Potential effects of "social" distancing measures and school lockdown on child and adolescent mental health

Age-related metabolic and renal changes predispose older people to an increased risk of diabetes mellitus and diabetic kidney disease, respectively. As the prevalence of the ageing population is increasing, because of increased life expectancy, the prevalence of older people with diabetic kidney disease is likely to increase. Diabetic kidney disease is associated with an increased risk of adverse outcomes and increased costs to healthcare systems. The management includes promotion of a healthy lifestyle and control of cardiovascular risk factors such as hyperglycaemia, hypertension and dyslipidaemia. Older people are a heterogeneous group of people from a community-living fit and independent person to a fully dependent individual residing in a care home. Therefore, management in this age group should be based on a patient's functional level adopting tight metabolic control in the fit individual and relaxed targets in the frail person. However, despite the maximum available therapy, a significant number of patients with diabetic kidney disease still progress to renal failure and experience adverse cardiac outcomes. Therefore, future research is required to explore methods of early detection of diabetic kidney disease and to investigate novel therapeutic interventions to further improve the outcomes.Age-related metabolic and renal changes predispose older people to an increased risk of diabetes mellitus and diabetic kidney disease, respectively. As the prevalence of the ageing population is increasing, because of increased life expectancy, the prevalence of older people with diabetic kidney disease is likely to increase. Diabetic kidney disease is associated with an increased risk of adverse outcomes and increased costs to healthcare systems. The management includes promotion of a healthy lifestyle and control of cardiovascular risk factors such as hyperglycaemia, hypertension and dyslipidaemia. Older people are a heterogeneous group of people from a community-living fit and independent person to a fully dependent individual residing in a care home. Therefore, management in this age group should be based on a patient's functional level adopting tight metabolic control in the fit individual and relaxed targets in the frail person. However, despite the maximum available therapy, a significant number of patients with diabetic kidney disease still progress to renal failure and experience adverse cardiac outcomes. Therefore, future research is required to explore methods of early detection of diabetic kidney disease and to investigate novel therapeutic interventions to further improve the outcomes.Age-related metabolic and renal changes predispose older people to an increased risk of diabetes mellitus and diabetic kidney disease, respectively. As the prevalence of the ageing population is increasing, because of increased life expectancy, the prevalence of older people with diabetic kidney disease is likely to increase. Diabetic kidney disease is associated with an increased risk of adverse outcomes and increased costs to healthcare systems. The management includes promotion of a healthy lifestyle and control of cardiovascular risk factors such as hyperglycaemia, hypertension and dyslipidaemia. Older people are a heterogeneous group of people from a community-living fit and independent person to a fully dependent individual residing in a care home. Therefore, management in this age group should be based on a patient's functional level adopting tight metabolic control in the fit individual and relaxed targets in the frail person. However, despite the maximum available therapy, a significant number of patients with diabetic kidney disease still progress to renal failure and experience adverse cardiac outcomes. Therefore, future research is required to explore methods of early detection of diabetic kidney disease and to investigate novel therapeutic interventions to further improve the outcomes.Non peer reviewe

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Preventing sepsis development in complicated urinary tract infections

Introduction: Urinary tract infections (UTIs) are the most prevalent infections in the community and the most common reason for antimicrobial prescribing in ambulatory care. A UTI is defined as complicated when urinary tract anatomical abnormalities or urinary devices are present, when it is recurrent and when associated with immunodeficiency. Complicated UTIs (cUTIs) have a higher risk of treatment failure and often require longer antimicrobial treatment courses. cUTIs, especially those which are healthcare-associated, are often due to multidrug resistant organisms (MDROs).Areas covered: This article will review the available evidence in relation to prevention of sepsis in cUTI, evaluating the risk factors associated with sepsis development. Published articles from January 2005 to September 2019 on UTIs and sepsis prevention in complicated UTIs were identified by using MEDLINE (National Library of Medicine Bethesda MD) and by reviewing the references of retrieved articles.Expert opinion: Prevention of sepsis relies on prompt and timely diagnosis of cUTI, early identification of the causative organism, removal of obstructions and source control, proper and adequate empirical/targeted antimicrobial treatment. In particular, source control, i.e. removal of urinary obstructions, infected stents, urinary catheters, nephrostomies, and drainage of hydronephrosis/abscess, is essential for preventing the development and progression of sepsis

At the metal–metabolite interface in Aspergillus fumigatus: towards untangling the intersecting roles of zinc and gliotoxin

Cryptic links between apparently unrelated metabolic systems represent potential new drug targets in fungi. Evidence of such a link between zinc and gliotoxin (GT) biosynthesis in Aspergillus fumigatus is emerging. Expression of some genes of the GT bio-synthetic gene cluster gli is influenced by the zinc-dependent transcription activator ZafA, zinc may relieve GT-mediated fungal growth inhibition and, surprisingly, GT biosynthesis is influenced by zinc availability. In A. fumigatus, dithiol gliotoxin (DTG), which has zinc-chelating properties, is converted to either GT or bis-dethiobis(methylthio)gliotoxin (BmGT) by oxidoreductase GliT and methyltransferase GtmA, respectively. A double deletion mutant lacking both GliT and GtmA was previously observed to be hypersensitive to exogenous GT exposure. Here we show that compared to wild-type exposure, exogenous GT and the zinc cheator N,N,N′,N′-tetrakis(2-pyridinylmethyl)−1,2-ethanediamine (TPEN) inhibit A. fumigatus ΔgliTΔgtmA growth, specifically under zinc-limiting conditions, which can be reversed by zinc addition. While GT biosynthesis is evident in zinc- depleted medium, addition of zinc (1μM) suppressed GT and activated BmGT production. In addition, secretion of the unferrated siderophore, tria- cetylfusarinine C (TAFC), was evident by A. fumigatus wild-type (at >5 μM zinc) and ΔgtmA (at >1 μM zinc) in a low-iron medium. TAFC secretion suggests that differential zinc-sensing between both strains may influence fungal Fe3+ requirement. Label-free quantitative proteomic analysis of both strains under equivalent differential zinc conditions revealed protein abundance alterations in accordance with altered metabolomic observations, in addition to increased GliT abundance in ΔgtmA at 5 μM zinc, compared to wild-type, supporting a zinc-sensing deficiency in the mutant strain. The relative abundance of a range of oxidore-ductase- and secondary metabolism- related enzymes was also evident in a zinc- and strain- dependent manner. Overall, we elaborate new linkages between zinc availability, natural product biosynthesis and oxidative stress homeostasis in A. fumigatuA.M.T. is funded by a John and Pat Hume PhD Scholarship from Maynooth University. This work was in part supported by the Ministerio de Ciencia e Innovación (Spain) through grant PID2019-110994RB-I00 to J.A.C. LC-MS and HPLC facilities were funded by competitive awards from Science Foundation Ireland [12/RI/2346 (3)], to S.D., and the Irish Higher Education Authority, respectively

False extended-spectrum -lactamase phenotype in clinical isolates of Escherichia coli associated with increased expression of OXA-1 or TEM-1 penicillinases and loss of porins

Objectives Two clinical isolates of Escherichia coli, EC18 and EC21, were non-susceptible (MICs 4–16 mg/L) to cefpirome and cefepime, with marked synergy with clavulanate, yet were susceptible to cefotaxime and ceftazidime (MICs =1 mg/L). EC19, from the same patient as EC21, was susceptible to all four cephalosporins. We sought to characterize the molecular basis of resistance in isolates EC18 and EC21. Methods PFGE was used to study the genetic relationships of the isolates, and MICs were determined. ß-Lactamases were characterized by PCR, isoelectric focusing (IEF), construction of genomic libraries and sequencing. A double mutant of E. coli J53 was constructed, lacking OmpC and OmpF porins. Plasmids from clinical isolates were transformed into E. coli J53 and J53?ompCF. Outer membrane proteins (OMPs) were analysed by SDS-PAGE and OmpA by matrix-assisted laser desorption ionization time-of-flight/time-of-flight mass spectrometry. Expression of omp and bla genes was analysed by RT–PCR. Results Isolates EC19 and EC21 had identical PFGE profiles, whereas EC18 was distinct. PCR and IEF confirmed ß-lactamases with pIs of 5.4 (TEM-1) in EC18 and 7.4 (OXA-1) in both EC19 and EC21. EC18 had blaTEM-1b with the strong promoter P5 and lacked OmpC and OmpF. RT–PCR showed stronger expression of blaOXA-1 in EC21 versus EC19, along with diminished expression of OmpC, though with increased OmpF. Plasmids extracted from EC18 and EC21 conferred increased MICs of cefpirome and cefepime, although susceptibility to cefotaxime and ceftazidime was retained. Conclusions The ‘cefpiromase’ or ‘cefepimase’ ESBL phenotype of the clinical isolates non-susceptible to cefpirome and cefepime resulted from high expression of TEM-1 or OXA-1 ß-lactamases combined with loss of porins

Potential effects of "social" distancing measures and school lockdown on child and adolescent mental health

Age-related metabolic and renal changes predispose older people to an increased risk of diabetes mellitus and diabetic kidney disease, respectively. As the prevalence of the ageing population is increasing, because of increased life expectancy, the prevalence of older people with diabetic kidney disease is likely to increase. Diabetic kidney disease is associated with an increased risk of adverse outcomes and increased costs to healthcare systems. The management includes promotion of a healthy lifestyle and control of cardiovascular risk factors such as hyperglycaemia, hypertension and dyslipidaemia. Older people are a heterogeneous group of people from a community-living fit and independent person to a fully dependent individual residing in a care home. Therefore, management in this age group should be based on a patient's functional level adopting tight metabolic control in the fit individual and relaxed targets in the frail person. However, despite the maximum available therapy, a significant number of patients with diabetic kidney disease still progress to renal failure and experience adverse cardiac outcomes. Therefore, future research is required to explore methods of early detection of diabetic kidney disease and to investigate novel therapeutic interventions to further improve the outcomes.Age-related metabolic and renal changes predispose older people to an increased risk of diabetes mellitus and diabetic kidney disease, respectively. As the prevalence of the ageing population is increasing, because of increased life expectancy, the prevalence of older people with diabetic kidney disease is likely to increase. Diabetic kidney disease is associated with an increased risk of adverse outcomes and increased costs to healthcare systems. The management includes promotion of a healthy lifestyle and control of cardiovascular risk factors such as hyperglycaemia, hypertension and dyslipidaemia. Older people are a heterogeneous group of people from a community-living fit and independent person to a fully dependent individual residing in a care home. Therefore, management in this age group should be based on a patient's functional level adopting tight metabolic control in the fit individual and relaxed targets in the frail person. However, despite the maximum available therapy, a significant number of patients with diabetic kidney disease still progress to renal failure and experience adverse cardiac outcomes. Therefore, future research is required to explore methods of early detection of diabetic kidney disease and to investigate novel therapeutic interventions to further improve the outcomes.Age-related metabolic and renal changes predispose older people to an increased risk of diabetes mellitus and diabetic kidney disease, respectively. As the prevalence of the ageing population is increasing, because of increased life expectancy, the prevalence of older people with diabetic kidney disease is likely to increase. Diabetic kidney disease is associated with an increased risk of adverse outcomes and increased costs to healthcare systems. The management includes promotion of a healthy lifestyle and control of cardiovascular risk factors such as hyperglycaemia, hypertension and dyslipidaemia. Older people are a heterogeneous group of people from a community-living fit and independent person to a fully dependent individual residing in a care home. Therefore, management in this age group should be based on a patient's functional level adopting tight metabolic control in the fit individual and relaxed targets in the frail person. However, despite the maximum available therapy, a significant number of patients with diabetic kidney disease still progress to renal failure and experience adverse cardiac outcomes. Therefore, future research is required to explore methods of early detection of diabetic kidney disease and to investigate novel therapeutic interventions to further improve the outcomes.Non peer reviewe

Heterogeneity in the half-life of factor VIII concentrate in patients with hemophilia A is due to variability in the clearance of endogenous von Willebrand factor

Background: Previous studies have reported marked interindividual variation in factor VIII (FVIII) clearance in patients with hemophilia (PWH) and proposed a number of factors that influence this heterogeneity. Objectives: To investigate the importance of the clearance rates of endogenous von Willebrand factor (VWF) compared with those of other FVIII half-life modifiers in adult PWH. Methods: The half-life of recombinant FVIII was determined in a cohort of 61 adult PWH. A range of reported modifiers of FVIII clearance was assessed (including plasma VWF:antigen and VWF propeptide levels; VWF-FVIII binding capacity; ABO blood group; and nonneutralizing anti-FVIII antibodies). The FVIII-binding region of the VWF gene was sequenced. Finally, the effects of variation in FVIII half-life on clinical phenotype were investigated. Results: We demonstrated that heterogeneity in the clearance of endogenous plasma VWF is a key determinant of variable FVIII half-life in PWH. Both ABO blood group and age significantly impact FVIII clearance. The effect of ABO blood group on FVIII half-life in PWH is modulated entirely through its effect on the clearance rates of endogenous VWF. In contrast, the age-related effect on FVIII clearance is, at least in part, VWF independent. In contrast to previous studies, no major effects of variation in VWF-FVIII binding affinity on FVIII clearance were observed. Although high-titer immunoglobulin G antibodies (≥1:80) were observed in 26% of PWH, these did not impact FVIII half-life. Importantly, the annual FVIII usage (IU/kg/y) was significantly (p = .0035) increased in patients with an FVIII half-life of Conclusion: Our data demonstrate that heterogeneity in the half-life of FVIII concentrates in patients with hemophilia A is primarily attributable to variability in the clearance of endogenous VWF.</p