Salvage strategy for long-term central venous catheter-associated Staphylococcus aureus infections in children: a multi-centre retrospective study in France.

OBJECTIVES: Catheter removal is recommended in adults with Staphylococcus aureus central-line-associated bloodstream infection (CLABSI) but is controversial in children with long-term central venous catheters (LTCVC). We evaluated the occurrence of catheter salvage strategy (CSS) in children with S. aureus LTCVC-associated CLABSI and assessed determinants of CSS failure. METHODS: We retrospectively included children (<18 years) with an LTCVC and hospitalized with S. aureus CLABSI in eight French tertiary-care hospitals (2010-2018). CSS was defined as an LTCVC left in place ≥72 h after initiating empiric antibiotic treatment for suspected bacteraemia. Characteristics of patients were reviewed, and multi-variable logistic regression was performed to identify factors associated with CSS failure (i.e., persistence, recurrence or complications of bacteraemia). RESULTS: We included 273 episodes of S. aureus LTCVC-associated CLABSI. CSS was chosen in 194 out of 273 (71%) cases and failed in 74 of them (38%). The main type of CSS failure was the persistence of bacteraemia (39 of 74 cases, 53%). Factors independently associated with CSS failure were: history of catheter infection (adjusted odds ratio (aOR) 3.18, 95% confidence interval (CI) 1.38-7.36), CLABSI occurring on an implantable venous access device (aOR 7.61, 95% CI 1.98-29.20) when compared with tunnelled-cuffed CVC, polymicrobial CLABSI (aOR 3.45, 95% CI 1.25-9.50), and severe sepsis at the initial stage of infection (aOR 4.46, 95% CI 1.18-16.82). CONCLUSIONS: CSS was frequently chosen in children with S. aureus LTCVC-associated CLABSI, and failure occurred in one-third of cases. The identified risk factors may help clinicians identify children at risk for CSS failure.

Association between advanced paternal age and congenital heart defects: a systematic review and meta-analysis.

STUDY QUESTION: Is there an association between advanced paternal age and congenital heart defects (CHD)? SUMMARY ANSWER: Advanced paternal age is associated with a 16% increase in the overall odds of CHD. WHAT IS KNOWN ALREADY: CHD are the most common congenital malformations. Several risk factors for CHD have been identified in the literature, but the association between advanced paternal age and CHD remains unclear. STUDY DESIGN, SIZE, DURATION: We conducted a systematic literature search on MEDLINE and EMBASE (1960-2019) to identify studies assessing the association between advanced paternal age (≥35 years) and the risk of CHD, unrestrictive of language or sample size. We used a combination of Medical Subject Headings (MeSH) terms and free text words such as 'paternal age', 'paternal factors', 'father's age', 'parental age', 'heart', 'cardiac', 'cardiovascular', 'abnormalities, congenital', 'birth defects', 'congenital malformations' and 'congenital abnormalities'. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included observational studies aiming at assessing the association between paternal age and CHD. The included population could be live births, fetal deaths and terminations of pregnancy for fetal anomaly. To be included, studies had to provide either odds ratios (OR) with their 95% confidence interval (CI) or sufficient information to recalculate ORs with 95% CIs per paternal age category. We excluded studies if they had no comparative group and if they were reviews or case reports. Two independent reviewers selected the studies, extracted the data and assessed risk of bias using a modified Newcastle-Ottawa Scale. We used random-effects meta-analysis to produce summary estimates of crude OR. Associations were also tested in subgroups. MAIN RESULTS AND THE ROLE OF CHANCE: Of 191 studies identified, we included nine studies in the meta-analysis (9 917 011 participants, including 34 447 CHD), including four population-based studies. Five studies were judged at low risk of bias. Only one population-based study specifically investigated isolated CHD. The risk of CHD was higher with advanced paternal age (summary OR 1.16, 95% CI, 1.07-1.25). Effect sizes were stable in population-based studies and in those with low risk of bias. LIMITATIONS AND REASONS FOR CAUTION: The available evidence did not allow to assess (i) the risk of isolated CHD in population-based studies, (ii) the association between paternal age and the risk for specific CHD and (iii) the association between paternal age and CHD after adjustment for other risk factors, such as maternal age. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that advanced paternal age may be a risk factor for CHD. However, because the association is modest in magnitude, its usefulness as a criterion for targeted screening for CHD seems limited. STUDY FUNDING/COMPETING INTEREST(S): None. PROSPERO REGISTRATION NUMBER: CRD42019135061.

Diagnostic accuracy of serum (1,3)-beta-d-glucan for neonatal invasive candidiasis: systematic review and meta-analysis.

OBJECTIVES: Neonatal invasive candidiasis (NIC) is a leading cause of infection-related morbidity and mortality in preterm neonates. Several studies have shown that (1,3)-Beta-d-glucan (BDG) was accurate in detecting invasive fungal infection in adults, but studies in neonates are scarce. The aim was to obtain summary estimates of the accuracy of BDG detection in serum for the diagnosis of NIC. METHODS: We searched Medline, Embase, Clinicaltrials.gov, and Google Scholar (inception to July 2019). We checked the reference lists of included studies, clinical guidelines, and review articles. We included studies that assessed the accuracy of BDG against a reference standard that defined groups of patients with ordinal levels of NIC probability (e.g. proven, probable, possible) and included fungal blood culture. Participants were neonates suspected of having NIC. The intervention was BDG measurement in serum (Fungitell® assay). We assessed risk of bias and applicability using QUADAS-2. We used bivariate meta-analysis to produce summary estimates of diagnostic accuracy at prespecified positivity thresholds of 80 and 120 pg/mL. This study was registered with PROSPERO (CRD42018089545). RESULTS: We included eight studies (465 participants). Of these, two were judged at low overall risk of bias. There was substantial variability across studies in the reference standards used. At a positivity threshold of 80 pg/mL, summary estimates of sensitivity and specificity of BDG were 89% (95% CI: 80-94%) and 60% (53-66%), respectively; summary sensitivity for detecting proven cases of NIC was 99% (93-100%). At a positivity threshold of 120 pg/mL, summary estimates of sensitivity and specificity were 81% (71-88%) and 80% (67-88%), respectively. CONCLUSIONS: Because of high sensitivity, BDG seems promising to rule-out NIC. It might be too early to recommend its use because of the scarcity of reliable clinical data, heterogeneity in case definitions, and unstable accuracy estimates.

The effect of healthy dietary consumption on executive cognitive functioning in children and adolescents: a systematic review.

A systematic review was conducted to evaluate whether healthier dietary consumption among children and adolescents impacts executive functioning. PubMed, Education Resources Information Center, PsychINFO and Thomson Reuters' Web of Science databases were searched, and studies of executive functioning among children or adolescents aged 6-18 years, which examined food quality, macronutrients and/or foods, were included. Study quality was also assessed. In all, twenty-one studies met inclusion criteria. Among the twelve studies examining food quality (n 9) or macronutrient intakes (n 4), studies examining longer-term diet (n 6) showed positive associations between healthier overall diet quality and executive functioning, whereas the studies examining the acute impact of diet (n 6) were inconsistent but suggestive of improvements in executive functioning with better food quality. Among the ten studies examining foods, overall, there was a positive association between healthier foods (e.g. whole grains, fish, fruits and/or vegetables) and executive function, whereas less-healthy snack foods, sugar-sweetened beverages and red/processed meats were inversely associated with executive functioning. Taken together, evidence suggests a positive association between healthy dietary consumption and executive functioning. Additional studies examining the effects of healthier food consumption, as well as macronutrients, on executive functioning are warranted. These studies should ideally be conducted in controlled environments and use validated cognitive tests.

Effect of clinical spectrum, inoculum size and physician characteristics on sensitivity of a rapid antigen detection test for group A streptococcal pharyngitis.

We aimed to assess the independent effect of clinical spectrum, bacterial inoculum size and physician characteristics on the sensitivity of a rapid antigen detection test (RADT) for group A streptococcus (GAS) in children. Double throat swabs were collected from 1,482 children with pharyngitis and 294 asymptomatic children in a French prospective, office-based, multicenter (n = 17) study, from October 2009 to May 2011. Patient- and physician-level factors potentially affecting RADT sensitivity were studied by univariate and multivariate multilevel analysis, with laboratory throat culture as the reference test. In children with pharyngitis and asymptomatic children, the prevalence of GAS was 38 % (95 % confidence interval 36-41 %) and 11 % (7-14 %), respectively. Overall, RADT sensitivity was 87 % (84-90 %). On stratified and multivariate multilevel analysis, RADT sensitivity was higher for children with pharyngitis than asymptomatic children (89 % vs. 41 %), children <9 than ≥ 9 years old (88 % vs. 79 %) and those with heavy than light inoculum (94 % vs. 53 %). RADT sensitivity was influenced by the physician performing the test (range 56-96 %, p = 0.01) and was higher for physicians with hospital-based clinical activity in addition to office-based practice (adjusted odds ratio 3.4 [95 % confidence interval 1.9-6.3], p < 0.001); inter-physician variations in RADT sensitivity were largely explained by this variable (proportional change in variance >99 %). The sensitivity of the RADT is independently affected by patient- and physician-level factors. Physicians who base their diagnosis of GAS pharyngitis on the results of a RADT alone should consider diagnostic accuracy monitoring and adequate training when needed.

N-Terminal dipeptides of D(-)-penicillamine as sequestration agents for acetaldehyde.

Since acetaldehyde (AcH), a toxic oxidation product of ethanol, may play an etiologic role in the initiation of alcoholic liver disease, we had earlier pioneered the development of beta, beta-disubstituted-beta-mercapto-alpha-amino acids as AcH-sequestering agents. We now report the synthesis of a series of N-terminal dipeptides of D(-)-penicillamine, prepared from the synthon 3-formyl-2,2,5,5-tetramethylthiazolidine-4S-carboxylic acid (3), a cyclized N-protected derivative of D(-)-penicillamine. These dipeptides were equally or more effective than penicillamine in trapping AcH in a cell-free system. In experiments using a hepatocyte culture system, two of the dipeptides, D-penicillamylglycine (6a) and D-penicillamyl-beta-alanine (6d), at 1/20 the molar concentration of ethanol, lowered the concentration of ethanol-derived AcH by 79% and 84%, respectively, at 2 h. The presence of cyanamide (an inhibitor of aldehyde dehydrogenase) in the incubation medium resulted in a 45-fold increase in ethanol-derived AcH; nevertheless, dipeptides 6a and 6c (D-penicillamyl-alpha-aminoisobutyric acid) were able to reduce this AcH level by approximately one-third.

Augmentation of human and rat lenticular glutathione in vitro by prodrugs of gamma-L-glutamyl-L-cysteine.

A marked age-related decrease in glutathione (GSH) levels as well as depression of gamma-glutamylcysteine synthetase activity are factors that are believed to render the aged lens more susceptible to oxidative stress and, therefore, to cataractogenesis. Providing gamma-L-glutamyl-L-cysteine, the dipeptide precursor of GSH, would effectively bypass the compromised first step in its biosynthesis and should protect the lens from GSH depletion. Accordingly, some bioreversible sulfhydryl-, amino-, and C-terminal carboxyl-protected prodrug forms of this dipeptide were prepared. Sulfhydryl protection was in the form of an acetyl thioester, while the carboxyl group was protected as the ethyl ester. These prodrugs were evaluated for their GSH-enhancing activity in cultured human and rat lenses in vitro using an assay that measured the incorporation of [14C]glycine into lens GSH. Ethyl S-acetyl-gamma-L-glutamyl-L-cysteinate (2) raised GSH levels in human lenses by 25% and in rat lenses by >150%. These data suggest that 2 may have potential as an anticataract agent since ethyl gamma-L-glutamyl-L-cysteinate (1a), the des-S-acetyl analog of 2, had been shown (by others) to protect against experimental rodent cataracts. GSH augmentation by 1a was 2% in human lenses and 25% in rat lenses, considerably less than that shown by 2.

Prevention of acetaminophen- and naphthalene-induced cataract and glutathione loss by CySSME.

PURPOSES: To assess the efficacy of 2-mercaptoethanol/L-cysteine mixed disulfide (CySSME) as an L-cysteine prodrug suitable for glutathione biosynthesis in rat lenses in vitro, as an agent for the prevention of acetaminophen- and naphthalene-induced murine cataract in genetically-susceptible mice, and as an agent for maintenance of near-normal glutathione levels in lenses and livers of mice subjected to acetaminophen and naphthalene at cataractogenic doses. METHODS: Synthetic CySSME was added as a prodrug to rat lens culture medium devoid of L-cystine and L-methionine but containing [14C(U)]-glycine. After a 48-hour period of incubation, extracts of rat lenses were prepared for separation of [14C]-glutathione by high-performance liquid chromatography (HPLC) with a radioisotope detector to determine the extent of its biosynthesis. Cytochrome P-450 isozymes were induced in C57 bl/6 mice by either beta-naphthoflavone or phenobarbital. Cataracts were induced by administration of either acetaminophen or naphthalene to the pretreated mice. CySSME was coadministered with either acetaminophen or naphthalene to other groups of mice. Both oxidized and reduced glutathione were determined in extracts of livers and lenses using the HPLC method above. RESULTS: CySSME served as an effective L-cysteine precursor for glutathione biosynthesis in cultured rat lenses. This L-Cysteine prodrug was also highly effective in preventing acetaminophen- and naphthalene-induced cataract in mice and in maintaining near-normal glutathione levels in lenses and livers of such treated animals. CONCLUSIONS: This investigation demonstrates that maintenance of adequate physiological levels of glutathione in the presence of specific known cataractogenic agents by pharmacologic intervention with CySSME, an L-cysteine prodrug, is sufficient to prevent cataract formation.

Protection against acetaminophen-induced hepatotoxicity by L-CySSME and its N-acetyl and ethyl ester derivatives.

We have recently observed that S-(2-hydroxyethylmercapto)-L-cysteine (L-CySSME), the mixed disulfide of L-cysteine and 2-mercaptoethanol, prevented cataracts induced in mice by acetaminophen (ACP) by functioning as a prodrug of L-cysteine and protecting the liver. This prompted the evaluation of the more lipophilic N-acetyl (Ac-CySSME) and ethyl ester (Et-CySSME) derivatives of L-CySSME as proprodrug forms, as well as the "D" enantiomer, as hepatoprotective agents. Serum ALT levels were measured at 24 hours after a toxic but nonlethal dose of ACP that insured 48 hour survival of the animals. Since the increases in ALT produced were highly variable (even after log transformation) and complicated the statistical analyses, we calculated confidence intervals for the mean ALT levels for each treatment group. This enabled comparisons to be made of the efficacy of L-CySSME as well as Ac-CySSME and Et-CySSME with other representative prodrugs of L-cysteine, namely, 2(RS)-methylthiazolidine-4(R)-carboxylic acid (MTCA), L-2-oxothiazolidine-4-carboxylic acid (OTCA), and N-acetyl-L-cysteine (NAC), in protecting the liver. It was shown that L-CySSME and MTCA administered intraperitoneally at 2.5 mmol/kg were superior to the other cysteine prodrugs at equimolar doses in protecting mice from hepatotoxicity elicited by a 400 mg/kg (2.65 mmol/kg) dose of ACP given i.p. 30 minutes prior to the prodrugs. The "D" form of CySSME was totally without protective effect. Oral doses of the prodrugs even at 2x the i.p. dose were less effective, although MTCA was the most protective.

Services for teenage pregnancy: provider perspectives.

PIP: The data on which the present work is based derive from a study was undertaken from 11/80-6/81 under the auspices of Community Health Information and Planning Services, Inc., (CHIPS), a sub-area council of the Central New York Health Systems Agency. This study surveyed 25 organizations servicing adolescents in Onondaga County in New York State and was designed to gather more comprehensive information about the magnitude of the adolescent pregnancy problem, the services provided in the county for high-risk teenagers, and the extent of coordination among these services. The results of this research project have deomnstrated that providers have responded to the problem of teenage pregnancy by offering a wider variety of services but that there are many gaps in these services due mainly to inadequate financing which affects personnel, facilities and medical care. Given the present moral and financial constraints, service delivery systems for adolescents must emphasis the need for augmenting prevention. More specifically, those efforts should include the availability of comprehensive family life education at all grade levels. In addition, it is deemed necessary to place emphasis on systemwide management strategies, communications, and coordination activites. It is more important than ever to use all existing resources efficiently and advantageously, and to create linkages among program services. It is also recommended that a system be established with the medical society's full support to encourage private physicians to assume greater responsibility in providing services to adolescents including sliding fee schedules, counseling, and direct and continuing participation with referral agencies. A wider data base of a comparative nature is needed to provide specific detail in depth and therefore maximize the validity of the results of this study.^ieng