Phenotypic variability and diffuse arterial lesions in a family with Loeys-Dietz syndrome type 4.

Syndromic thoracic aortic aneurysm and dissection (TAAD) can suggest Marfan, vascular Ehlers-Danlos or Loeys-Dietz (LDS) syndromes. Several of the TGFß-pathway-related genes predispose to different types of LDS. Heterozygous loss-of-function variations in TGFß2 have been shown to be responsible for a novel form of syndromic TAAD associated with an impairment of the mitral valve and cerebrovascular disease called Loeys-Dietz syndrome type 4 (LDS4). We report the clinical characterization of a LDS4 French family with sudden deaths and diffuse vascular lesions, caused by a frameshift mutation in TGFß2 gene: c.[995del]; p.(Leu332TrpfsTer27). Clinical characteristics include aneurysm of aortic sinus, skeletal and cutaneous features compatible with a syndromic form of TAAD (joint hypermobility, scoliosis, and easy bruises), intracranial aneurysms and rare mitral valve involvement. Iliac aneurysms, systemic medium caliber arteries dissections, and mild developmental delay were present in the family, and have not been described in LDS4. Phenotypic variability was also an important finding, including absence of clinical vascular events at advanced age in one case. Our data expand the phenotype of LDS4: we confirm that TGFß2 mutations are responsible for true LDS syndrome with non-specific features of connective tissue disorders and diffuse vascular lesions. Adapted vascular follow up and prevention has to be proposed for these patients.

Antibiotic resistance: are we all doomed?

Antibiotic resistance is a growing and worrying problem associated with increased deaths and suffering for people. Overall, there are only two factors that drive antimicrobial resistance, and both can be controlled. These factors are the volumes of antimicrobials used and the spread of resistant micro-organisms and/or the genes encoding for resistance. The One Health concept is important if we want to understand better and control antimicrobial resistance. There are many things we can do to better control antimicrobial resistance. We need to prevent infections. We need to have better surveillance with good data on usage patterns and resistance patterns available across all sectors, both human and agriculture, locally and internationally. We need to act on these results when we see either inappropriate usage or resistance levels rising in bacteria that are of concern for people. We need to ensure that food and water sources do not spread multi-resistant micro-organisms or resistance genes. We need better approaches to restrict successfully what and how antibiotics are used in people. We need to restrict the use of 'critically important' antibiotics in food animals and the entry of these drugs into the environment. We need to ensure that 'One Health' concept is not just a buzz word but implemented. We need to look at all sectors and control not only antibiotic use but also the spread and development of antibiotic resistant bacteria - both locally and internationally.

Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability.

The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males and 29 females) with a MH and ID were recruited. Custom-designed 244K array-CGH (Agilent®; Agilent Technologies Inc., Santa Clara, CA) and MED12, ZDHHC9, UPF3B, FBN1, TGFBR1 and TGFBR2 sequencing analyses were performed. Eighty patients could be classified as isolated MH and ID: 12 chromosomal imbalances, 1 FBN1 mutation and 1 possibly pathogenic MED12 mutation were found (17%). Twenty patients could be classified as ID with other extra-skeletal features of the Marfan syndrome (MFS) spectrum: 4 pathogenic FBN1 mutations and 4 chromosomal imbalances were found (2 patients with both FBN1 mutation and chromosomal rearrangement) (29%). These results suggest either that there are more loci with genes yet to be discovered or that MH can also be a relatively non-specific feature of patients with ID. The search for aortic complications is mandatory even if MH is associated with ID since FBN1 mutations or rearrangements were found in some patients. The excess of males is in favour of the involvement of other X-linked genes. Although it was impossible to make a diagnosis in 80% of patients, these results will improve genetic counselling in families.

Key lessons from the COVID-19 public health response in Australia.

Australia avoided the worst effects of the COVID-19 pandemic, but still experienced many negative impacts. Reflecting on lessons from Australia's public health response, an Australian expert panel composed of relevant discipline experts identified the following key lessons: 1) movement restrictions were effective, but their implementation requires careful consideration of adverse impacts, 2) disease modelling was valuable, but its limitations should be acknowledged, 3) the absence of timely national data requires re-assessment of national surveillance structures, 4) the utility of advanced pathogen genomics and novel vaccine technology was clearly demonstrated, 5) decision-making that is evidence informed and consultative is essential to maintain trust, 6) major system weaknesses in the residential aged-care sector require fixing, 7) adequate infection prevention and control frameworks are critically important, 8) the interests and needs of young people should not be compromised, 9) epidemics should be recognised as a 'standing threat', 10) regional and global solidarity is important. It should be acknowledged that we were unable to capture all relevant nuances and context specific differences. However, the intent of this review of Australia's public health response is to critically reflect on key lessons learnt and to encourage constructive national discussion in countries across the Western Pacific Region.

Prolonged carriage of resistant E. coli by returned travellers: clonality, risk factors and bacterial characteristics.

The aim of this study was to delineate the potential risks and dynamics of the prolonged carriage of resistant E. coli in returned travellers. A sample of 274 previously collected E. coli resistant to ceftriaxone (CRO), ciprofloxacin, gentamicin and/or nalidixic acid recovered from 102 travellers was studied. Travellers were assessed pre-travel then longitudinally (maximum 6 months) with peri-rectal/rectal swabs. Clonality was determined by REP-PCR and the presence of O25b-ST131 was assessed. Comparison was made longitudinally for individuals and between identified co-travellers. The risk of prolonged carriage was lower for CRO than for ciprofloxacin or gentamicin resistance. Repeated isolation of the same phenotype at different time points occurred in 19% of initial CRO-resistant carriers compared with 50% of ciprofloxacin- or gentamicin-resistant carriers. The duration of carriage was also longer for the latter resistance phenotypes (75th quartile 8 vs 62 and 63 days respectively). In multivariate analysis, risks of prolonged carriage included antimicrobial use whilst travelling (3.3, 1.3-8.4) and phylogenetic group B2 (9.3, 3.4-25.6) and D (3.8, 1.6-8.8). Clonality amongst longitudinal isolates from the same participant was demonstrated in 92% of participants who were assessable and most marked amongst CRO-resistant isolates. ST-131 was surprisingly infrequent (3% of participants). Prolonged carriage of ciprofloxacin- and gentamicin-resistant isolates is more frequent and prolonged than CRO resistance after travel. Risks of prolonged carriage indicate a contribution of host and bacterial factors to this carriage. These require further elucidation. The strong clonality identified suggests that carriage of a "phenotype" was mediated by persistence of bacteria/plasmid combinations rather than persistence of the plasmid after horizontal transfer to other bacteria.

What do French patients and geneticists think about prenatal and preimplantation diagnoses in Marfan syndrome?

OBJECTIVES: Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with manifestations mainly involving the skeletal, ocular, and cardiovascular systems. The phenotypic variability observed in MFS makes genetic counselling difficult. Prenatal diagnosis (PND) and preimplantation genetic diagnosis are technically feasible when a causal mutation is identified, but both raise many ethical questions in this condition. Little is known about opinions and practices in such reproductive issues in MFS. The goal of this study was to report on patients' points of view and geneticists' standard practices. METHODS: Two different questionnaires were produced. RESULTS: Fifty geneticists filled in the questionnaire. Twenty-two per cent thought that PND was acceptable, 72% debatable and 6% not acceptable. Preimplantation genetic diagnosis was more often reported acceptable (34% of answers). Results varied according to the physician's experience with the disease. Fifty-four answers were collected for patients' questionnaires. Most of them (74%) were favourable to the development of prenatal testing, and believed that the choice should be given to parents. However, only a minority would opt for prenatal diagnosis for themselves. CONCLUSION: This study showed that the majority of patients were in favour of PND and that opinions among practitioners varied widely, but that overall, practitioners favoured a systematic multidisciplinary evaluation of the couple's request.

Clinical impact of antimicrobial resistance in humans.

The dramatic rise in the number and spread of resistant bacterial species continues. This involves not only bacteria that cause infections in the healthcare sector but also those that originate in the community. Antibiotic resistance rates are rising in almost all bacterial species, including those that are the most common bacterial pathogens in people (Escherichia coli and Staphylococcus aureus). Serious infections caused by resistant bacteria do not respond well to therapy and these infections are often associated with worse outcomes, including increased rates of complications, additional expense, higher associated mortality rates and prolonged hospital stays.

Colonisation with Escherichia coli resistant to "critically important" antibiotics: a high risk for international travellers.

Antimicrobial resistance among community-acquired isolates of Escherichia coli is increasing globally, with international travel emerging as a risk for colonisation and infection. The aim was to determine the rate and duration of colonisation with resistant E. coli following international travel. One hundred and two adult hospital staff and contacts from Canberra, Australia, submitted perianal/rectal swabs before and following international travel. Swabs were cultured selectively to identify E. coli resistant to gentamicin, ciprofloxacin and/or third-generation cephalosporins. Those with resistant E. coli post-travel were tested monthly for persistent colonisation. Colonisation with antibiotic-resistant E. coli increased significantly from 7.8% (95% confidence interval [CI] 3.8-14.9) pre-travel to 49% (95% CI 39.5-58.6) post-travel. Those colonised were more likely to have taken antibiotics whilst travelling; however, travel remained a risk independent of antibiotic use. Colonisation with resistant E. coli occurred most frequently following travel to Asia. While over half of those carrying resistant E. coli post-travel had no detectable resistant strains two months after their return, at least 18% remained colonised at six months. Colonisation with antibiotic-resistant E. coli occurs commonly after international travel, and can be persistent. Medical practitioners should be aware of this risk, particularly when managing patients with suspected Gram-negative sepsis.

Human health consequences of use of antimicrobial agents in aquaculture.

Intensive use of antimicrobial agents in aquaculture provides a selective pressure creating reservoirs of drug-resistant bacteria and transferable resistance genes in fish pathogens and other bacteria in the aquatic environment. From these reservoirs, resistance genes may disseminate by horizontal gene transfer and reach human pathogens, or drug-resistant pathogens from the aquatic environment may reach humans directly. Horizontal gene transfer may occur in the aquaculture environment, in the food chain, or in the human intestinal tract. Among the antimicrobial agents commonly used in aquaculture, several are classified by the World Health Organisation as critically important for use in humans. Occurrence of resistance to these antimicrobial agents in human pathogens severely limits the therapeutic options in human infections. Considering the rapid growth and importance of aquaculture industry in many regions of the world and the widespread, intensive, and often unregulated use of antimicrobial agents in this area of animal production, efforts are needed to prevent development and spread of antimicrobial resistance in aquaculture to reduce the risk to human health.

Expanding CEP290 mutational spectrum in ciliopathies.

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

Serratia sp. bacteremia in Canberra, Australia: a population-based study over 10 years.

The purpose of this paper was to determine the population incidence and clinical features of Serratia sp. bacteremia in Canberra, Australia. Demographic and clinical data were collected prospectively for episodes of Serratia sp. bacteremia over a 10-year period, and was confined to Canberra residents using residential postal codes. Thirty-eight episodes of Serratia sp. bacteremia occurred, with a yearly incidence of 1.03 per 100,000 population. The majority of episodes occurred in males (68%). The respiratory tract was the most common focus of infection (21%). Twenty-nine percent of episodes were community-associated. A further 18% of episodes had their onset in the community but were healthcare-associated. The 7-day and 6-month mortality rates were 5 and 37%, respectively. Antibiotic resistance to gentamicin (3%) and ciprofloxacin (0%) was low. Serratia sp. bacteremia is more common than generally appreciated, with a large proportion (47%) of episodes having their onset in the community.

[Neonatal presentation of Prader-Willi syndrome: A report of five cases]. / Présentation néonatale du syndrome de Prader-Willi : à propos de 5 cas.

Prader-Willi syndrome (PWS) is a fingerprint disease caused by the loss of paternally inherited chromosome 15q11.2-q13. In several populations studied, prevalence is estimated to be from 1/10,000 to 1/25,000 births. The disease initially manifests by neonatal hypotonia associated with orality disorders. Secondly, hyperphagia appears with significant obesity and hypogonadism. Motor milestones and language development are delayed, and all individuals have variable degrees of cognitive disability during childhood. Frequently, the most prominent features do not become evident until the later childhood stage, which can lead to underdiagnosis or late diagnosis in early childhood. Because of the long-term implications of this syndrome, it is important to recognize its features as soon as possible so that early counseling of parents and the affected child is possible. The diagnosis is suspected on clinical grounds and confirmed by genetic analysis. Prenatal diagnosis is possible and can be considered in polyhydramnios, decreased fetal active movements, malpresentation, oddly positioned hands and feet, and abnormal fetal heart rhythm. Since PWS can also lead to complications in both pregnancy and labor, proper prenatal diagnosis can also help optimize perinatal care for affected children. We report a series of five newborns for whom PWS was diagnosed in the neonatal period over 6 years. During this period, no prenatal signs of PWS were detected. The incidence in our population was 1/7937 births. The disease was diagnosed on clinical criteria: severe hypotonia, failure to thrive with poor sucking, and dysmorphic and abnormalities of the genitalia. Polyhydramnios was observed in only one case. The delivery was normal for only one patient. All except one were term newborns. There were three males and two females. We noted abnormal fetal heart rate for 80 % of the patients. The birth weight was close to the 10th percentile for two patients, less than the 3rd percentile for two others. All individuals had eutrophic cranial perimeter and four presented peculiar position of fingers. Genetic analyses found a deletion of the paternal chromosome 15 in three patients (60 %) and maternal uniparental disomy for the two others (40 %). The distribution by sex, weight, cranial perimeter, and mutations are those reported in the literature. PWS should be sought in cases of severe neonatal hypotonia, most particularly if it combines dysmorphism, hypogonadism, malposition of the fingers, and suggestive prenatal history. An early diagnosis provides better multidisciplinary care for the patient and family. We have no explanation for the higher incidence of the disease than in the general population. It is possible that this incidence is only fortuitous, but further studies would help to identify potential risk factors for the disease.

Profound lymphopenia and bacteraemia.

Bacteraemia often carries a poor prognosis despite prompt antibiotic therapy and is associated with late morbidity and mortality that is difficult to explain. Here, we describe perisistent B- and T- cell lymphopenia in a cohort of patients with Gram-positive and Gram-negative bacteraemia. This suggests previously unrecognized mechanisms of subversion of immunity by pathogens and might explain the comorbidity of blood stream infection with bacteria.

Sequence family variant loss from the AZFc interval of the human Y chromosome, but not gene copy loss, is strongly associated with male infertility.

BACKGROUND: Complete deletion of the complete AZFc interval of the Y chromosome is the most common known genetic cause of human male infertility. Two partial AZFc deletions (gr/gr and b1/b3) that remove some copies of all AZFc genes have recently been identified in infertile and fertile populations, and an association study indicates that the resulting gene dose reduction represents a risk factor for spermatogenic failure. METHODS: To determine the incidence of various partial AZFc deletions and their effect on fertility, we combined quantitative and qualitative analyses of the AZFc interval at the DAZ and CDY1 loci in 300 infertile men and 399 control men. RESULTS: We detected 34 partial AZFc deletions (32 gr/gr deletions), arising from at least 19 independent deletion events, and found gr/gr deletion in 6% of infertile and 3.5% of control men (p>0.05). Our data provide evidence for two large AZFc inversion polymorphisms, and for relative hot and cold spots of unequal crossing over within the blocks of homology that mediate gr/gr deletion. Using SFVs (sequence family variants), we discriminate DAZ1/2, DAZ3/4, CDY1a (proximal), and CDY1b (distal) and define four types of DAZ-CDY1 gr/gr deletion. CONCLUSIONS: The only deletion type to show an association with infertility was DAZ3/4-CDY1a (p = 0.042), suggesting that most gr/gr deletions are neutral variants. We see a stronger association, however, between loss of the CDY1a SFV and infertility (p = 0.002). Thus, loss of this SFV through deletion or gene conversion could be a major risk factor for male infertility.

Rapid diagnosis of intravascular catheter-related sepsis.

The use of Gram-stained "impression smears" of the external surface of intravascular catheters for rapid detection of catheter-associated infection was studied. Gram's stain results of 322 catheters were correlated with clinical episodes of systemic sepsis and semiquantitative cultures of the catheters. Organisms were seen on Gram's stain of 82 catheters, 37 of which were positive on semiquantitative cultures (greater than or equal to 15 colonies per plate). Catheter-related bacteremia occurred on three occasions. All three catheters showed numerous organisms on Gram's stain, although one was negative on semiquantitative culture. All five catheters, in place during bacteremic episodes that were unrelated to catheter infection, were negative on Gram's stain. If the presence of any organisms on Gram's stain was taken as a positive test result, the sensitivity of Gram's stain in predicting the result of semiquantitative culture was 83%, the specificity was 81%, and the predictive value of a positive and negative culture was 44% and 96%, respectively. Slides took two to five minutes to examine microscopically. Gram-stained impression smears of intravenous catheters can be made by a simple, inexpensive, and rapid technique that is accurate in diagnosing catheter-related infection. However, in this study in which a relatively low prevalence of catheter-related bacteremia occurred, the positive predictive value of the Gram's stain result in the diagnosis of catheter-related bacteremia, in contrast to catheter colonization, was low. Only in a patient group with a high prevalence of catheter-related bacteremia would the test be likely to have a high positive predictive value. Thus, selectivity should be exercised in the application of this method.

[Cytochrome c oxydase-deficient Leigh syndrome with homozygous mutation in SURF1 gene]. / Syndrome de Leigh avec déficit en cytochrome c oxydase lié à une mutation homozygote du gène SURF1.

Leigh syndrome is a heterogeneous disorder, usually due to a defect in oxidative metabolism. Mutations in SURF1 gene have been identified in patients with cytochrome c oxidase deficiency. We report a homozygous splice site deletion [516-2_516-1delAG] in a young girl presenting with cytochrome c oxidase-deficient Leigh syndrome. Identification of molecular defect is indispensable for genetic counselling and prenatal diagnosis.

Allelic heterogeneity of SMARD1 at the IGHMBP2 locus.

Spinal Muscular Atrophy with Respiratory Distress (SMARD) is an autosomal recessive disorder characterized by neurogenic muscular atrophy due to progressive anterior horn cell degeneration and early life-threatening respiratory failure ascribed to diaphragmatic dysfunction. SMARD is clinically and genetically heterogeneous. SMARD type 1 is characterized by onset of respiratory failure within the first weeks of life and has been ascribed to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. We report here the identification of nine novel IGHMBP2 mutations in five SMARD1 patients, including seven missense [ c.587A>G (p.Gln196Arg), c.647C>T (p.Pro216Leu), c.752T>C (p.Leu251Pro), c.1693G>A (p.Asp565Asn), c.1730T>C (p.Leu577Pro), c.1807C>T (p.Arg603Cys), c.1909C>T (p.Arg637Cys)] and two nonsense mutations [ c.1488C>A (p.Cys496X), c.2368C>T (p.Arg790X)]. Interestingly, 7 of 9 mutations occurred at highly conserved residues of the putative DNA helicase domain. The identification of novel IGHMBP2 variants will hopefully help diagnosing SMARD1 and contribute to a better functional characterization of IGHMBP2 gene product.

Xenografts: are the risks so great that we should not proceed?

Animal organs could save patients needing transplants, but further research is necessary to resolve remaining problems with organ rejection. Furthermore, xenotransplantation risks transmitting animal pathogens to patients and to the general population. It would be unethical to proceed with clinical trials before principles and procedures for dealing with this risk are in place.

Hemodynamic effects of intravenous diltiazem with impaired left ventricular function.

The acute hemodynamic effects of intravenous diltiazem were studied in 8 patients with coronary artery disease, left ventricular (LV) failure (New York Heart Association functional class III), a rest ejection fraction (EF) less than 40% or a cardiac index less than 2.4 liters/min/m2. Hemodynamic measurements and LV angiograms were performed at rest before and after the administration of diltiazem, 0.5 mg/kg, administered at a speed of 5 mg/min. Diltiazem treatment induced a decrease in heart rate from 68 +/- 12 to 55 +/- 9 beats/min (p less than 0.001). Mean aortic pressure decreased from 94 +/- 14 to 81 +/- 15 mmHg (p less than 0.05). Thus, the pressure-rate product significantly decreased under the influence of the drug, from 8,791 +/- 2,465 to 6,342 +/- 1,808 beats mm Hg/min, (p less than 0.001). Diltiazem induced no significant change of LV end-diastolic pressure, pulmonary wedge pressure, cardiac index and LV stroke work index. Systemic vascular resistance decreased (p less than 0.01), whereas pulmonary vascular resistance showed no change. End-systolic volume diminished (p less than 0.02), which accounts for the increase of stroke volume and ejection fraction (p less than 0.001). Disorders of regional contractility were not aggravated by diltiazem, and even improved in individual cases. Thus, intravenous diltiazem may be used safely in patients with heart failure. However, in view of the marked bradycardic effects seen in some cases, heart rate should be carefully monitored.

Hemodynamic effects of a new antiarrhythmic agent, flecainide (R-818), in coronary heart disease.

The hemodynamic effects of flecainide acetate, a new class I antiarrhythmic agent, were studied in 10 patients with coronary heart disease. The drug was injected intravenously at a dose of 2 mg/kg over 30 minutes. The mean drug plasma level achieved was 394 ng/ml (range 329 to 470). The heart rate did not change, but a significant increase (p less than 0.001) in P-R (+17%), QRS (+15%), and Q-T (+7%) duration occurred after drug administration. Negative inotropic effects also were observed and consisted of an increase (p less than 0.01) in pulmonary wedge pressure (+27%) and a decrease (p less than 0.01) in stroke index (-10%), left ventricular stroke work index (-12%), and left ventricular ejection rate (-11%). No significant change in mean aortic pressure or systemic and pulmonary vascular resistance occurred. Left ventriculography performed after drug infusion revealed a significant increase (p less than 0.01) in systolic volume (+9%) and a decrease in ejection fraction (-9%) and mean velocity of circumferential fiber shortening (Vcf) (-13%). A progressive and significant decrease of dP/dt was observed during drug infusion, but 15 minutes after the injection, dP/dt had returned to near basal values. Thus, flecainide acetate has slight, but significant negative inotropic effects, particularly conspicuous during drug infusion. The drug should be administered with caution in patients with poorly compensated heart.