Characterization of fracture liaison service non-responders after invitation by home visits and questionnaires.

This study aimed to gain insight in specific characteristics and beliefs of FLS non-responders. INTRODUCTION: The proportion of non-responding fracture liaison service (FLS) invitees is high but characteristics of FLS non-responders are unknown. METHODS: We contacted FLS non-responders by telephone to consent with home visit (HV) and to fill in a questionnaire or, if HV was refused, to receive a questionnaire by post (Q), to gain insight in beliefs on fracture cause and subsequent fracture risk. RESULTS: Out of 716 FLS invitees, 510 attended, nine declined, and 197 did not respond. Of these non-responders, 181 patients were consecutively traced and phoned until 50 consented with HV. Forty-two declined HV but consented with Q. Excluded were eight Q-consenters in whom no choice was offered (either HV or Q) and 81 patients who declined any proposition (non-HV|Q). 62% HV and Q could recall the FLS invitation letter. The fracture cause was differently believed between HV and Q; the fall (96% versus 79%, p = .02), bad physical condition (36% versus 2%, p = .0001), dizziness or imbalance (24% versus Q 7%, p = .03), osteoporosis (16% versus 2%, p = .02), and increased fracture risk (26% versus 17%, NS). Age ≥ 70, woman, and major fracture were significantly associated with HV consent compared to Q (OR 2.7, 2.5, and 2.4, respectively) and HV compared to non-HV|Q (OR 16.8, 5.3, and 6.1). CONCLUSION: FLS non-responders consider fracture risk as low. Note, 50 patients (about 25%) consented with a home visit after one telephone call, mainly older women with a major fracture. This non-responder subgroup with high subsequent fracture risk is therefore approachable for secondary fracture prevention.

Challenges and opportunities to improve fracture liaison service attendance: fracture registration and patient characteristics and motivations.

This questionnaire-based study evaluated the reasons for attendance or non-attendance at the fracture liaison service in patients with a recent fracture. Frailty, male sex, living alone, and low education were associated with non-attendance, and the information perceived by the patient was associated with attendance. INTRODUCTION: The purpose of this study was to evaluate hospital registration- and patient-related factors associated with attendance or non-attendance to the Fracture Liaison Service (FLS). METHODS: Out of 1728 consecutive patients registered with a recent fracture at hospital entry, and after exclusion of 440 patients because of death, residence in a nursing home, already on osteoporosis treatment, or recent DXA, 1288 received an FLS invitation. We evaluated the hospital registration of fractures at entry and exit of the hospital. A questionnaire was sent to all invited patients to evaluate factors related to non-attendance (including age, gender, frailty, living alone, income, education, extrinsic motivations (impact of perceived information) and intrinsic motivations (patient's own perceived views and opinions) and to attendance (personal impact of clinical professionals' advice). RESULTS: There were 278 more hospital exit codes than entry codes. Of the 1288 invited patients, 745 returned analyzable questionnaires (537 attenders and 208 non-attenders). Non-attendance was associated with male gender (OR: 2.08, 95% CI: 1.35, 3.21), frailty (OR: 1.62, CI: 1.08, 2.45), living alone (OR:2.05, CI: 1.48, 2.85), low education (OR: 1.82, CI: 1.27, 2.63), not interested in bone strength (OR: 1.85, CI: 1.33, 2.63), and being unaware of increased subsequent fracture risk (OR: 1.75, CI: 1.08, 2.86). Information perceived by the patient was significantly associated with attendance (OR: 3.32, CI: 1.75, 6.27). CONCLUSION: Fracture entry registration inaccuracies, male gender, frailty, living alone, having low general education, or low interest in bone health and subsequent fracture risk were independently associated with FLS non-attendance. Adequately perceived advice (to have a bone densitometry and attend the FLS) was strongly associated with FLS attendance.

A dedicated Fracture Liaison Service telephone program and use of bone turnover markers for evaluating 1-year persistence with oral bisphosphonates.

Telephone call intervention did not improve alendronate persistence in Fracture Liaison Service (FLS) patients in this study. A bone turnover marker cut-off point for alendronate persistence is proposed for individual FLS patients. INTRODUCTION: FLS aims to prevent subsequent fractures, which should include improving patients' persistence with prescribed oral bisphosphonates. We studied the influence of telephone calls and the predictive value of changes in bone turnover markers (BTMs) for evaluating persistence with alendronate. METHODS: Postmenopausal women with a recent fracture and osteoporosis who started alendronate were randomized to receive three phone calls (PC) (after 1, 4, and 12 months) or no phone calls (no PC). s-CTX and P1NP were measured at baseline and after 3, 6, 9, and 12 months. As a reference group, 30 postmenopausal osteopenic patients with a recent fracture were analyzed as well. Persistence was assessed using the Dutch National Switch Point Pharmacies-GPs database and cross-referenced with PC, no PC, and BTM changes. Cut-off values of BTMs were calculated based on least significant change (LSC) and also on underrunning median values of the untreated osteopenic postmenopausal reference group with a recent fracture. RESULTS: Out of 119 patients, 93 (78%) completed 12 months follow-up (45 PC and 48 no PC). Mean age was 69 years. Persistence was similar in PC and no PC participants. The cut-off value > 29% (< 415 ng/L) as LSC of s-CTX and > 36% (< 53.1 µg/L) as LSC of P1NP was determined optimally showing alendronate persistence after 1 year (being 93 and 88%, respectively). CONCLUSIONS: In this context, telephone calls did not improve persistence. In around 90% of patients, 1-year alendronate persistence was confirmed by achieving LSC of s-CTX and of P1NP at 12 months.

Meeting international standards of secondary fracture prevention: a survey on Fracture Liaison Services in the Netherlands.

UNLABELLED: The Fracture Liaison Service (FLS) is advocated to be effective for the prevention of secondary fractures, but implementation is variable. A questionnaire based on the International Osteoporosis Foundation (IOF) Capture the Fracture® FLS standards was used in the current study. The results showed high compliancy with the IOF standards in the Dutch responding hospitals. INTRODUCTION: The FLS is advocated for the prevention of secondary fractures, but its implementation varies between hospitals and countries. The present survey applied the standards proposed by the IOF to evaluate the implementation of FLSs in non-university hospitals in the Netherlands. METHODS: A questionnaire based on the IOF FLS standards was used in this study, requesting the selection, evaluation and treatment data of patients older than 50 years with a recent fracture. RESULTS: Of 90 invited hospitals, 24 (27 %) fully responded, providing data of 24,468 consecutive patients, corresponding with 25 % of fracture patients in the Netherlands in the year 2012. After excluding skull and toe fractures and patients exceeding the upper age limits applied by individual hospitals, 11,983 patient data were available for analysis. The data showed high compliance (>90 %) for fracture patient identification, invitation for FLS, timing of assessment, identification of vertebral fractures, application of national guidelines, evaluation of secondary osteoporosis, drug initiation when indicated, communication with the general practitioner and application of follow-up strategy and 70 % for fall prevention. The response rate was on average (49 %). CONCLUSIONS: The available data also showed that patients attending the FLSs were evaluated, treated and followed in high compliancy with the IOF standards. Some standards are open to different interpretations and may need further specification. The major shortcoming in FLS practice was that patients invited to attend the FLSs showed a low response rate. None of the hospitals achieved the IOF standard patient response rate of over 90 %.

The impact of disease severity, age and surgical approach on the outcome of acute appendicitis in children.

PURPOSE: Although a national guideline has been implemented, the optimal approach for appendectomy in children remains subject of debate in the Netherlands. Opponents of laparoscopy raise their concerns regarding its use in complex appendicitis as it is reported to be associated with an increased incidence of intra-abdominal abscesses. The aim of this study was to evaluate the outcome of surgical approaches in both simple and complex appendicitis in paediatric patients. METHODS: A 10-year retrospective cohort study was performed (2001-2010) in paediatric patients treated for suspected acute appendicitis. Patients were divided into either simple or complex appendicitis and into different age groups. Primary outcome parameters were complication rate (intra-abdominal abscess (IAA), superficial surgical site infection (SSI) and readmission) and hospital stay. RESULTS: In total, 878 patients have been treated (median age 12, range 0-17 years). Two-thirds of the patients younger than 6 years had complex appendicitis, compared to one quarter in the group aged 13-18. In the complex appendicitis group, LA was associated with more IAA and early readmissions. In the simple appendicitis group, the complication rate was comparable between the two approaches. Significantly more IAAs were seen after LA in the youngest age group. CONCLUSION: This study demonstrates the unfavourable outcome of LA in the youngest age group and in patients with complex appendicitis. Therefore, we advise to treat these patients with an open approach.

Introduction of enteral feeding in neonates on extracorporeal membrane oxygenation after evaluation of intestinal permeability changes.

BACKGROUND/PURPOSE: Neonates meeting criteria for extracorporeal membrane oxygenation (ECMO) often suffer from variable periods of hypoxia. During ECMO, starvation of the gut is common practice in many centres as splanchnic ischemia results in loss of intestinal integrity, which in turn predisposes for bacterial translocation and sepsis and eventually necrotizing enterocolitis (NEC) and multiorgan failure. However, minimal enteral feeding is thought to be of benefit in the critically ill. Data on intestinal integrity in newborns on ECMO and the effects of enteral nutrition are not available. This study prospectively evaluates the changes in small intestinal integrity in 16 neonatal ECMO patients. METHODS: With 2-day intervals, excretion percentages of lactulose/L-rhamnose (nonmediated diffusion), D-xylose (passive), and 3-O-methyl-D-glucose (active carrier-mediated transport) were measured by gas-liquid chromatography in a 4-hour urine sample. After obtaining baseline data in nine patients, enteral feeding was started in the next seven patients between the third and the ninth day of ECMO. RESULTS: Thirteen patients had increased lactulose/L-rhamnose ratios (>0.05) consistent with increased intestinal permeability. In three patients the lactulose/L-rhamnose ratios were within the normal range. D-xylose excretion percentages were normal (or slightly increased) in 11 patients consistent with normal (or increased) passive carrier-mediated transport. 3-O-methyl-D-glucose excretion percentages were decreased (<10%) in all but one patient, consistent with decreased active carrier-mediated transport. After introduction of enteral nutrition no significant changes of these parameters were seen. CONCLUSIONS: The authors conclude that intestinal integrity is compromised in neonates on ECMO and that introduction of enteral nutrition does not result in further deterioration. This conclusion does not support the practice of withholding enteral nutrition in critically ill newborns supported by ECMO.

Gastrointestinal blood loss after non-steroidal anti-inflammatory drugs. Measurement by selective determination of faecal porphyrins.

1. A method for the detection of gastrointestinal blood loss based upon the selective measurement of faecal porphyrins was tested in two studies in healthy volunteers. 2. In the first study subjects (n = 6) received intragastric autologous blood (saline, 2 and 6 ml as a single dose) resulting in a dose dependent increase in faecal porphyrins. 3. In a subsequent placebo controlled cross over study in 12 subjects acetylsalicylic acid (ASA), nabumetone (a new NSAID) or placebo were administered for 5 days with a washout period of 9 days. They were no dietary restrictions. 4. All faeces were collected during the treatment period and both the full faecal homogenate and a random faecal sample were analyzed for deutero- and pemptoporphyrin content by h.p.l.c. Additionally a benzidine reaction was performed. 5. There was a highly significant correlation (r = 0.95) between the values obtained from random samples and the full homogenate. ASA increased the faecal porphyrin excretion (P less than 0.001) compared with placebo in contrast to nabumetone. Complaints of dyspepsia were most common after ASA. 6. Measurement of faecal porphyrins is useful for monitoring NSAID induced upper gastrointestinal blood loss and lacks some of the practical constraints of other methods.

Vitamin K1 levels and K1-dependent coagulation factors II and X in preterm and small-for-date neonates.

In 17 preterm neonates and 7 small-for-date neonates, all formula-fed, vitamin K-dependent coagulation factors II and X remained near 45% of adult values from the moment of birth until 28 days postnatally. Vitamin K1 levels, however, showed a remarkable rise from below the detection limit of 0.022 ng/ml in umbilical cord blood, to serum levels with a range of 0.99-7.29 ng/ml vitamin K1 on day 3, with a further rise on days 7 and 28 postnatally. Vitamin K1 (Konakion) parenterally given to a third group of four preterm neonates as a 1 mg dose resulted in very high serum levels of vitamin K1 (64.08-157.10 ng/ml), but without any significant increase in plasma levels of vitamin K-dependent coagulation factors II and X, compared to the group without any extra vitamin K1. It is concluded that in healthy preterm and small-for-date neonates no correlation is seen between serum levels of vitamin K1 and plasma levels of coagulation factors II and X. After administration of 1 mg Konakion no accelerated increase is seen in coagulation factor activities.

Vitamin K1 levels and coagulation factors in healthy term newborns till 4 weeks after birth.

Vitamin K1 serum levels were assessed by means of an off-line multidimensional liquid chromatography in 18 mothers, shortly after delivery, and in their healthy term infants. Umbilical cord and venous blood samples were assayed up to 4 weeks of life. Concurrently, levels of coagulation factors II and X, antithrombin III and platelets were established. Although the detection limit of the assay was as low as 22 pg/ml, vitamin K1 concentration appeared to be still beyond that level in cord blood or in newborn serum within 30 min after birth, whereas vitamin-K-dependent coagulation factors are already at a level of 40%, without evidence for the presence of descarboxy prothrombin, in any of the investigated neonates. After 3 days, breast-fed neonates had lower vitamin K1 levels than formula-fed infants (0.76 and 1.44 ng/ml, respectively). The levels of the vitamin-K-dependent coagulation factors II and X, however, were comparable, regardless of the kind of feeding. After 28 days, breast-fed neonates had even lower vitamin K1 levels (0.49 ng/ml, while the formula-fed infants showed higher vitamin K1 levels (4.45 ng/ml). But even then, the levels of vitamin-K-dependent coagulation factors II and X were comparable, regardless of the kind of feeding. From this we conclude that the serum levels of vitamin K1 in formula-fed neonates exceed those of breast-fed infants from the moment of feeding (24 h and later) without a concomitant rise in vitamin-K-dependent coagulation factors. A relationship between vitamin K1 levels and vitamin-K-dependent coagulation factors could not be established in healthy term breast-fed or formula-fed infants.

Chromatography of urinary indole derivatives.

Latest strategies are discussed for the routine chromatographic analysis of clinically important indole derivatives in urine. Analysis of 5-hydroxyindoleacetic acid and, perhaps more importantly, serotonin and 5-hydroxytryptophan remains attractive in the screening for carcinoid tumours and their differentiation. Analyses of two precursors of the skin pigment eumelanin seem to be promising in the monitoring of treatment of malignant melanoma and screening for pigmentation disorders and gallstone formation. Studies on the clinical relevance of the determination of tetrahydro-beta-carbolines and melatonin-related indoles await routine application of chromatographic methods designed to take into consideration the relative instability of these compounds. Application of GC-MS, although confined to larger and/or governmental laboratories remains attractive as a way of improving the specificity of analyses and in establishing reference methods. As for HPLC, the recent development of chromatographic and detection methods for the concurrent determination of different clinically important and metabolically related compounds from the same sample, preferably by direct injection techniques, seems to be fruitful and should be continued.

Routine clinical determination of carotene, vitamin E, vitamin A, 25-hydroxy vitamin D3 and trans-vitamin K1 in human serum by straight phase HPLC.

A universal extraction procedure is described for fat-soluble vitamins in human serum. Methods are presented for routine quantitative analysis by isocratic straight phase HPLC with UV-detection of (alpha + beta)-carotene, vitamin E (alpha-tocopherol) and vitamin A (all-trans-retinol) in one single run, and of vitamin K1 (trans-phylloquinone) and 25-hydroxy vitamin D3 after sample clean-up using disposable reversed-phase cartridges. The limits of detection, precisions and selectivities of the developed assays are shown to be satisfactory after more than three years' experience. The routine clinical determination of fat-soluble vitamins can be performed in less than 5 mL of serum. Analyses of external quality control and randomly taken outpatient samples are shown to be of great value in assessing laboratory performance.

Direct concurrent measurement of urinary vanillylmandelic acid, 5-hydroxyindoleacetic acid and homovanillic acid by HPLC. Three methodologies compared.

Three different direct HPLC methods for the determination of 3-methoxy-4-hydroxymandelic acid (VMA, vanillylmandelic acid), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylacetic acid (HVA, homovanillic acid) in urine were compared: two spectrofluorometric methods, applying discontinuous gradients, and one serial coulometric linear gradient method. The imprecision study (n = 6) revealed comparable coefficients of variation (CV), intra-assay ranging 1.4-11.1%, and inter-assay ranging 5.9-11.8% for physiological and moderately elevated levels of VMA, 5-HIAA and HVA. All methods showed good linearities up to 100 mumol/L for each of the three compounds studied. Analytical recoveries were 97-114% for VMA, 87-103% for 5-HIAA, and 80-95% for HVA. Recoveries were not dependent on urinary relative densities in the range 1.010-1.030 kg/L or on protein content (prior to acidification) in the range 0.1-3 g/L, or on the pH of conservation in the range 2-5 or on storage temperature in the range -20 - +22 degrees C for three weeks. The distributed-sample comparison revealed acceptable correlations and clinically unimportant accuracy differences between the methods. It is concluded that direct fluorometric and electrochemical HPLC methods can be used in the determination of major catecholamine and serotonin metabolites in human urine for clinical diagnosis and follow-up of neural crest and carcinoid tumours.

Assay of urinary 5-hydroxyindole-3-acetic acid: two methodologies compared.

Udenfriend's (Sjoerdsma A, Weissbach H, Udenfriend S. J Am Med Assoc 1955; 159: 397) classical screening method for urinary 5-hydroxyindole-3-acetic acid (5-HIAA) is known to be subject to error due to food and drug interferences. Goldenberg (Goldenberg H. Clin Chem 1973; 19: 38-44) introduced a more specific and sensitive method, which has recently been modified by Zouheir Habbal (Zouheir Habbal M. Clin Chim Acta 1983; 130: 251-256). The latter method is shown to correlate fairly well with a high-pressure liquid chromatography (HPLC) method in the 0-100 mumol/24 h range (reference values up to 34 mumol/24 h). It is suggested that elevated values in Udenfriend's screening method can be reliably checked by applying either method.

Quantitation of trans-vitamin K1 in small serum samples by off-line multidimensional liquid chromatography.

A sensitive high-performance liquid chromatography method for vitamin K1 using normal-phase fractionation was updated in order to cope with the limited volume of blood samples obtained from newborns. The method combines sample clean-up, normal-phase fractionation with reversed-phase chromatography using post-column electrochemical reduction and fluorescence detection. It was possible to measure vitamin K1 concentration in at least 0.2 ml of (potentially lipemic) serum even at a level of 0.3 nmol/l. The normal-phase method was compared to the updated method. The updated method shows about a twenty-fold lower limit of detectability than the previously described method.

Vitamin K1 in the newborn.

By a sensitive high-performance liquid chromatography method it was possible to measure vitamin K1 concentrations in mothers and their newborn children, even at a level of 0.5 nmol/l. All neonates were born after an uncomplicated and full-term pregnancy. The vitamin K1 concentration in neonates proved to be about half the value of their mothers, which is consistent with earlier studies of vitamin K1 dependent clotting factors. One may assume the existence of a partial placental barrier to vitamin K1. Venous, arterial and mixed cord blood did not differ significantly, so puncturing the vena umbilicalis is sufficient to measure vitamin K1 concentrations in cord blood.

Two serum pancreatic isoamylase determinations compared.

Serum pancreatic isoamylase activity was measured by a method involving inhibition of salivary isoamylase and by a well-known agarose electrophoretic method, modified by us. We saw changes in electrophoretic patterns of pancreatic isoamylase fractions after storage of serum samples for three weeks at 4-8 degrees C, but with the inhibition method no alterations in activities were found. Within-assay and between-assay imprecisions of both methods were about the same. Serum pancreatic amylase activities as measured by the inhibition method exceeded by about 10% those obtained by the electrophoretic method. The inhibition method seems to be a reasonable candidate for routine application, whereas the electrophoretic method is still time-consuming and requires special skill to perform. Some suggestions are given for improving the calibration of the inhibition method recommended by the manufacturer.

Studies on (Na+ + K+)-activated ATPase. XLVI. Effect of cation-induced conformational changes on sulfhydryl group modification.

(1) (Na+ + K+)-ATPase (ATP phosphohydrolase, EC 3.1.6.3) contains 34 sulfhydryl groups on the catalytic subunit, and two on the glycoprotein subunit. Under native conditions, only sulfhydryl groups on the catalytic subunit are accessible to modifying reagents. (2) The degree of inhibition of (Na+ + K+)-ATPase activity by N-ethylmaleimide and 5,5'-dithiobis(2-nitrobenzoic acid) depends on the cations present in the reaction medium. Mg2+ strongly enchances the inhibitory effects of both sulfhydryl reagents. The effects of Mg2+ on the inhibition by 5,5'-dithiobis(2-nitrobenzoic acid) are counteracted by the addition of Na+ or K+. Na+ has no more effect than choline on the inhibition by 5,5'-dithiobis(2-nitrobenzoic acid), but it enhances the inhibitory effect of N-ethylmaleimide at low Na+ concentrations (less than 10 mM). Low concentrations of K+ (less than 10 mM) slightly protect the enzyme against modification. (3) Titration of residual sulfhydryl groups reveals that these ions do not only influence modification of essential sulfhydryl groups, but also that of sulfhydryl groups which are not essential for the enzyme activity. (4) These results indicate that Na+, K+ and Mg2+ have marked effects on the conformation of the catalytic subunit of (Na+ + K+)-ATPase. Various enzyme conformations can be induced, depending on the concentration and the kind of cation added. The largest effects are observed after addition of Mg2+.

Pyrolysis mass spectra, sulfhydryl and tryptophan content of the embryonic nuclei from adult human normal and nuclear-cataractous lenses.

Cataractous state-related alterations were studied by Curie-point pyrolysis low voltage mass spectrometry performed on the embryonic nuclei from adult normal and nuclear-cataractous human lenses. It was shown that the relative intensities of ion signals assigned to sulfur dioxide and tentatively, to other sulfur oxidation products correlate with the increase in lens nuclear color. Since these ion signals may represent pyrolysis fragments from methionine sulfoxide, methionine sulfone, cysteic acid and disulfide compounds present in the parent material, it is concluded that progressive oxidation of sulfur compounds appears to take place during nuclear cataractogenesis. Automated pyrolysis mass spectrometry coupled with multivariate analysis of the spectral data by computer turned out to be a rapid method of characterizing sub-milligram samples of lens material. The results were supported by data obtained by conventional determination of sulfhydryl and tryptophan groups.