The impact of clinical practice on the outcome of central venous access devices in children with haemophilia.

INTRODUCTION: Central venous access devices facilitate home treatment in boys with haemophilia. These are usually fully implanted lines, referred to as ports. Caregivers are taught to manage the port using sterile techniques and maintaining patency by flushing with saline or heparin solution. National and international guidelines for the home care of ports are lacking. AIM: To evaluate if infection or occlusion rates differ between home care regimens used for ports in children with haemophilia. METHODS: Children with ports were identified from the PedNet registry. Data on the homecare policy were acquired from each centre. To ensure a complete data set for each port, only ports that had been removed were included in the study. Three care groups were defined: 'aseptic non touch technique', 'sterile technique' and 'fully sterile technique'. Outcomes within and between the groups were analysed. RESULTS: A total of 240 children with 352 ports were studied. Insertion occurred at a median age of 1.32 years. The median port duration was 2.94 years with a total of 215 688 port days in children without and 183 852 in children with inhibitors. Infection was the most common cause of port removal (34%); there was no significant difference with infection as reason for removal between the different care groups. Occlusion was not more frequent in centres that did not use heparin. CONCLUSION: Use of sterile gloves and gowns did not reduce the risk of port infection. Using less stringent sterile techniques for accessing ports is easier for caregivers and in addition may have health economic benefits.

Venous thrombosis in children and adolescents with Hodgkin lymphoma in Sweden.

INTRODUCTION: Pediatric patients with Hodgkin lymphoma (HL) have several risk factors for venous thromboembolism (VTE). Although these patients are occasionally treated with thromboprophylaxis, no guidelines are implemented in Sweden. Scarce data from adult patients indicate an increased risk of VTE, but pediatric data is largely missing. Given the favorable overall survival of HL, there should reasonably be more focus on preventing complications. MATERIALS AND METHODS: We conducted a retrospective cohort study, including all patients registered in the Childhood Cancer Registry under the age of 18years diagnosed with HL between January 2005 and December 2015 in Sweden. RESULTS: Data was retrieved from the medical records of all 163 patients (100%) at six Swedish pediatric cancer centers. The incidence of VTE was 7.7% (symptomatic VTE 3.9%). The median follow-up was 3.4years (range 0.3-10.5). Only five patients (3.1%) were treated with thromboprophylaxis. All VTE events occurred in the older age category (11-17years) and all but one (92.7%) had a mediastinal mass. While the VTE did not significantly affect the treatment of HL, it caused increased morbidity and 2/12 developed a post-thrombotic syndrome. No significant risk factors for VTE were identified. CONCLUSIONS: VTE is a relatively common complication of HL and its treatment, causing increased acute and long-term morbidity. However, due to limited number of events we could not demonstrate risk-factors for VTE that would identify patients who might benefit from thromboprophylaxis.

Prospective study of thromboembolism in 1038 children with acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology (NOPHO) study.

UNLABELLED: ESSENTIALS: Children with acute lymphoblastic leukemia (ALL) are at risk of thromboembolism (TE). This is a prospective evaluation of the incidence, risk factors and outcomes of TE in 1038 children with ALL. TE occurred in 6.1% of children, with the highest incidence (20.5%) among those aged 15-17 years. A TE-associated case fatality of 6.4% indicates that TE is a severe complication of ALL treatment. BACKGROUND: Thromboembolism (TE) is a major toxicity in children with acute lymphoblastic leukemia (ALL) and may have a negative impact on ALL treatment. OBJECTIVES: To examine the cumulative incidence, outcomes and risk factors associated with TE in children with leukemia. PATIENTS/METHODS: We prospectively evaluated TE in 1038 Nordic children and adolescents (≥ 1 and < 18 years) diagnosed with ALL during 2008-2013 and treated according to the NOPHO (Nordic Society of Pediatric Hematology and Oncology)-ALL 2008 protocol. The cohort was followed until December 2014. Cox proportional regression was used to compute hazard ratios (HRs). RESULTS: TE events (n = 63) occurred most frequently in conjunction with asparaginase (ASP) administration (52/63). The cumulative incidence of TE was 6.1% (95% confidence interval [CI], 4.8-7.7). Being aged 15-17 years was associated with an increased risk of TE (adjusted HR of 4.0; 95% CI, 2.1-7.7). We found a TE-associated 30-day case fatality of 6.4% (95% CI, 1.8-15.5) and TE-related truncation of ASP therapy in 36.2% (21/58). Major hemorrhage occurred in 3.5% (2/58) of anticoagulated patients. Minor hemorrhage was reported in two out of 58 patients. No major bleeds occurred in children who received low-molecular-weight heparin. CONCLUSIONS: Methods to identify children and adolescents who will benefit from thromboprophylaxis during ALL treatment are called for. The truncation of ASP should be avoided. The long-term survival outcomes for ALL patients with TE require close monitoring in the future.

Recurrent venous thromboembolism in anticoagulated patients with cancer: management and short-term prognosis.

BACKGROUND: Recommendations for management of cancer-related venous thromboembolism (VTE) in patients already receiving anticoagulant therapy are based on low-quality evidence. This international registry sought to provide more information on outcomes after a breakthrough VTE in relation to anticoagulation strategies. METHODS: Patients with cancer and VTE despite anticoagulant therapy were reported to the registry. Data on treatments, VTE events, major bleeding, residual thrombosis symptoms and death were collected for the following 3 months. Breakthrough VTE and subsequent recurrences were objectively verified. Outcomes with different treatment strategies were compared with Cox proportional hazards regression. RESULTS: We registered 212 patients with breakthrough VTE. Of those, 59% had adenocarcinoma and 73% had known metastases. At the time of the breakthrough event, 70% were on low-molecular-weight heparin (LMWH) and 27% on a vitamin K antagonist (VKA); 70% had a therapeutic or supratherapeutic dose. After breakthrough the regimen was: unchanged therapeutic dose in 33%, dose increased in 31%, switched to another drug in 24%; and other management in 11%. During the following 3 months 11% had another VTE, 8% had major bleeding and 27% died. Of the survivors, 74% had residual thrombosis symptoms. Additional VTE recurrence was less common with LMWH than with a VKA (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.11-0.70) but similar with unchanged or increased anticoagulant intensity (HR, 1.09; 95% CI, 0.45-2.63). The bleeding rate did not increase significantly with dose escalation. CONCLUSION: Morbidity and mortality are high after recurrence of cancer-related VTE despite anticoagulation. Further treatment appears to be more effective with LMWH than with a VKA.

Oral health care in children with haemophilia in Helsinki, Finland.

BACKGROUND: The bleeding tendency and fear of bleeds may have a negative effect on preventive dental care of patients with haemophilia both at home and at dental appointments. AIM: To describe the clinical practice of dental care in children with haemophilia in Helsinki, Finland. METHODS: This study evaluated retrospectively the medical records of 28 paediatric patients with haemophilia (aged 5.3-17.4 years) from dental visits during 2009-2010. Decayed, missing and filled teeth in the primary (dmft) and permanent dentition (DMFT), Community Periodontal Index (CPI), signs of developmental dental defects in enamel and the number of preventive and restorative procedures were gathered. Dmft + DMFT scores were compared with those of 17,079 non-haemophiliac boys. The Mann-Whitney U-test was used to compare the data between the groups of different severity of haemophilia. RESULTS: The median number of dental visits per patient was three (range 1-11). Twenty-two patients (79 %) had dmft + DMFT-scores within the 95 % reference range for age. None of the children had a CPI >2. Twelve (43 %) patients had developmental enamel defects. Half had received restorative dental care and three out of four preventive procedures. CONCLUSIONS: Dental care during hospital visits in children with haemophilia may enhance confidence in the preventive dental care and help minimise bleeding during dental procedures.

Hypercalciuria and kidney function in children with haemophilia.

Adults with haemophilia have a higher incidence of chronic kidney disease than general male population. We recently showed that children with haemophilia have higher urinary calcium excretion and lower whole body bone mineral density than controls in spite of prophylaxis with the deficient coagulation factor concentrate, serum vitamin D concentrations comparable to those of healthy children and physically active lifestyle. Persistent hypercalciuria may result in nephrocalcinosis and impact renal function. This study sought to assess persistence of urinary calcium excretion and kidney function in children with haemophilia. We investigated retrospectively urinary calcium excretion in 30 children with haemophilia (mean age 12.5 years) from consecutive urine samples over a 2-year period. Renal evaluation included blood and urine specimen, blood pressure, and renal ultrasound. High number of children with haemophilia had intermittent hypercalciuria. Hypercalciuria was not associated with age, severity of haemophilia or previous hypercalciuria. Kidney function and renal ultrasound were normal with the exception of suspected kidney stone in one patient with haemophilia and transient hypercalciuria. Vitamin D concentrations improved after the families had received information and recommendations concerning vitamin D substitution. Our findings indicate that haemophilia per se predisposes to hypercalciuria which may in turn affect bone mineral content and kidney function. Whether childhood-onset intermittent hypercalciuria contributes to hypertension and renal complications in adulthood remains to be elucidated in future studies.

Peripheral quantitative computed tomography (pQCT) reveals alterations in the three-dimensional bone structure in children with haemophilia.

Children with haemophilia are at risk of suboptimal bone mass accrual and low bone mineral density (BMD). We recently demonstrated that although BMD in Finnish children with haemophilia was within the normal range, their whole body BMD was significantly lower and hypercalciuria more prevalent than in controls. This study sought to determine the bone structure and strength in physically active children with haemophilia. To investigate the underlying mechanisms in this group, we conducted a case-control study to assess bone structure and strength by peripheral quantitative computed tomography (pQCT) at the radius. The study group comprised 29 patients (mean age 12.2 years) and 46 age-matched controls. Children with haemophilia had decreased total BMD Z-score at the distal radius (P ≤ 0.001), but increased cortical bone density at the proximal radius (P ≤ 0.001). Total bone area at the proximal radius was significantly lower in children with haemophilia (P = 0.002), whereas there were no differences in cortical bone area or in polar Strength-Strain Index, a parameter of bone strength, between the patients and controls. Patients with mild to moderate haemophilia and on-demand treatment had inferior bone strength compared to those with moderate to severe haemophilia and prophylaxis. Our findings suggest altered skeletal development in patients with haemophilia in the radius, resulting in smaller bone size and higher cortical bone density. Importantly, bone strength at the radius appears equal to healthy children. Prophylactic treatment seems to have a beneficial effect on bone health.

Femtosecond mode-locked holmium fiber laser pumped by semiconductor disk laser.

We report on a 2085 nm holmium-doped silica fiber laser passively mode-locked by semiconductor saturable absorber mirror and carbon nanotube absorber. The laser, pumped by a 1.16 µm semiconductor disk laser, produces 890 femtosecond pulses with the average power of 46 mW and the repetition rate of 15.7 MHz.

MRI after removal of central venous access device reveals a high number of asymptomatic thromboses in children with haemophilia.

Central venous access devices (CVADs) are often required in children with haemophilia to secure venous access for prophylactic treatment or immune tolerance therapy. Complications of CVADs include infections, thrombosis and mechanical problems. This study sought to determine the outcome of the vessels by magnetic resonance imaging (MRI) in children with haemophilia and to assess risk factors for development of catheter-related deep venous thrombosis (DVT). After the removal of CVAD an MRI of the chest and neck was performed to 20 boys with haemophilia who each had 1-3 (total number 27) CVADs placed. MRI revealed DVT in five children (25%). As their CVADs were functional at the time of the removal, the DVTs were clinically silent. However, there had been suspicion of DVT leading to replacement of the CVAD in one case. All the children with DVT had their CVADs inserted initially below the age of 1 year. The clinical signs of mild post-thrombotic syndrome (PTS) were common: dilated chest wall veins were observed in 11 (55%) children and were associated with DVT in three cases. Arm circumference discrepancy was observed in one child with DVT. No correlation between the duration or number of CVADs and DVT was detected. None of the patients had subjective symptoms of PTS. Silent DVT is a common complication of CVAD. Catheter insertion at a young age seems to predispose to thrombosis. The long-term consequences of the DVTs remain unknown.

Raman fiber laser pumped by a semiconductor disk laser and mode locked by a semiconductor saturable absorber mirror.

A 1.6µm mode-locked Raman fiber laser pumped by a 1480nm semiconductor disk laser is demonstrated. Watt-level core pumping of the single-mode fiber Raman lasers with low-noise disk lasers together with semiconductor saturable absorber mirror mode locking represents a highly practical solution for short-pulse operation.

Patient complaints in Finland 2000-2004: a retrospective register study.

Today, monitoring of patient complaints in healthcare services is being used as a tool for quality assurance systems and in the future development of services. This nationwide register study describes the number of all complaints processed, number of complaints between different state provinces, healthcare services and healthcare professionals, and outcomes of complaints in Finland during the period 2000-2004. All complaints processed at the State Provincial Offices and the National Authority for Medicolegal Affairs were analysed by statistical methods. Complaints about mental healthcare were explored in greater detail. The analysis showed that the number of patient complaints increased considerably during the study period. There were changes in the number of complaints between study years in different provinces. Out of different healthcare services, an especially marked increase was seen in private healthcare. Nearly all complaints were lodged against physicians, and over half of the complaints were made because of medical error. In mental health care, patients more often complained about unsatisfactory certificates and statements and the use of compulsory hospital care. An analysis of the outcomes revealed that in mental health care complaints more seldom led to consequences. The results need to be utilised when planning interventions for advanced supervision, prevention of adverse events and patient safety in healthcare, and especially in mental health care. From the patients' perspective, it is important to create a culture where most problem situations are handled where the treatment was provided, thus avoiding a complex complaints process.

Impact of age, submersion time and water temperature on outcome in near-drowning.

BACKGROUND: Because children have less subcutaneous fat, and a higher surface area to body weight ratio than adults, it has been suggested that children cool more rapidly during submersion, and therefore have a better outcome following near-drowning incidents. AIM OF THE STUDY: To study the impact of age, submersion time, water temperature and rectal temperature in the emergency room on outcome in near-drowning. MATERIAL AND METHODS: This retrospective study included all near-drowning victims admitted to the intensive care units of Helsinki University Central Hospital after successful cardiopulmonary resuscitation between 1985 and 1997. RESULTS: There were 61 near-drowning victims (age range: 0.5-60 years, median 29 years). Males were in the majority (40), and 26 were children (<16 years). The median water temperature was 17 degrees C (range: 0-33 degrees C). The median submersion time for the 43 survivors (70%) was 10 min (range: 1-38 min). Intact survivors and those with mild neurological disability (n=26, 43%) had a median submersion time of 5 min (range: 1-21 min). In non-survivors the median submersion time was 16 min (range: 2-75 min). Submersion time was the only independent predictor of survival in linear regression analysis (P<0.01). Patient age, water temperature and rectal temperature in the emergency room were not significant predictors of survival. CONCLUSIONS: Although submersion time is usually an estimate, it is the best prognostic factor after a near drowning incident. Children did not have a better outcome than adults.

Levonorgestrel concentrations during 7 years of continuous use of Jadelle contraceptive implants.

Serum levonorgestrel concentrations were assayed in a multicenter, 7-year study of 199 users of Jadelle rod implants. We examined drug levels, patterns of changes, factors affecting drug levels, and concentrations at which pregnancies occurred. Mean levonorgestrel concentrations declined from 435 pg/mL at 1 month of use to 64% of that value (280 pg/mL) at the end of 3 years. Between the end of the third and fifth years neither mean nor median serum levels varied markedly. At 5 years the mean concentration was again 64% of the first month's mean. Declining levels were observed thereafter through the end of 7 years when the mean, 224 pg/mL, was 52% of the 1-month value. Last measured drug concentrations of women who became pregnant during Jadelle use had mean and median values of 152 and 144 pg/mL, respectively, and a maximum value of 180 pg/mL. Analyses indicated ponderal index, body weight, duration of use, and a single clinical center were the most important variables affecting measured levonorgestrel levels. Approximately one-third of assays in the sixth and seventh years were found to be below 180 pg/mL, suggesting that Jadelle levonorgestrel implants would not maintain sufficiently high levels of effectiveness against pregnancy after 5 years and that heavier women would then be at greater risk of pregnancy.

Studies of homogenous populations: CLN5 and CLN8.

Finland and the Finns have been the subject of numerous genetic and genealogical studies, owing to enrichment of certain rare hereditary disorders in the Finnish population. Two types of NCL have so-far been found almost exclusively in Finland: Finnish variant late infantile NCL, vLINCL (CLN5), and the Northern epilepsy syndrome or Progressive epilepsy with mental retardation, EPMR (CLN8). The first symptoms of Finnish vLINCL are concentration problems or motor clumsiness by 3 to 6 years of age, followed by mental retardation, visual failure, ataxia, myoclonus, and epilepsy. Northern epilepsy, the newest member of the NCL family with the most protracted course, is characterized by the onset of generalized seizures between 5 and 10 years of age and subsequent progressive mental retardation. Visual problems are slight and late, while myoclonus has not been observed. Both the Finnish vLINCL and Northern epilepsy are pathologically characterized by intraneuronal cytoplasmic deposits of autofluorescent granules which are Luxol fast blue-, PAS-, and Sudan black B-positive in paraffin sections. In Northern epilepsy the intraneuronal storage process and neuronal destruction are generally of mild degree but highly selective and, in contrast to other forms of childhood onset NCL, the cerebellar cortex is relatively spared. By electron microscopy the storage bodies mainly contain rectilinear complex type and fingerprint profiles in Finnish vLINCL and structures resembling curvilinear profiles in Northern epilepsy. Mitochondrial ATP synthase subunit c is the main stored protein in both disorders. Both the DCLN5 and CLN8 genes encode putative membrane proteins with yet unknown functions. Furthermore, a well studied spontaneously occurring autosomal recessive mouse mutant, motor neuron degeneration (mnd) mouse, is a homolog for CLN8.

The possible role of enterohepatic cycling on bioavailability of norethisterone and gestodene in women using combined oral contraceptives.

Using steady-state conditions we aimed to test if administration of oral activated charcoal affects the bioavailability of norethisterone acetate (NET Ac) and gestodene (GEST) by inhibiting their enterohepatic recirculation. Thirteen volunteers received, in a randomized order, Minulet (75 microg GEST and 30 microg ethinylestradiol [EE(2)]) and Econ/30 (1 mg NET Ac and 30 microg EE(2)), each for 4 months. Serum GEST and norethisterone (NET) levels were evaluated with respect to C(max,) t(max) and 24-h area under the curve (AUC(0-24h)) in the middle of the control (3rd) cycle and the charcoal treatment (4th) cycle during both pill treatments. No statistically significant difference was seen in any of the aforementioned variables between the control and charcoal treatment cycles of either pill. Neither was a difference seen in the bioavailability of GEST and NET as evaluated by the ratios of two 24-h AUCs calculated in the control and charcoal cycles of each pill treatment (p = 0.29). The results suggest that enterohepatic circulation of GEST and NET is not of clinical importance. We conclude that women on oral contraceptives can take activated charcoal for the treatment of diarrhea when administered 3 h after and at least 12 h before pill intake.

Charcoal treatment and risk of escape ovulation in oral contraceptive users.

Ovulatory potential was studied during the use of two oral contraceptive pill preparations, after repeated mid-cycle administration of activated charcoal. Eleven women used monophasic pills containing gestodene, 75 microgram, plus ethinyl oestradiol, 30 microgram, or norethisterone acetate, 1 mg, plus ethinyl oestradiol, 30 microgram, for 4 months each, in randomized order. During both pill treatments the third cycle was a control cycle, and during the fourth cycle of both pill types, 5 g of activated charcoal was ingested four times a day, starting 3 h after pill intake, on cycle days 12, 13 and 14. Ovarian activity was monitored by intravaginal ultrasonography of follicles and by measurements of serum concentrations of LH, FSH, oestradiol and progesterone throughout the control and charcoal-treatment cycles of both pill treatments. None of the women ovulated. Follicular activity seen in two women did not correlate with charcoal administration. It is concluded that the possible enterohepatic recirculation of gestodene and norethisterone is not of clinical importance. Repeated charcoal treatment, when administered 3 h after but at least 12 h before pill intake, can be used to treat diarrhoea in women taking oral contraceptives.

Alterations in sex steroids and gonadotropins in post-menopausal women subsequent to long-term mifepristone administration.

Long-term administration of progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) has been proposed as a novel hormonal therapy for various hormone dependent maladies. We studied the long-term endocrine effects of mifepristone on the kinetics of estradiol (E(2)) and its precursors, and on gonadotropin levels in five postmenopausal women treated for unresectable meningioma with mifepristone [200 mg/day] for at least 15 months. Serum samples were analyzed for LH, FSH and SHBG with fluoroimmunoassay; androstenedione (A), testosterone (T), estrone (E(1)) and E(2) were measured with radioimmunoassay (RIA). Serum levels of mifepristone were measured using both RIA and high performance-liquid chromatography (HPLC). Serum levels (mean +/- SD) of LH and FSH were suppressed from pretreatment values of 32 +/- 16 and 65 +/- 30 IU/l to 13 +/- 7 and 33 +/- 16 IU/l at 6 months (P < 0.05), respectively. Serum (mean +/- SD) A, T, E(1), and E(2) were increased from initial values of 6.9 +/- 0.9 nmol/l, 1.2 +/- 0.3 nmol/l, 77 +/- 25 pmol/l, and 29 +/- 14 pmol/l to 6 month values of 13.1 +/- 5.6 nmol/l, 1.8 +/- 0.6 nmol/l, 178 +/- 60 pmol/l, and 45 +/- 22 pmol/l (n.s.). The correlation coefficients between the levels of A, T, E(1), and E(2) were statistically significant, whereas the ratios of T/A, E(1)/A, E(2)/E(1), and E(2)/T remained unchanged. The levels of SHBG remained stable, and ranged from 48 +/- 10 to 65 +/- 9 nmol/l (mean +/- SD). Thus, prolonged mifepristone treatment marginally increased the serum levels of A, T, E(1) and E(2). These effects of mifepristone are likely due to its antiglucocorticoid effect and thus increased secretion of adrenal A. Serum levels of LH and FSH declined. The serum levels of gonadotropins and those of T, E(1) and E(2) were inversely, yet significantly, correlated. Therefore the decrease in LH and FSH might reflect the slightly increased levels of T, E(1) and E(2). However, the lack of change in SHBG and the low E(2) levels suggest that enhanced systemic estrogen effects are unlikely during long-term mifepristone treatment.

Northern epilepsy, a new member of the NCL family.

Northern epilepsy, or progressive epilepsy with mental retardation (EPMR), is an autosomal recessive disorder characterized by normal early development, onset of generalized tonic-clonic seizures between the ages of 5 and 10 years, and subsequent progressive mental retardation. The seizures increase in frequency until puberty after which the epileptic activity starts to decline. Mental retardation begins 2-5 years after the onset of seizures and continues through adulthood. Neuropathological findings have shown that EPMR is a new member (CLN8) of the neuronal ceroid lipofuscinosis (NCL) group of neurodegenerative disorders. The CLN8 gene was identified recently. It encodes a 286 amino acid putative transmembrane protein with no homology to previously known proteins. Subsequently, the homologous mouse gene (Cln8) was sequenced and localized to the region of the mouse genome linked to motor neuron degeneration, mouse mnd. Mnd is a naturally occurring mouse mutant with intracellular autofluorescent inclusions similar to those seen in human CLN8. A mutation in mnd mouse DNA was identified, indicating that mnd is a murine model for CLN8.