Search

Objective To describe clinical, laboratory, and genetic characteristics of three unrelated cases from Chile, Portugal, and Saudi Arabia with severe insulin resistance, SOFT syndrome, and biallelic pathogenic POC1A variants. Design Observational study. Methods Probands’ phenotypes, including short stature, dysmorphism, and insulin resistance, were compared with previous reports. Results Cases 1 (female) and 3 (male) were homozygous for known pathogenic POC1A variants: c.649C>T, p.(Arg217Trp) and c.241C>T, p.(Arg81*), respectively. Case 2 (male) was compound heterozygous for p.(Arg217Trp) variant and the rare missense variant c.370G>A, p.(Asp124Asn). All three cases exhibited severe insulin resistance, acanthosis nigricans, elevated serum triglycerides and decreased HDL, and fatty liver, resembling three previously reported cases. All three also reported severe muscle cramps. Aggregate analysis of the six known cases with biallelic POC1A variants and insulin resistance showed decreased birth weight and length mean (s.d.): −2.8 (0.9) and −3.7 (0.9) SDS, respectively), severe short stature mean (s.d.) height: −4.9 (1.7) SDS) and moderate microcephaly (mean occipitofrontal circumference −3.0 (range: −4.7 to −1.2)). These findings were similar to those reported for patients with SOFT syndrome without insulin resistance. Muscle biopsy in Case 3 showed features of muscle involvement secondary to a neuropathic process. Conclusions Patients with SOFT syndrome can develop severe dyslipidaemic insulin resistance, independent of the exonic position of the POC1A variant. They also can develop severe muscle cramps. After diagnosis, patients should be regularly screened for insulin resistance and muscle complaints.

Background Escherichia coli sequence type ST131 is a recently emerged worldwide pandemic clonal group. Antibiotic resistance, virulence factors or colonisation fitness are mentioned among other as possible factors contributing to the worldwide success. In this study, we assessed the duration of rectal ESBL- producing E. coli colonisation in the residents, and compare duration of colonisation for ESBL-ST131 versus ESBL-non-ST131.MethodsRectal or faecal samples were obtained from residents of nursing home A between 2013 and 2019 and nursing home B between 2017 and 2019, with repeated point prevalence surveys at intervals of three to six months. Extended-spectrum β-lactamase (ESBL)-producing strains of E. coli were identified on selective culture and selective enrichment broth, and examined by antimicrobial susceptibility testing. In nursing home A multilocus sequence typing (MLST) and cluster analyse was performed by respectively O25:ST131-specific PCR and amplified fragment length polymorphism (AFLP). In nursing home B whole genome sequencing data were used to determine MLST and to perform a cluster analyse. Kaplan Meier survival analysis was performed to calculate the median time of rectal colonisation of ESBL-EC with a Log-Rank analysis to test for differences between ESBL-ST131 and ESBL-non-ST131.ResultsA total of 144 residents were included: 84 residents (58%) with ESBL-ST131 rectal colonisation and 60 residents (42%) with ESBL-non-ST131 rectal colonisation. Survival analysis showed a median colonisation length of 13 months for ESBL-ST131 (95%CI: 7,2 – 18,7) versus 8,3 months (95%CI: 2,8 – 13,8) for ESBL-non-ST131 (p = 0,028). Remarkably, in the subgroup ST131 the median colonisation length was significantly longer in female than in males: 25,7 months versus 8,1 months (p = 0,013).ConclusionHere we found a prolonged colonisation duration of ESBL-ST131 compared to ESBL-non-ST131 in residents of Dutch nursing homes. Prolonged colonisation duration complicates the controlling and ending an ESBL-ST131 outbreak, especially in long stay settings such as nursing homes.

Contains fulltext : 218925.pdf (Publisher’s version ) (Open Access) NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course. 01 april 2020

OBJECTIVERisk factors for rectal carriage of ESBL-E and transmission were investigated in an outbreak of extended-spectrum β-lactamase–producing Enterobacteriaceae (ESBL-E).DESIGNRectal carriage of ESBL-E was determined in a cross-sectional survey by culture of perianal swabs or fecal samples. Both phenotypical and genotypical methods were used to detect the production of ESBL. Nosocomial transmission was defined as the presence of genotypically related strains in ≥2 residents within the NH. Patient characteristics and variables in infection control practices were registered to investigate risk factors for transmission.SETTINGA nursing home (NH) in the southern Netherlands.PARTICIPANTSOf 189 residents, 160 residents (84.7%) were screened for ESBL-E carriage. Of these 160 residents, 33 (20.6%) were ESBL-E positive. ESBL carriage rates varied substantially between wards (range, 0–47%). Four different ESBL-E clusters were observed. AblaCTX-M1-15positiveE. coliST131 constituted the largest cluster (n=21) and was found in multiple wards (n=7).RESULTSOur investigation revealed extensive clonal dissemination ofblaCTX-M1-15-positiveE. coliST131 in a nursing home. Unexplained differences in ESBL prevalence were detected among the wards.CONCLUSIONSAs NHs constitute potential sources of multidrug-resistant bacteria, it is important to gain a better understanding of the risks factors and routes of transmission of ESBL-E.Infect Control Hosp Epidemiol 2014;00(0): 1–7

Chudley-McCullough syndrome (CMS) is characterized by profound sensorineural hearing loss and brain anomalies. Variants in GPSM2 have recently been reported as a cause of CMS by Doherty et al. In this study we have performed exome sequencing of three CMS patients from two unrelated families from the same Dutch village. We identified one homozygous frameshift GPSM2 variants c.1473delG in all patients. We show that this variant arises from a shared, rare haplotype. Since the c.1473delG variant was found in Mennonite settlers, it likely originated in Europe. To support DNA diagnostics, we established an LOVD database for GPSM2 containing all variants thus far described.

Genomic sequence interpretation can miss clinically relevant missense variants for several reasons. Rare missense variants are numerous in the exome and difficult to prioritise. Affected genes may also not have existing disease association. To improve variant prioritisation, we leverage population exome data to identify intragenic missense-depleted regions (MDRs) genome-wide that may be important in disease. We then use missense depletion analyses to help prioritise undiagnosed disease exome variants. We demonstrate application of this strategy to identify a novel gene association for human brain malformation. We identified de novo missense variants that affect the GDP/GTP-binding site of ARF1 in three unrelated patients. Corresponding functional analysis suggests ARF1 GDP/GTP-activation is affected by the specific missense mutations associated with heterotopia. These findings expand the genetic pathway underpinning neurologic disease that classically includes FLNA. ARF1 along with ARFGEF2 add further evidence implicating ARF/GEFs in the brain. Using functional ontology, top MDR-containing genes were highly enriched for nucleotide-binding function, suggesting these may be candidates for human disease. Routine consideration of MDR in the interpretation of exome data for rare diseases may help identify strong genetic factors for many severe conditions, infertility/reduction in reproductive capability, and embryonic conditions contributing to preterm loss.

We describe an outbreak of methicillin-resistant Staphybcoccus aureus (MRSA) ST398 in a nursing home in the Netherlands. Seven residents and 4 healthcare workers were identified with MRSA ST398, but 2 of the healthcare workers carried other strains. This study demonstrates that MRSA ST398 can spread in nursing homes.

The clinical use of array comparative genomic hybridization in the evaluation of patients with multiple congenital anomalies and/or mental retardation has recently led to the discovery of a number of novel microdeletion and microduplication syndromes. We present four male patients with overlapping molecularly defined de novo microdeletions of 16q24.3. The clinical features observed in these patients include facial dysmorphisms comprising prominent forehead, large ears, smooth philtrum, pointed chin and wide mouth, variable cognitive impairment, autism spectrum disorder, structural anomalies of the brain, seizures and neonatal thrombocytopenia. Although deletions vary in size, the common region of overlap is only 90 kb and comprises two known genes, Ankyrin Repeat Domain 11 (ANKRD11) (MIM 611192) and Zinc Finger 778 (ZNF778), and is located approximately 10 kb distally to Cadherin 15 (CDH15) (MIM 114019). This region is not found as a copy number variation in controls. We propose that these patients represent a novel and distinctive microdeletion syndrome, characterized by autism spectrum disorder, variable cognitive impairment, facial dysmorphisms and brain abnormalities. We suggest that haploinsufficiency of ANKRD11 and/or ZNF778 contribute to this phenotype and speculate that further investigation of non-deletion patients who have features suggestive of this 16q24.3 microdeletion syndrome might uncover other mutations in one or both of these genes.

Contains fulltext : 137420.pdf (Publisher’s version ) (Open Access) BACKGROUND: We developed a standardised method to assess the quality of infection control in Dutch Nursing Home (NH), based on a cross-sectional survey that visualises the results. The method was called the Infection control RIsk Infection Scan (IRIS). We tested the applicability of this new tool in a multicentre surveillance executed June and July 2012. METHODS: The IRIS includes two patient outcome-variables, i.e. the prevalence of healthcare associated infections (HAI) and rectal carriage of Extended-Spectrum Beta-Lactamase (ESBL) producing Enterobacteriaceae (ESBL-E); two patient-related risk factors, i.e. use of medical devices, and antimicrobial therapy; and three ward-related risk factors, i.e. environmental contamination, availability of local guidelines, and shortcomings in infection prevention preconditions. Results were categorised as low-, intermediate- and high risk, presented in an easy-to-read graphic risk spider-plot. This plot was given as feedback to management and healthcare workers of the NH. RESULTS: Large differences were found among most the variables in the different NH. Common shortcomings were the availability of infection control guidelines and the level of environmental cleaning. Most striking differences were observed in the prevalence of ESBL carriage, ranged from zero to 20.6% (p < 0.001). CONCLUSIONS: The IRIS provided a rapid and easy to understand assessment of the infection control situation of the participating NH. The results can be used to improve the quality of infection control based on the specific needs of a NH but needs further validation in future studies. Repeated measurement can determine the effectiveness of the interventions. This makes the IRIS a useful tool for quality systems.

Registration of complications of treatment is an important instrument for measuring the quality of health care. Reliable registration depends on definitions, the case-finding method that is used, and the registration method itself. We conducted a comparative study of two different methods of registration for the surveillance of surgical site infections (SSIs) in a single hospital.The study included all patients in both the surgical database and the microbiology and infection-prevention database of the hospital who underwent surgery on the abdominal aorta or peripheral vascular procedures from March 1, 2009 to March 1, 2010. The surgical database included positive scores for SSI in cases of positive wound swabs, the need for incision drainage, or the need for antibiotic treatment. The microbiology and infection-prevention database used criteria from the U.S. Centers for Disease Control and Prevention (CDC), and based positive scores on redness, heat, swelling, or pain in the area of a surgical incision within 30 d after a procedure, and on a positive swab, drainage from an incision, or the presence of pus following a diagnostic puncture.The surgical complication database included 218 patients, of whom 20 (9.2%) had a SSI. The microbiology and infection-prevention database included 236 patients, of whom 33 (14%) had a SSI. The databases were merged and all infections were ascertained by an expert team. The surgical database had a sensitivity of 57% for SSIs, whereas the microbiology and infection-prevention database had a sensitivity of 93% (p0.05).Physicians provided less reliable scores for SSI than did trained infection-control practitioners. This raises questions about the comparability of rates of SSI in different institutions as a means for judging the quality of hospital care.

Introduction Staphylococcus aureus is the most important pathogen in the development of surgical site infections (SSI). Patients who carry S. aureus in the nose are at increased risk for the development of SSI in cardiothoracic and orthopedic surgery. In these populations it has been shown that the risk for SSI can be substantially reduced by eradicating S. aureus carriage. For vascular surgery the relation between nasal carriage and surgical site infections has not been clearly investigated. For this reason we performed this study to analyze the relation between S. aureus nasal carriage and SSI in our vascular surgery population. Methods A prospective cohort study was undertaken, including all patients undergoing vascular surgery between January first 2010 and December 31th 2010. Before surgery patients were screened for S. aureus nasal carriage using a PCR technique. The presence of SSI was recorded based on criteria of the CDC. Results Screening was performed in 224. Of those, 55 (24.5%) were positive, 159 (71.0%) were negative and 10 (4.5%) were inconclusive. In the screened vascular population 4 S. aureus SSI occurred in the 55 carriers compared with 6 in 159 non-carriers (p = 0.24). A stratified analysis revealed a 10-fold increased risk in nasal carriers undergoing central reconstruction surgery (3 S. aureus SSI in 20 procedures versus 1 in 65 procedures in non-carriers, p = 0.039). Discussion In patients undergoing central reconstruction surgery nasals carriers are at increased risk for the development of S. aureus SSI. These patients will probably benefit from perioperative treatment to eradicate nasal carriage.

BACKGROUND: Surgical Site Infections (SSI) are relatively frequent complications after colorectal surgery and are associated with substantial morbidity and mortality. OBJECTIVE: Implementing a bundle of care and measuring the effects on the SSI rate. DESIGN: Prospective quasi experimental cohort study. METHODS: A prospective surveillance for SSI after colorectal surgery was performed in the Amphia Hospital, Breda, from January 1, 2008 until January 1, 2012. As part of a National patient safety initiative, a bundle of care consisting of 4 elements covering the surgical process was introduced in 2009. The elements of the bundle were perioperative antibiotic prophylaxis, hair removal before surgery, perioperative normothermia and discipline in the operating room. Bundle compliance was measured every 3 months in a random sample of surgical procedures. RESULTS: Bundle compliance improved significantly from an average of 10% in 2009 to 60% in 2011. 1537 colorectal procedures were performed during the study period and 300 SSI (19.5%) occurred. SSI were associated with a prolonged length of stay (mean additional length of stay 18 days) and a significantly higher 6 months mortality (Adjusted OR: 2.71, 95% confidence interval 1.76-4.18). Logistic regression showed a significant decrease of the SSI rate that paralleled the introduction of the bundle. The adjusted Odds ratio of the SSI rate was 36% lower in 2011 compared to 2008. CONCLUSION: The implementation of the bundle was associated with improved compliance over time and a 36% reduction of the SSI rate after adjustment for confounders. This makes the bundle an important tool to improve patient safety.

Bacterial surface contamination is an important reservoir for micro-organisms and a potential route for transmission. ATP bioluminescence is a relatively new method to assess environmental contamination, and gives direct results.

Fondaparinux is a synthetic selective inhibitor of factor Xa recently approved for thromboprophylaxis after major orthopedic surgery. Determination of its concentration gives valuable insight into specific pharmacokinetics or safety studies. The aim of the study was to develop direct, sensitive, precise and accurate assays of fondaparinux sodium in different biological matrices. Consistency with the recommended chromogenic assay for low molecular weight heparin required a similar method. However, recent data indicated some variability in the determination of anti-Xa level between commercial chromogenic assays. Consequently, we developed and validated two chromogenic methods (A and B) for assaying fondaparinux in plasma and other biological matrices. The assays are calibrated with fondaparinux, a pure chemical entity, and the result is expressed as amount (microg) of the fondaparinux calibrator. Results showed that precision was lower than 5.2% in plasma or plasma water and 13% in placental medium. The accuracy was lower than 7.6% in plasma or plasma water and 10.2% in placental medium. The lower limit of quantification in plasma was 0.042 microg/mL with automated Method A and 0.019 microg/mL with Method B. The assay was not affected by the source of the samples, the presence of blood cells, EDTA, citrate or repeated cycles of freezing and thawing. The two chromogenic assays calibrated with fondaparinux sodium reach the equivalence criteria for plasma samples and provide reliable and reproducible results.

We describe an outbreak of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) in a nursing home in the Netherlands from October 2010 to February 2011. The nursing home consists of three separate wards and is located in the southeast of the Netherlands, an area with a high pig-density.

Bundles (BUN) have been proposed to improve the process of care. We describe the implementation of a BUN in surgical patients (SP).