS to be premalignant, but 52% believed it was associated with cancer; 80% believed that LS could involve the urethra (DP (92%) versus GUP (67%); p = 0.272). Of those diagnosing urethral GLS, 80% of DUP believed that GLS must first involve the glans/prepuce before involving the urethra, while all GUP believed that urethral disease could exist in isolation (p = 0.007). CONCLUSIONS: There was significant disagreement in this specialized cohort of pathologists when diagnosing GLS. A logical first step appears to be improving agreement on how to best describe and classify the disease. This may lead to improve treatments.

Single Centre Experience - Clinical Presentation and Frequency of Paediatric Diabetic Ketoacidosis (DKA) At Diagnosis over a 5-Year Period.

Type 1 diabetes (T1D) symptoms are subtle and easily overlooked. Delayed diagnosis can result in Diabetic ketoacidosis (DKA), a life threatening complication with lasting consequences. We sought to define the presenting features of T1D and DKA frequency, in children <15 years diagnosed in a single national tertiary centre, and identify predictive factors for DKA. A review of T1D incident cases was undertaken from 2008-2012 using the National Diabetes Register (ICDNR) and clinical case notes. Data were compared with a 1997/8 national study. We found DKA at presentation in 28.7 % of children and 15.5% had moderate/severe DKA. Commonest symptoms were polydipsia, polyuria, weight loss, and lethargy. Median symptom duration was 17 days. Clinical presentation was similar and frequency of DKA at T1D diagnosis remains high. The proportion with moderate/severe DKA is lower than the 25% previously reported (p=0.038). National monitoring and targeted action to reduce DKA at diagnosis is required.

Changes in elevated cholesterol in the era of tenofovir in South Africa: risk factors, clinical management and outcomes.

OBJECTIVES: Antiretroviral therapy (ART) has been associated with unfavourable lipid profile changes and increased risk of cardiovascular disease (CVD). With a growing population on ART in South Africa, there has been concern about the increase in noncommunicable diseases such as CVD. We determined risk factors associated with increased total cholesterol (TC) in a large cohort on ART and describe the clinical management thereof. METHODS: We conducted an observational cohort study of ART-naïve adults initiating standard first-line ART in a large urban clinic in Johannesburg, South Africa. TC was measured annually for most patients. A proportional hazards regression model was used to determine risk factors associated with incident high TC (≥ 6 mmol/L). RESULTS: Significant risk factors included initial regimen non-tenofovir vs. tenofovir [hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.14-2.08], age ≥40 vs. <30 years (HR 3.22; 95% CI 2.07-4.99), body mass index (BMI) ≥ 30 kg/m2 (HR 1.65; 95% CI 1.18-2.31) and BMI 25-29.9 kg/m2 (HR 1.70; 95% CI 1.30-2.23) vs. 18-24.9 kg/m2 , and baseline CD4 count < 50 cells/µL (HR 1.55; 95% CI 1.10-2.20) and 50-99 cells/µL (HR 1.40; 95% CI 1.00-1.97) vs. > 200 cells/µL. Two-thirds of patients with high TC were given cholesterol-lowering drugs, after repeat TC measurements about 12 months apart, while 31.8% were likely to have received dietary counselling only. CONCLUSIONS: Older age, higher BMI, lower CD4 count and a non-tenofovir regimen were risk factors for incident elevated TC. Current guidelines do not indicate regular cholesterol testing at ART clinic visits, which are the main exposure to regular clinical monitoring for most HIV-positive individuals. If regular cholesterol monitoring is conducted, improvements can be made to identify and treat patients sooner.

Cost-effectiveness of population-based, community, workplace and individual policies for diabetes prevention in the UK.

AIM: To analyse the cost-effectiveness of different interventions for Type 2 diabetes prevention within a common framework. METHODS: A micro-simulation model was developed to evaluate the cost-effectiveness of a range of diabetes prevention interventions including: (1) soft drinks taxation; (2) retail policy in socially deprived areas; (3) workplace intervention; (4) community-based intervention; and (5) screening and intensive lifestyle intervention in individuals with high diabetes risk. Within the model, individuals follow metabolic trajectories (for BMI, cholesterol, systolic blood pressure and glycaemia); individuals may develop diabetes, and some may exhibit complications of diabetes and related disorders, including cardiovascular disease, and eventually die. Lifetime healthcare costs, employment costs and quality-adjusted life-years are collected for each person. RESULTS: All interventions generate more life-years and lifetime quality-adjusted life-years and reduce healthcare spending compared with doing nothing. Screening and intensive lifestyle intervention generates greatest lifetime net benefit (£37) but is costly to implement. In comparison, soft drinks taxation or retail policy generate lower net benefit (£11 and £11) but are cost-saving in a shorter time period, preferentially benefit individuals from deprived backgrounds and reduce employer costs. CONCLUSION: The model enables a wide range of diabetes prevention interventions to be evaluated according to cost-effectiveness, employment and equity impacts over the short and long term, allowing decision-makers to prioritize policies that maximize the expected benefits, as well as fulfilling other policy targets, such as addressing social inequalities.

The impact of Type 2 diabetes prevention programmes based on risk-identification and lifestyle intervention intensity strategies: a cost-effectiveness analysis.

AIMS: To develop a cost-effectiveness model to compare Type 2 diabetes prevention programmes targeting different at-risk population subgroups with a lifestyle intervention of varying intensity. METHODS: An individual patient simulation model was constructed to simulate the development of diabetes in a representative sample of adults without diabetes from the UK population. The model incorporates trajectories for HbA1c , 2-h glucose, fasting plasma glucose, BMI, systolic blood pressure, total cholesterol and HDL cholesterol. Patients can be diagnosed with diabetes, cardiovascular disease, microvascular complications of diabetes, cancer, osteoarthritis and depression, or can die. The model collects costs and utilities over a lifetime horizon. The perspective is the UK National Health Service and personal social services. We used the model to evaluate the population-wide impact of targeting a lifestyle intervention of varying intensity to six population subgroups defined as high risk for diabetes. RESULTS: The intervention produces 0.0003 to 0.0009 incremental quality-adjusted life years and saves up to £1.04 per person in the general population, depending upon the subgroup targeted. Cost-effectiveness increases with intervention intensity. The most cost-effective options are to target individuals with HbA1c > 42 mmol/mol (6%) or with a high Finnish Diabetes Risk (FINDRISC) probability score (> 0.1). CONCLUSION: The model indicates that diabetes prevention interventions are likely to be cost-effective and may be cost-saving over a lifetime. In the model, the criteria for selecting at-risk individuals differentially impact upon diabetes and cardiovascular disease outcomes, and on the timing of benefits. These findings have implications for deciding who should be targeted for diabetes prevention interventions.

Intradermal delivery of DNA encoding HCV NS3 and perforin elicits robust cell-mediated immunity in mice and pigs.

Currently, no vaccine is available against hepatitis C virus (HCV), and although DNA vaccines have considerable potential, this has not been realised. Previously, the efficacy of DNA vaccines for human immunodeficiency virus (HIV) and HCV was shown to be enhanced by including the gene for a cytolytic protein, viz. perforin. In this study, we examined the mechanism of cell death by this bicistronic DNA vaccine, which encoded the HCV non-structural protein 3 (NS3) under the control of the CMV promoter and perforin is controlled by the SV40 promoter. Compared with a canonical DNA vaccine and a bicistronic DNA vaccine encoding NS3 and the proapoptotic gene NSP4, the perforin-containing vaccine elicited enhanced cell-mediated immune responses against the NS3 protein in vaccinated mice and pigs, as determined by ELISpot and intracellular cytokine staining, whereas a mouse challenge model suggested that the immunity was CD8(+) T-cell-dependent. The results of the study showed that the inclusion of perforin in the DNA vaccine altered the fate of NS3-positive cells from apoptosis to necrosis, and this resulted in more robust immune responses in mice and pigs, the latter of which represents an accepted large animal model in which to test vaccine efficacy.

Clopidogrel, prasugrel or ticagrelor in patients with acute coronary syndromes undergoing percutaneous coronary intervention.

BACKGROUND: Guidelines recommend prasugrel or ticagrelor instead of clopidogrel in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary interventions (PCI). AIM: We sought to describe the trends in uptake of the newer agents and analyse the clinical characteristics and short-term outcomes of patients treated with clopidogrel, prasugrel or ticagrelor. METHODS: We analysed the temporal trends of antiplatelet use since the availability of prasugrel (2009-2013) in patients with ACS from the Melbourne Interventional Group registry. To assess clinical characteristics and outcomes, we included 1850 patients from 2012 to 2013, corresponding to the time all three agents were available. The primary outcome was major adverse cardiovascular events (MACE). The safety end-point was in-hospital bleeding. RESULTS: For the period of 2009-2013, the majority of patients were treated with clopidogrel (72%) compared with prasugrel (14%) or ticagrelor (14%). There was a clear trend towards ticagrelor by the end of 2013. Patients treated with clopidogrel were more likely to present with non-ST-elevation ACS, be older, and have more comorbidities. There was no difference in unadjusted 30-day mortality (0.9 vs 0.5 vs 1.0%, P = 0.76), myocardial infarction (2 vs 1 vs 2%, P = 0.52) or MACE (3 vs 3 vs 4%, P = 0.57) between the three agents. There was no difference in in-hospital bleeding (3 vs 2 vs 2%, P = 0.64). CONCLUSION: Prasugrel and ticagrelor are increasingly used in ACS patients treated with PCI, predominantly in a younger cohort with less comorbidity. Although antiplatelet therapy should still be individualised based on the thrombotic and bleeding risk, our study highlights the safety of the new P2Y12 inhibitors in contemporary Australian practice.

The multi-year cumulative effects of alternative stocking rate and grazing management practices on pasture productivity and utilization efficiency.

The production and utilization of increased quantities of high quality pasture is of paramount importance in pasture-based milk production systems. The objective of this study was to evaluate the cumulative effects of alternative integrated grazing strategies, incorporating alternative stocking rate (SR) and grazing severities, on pasture productivity and grazing efficiency over multiple years within farm systems using perennial ryegrass dominant pastures. Three whole-farm SR treatments were compared over 4 complete grazing seasons (2009 to 2012 inclusive): low (2.51 cows/ha; LSR), medium (2.92 cows/ha; MSR), and high (3.28 cows/ha; HSR). Each system had its own farmlet containing 18 paddocks and remained on the same treatment for the duration of the study. Stocking rate had a significant effect on all grazing variables with the exception of soil fertility status and sward density. Increased SR resulted in increased total annual net pasture accumulation, improved sward nutritive value, and increased grazed pasture utilization. Total annual net pasture accumulation was greatest in HSR [15,410kg of dry matter (DM)/ha], intermediate for MSR (14,992kg of DM/ha), and least for LSR (14,479kg of DM/ha) during the 4-yr study period. A linear effect of SR on net pasture accumulation was detected with an increase in net pasture accumulation of 1,164.4 (SE=432.7) kg of DM/ha for each 1 cow/ha increase in SR. Pregrazing pasture mass and height and postgrazing residual pasture mass and height were greatest for LSR, intermediate for the MSR, and lowest for the HSR. In comparison with the LSR, the imposition of a consistently increased grazing severity coupled with increased whole farm SR in MSR and HSR treatments arrested the decline in sward nutritive value, typically observed during mid-season. Incorporating the individual beneficial effects of SR on pasture accumulation, nutritive value, and utilization efficiency, total proportional energy (unité fourragère lait) utilization per hectare increased significantly with increasing SR (+0.026 and +0.081 for MSR and HSR, respectively). These results quantify the significant effect of grazing management practices on the feed production capability of modern perennial ryegrass pastures for intensive grazing dairy production systems. Furthermore, these results highlight the importance of consistently imposing grazing treatments over multiple years, and within integrated whole farm systems, to accurately assess the longer term effects of alternate grazing management practices on pasture productivity.