Sex- and Age-Specific Differences in Risk Profiles and Early Outcomes in Adults With Acute Coronary Syndromes.

BACKGROUND: Adults <55 years of age comprise a quarter of all acute coronary syndromes (ACS) hospitalisations. There is a paucity of data characterising this group, particularly sex differences. This study aimed to compare the clinical and risk profile of patients with ACS aged <55 years with older counterparts, and measure short-term outcomes by age and sex. METHOD: The study population comprised patients with ACS enrolled in the AUS-Global Registry of Acute Coronary Events (GRACE), Cooperative National Registry of Acute Coronary Syndrome Care (CONCORDANCE) and SNAPSHOT ACS registries. We compared clinical features and combinations of major modifiable risk factors (hypertension, smoking, dyslipidaemia, and diabetes) by sex and age group (20-54, 55-74, 75-94 years). All-cause mortality and major adverse events were identified in-hospital and at 6-months. RESULTS: There were 16,658 patients included (22.3% aged 20-54 years). Among them, 20-54 year olds had the highest proportion of ST-elevation myocardial infarction compared with sex-matched older age groups. Half of 20-54 year olds were current smokers, compared with a quarter of 55-74 year olds, and had the highest prevalence of no major modifiable risk factors (14.2% women, 12.7% men) and of single risk factors (27.6% women, 29.0% men), driven by smoking. Conversely, this age group had the highest proportion of all four modifiable risk factors (6.6% women, 4.7% men). Mortality at 6 months in 20-54 year olds was similar between men (2.3%) and women (1.7%), although lower than in older age groups. CONCLUSIONS: Younger adults with ACS are more likely to have either no risk factor, a single risk factor, or all four modifiable risk factors, than older patients. Targeted risk factor prevention and management is warranted in this age group.

Gene editing and cardiac disease modelling for the interpretation of genetic variants of uncertain significance in congenital heart disease.

BACKGROUND: Genomic sequencing in congenital heart disease (CHD) patients often discovers novel genetic variants, which are classified as variants of uncertain significance (VUS). Functional analysis of each VUS is required in specialised laboratories, to determine whether the VUS is disease causative or not, leading to lengthy diagnostic delays. We investigated stem cell cardiac disease modelling and transcriptomics for the purpose of genetic variant classification using a GATA4 (p.Arg283Cys) VUS in a patient with CHD. METHODS: We performed high efficiency CRISPR gene editing with homology directed repair in induced pluripotent stem cells (iPSCs), followed by rapid clonal selection with amplicon sequencing. Genetic variant and healthy matched control cells were compared using cardiomyocyte disease modelling and transcriptomics. RESULTS: Genetic variant and healthy cardiomyocytes similarly expressed Troponin T (cTNNT), and GATA4. Transcriptomics analysis of cardiomyocyte differentiation identified changes consistent with the patient's clinical human phenotype ontology terms. Further, transcriptomics revealed changes in calcium signalling, and cardiomyocyte adrenergic signalling in the variant cells. Functional testing demonstrated, altered action potentials in GATA4 genetic variant cardiomyocytes were consistent with patient cardiac abnormalities. CONCLUSIONS: This work provides in vivo functional studies supportive of a damaging effect on the gene or gene product. Furthermore, we demonstrate the utility of iPSCs, CRISPR gene editing and cardiac disease modelling for genetic variant interpretation. The method can readily be applied to other genetic variants in GATA4 or other genes in cardiac disease, providing a centralised assessment pathway for patient genetic variant interpretation.

Vittatalactone is the Male-Produced Aggregation Pheromone of the Western Striped Cucumber Beetle, Acalymma trivittatum.

We found that vittatalactone, specifically (3R,4R)-3-methyl-4-[(1S,3S,5S)-1,3,5,7-tetramethyloctyl]oxetan-2-one, is the male-produced aggregation pheromone of the western striped cucumber beetle, Acalymma trivittatum (Mannerheim), as was previously shown for the striped cucumber beetle, Acalymma vittatum (F.) (Coleoptera: Chrysomelidae). A synthetic mixture containing 9% of the authentic natural pheromone, is attractive to both sexes of both species in the field, as demonstrated by trapping using baited and unbaited sticky panels in California and earlier in Maryland. Females of both species do not produce detectable vittatalactone. This finding expands the usefulness of the synthetic vittatalactone mixture for pest management throughout the range of both A. vittatum and A. trivittatum. Development of vittatalactone time-release formulations combined with cucurbitacin feeding stimulants offer the potential for selective and environmentally-friendly cucurbit pest management tactics.

Effects of oxytetracycline on aerobic granular sludge process: Granulation, biological nutrient removal and microbial community structure.

Formation of aerobic granular sludge (AGS), process performance and microbial community structure were investigated in lab-scale sequencing batch reactors (SBR) operated without and with oxytetracycline (OTC). Granulation of activated sludge and appearance of AGS was observed in parallel SBRs operated without and with OTC. However, formation of well-settling aerobic granules was relatively faster in the SBR fed with 100 µg/L OTC and observed within 2 weeks of start-up. Ammonium, total nitrogen, and phosphorus removals were quickly established in the AGS cultivated without OTC. In contrast, nitrogen and phosphorus removals were lower in the OTC fed SBR. But, a gradual improvement in nitrogen and phosphorus removals was observed. After 45 days, nitrogen and phosphorous removals were stabilized at 99% and 70%, respectively, due to establishment of OTC-tolerant community. qPCR revealed the impact of OTC on ammonium oxidizing bacteria, polyphosphate accumulating organisms and their enrichment during exposure to OTC. Ammonium and phosphorus were majorly removed via nitritation-denitritation and enhanced biological phosphorus removal (EBPR) pathways, respectively, in the presence of OTC. Brevundimonas (35%), Thaurea (14%) sp. Ca. Competibacter (5.6%), and Ca. Accumulibacter (4.2%) were enriched in OTC-fed AGS. Of the two OTC-tolerant strains isolated, Micrococcus luteus exhibited growth and efficient OTC biotransformation at different OTC concentrations. Moreover, M. luteus was predominantly growing in the form of aggregates. Key traits such as tolerance, biotransformation and high autoaggregation ability allowed a niche for this strain in the granules. This work has important implications in understanding the effect of antibiotics on AGS and designing AGS based treatment for antibiotic-laden wastewaters.

Elemental Stoichiometry and Photophysiology Regulation of Synechococcus sp. PCC7002 Under Increasing Severity of Chronic Iron Limitation.

Iron (Fe) is an essential cofactor for many metabolic enzymes of photoautotrophs. Although Fe limits phytoplankton productivity in broad areas of the ocean, phytoplankton have adapted their metabolism and growth to survive in these conditions. Using the euryhaline cyanobacterium Synechococcus sp. PCC7002, we investigated the physiological responses to long-term acclimation to four levels of Fe availability representative of the contemporary ocean (36.7, 3.83, 0.47 and 0.047 pM Fe'). With increasing severity of Fe limitation, Synechococcus sp. cells gradually decreased their volume and growth while increasing their energy allocation into organic carbon and nitrogen cellular pools. Furthermore, the total cellular content of pigments decreased. Additionally, with increasing severity of Fe limitation, intertwined responses of PSII functional cross-section (σPSII), re-oxidation time of the plastoquinone primary acceptor QA (τ) and non-photochemical quenching revealed a shift in the photophysiological response between mild to strong Fe limitation compared with severe limitation. Under mild and strong Fe limitation, there was a decrease in linear electron transport accompanied by progressive loss of state transitions. Under severe Fe limitation, state transitions seemed to be largely supplanted by alternative electron pathways. In addition, mechanisms to dissipate energy excess and minimize oxidative stress associated with high irradiances increased with increasing severity of Fe limitation. Overall, our results establish the sequence of physiological strategies adopted by the cells under increasing severity of chronic Fe limitation, within a range of Fe concentrations relevant to modern ocean biogeochemistry.

Ocean acidification stimulates particulate organic carbon accumulation in two Antarctic diatom species under moderate and high natural solar radiation.

Impacts of rising atmospheric CO2 concentrations and increased daily irradiances from enhanced surface water stratification on phytoplankton physiology in the coastal Southern Ocean remain still unclear. Therefore, in the two Antarctic diatoms Fragilariopsis curta and Odontella weissflogii, the effects of moderate and high natural solar radiation combined with either ambient or future pCO2 on cellular particulate organic carbon (POC) contents and photophysiology were investigated. Results showed that increasing CO2 concentrations had greater impacts on diatom physiology than exposure to increasing solar radiation. Irrespective of the applied solar radiation regime, cellular POC quotas increased with future pCO2 in both diatoms. Lowered maximum quantum yields of photochemistry in PSII (Fv /Fm ) indicated a higher photosensitivity under these conditions, being counteracted by increased cellular concentrations of functional photosynthetic reaction centers. Overall, our results suggest that both bloom-forming Antarctic coastal diatoms might increase carbon contents under future pCO2 conditions despite reduced physiological fitness. This indicates a higher potential for primary productivity by the two diatom species with important implications for the CO2 sequestration potential of diatom communities in the future coastal Southern Ocean.

Two Southern Ocean diatoms are more sensitive to ocean acidification and changes in irradiance than the prymnesiophyte Phaeocystis antarctica.

To better understand the impact of ocean acidification (OA) and changes in light availability on Southern Ocean phytoplankton physiology, we investigated the effects of pCO2 (380 and 800 µatm) in combination with low and high irradiance (20 or 50 and 200 µmol photons m-2 s-1 ) on growth, particulate organic carbon (POC) fixation and photophysiology in the three ecologically relevant species Chaetoceros debilis, Fragilariopsis kerguelensis and Phaeocystis antarctica. Irrespective of the light scenario, neither growth nor POC per cell was stimulated by OA in any of the tested species and the two diatoms even displayed negative responses in growth (e.g. C. debilis) or POC content (e.g. F. kerguelensis) under OA in conjunction with high light. For both diatoms, also maximum quantum yields of photosystem II (Fv /Fm ) were decreased under these conditions, indicating lowered photochemical efficiencies. To counteract the negative effects by OA and high light, the two diatoms showed diverging photoacclimation strategies. While cellular chlorophyll a (Chl a) and fucoxanthin contents were enhanced in C. debilis to potentially maximize light absorption, F. kerguelensis exhibited reduced Chl a per cell, increased disconnection of antennae from photosystem II reaction centers and strongly lowered absolute electron transport rates (ETR). The decline in ETRs in F. kerguelensis might be explained in terms of different species-specific strategies for tuning the available flux of adenosine triphosphate and nicotinamide adenine dinucleotide phosphate. Overall, our results revealed that P. antarctica was more tolerant to OA and changes in irradiance than the two diatoms, which may have important implications for biogeochemical cycling.

Evaluation of the expression of P-selectin, ICAM-1, and TNF-alpha in bacteria-free lesional skin of atopic dogs with low-to-mild inflammation.

Canine atopic dermatitis (AD) is a pruritic skin condition that shares many clinical and pathophysiological features with its human counterpart. A major therapeutic challenge of AD is the control of the skin inflammatory process. A detailed knowledge of the pro-inflammatory molecules involved in cell recruitment in AD would allow for a better control of the disease. We thus have studied the protein expression of P-selectin, ICAM-1 and TNF-alpha in the lesional and non-lesional skin of atopic dogs that had been treated for bacterial infections. Despite a low-to-mild inflammatory process, P-selectin protein was clearly upregulated in the lesional skin areas when compared with non-lesional skin (four-fold average increase). This P-selectin upregulation was accompanied by signs of functional changes such as increased cell margination, and membrane-associated protein expression. Although the expression of ICAM-1 and TNF-alpha was not enhanced in the lesional versus the non-lesional skin, there was a trend towards a correlated upregulation of both molecules. Further studies will help elucidate the significance of the substantial overexpression of P-selectin in canine AD, in particular in a scenario where bacterial antigens are not contributing as pro-inflammatory stimuli.

Prospective study of bacterial overgrowth syndrome in eight dogs.

Eight dogs with cutaneous lesions, clinical signs and cytological findings compatible with bacterial overgrowth syndrome were compared with four healthy dogs. The affected dogs were treated for 28 days with 30 mg/kg/day cephalexin. The results showed that the syndrome was a superficial cutaneous disorder characterised by marked pruritus, greasy seborrhoea, offensive odour, erythema, lichenification, hyperpigmentation, excoriations and alopecia involving principally the ventral aspect of the body, but no papules, pustules, epidermal collarettes or crusts; it was caused by overgrowths of Staphylococcus intermedius all over the body surface. Histopathological findings included a superficial, perivascular, hyperplastic and spongiotic dermatitis with a mixed inflammatory infiltrate, but no lesions suggestive of a true pyoderma. In the affected dogs, anti-staphylococcal immunoglobulin G levels were high, but anti-staphylococcal immunoglobulin E levels were low, suggesting that staphylococcal hypersensitivity is not the underlying pathogenic process. The antibiotic treatment improved the condition of all the dogs, but five of the eight had an underlying allergic skin disease.

Treatment of Neotrombicula autumnalis dermatitis in dogs using two topical permethrin-pyriproxyfen combinations.

Few data are available in the literature on the dermatological consequences and treatment of Neotrombicula autumnalis infestation in dogs and cats. In this study, 15 dogs naturally infested with Neotrombicula were affected with moderate to severe pruritic dermatitis. The dermatitis resolved with successful treatment of the parasitic infestation. In 14 dogs, treatment using a topical permethrin-pyriproxyfen combination (pump-spray or 'line-on') was effective within one to three weeks. Two applications were necessary in four dogs. Careful follow-up was conducted in all cases. Statistical analysis was performed to assess the impact of treatment on the parasite population and clinical signs over the three-week study period.

Therapy of difficult cases of canine pyoderma with marbofloxacin: a report of 39 dogs.

Thirty-nine dogs with severe and/or recurrent lesions of pyoderma were treated with marbofloxacin at an average dosage of 2.12 mg/kg bodyweight, once daily, for time periods varing from 10 to 213 days. Forty-seven strains of bacteria, isolated from 34 cultures, were tested for sensitivity to various antibiotics. At day 0, no resistance to marbofloxacin was found, but one refractory case, a strain of Staphylococcus intermedius resistant to marbofloxacin, was cultured at day 28. Thirty-three dogs (84.6 per cent) showed an excellent response (cure), one (2.6 per cent) a clear improvement and one (2.6 per cent) a smaller improvement, while the remaining four dogs showed no response after 11 to 60 days. Fifteen dogs (45.5 per cent) relapsed over the follow-up period of three to 191 days, but none of the dogs in the study exhibited any adverse effects.