Cognitive outcome in congenital central hypothyroidism: a systematic review with meta-analysis of individual patient data.

Objective: To provide an overview of cognitive and motor outcome, and quality of life (QoL) in patients with congenital central hypothyroidism (CH-C). Design: Systematic review with individual patient data (IPD) meta-analysis. Methods: OVID MEDLINE, EMBASE and PsycInfo were searched from inception to June 11th, 2019. Studies in patients with CH-C, either isolated or with multiple pituitary hormone deficiency (MPHD), were included if CH-C patients could be separated from any additional patient groups. Primary outcomes were full-scale intelligence quotient (FSIQ) and motor outcome; secondary outcome was QoL. Following data-extraction, one-stage IPD meta-analysis was performed, fitting a linear mixed model with FSIQ as dependent variable. Random intercepts were fitted for each study. Results: Six studies measuring FSIQ were eligible for meta-analysis, comprising 30 CH-C patients (20 males; 27 MPHD patients). FSIQ range was wide (64-123). Mean weighted FSIQ was 97 (95% CI: 88-105). Twenty-seven percent had an FSIQ below 85 (≥1 s.d. below norm score), and 10% below 70 (≥2 s.d. below norm score). There was no significant association between FSIQ and sex or age. Age at treatment initiation was available from three studies only, thus impeding a reliable analysis of this parameter. Motor outcome and QoL were each studied in one study; no quantitative analyses could be performed for these outcomes. Conclusion: A wide range in FSIQ scores was observed in CH-C patients. Results should be interpreted with caution, because included patients mainly had MPHD and age at treatment initiation was unknown for the majority of patients.

Combination of Amphotericin B and Terbinafine against Melanized Fungi Associated with Chromoblastomycosis.

Our in vitro studies showed that a combination of amphotericin B and terbinafine had synergistic effects against the majority of melanized fungi associated with chromoblastomycosis (CBM) and similar infections, including those with Cladophialophora carrionii, Cladophialophora arxii, Exophialadermatitidis, Exophialaspinifera, Fonsecaea monophora, Fonsecaea nubica, Fonsecaea pedrosoi, and Phialophora verrucosa. This drug combination could provide an option for the treatment of severe or unresponsive cases of CBM, particularly in cases due to species of Fonsecaea and Cladophialophora.

Single-Center Evaluation of an Agar-Based Screening for Azole Resistance in Aspergillus fumigatus by Using VIPcheck.

Antifungal susceptibility testing is an essential tool for guiding therapy, although EUCAST and CLSI reference methods are often available only in specialized centers. We studied the performance of an agar-based screening method for the detection of azole resistance in Aspergillus fumigatus cultures. The VIPcheck consists of four wells containing voriconazole, itraconazole, posaconazole, or a growth control. Ninety-six A. fumigatus isolates were used. Thirty-three isolates harbored a known resistance mechanism: TR34/L98H (11 isolates), TR46/Y121F/T289A (6 isolates), TR53 (2 isolates), and 14 isolates with other cyp51A gene point mutations. Eighteen resistant isolates had no cyp51A-mediated azole resistance. Forty-five isolates had a wild-type (WT) azole phenotype. Four technicians and two inexperienced interns, blinded to the genotype/phenotype, read the plates visually after 24 h and 48 h and documented minimal growth, uninhibited growth, and no growth. The performance was compared to the EUCAST method. After 24 h of incubation, the mean sensitivity and specificity were 0.54 and 1.00, respectively, with uninhibited growth as the threshold. After 48 h of incubation, the performance mean sensitivity and specificity were 0.98 and 0.93, respectively, with minimal growth. The performance was not affected by observer experience in mycology. The interclass correlation coefficient was 0.87 after 24 h and 0.85 after 48 h. VIPcheck enabled the selection of azole-resistant A. fumigatus colonies, with a mean sensitivity and specificity of 0.98 and 0.93, respectively. Uninhibited growth on any azole-containing well after 24 h and minimal growth after 48 h were indicative of resistance. These results indicate that the VIPcheck is an easy-to-use tool for azole resistance screening and the selection of colonies that require MIC testing.

Point-of-use filtration method for the prevention of fungal contamination of hospital water.

Published data implicate hospital water as a potential source of opportunistic fungi that may cause life-threatening infections in immunocompromised patients. Point-of-care filters are known to retain bacteria, but little is known about their efficacy in reducing exposure to moulds. We investigated the effect of point-of-use filters (Pall-Aquasafe) on the level of contamination of Aspergillus fumigatus and other filamentous fungi. The point-of-use filters were applied to several outlets (taps and showers) on the paediatric bone marrow transplantation (BMT) unit of the National Hospital in Oslo, Norway. In addition the efficacy was investigated using a test rig. The laboratory experiments showed that the filters were highly effective in reducing the number of colony-forming units for a period of at least 15 days. In the BMT unit the filters eliminated the fungi from the water on day 1 but due to particles present in the water the filters occluded, which prevented further evaluations. Our results show that point-of-use filtration might be an effective preventive measure to eliminate filamentous fungi at individual points of water use, thereby reducing patients' exposure.

Circulating Candida-specific anti-mannan antibodies precede invasive candidiasis in patients undergoing myelo-ablative chemotherapy.

The kinetics of circulating Candida mannan and anti-mannan antibodies were studied in consecutive plasma samples, obtained upon hospital admission, of 21 patients with microbiologically proven invasive candidiasis and 30 control patients who underwent myelo-ablative chemotherapy. The detection of Candida anti-mannan antibodies preceded the diagnosis of invasive candidiasis in infected patients, and the antibodies were detected significantly more often in patients who had experienced multiple episodes of neutropenia than in the control group (OR 8.9, 95% CI 5.6-14.3; p <0.05). Mannan was predominantly detected in patients who developed invasive candidiasis during their first episode of neutropenia (OR 3.7, 95% CI 1.4-9.7; p <0.05). This observation suggests that patients with multiple episodes of neutropenia have been previously exposed to Candida and that the presence of anti-mannan antibodies in these patients might be associated with an increased risk of developing clinically manifest invasive candidiasis.

Effect of pH on the in vitro activities of amphotericin B, itraconazole, and flucytosine against Aspergillus isolates.

The in vitro susceptibilities of 21 Aspergillus isolates were tested against three antifungal agents in RPMI 1640 and yeast nitrogen base at pH 5.0 and 7.0 by a broth microdilution format of the NCCLS method. The MICs of amphotericin B and itraconazole were higher, while those of flucytosine were lower, at pH 5.0 than at pH 7.0. The poor correlation between in vitro results and clinical outcome could be due to a difference in pH between the in vitro susceptibility test and at the site of infection.

Interactions of Yersinia enterocolitica with polarized human intestinal Caco-2 cells.

The in vitro interactions of Yersinia enterocolitica, Salmonella typhimurium and Escherichia coli with polarized human colonic carcinoma (Caco-2) cells are described. Invasion of a confluent Caco-2 cell monolayer by Yersinia and Salmonella took place within 4 h after contact, which was in marked contrast to E. coli which did not invade Caco-2 cells. Cytoplasmic extrusions developed on the apical membrane and indicated the site of entrance of bacteria into the Caco-2 cells. Intracellular Yersinia and Salmonella were surrounded by a vacuolar membrane. Single as well as multiple bacteria were enclosed within a single vacuole. At 6 h after contact some of the intracellular yersiniae were found free in the cytoplasm. Furthermore, morphological signs of degeneration of Caco-2 cells such as vacuolization and autophagy were observed. Caco-2 cells infected with Salmonella also showed degenerative changes but the salmonellae resided within membrane-bound vacuoles in contrast to Yersinia. These observations are in contrast to those described for the invasion of other cells lines (not derived from intestinal epithelium) by Yersinia and may reflect more closely the interactions between Yersinia and the intestinal epithelium during gastrointestinal infection.

Persistent Yersinia enterocolitica infection in three rat strains.

Yersinia enterocolitica may persist for prolonged periods of time in humans sometimes resulting in the development of reactive arthritis. To elucidate factors predisposing for persistence we developed animal models. In Lewis and Fischer rats, viable bacteria could be demonstrated for prolonged time and abscesses could be found in the liver, spleen and lungs. Splenic abscesses were observed for more than 20 weeks. Yersinia enterocolitica persisted in Lewis and Fischer rats, but only Lewis rats developed reactive arthritis. In Brown Norway rats abscesses developed early during infection but in contrast to the other strains disappeared after 3 weeks. Culture of homogenized abscess-containing tissue of all three rat strains yielded Yersiniae. Immunofluorescence studies of the abscesses showed diffuse staining inside the abscesses only, indicating the presence of Yersinia enterocolitica antigen. Brown Norway rats, in contrast to Lewis and Fischer rats, developed a different serological reaction pattern against Yersinia enterocolitica antigens and this correlated with the disappearance of the abscesses.

Increased expression of a 68-kDa protein in the corpus cavernosum of some men with erectile dysfunction.

Erectile dysfunction (ED) may be caused by abnormalities of intracavernous penile structures. In order to investigate whether specific proteins could be identified that might be related to ED, the composition of structural proteins in cavernous tissues of patients with ED was compared to that of normal cavernous tissues by gel electrophoresis. Increased expression of a 68-kDa nonionic detergent extraction-resistant protein was demonstrated in tissues of more than half of the patients with vasculogenic ED, whereas only one out of nine normal cavernous tissues showed the same phenomenon. Increased expression was not related to a specific type of vascular insufficiency, aging, or diabetic constituency. Histochemical and immunochemical studies revealed that the increased amount of the 68-kDa protein is not merely the result of a surplus of nervous, smooth muscle, or elastic tissues. Furthermore, antibodies specific for 68-kDa neurofilament and 62- to 67.5-kDa tropoelastin did not recognize the 68-kDa protein on Western blots. The possibility that the 68-kDa protein may help us understand the etiology of certain cases of erectile dysfunction is discussed.