Identifying heterogeneity in the Hawthorne effect on hand hygiene observation: a cohort study of overtly and covertly observed results.

BACKGROUND: Observation and feedback are core strategies of hand hygiene (HH) improvement. Direct overt observation is currently the gold standard method. Observation bias, also known as the Hawthorne effect, is a major disadvantage of this method. Our aim was to examine the variation of the Hawthorne effect on HH observation in different healthcare groups and settings. METHODS: A prospective cohort study was performed in a tertiary teaching hospital during a 15-month period. Up to 38 overt observers (82% nurses) and 93 covert observers (81% medical students) participated in HH observation. The HH events observed overtly were matched for occupation, department, observation time, and location with those observed covertly. The data of matched pairs were then analysed to detect possible Hawthorne effects on different variables. RESULTS: A total of 31,522 HH opportunities were observed (4581 overtly, 26,941 covertly). There were 3047 matched pairs after 1:1 matching of overt and covert observations. The overall HH compliance was higher with overt observation than with covert observation (78% vs. 55%, p < 0.001). The Hawthorne effect was nearly three times larger in nurses (30 percentage points) than in physicians (11 percentage points) and was significantly greater in outpatient clinics (41 percentage points) than in intensive care units (11 percentage points). The magnitude of the Hawthorne effect varied among healthcare worker occupations and observation locations (p values both < 0.001) but not among departments, observation times, or HH indications. CONCLUSIONS: Heterogeneity in the Hawthorne effect may influence the interpretation of overt observations and prevent the correct identification of target populations with poor HH compliance. Therefore, directly observed HH compliance may not be an adequate performance indicator for infection control.

Causes of death and clinical characteristics of 34 patients with Mucopolysaccharidosis II in Taiwan from 1995-2012.

BACKGROUND: Mucopolysaccharidosis type II (MPS II) is an X-linked recessive, multisystemic lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase. MPS II has a variable age of onset and variable rate of progression. In Asian countries, there is a relatively higher incidence of MPS II compared to other types of MPS. METHODS: A retrospective analysis was carried out of 34 Taiwanese MPS II patients who died between 1995 and 2012. The clinical characteristics, medical records, age at death, and cause of death were evaluated to better understand the natural progression of this disease. RESULTS: The mean age at death of 31 of the patients with a severe form of the disease with significant cognitive impairment was 13.2 ± 3.2 years, compared with 22.6 ± 4.3 years in the three patients with a mild form of the disease without cognitive involvement (n = 2) or the intermediate form (n = 1) (p < 0.001). The mean ages at onset of symptoms and confirmed diagnosis were 2.5 ± 2.1 and 4.8 ± 3.1 years, respectively (n = 32). Respiratory failure was the leading cause of death (56 %), followed by cardiac failure (18 %), post-traumatic organ failure (3 %), and infection (sepsis) (3 %) (n = 27). Age at onset of symptoms was positively correlated with life expectancy (p < 0.01). Longevity gradually increased over time from 1995 to 2012 (p < 0.05). CONCLUSIONS: Respiratory failure and cardiac failure were the two major causes of death in these patients. The life expectancy of Taiwanese MPS II patients has improved in recent decade.

Impact of implementation of the World Health Organization multimodal hand hygiene improvement strategy in a teaching hospital in Taiwan.

BACKGROUND: Hand hygiene (HH) is considered to be the most simple, rapid, and economic way to prevent health care-associated infection (HAI). However, poor HH compliance has been repeatedly reported. Our objective was to evaluate the impact of implementing the updated World Health Organization (WHO) multimodal HH guidelines on HH compliance and HAI in a tertiary hospital in Taiwan. METHODS: We conducted a before-and-after interventional study during 2010-2011. A multimodal HH promotion campaign was initiated. Key strategies included providing alcohol-based handrub dispensers at points of care, designing educational programs tailored to the needs of different health care workers, placement of general and individual reminders in the workplace, and establishment of evaluation and feedback for HH compliance and infection rates. RESULTS: Overall HH compliance increased from 62.3% to 73.3% after 1 year of intervention (P < .001). The rate of overall HAI decreased from 3.7% to 3.1% (P < .05), urinary tract infection rate decreased from 1.5% to 1.2% (P < .05), and respiratory tract infection rate decreased from 0.53% to 0.35% (P < .05). This campaign saved an estimated $940,000 and 3,564 admission patient days per year. CONCLUSION: The WHO multimodal HH guidelines are feasible and effective for the promotion of HH compliance and are associated with the reduction of HAIs.

Liver metastasis from hepatoid adenocarcinoma of the stomach mimicking hepatocellular carcinoma: Dynamic computed tomography findings.

AIM: To evaluate the dynamic computed tomography (CT) findings of liver metastasis from hepatoid adenocarcinoma of the stomach (HAS) and compared them with hepatocellular carcinoma (HCC). METHODS: Between January 2000 and January 2015, 8 patients with pathologically proven HAS and liver metastases were enrolled. Basic tumor status was evaluated for the primary tumor location and metastatic sites. The CT findings of the liver metastases were analyzed for tumor number and size, presence of tumor necrosis, hemorrhage, venous tumor thrombosis, and dynamic enhancing pattern. RESULTS: The body and antrum were the most common site for primary HAS (n = 7), and observed metastatic sites included the liver (n = 8), lymph nodes (n = 7), peritoneum (n = 4), and lung (n = 2). Most of the liver metastases exhibited tumor necrosis regardless of tumor size. By contrast, tumor hemorrhage was observed only in liver lesions larger than 5 cm (n = 4). Three patterns of venous tumor thrombosis were identified: direct venous invasion by the primary HAS (n = 1), direct venous invasion by the liver metastases (n = 7), and isolated portal vein tumor thrombosis (n = 2). Dynamic CT revealed arterial hyperattenuation and late phase washout in all the liver metastases. CONCLUSION: On dynamic CT, liver metastasis from HAS shared many imaging similarities with HCC. For liver nodules, the presence of isolated portal vein tumor thrombosis and a tendency for tumor necrosis are imaging clues that suggest the diagnosis of HAS.

Heterozygous carriers of classical homocystinuria tend to have higher fasting serum homocysteine concentrations than non-carriers in the presence of folate deficiency.

BACKGROUND & AIMS: Many studies have reported that serum total homocysteine (tHcy) levels in cystathionine-beta-synthase (CBS) carriers are usually normal and only elevated after a methionine load. However, the amount of methionine required for a loading test is non-physiological and is never reached with regular feeding. Therefore, CBS carriers do not seem to be at an increased risk of cardiovascular diseases. However, the risk of cardiovascular diseases of CBS carriers with folate deficiency has not been studied. We recently found an extraordinarily high carrier rate (1/7.78) of a novel CBS mutation (p.D47E, c.T141A) in an Austronesian Taiwanese Tao tribe who live in a geographic area with folate deficiency. We evaluated if the CBS carriers tend to have higher fasting serum tHcy concentrations than non-carriers in presence of folate deficiency. METHODS: The serum tHcy and folate levels before and after folate replacement were measured in 48 adult Tao carriers, 40 age-matched Tao non-carriers and 40 age-matched Han Taiwanese controls. RESULTS: The serum tHcy level of the Tao CBS carriers (17.9 ± 3.8 µmol/l) was significantly higher than in Tao non-carriers (15.7 ± 3.5 µmol/l; p < 0.008) and Taiwanese controls (11.8 ± 2.9 µmol/l; p < 0.001). Furthermore, a high prevalence of folate deficiency in the Tao compared with the Taiwanese controls (4.9 ± 1.8 ng/ml vs. 10.6 ± 5.5 ng/ml; p < 0.001) was also noted. Of note, the difference in tHcy levels between the carriers and non-carriers was eliminated by folate supplementation. (carriers:13.65 ± 2.13 µmol/l; non-carriers:12.39 ± 3.25 µmol/l, p = 0.321). CONCLUSIONS: CBS carriers tend to have a higher tHcy level in the presence of folate deficiency than non-carriers. Although many reports have indicated that CBS carriers are not associated with cardiovascular disease, the risk for CBS carriers with folate deficiency has not been well studied. Owing to a significantly elevated level of fasting tHcy without methionine loading, it is important to evaluate the risk of cardiovascular disease in CBS carriers with folate deficiency.

Endomyocardial biopsies in patients with left ventricular hypertrophy and a common Chinese later-onset Fabry mutation (IVS4 + 919G > A).

BACKGROUND: In Taiwan, DNA-based newborn screening showed a surprisingly high incidence of a cardiac Fabry mutation (IVS4 + 919G > A). The prevalence of this mutation is too high to be believed that it is a real pathogenic mutation. The purpose of this study is to identify the cardiac pathologic characteristics in patients with left ventricular hypertrophy and this mutation METHODS AND RESULTS: Endomyocardial biopsies were obtained in 22 patients (Median age: 61, males: 17; females: 5) with left ventricular hypertrophy and the IVS4 + 919G > A mutation; five patients had not received enzyme replacement therapy (ERT) before biopsy, while the other 17 patients had received ERT from 8 months to 51 months. Except for three patients who had received ERT for more than 3 years, all other patients showed significant pathological change and globotriaosylceramide (Gb3) accumulation in their cardiomyocytes. In contrast to classical Fabry patients, no Gb3 accumulation was found in the capillary endothelial cells of any of our patients. Fourteen patients (63.6%) were found to have myofibrillolysis. CONCLUSIONS: All of the untreated and most of the treated IVS4 + 919G > A patients showed typical pathological changes of Fabry disease in their cardiomyocytes. No endothelial accumulation of Gb3 was found, which is similar to the findings of several previous reports regarding later-onset Fabry disease. This result highly suggests that the IVS4 + 919G > A is a real pathogenic later-onset Fabry mutation.

Detecting multiple lysosomal storage diseases by tandem mass spectrometry--a national newborn screening program in Taiwan.

BACKGROUND: Interest in lysosomal storage diseases in newborn screening programs has increased in recent years. Two techniques, fluorescence (4-MU) and tandem mass spectrometry (MS/MS) methods are frequently used. We report a pilot study of large scale newborn screening for Fabry, Pompe, Gaucher, and MPS I diseases by using the MS/MS method in Taiwan and compared the performance of the MS/MS with 4-MU methods. METHODS: More than 100,000 dried blood spots (DBSs) were collected consecutively as part of the national Taiwan newborn screening programs. The enzyme activities were detected by the MS/MS method from a DBS punch. Mutation analysis was further performed for newborns with detected enzyme deficiency. RESULTS: The DNA sequence analysis for suspected cases revealed 64 newborns with confirmed Fabry mutations, 16 were classified as infantile or late-onset Pompe disease, and 1 was characterized as Gaucher disease. The positive predict value increased from 4.0% to 7.1% in the Pompe study, and from 61.0% to 95.5% in the Fabry study by the MS/MS method compared to 4-MU assay. CONCLUSIONS: The MS/MS method has been validated as a more specific, powerful and efficient tool than the 4-MU assay. It also provided a multiplex solution of newborn screening for lysosomal storage diseases.

Clinical observations on enzyme replacement therapy in patients with Fabry disease and the switch from agalsidase beta to agalsidase alfa.

BACKGROUND: Fabry disease is an X-linked inherited lysosomal storage disease that can be treated with the enzymes of agalsidase beta (Fabrazyme) and agalsidase alfa (Replagal). Since June 2009, viral contamination of Genzyme's production facility has resulted in a worldwide shortage of agalsidase beta, leading to the switch to agalsidase alfa for patients with Fabry disease in Taiwan. METHODS: The medical records were retrospectively reviewed for nine male patients with Fabry disease from the start of agalsidase beta treatment until the switch to agalsidase alfa for at least 1 year. RESULTS: After 12-112 months of enzyme replacement therapy (ERT), decreased plasma globotriaosylsphingosine (lyso-Gb3) was found in five out of seven patients, indicating improvement in disease severity. Among the six patients with available echocardiographic data at baseline and after ERT, all six experienced reductions of left ventricular mass index. Renal function, including microalbuminuria and estimated glomerular filtration rate, showed stability after ERT. Mainz Severity Score Index scores revealed that all nine patients remained stable at 12 months after switching to agalsidase alfa. ERT improved or stabilized cardiac status and stabilized renal function, while reducing plasma lyso-Gb3. ERT was well tolerated, even among the three patients who had hypersensitivity reactions. CONCLUSION: The switch of ERT from agalsidase beta to agalsidase alfa appears to be safe after 1 year of follow-up for Taiwanese patients with Fabry disease.

Plasma globotriaosylsphingosine (lysoGb3) could be a biomarker for Fabry disease with a Chinese hotspot late-onset mutation (IVS4+919G>A).

BACKGROUND: Previous studies revealed a high incidence of late-onset Fabry disease mutation, IVS4+919G>A, in Taiwan. However, the natural course is largely unclear and suitable biomarkers for monitoring disease progress are unavailable. METHODS AND RESULTS: Patients carrying IVS4+919G>A or classical Fabry mutations were enrolled in this study. The subjects ranged from newborn to eighty year old adults. Plasma globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) were measured by LC-MS/MS in subjects to evaluate the sensitivity of these two biomarkers. All adult males and symptomatic females could be distinguished from healthy controls by an elevated plasma lysoGb3 level. The lysoGb3 level was also related to the left ventricular mass considering gender and age (p<0.01). Moreover, approximately 70% of male and 45% of female newborns already had an elevated plasma lysoGb3 level which increased gradually as the subjects got older (p<0.01). CONCLUSIONS: Plasma lysoGb3 is a more sensitive and reliable biomarker than plasma Gb3. LysoGb3 also correlated with age and left ventricular mass index in Fabry patients with IVS4+919G>A mutation. Because lots of infants with the IVS4+919G>A mutation already had elevated lysoGb3 levels at birth, that indicates that the development of hypertrophic cardiomyopathy may require a long and insidious course after lysoGb3 accumulation.

Effects of enzyme replacement therapy for cardiac-type Fabry patients with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A).

OBJECTIVE: Current studies of newborn screening for Fabry disease in Taiwan have revealed a remarkably high prevalence of cardiac-type Fabry disease with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A). DESIGN: Retrospective cohort study. SETTING: Tertiary medical centre. PARTICIPANTS: 21 patients with cardiac-type Fabry disease (15 men and 6 women) as well as 15 patients with classic Fabry disease (4 men and 11 women) treated with biweekly intravenous infusions of agalsidase ß (1 mg/kg) or agalsidase α (0.2 mg/kg) for at least 6 months. OUTCOME MEASURES: These data were collected at the time before enzyme replacement therapy (ERT) began and followed up after ERT for at least 6 months, including patient demographics, medical history, parameter changes of cardiac status and renal functions, plasma globotriaosylsphingosine (lyso-Gb3) and Mainz Severity Score Index. RESULTS: After 6-39 months of ERT, plasma lyso-Gb3 was found to be reduced in 89% (17/19) and 93% (14/15) of patients with cardiac-type and classic Fabry disease, respectively, which indicated an improvement of disease severity. For patients with cardiac-type Fabry disease, echocardiography revealed the reduction or stabilisation of left ventricular mass index (LVMI), the thicknesses of intraventricular septum (IVS) and left posterior wall (LPW) in 83% (15/18), 83% (15/18) and 67% (12/18) of patients, respectively, as well as 77% (10/13), 73% (11/15) and 60% (9/15) for those with classic type. Most patients showed stable renal function after ERT. There were statistically significant improvements (p<0.05) between the data at baseline and those after ERT for values of plasma lyso-Gb3, LVMI, IVS, LPW and Mainz Severity Score Index. No severe clinical events were reported during the treatment. CONCLUSIONS: ERT is beneficial and appears to be safe for Taiwanese patients with cardiac-type Fabry disease, as well as for those with the classic type.

Hand hygiene among patients: attitudes, perceptions, and willingness to participate.

BACKGROUND: Patient participation has been proven to increase hand hygiene compliance of health care workers. The objective of the study is to better understand patients' attitudes and perceptions toward hand hygiene, and to identify patients with the highest motivation to participate in hand hygiene. DESIGN: A 2-week, cross-sectional survey of hospitalized patients and their family members was conducted using an anonymous, self-reporting questionnaire in a large teaching hospital in Taiwan. RESULTS: Of the 859 respondents, 89.8% considered hand hygiene important, and 75.9% would take hand hygiene practices into consideration when they choose a hospital. Most respondents (78.4%) would like more information on hand hygiene, particularly persons who have had experience with health care-associated infection (odds ratio, 2.48; 95% confidence interval, 1.57-3.89; P < .001). Respondents would be more willing to ask a doctor or nurse to wash his or her hands if they knew that the doctor or nurse would appreciate the reminder (doctor: from 48.9% to 74.6% [P < .001]; nurse: from 50.8% to 76.3% [P < .001]). CONCLUSIONS: Hand hygiene is considered important by most patients and family members and plays an influential role in their choice of a hospital or doctor. Persons with experience with health care-associated infections have the greatest motivation to participate in hand hygiene.

Misdiagnosis as steatohepatitis in a family with mild glycogen storage disease type 1a.

The manifestations of glycogen storage disease type 1a (GSD 1a) are usually so prominent in childhood that it is readily diagnosed by pediatricians. However, a mild form of the disease may only become apparent during adolescence or adulthood. We observed a brother and sister with subtle manifestations of the disease, which was discovered after the brother's son was diagnosed with typical GSD 1a. The adult siblings never suffered from hypoglycemia, had normal fasting blood glucose and liver transaminases at the time of diagnosis, and were taller than average for Chinese. Their only notable disease manifestations were recurrent gouty arthritis associated with hyperuricemia and hyperlipidemia during adolescence. When diagnosed, the brother had multiple benign and malignant hepatic tumors, and died of fulminant metastatic hepatocellular carcinoma 6 months after liver transplantation. p.M121V/p.R83H and p.M121V/p.M121V genotypic constellations of the G6PC gene were identified in this family. Both siblings were homozygous for the newly identified p.M121V mutation. The infant had compound heterozygous mutations, p.R83H and p.M121V. We recommend that mild GSD should be considered in the adolescents with unexplained hyperuricemia and hyperlipidemia, despite the presence of normal blood glucose levels. This report also reminds us that hepatocellular carcinoma could develop even in very mild GSD 1a patients.

Recessive congenital methemoglobinemia caused by a rare mechanism: maternal uniparental heterodisomy with segmental isodisomy of a chromosome 22.

Recessive congenital methemoglobinemia (RCM) is a very rare disorder caused by NADH-cytochrome b5 reductase (cb5r) deficiency. Two distinct clinical forms, types I and II, caused by cb5r deficiency have been recognized. In type I, the enzyme deficiency is restricted only to erythrocytes with cyanosis being the only major symptom. In contrast, in type II, the enzyme deficiency is generalized to all tissues and associated with neurological impairment, mental and growth retardation and reduced life expectancy, in addition to cyanosis. Recently, we conducted a study on an 11-year-old boy with cb5r deficiency type I. The mutational analysis of the CYB5R3 gene revealed that the boy is homozygous for L72P mutation. Surprisingly, his mother is heterozygous for this L72P mutant, but not his father. Thirteen microsatellite markers of chromosome 22 were selected to analyze the origins of the patient's chromosome 22. The result showed that both of the chromosome 22(s) of this patient came from the maternal side (uniparental heterodisomy of chromosome 22 with segmental isodisomy). This is the first case report of a patient with cb5r deficiency type I resulting from uniparental disomy and also discloses an alternate mechanism whereby this enzymatic disorder can be derived from a single parent.

Homocystinuria in Taiwan: an inordinately high prevalence in an Austronesian aboriginal tribe, Tao.

The newborn screening of homocystinuria in Taiwan has never been formally reported before. Since 1984, out of 5 million newborns screened, only 3 newborns (Han Taiwanese) suffering from homocystinuria were detected in this newborn screening program. Four mutations (p.R121L [c.362G>T], p.E176K [c.526G>A], p.V320G [c.959T>G] and p.G259D [c.776G>A]) were identified in these 3 patients. Unexpectedly, we recently found 8 patients presenting with homocystinuria in an Austronesian Taiwanese Tao tribe. Out of them, three patients participated in the newborn screening program but were unidentified by the current newborn homocystinuria (using methionine as a marker) screening. All the Tao patients are homozygous for a new p.D47E (c.141T>A) mutation. Among the 428 adult islanders screened for the D47E mutation, approximately 1 in 7.78 is a carrier of the mutation, and an estimated 1 in 240 islanders suffered from homocystinuria. This is the highest known prevalence of homocystinuria worldwide. The result of expression studies of all the mutations identified in Taiwan revealed that, except for p.D47E mutation, all mutations were severely limited in their ability to form functional tetramers. The clinical manifestations of the Tao patients varied widely, despite sharing the same mutation and very similar genetic and environmental backgrounds. Comparisons of clinical and biochemical phenotypes of these patients were presented in this report.

The use of high resolution melting analysis to detect Fabry mutations in heterozygous females via dry bloodspots.

BACKGROUND: As an X-linked genetic disorder, Fabry disease was first thought to affect males only, and females were generally considered to be asymptomatic carriers. However, recent research suggests that female carriers of Fabry disease may still develop vital organ damage causing severe morbidity and mortality. In the previous newborn screening, from 299,007 newborns, we identified a total of 20 different Fabry mutations and 121 newborns with Fabry mutations. However, we found that most female carriers are not detected by enzyme assays. METHODS: A streamlined method for high resolution melting (HRM) analysis was designed to screen for GLA gene mutations using a same PCR and melting program. Primer sets were designed to cover the 7 exons and the Chinese common intronic mutation, IVS4+919G>A of GLA gene. RESULTS: The HRM analysis was successful in identifying heterozygous and hemizygous patients with the 20 surveyed mutations. We were also successful in using this method to test dry blood spots of newborns afflicted with Fabry mutations without having to determine DNA concentration before PCR amplification. CONCLUSION: The results of this study show that HRM could be a reliable and sensitive method for use in the rapid screening of females for GLA mutations.