Breaking the chains of lipoprotein lipase deficiency: A pediatric perspective on the efficacy and safety of Volanesorsen.

RATIONALE: Lipoprotein lipase (LPL) deficiency, a rare inherited metabolic disorder, is characterized by high triglyceride (TG) levels and life-threatening acute pancreatitis. Current treatment for pediatric patients involves a lifelong severely fat-restricted diet, posing adherence challenges. Volanesorsen, an EMA-approved RNA therapy for adults, effectively reduces TG levels by decreasing the production of apolipoprotein C-III. This 96-week observational open-label study explores Volanesorsen's safety and efficacy in a 13-year-old female with LPL deficiency. METHODS: The patient, with a history of severe TG elevations, 53 hospital admissions, and life-threatening recurrent pancreatitis despite dietary restrictions, received weekly subcutaneous Volanesorsen injections. We designed a protocol for this investigator-initiated study, primarily focusing on changes in fasting TG levels and hospital admissions. RESULTS: While the injections caused occasional pain and swelling, no other adverse events were observed. TG levels decreased during treatment, with more measurements below the pancreatitis risk threshold compared to pre-treatment. No hospital admissions occurred in the initial 14 months of treatment, contrasting with 21 admissions in the 96 weeks before. In the past 10 months, two pancreatitis episodes may have been linked to dietary noncompliance. Dietary restrictions were relaxed, increasing fat intake by 65% compared to baseline. While not fully reflected in the PedsQL, both parents and the patient narratively reported an improved quality of life. CONCLUSION: This study demonstrates, for the first time, that Volanesorsen is tolerated in a pediatric patient with severe LPL deficiency and effectively lowers TG levels, preventing life-threatening complications. This warrants consideration for expanded access in this population.

Effects of early childhood otitis media and ventilation tubes on psychosocial wellbeing - A prospective cohort study within the Danish National Birth Cohort.

BACKGROUND: Otitis Media (OM) is one of the most common infections among children in developed countries and may result in temporary conductive hearing loss (HL) if accompanied by middle ear effusion (MEE). Ventilation tube insertion (VTI) is recommended as treatment for recurrent acute OM or chronic MEE with HL. HL may lead to impaired development of psychosocial skills. However, evidence for the developmental consequences of OM and the effect of VTI is inconsistent. The objectives of this study were to investigate 1) whether OM in early childhood is associated with long-term consequences of psychosocial development and 2) if VTI prevents the possible negative consequences of OM. METHODS: This study examined prospectively collected data from 52.877 children registered in the Danish National Birth Cohort (DNBC). Information about previous OM-episodes and VTI was obtained through systematic follow-up interviews at seven years, and The Strength and Difficulties Questionnaire (SDQ) containing questions about psychological wellbeing was completed. Five groups were defined based on OM-exposure and the presence of VTI. Baseline characteristics were analysed, and comparison of mean SDQ-scores for the five exposure groups was conducted. Means were adjusted for à priori defined confounding factors. RESULTS: Data from 52,877 children in the DNBC showed an association between OM and poorer SDQ-scores. VTI was associated with an additional increase, i.e. worsening, of the SDQ-score for boys, and only a slight beneficial effect on the girls' outcome. The groups differed in their baseline characteristics in e.g. maternal education, socio-economic status, breastfeeding, and prematurity. CONCLUSION: Significant associations between parent-reported OM in early childhood and later psychosocial health difficulties were found. VTI did not resolve this association.

Use of other antimicrobial drugs is associated with trimethoprim resistance in patients with urinary tract infections caused by E. coli.

In recent years, high frequencies of trimethoprim resistance in urinary tract infections (UTIs) caused by E. coli are have been reported. Co-resistance to other antimicrobial drugs may play a role in this increase. Therefore, we investigated whether previous use of other antimicrobial drugs was associated with trimethoprim resistance. We conducted a nested case-control study with urinary cultures with E. coli from participants of the Rotterdam Study sent in by general practitioners to the regional laboratory between 1 January 2000 and 1 April 2016. Multivariable logistic regression analysis was performed to study the association between prior prescriptions of several antimicrobial drug groups and trimethoprim resistance using individual participant data. Urinary cultures of 1264 individuals with a UTI caused by E. coli were included. When adjusted for previous other antimicrobial drug use, a history of > 3 prescriptions of extended-spectrum penicillins (OR 1.68; 95% CI 1.10-2.55) was significantly associated with trimethoprim resistance of E. coli as was the use of > 3 prescriptions of sulfonamides and trimethoprim (OR 2.22; 95% CI 1.51-3.26). The use of > 3 prescriptions of nitrofuran derivatives was associated with a lower frequency of trimethoprim resistance (OR 0.60; 95% CI 0.39-0.92), after adjustment for other antimicrobial drug prescriptions. We found that previous use of extended-spectrum penicillins is associated with trimethoprim resistance. On the contrary, previous nitrofurantoin use was associated with a lower frequency of trimethoprim resistance. Especially in individuals with recurrent UTI, co-resistance should be taken into account and susceptibility testing before starting trimethoprim should be considered.

Danish guidelines on management of otitis media in preschool children

"INTRODUCTION: Otitis media is one of the most common diseases in small children. This underlines the importance of optimizing diagnostics and treatment of the condition. Recent literature points toward a stricter approach to diagnosing acute otitis media (AOM). Moreover, ventilating tube treatment for recurrent AOM (RAOM) and chronic otitis media with effusion (COME) has become the most frequently performed surgical procedure in pre-school children. Therefore, the Danish Health and Medicines Authority and the Danish Society of Otorhinolaryngology, Head and Neck Surgery deemed it necessary to update the Danish guidelines regarding the diagnostic criteria for acute otitis media and surgical treatment of RAOM and COME. METHODS: The GRADE system (The Grading of Recommendations Assessment, Development and Evaluation) was used in order to comply with current standards of evidence assessment in formulation of recommendations. An extensive literature search was conducted between July and December 2014. The quality of the existing literature was assessed using AGREE II (Appraisal of Guidelines for Research & Evaluation), AMSTAR (assessing the Methodological Quality of Systematic Reviews), QUADAS-2 (Quality of Diagnostic Accuracy Studies), Cochrane Risk of Bias Tool for randomized trials and ACROBAT-NRSI (A Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies). The working group consisted of otolaryngologists, general practitioners, pediatricians, microbiologists and epidemiologists. CONCLUSION: Recommendations for AOM diagnosis, surgical management for RAOM and COME, including the role of adenoidectomy and treatment of ventilating tube otorrhea, are proposed in the guideline"

Danish guidelines on management of otitis media in preschool children.

INTRODUCTION: Otitis media is one of the most common diseases in small children. This underlines the importance of optimizing diagnostics and treatment of the condition. Recent literature points toward a stricter approach to diagnosing acute otitis media (AOM). Moreover, ventilating tube treatment for recurrent AOM (RAOM) and chronic otitis media with effusion (COME) has become the most frequently performed surgical procedure in pre-school children. Therefore, the Danish Health and Medicines Authority and the Danish Society of Otorhinolaryngology, Head and Neck Surgery deemed it necessary to update the Danish guidelines regarding the diagnostic criteria for acute otitis media and surgical treatment of RAOM and COME. METHODS: The GRADE system (The Grading of Recommendations Assessment, Development and Evaluation) was used in order to comply with current standards of evidence assessment in formulation of recommendations. An extensive literature search was conducted between July and December 2014. The quality of the existing literature was assessed using AGREE II (Appraisal of Guidelines for Research & Evaluation), AMSTAR (assessing the Methodological Quality of Systematic Reviews), QUADAS-2 (Quality of Diagnostic Accuracy Studies), Cochrane Risk of Bias Tool for randomized trials and ACROBAT-NRSI (A Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies). The working group consisted of otolaryngologists, general practitioners, pediatricians, microbiologists and epidemiologists. CONCLUSION: Recommendations for AOM diagnosis, surgical management for RAOM and COME, including the role of adenoidectomy and treatment of ventilating tube otorrhea, are proposed in the guideline.

Bowel dysfunction after low anterior resection with and without neoadjuvant therapy for rectal cancer: a population-based cross-sectional study.

AIM: Bowel dysfunction was assessed after low anterior resection with and without neoadjuvant therapy (NT) for rectal cancer using a novel symptom-based scoring system correlated with quality of life. METHOD: We identified all patients who underwent curative resection for rectal cancer in Denmark between 2001 and 2007. A questionnaire on bowel function and quality of life, including the recently validated low anterior resection syndrome score (LARS score; range 0-42) was administered to recurrence-free patients in 2009. We used multivariate analysis to examine the association between major LARS (LARS score ≥ 30) and a number of patient and treatment-related factors. RESULTS: Of 1087 eligible patients, 980 agreed to participate and, of these, 938 were included in the analysis. Major LARS was observed in 41%. The use of NT (OR = 2.48; 95% CI: 1.73-3.55), long-course chemoradiotherapy vs short-course radiotherapy (OR = 0.90; 95% CI: 0.44-1.87), total mesorectal excision (TME) vs partial mesorectal excision (PME) (OR = 2.31; 95% CI: 1.69-3.16), anastomotic leakage (OR = 2.06; 95% CI: 0.93-4.55), age ≤ 64 years at surgery (OR = 1.90; 95% CI: 1.43-2.51) and female gender (OR = 1.35; 95% CI 1.02-1.79) were associated with major LARS. No association was found between major LARS and the time since surgery (OR = 0.78; 95% CI: 0.59-1.04) or neorectal reconstruction (colonic pouch vs straight colorectal or side-to-end anastomosis (OR = 0.96; 95% CI: 0.63-1.46). CONCLUSION: Severe bowel dysfunction is a frequent long-term outcome after resection for rectal cancer. Use of NT, regardless of a long- or short-course protocol, and TME (compared with PME) are strong independent risk factors for major LARS.

Grommets (ventilation tubes) for hearing loss associated with otitis media with effusion in children.

BACKGROUND: Otitis media with effusion (OME), or 'glue ear', is very common in children, especially between the ages of one and three years with a prevalence of 10% to 30% and a cumulative incidence of 80% at the age of four years. OME is defined as middle ear effusion without signs or symptoms of an acute infection. OME may occur as a primary disorder or as a sequel to acute otitis media. The functional effect of OME is a conductive hearing level of about 25 to 30 dB associated with fluid in the middle ear. Both the high incidence and the high rate of spontaneous resolution suggest that the presence of OME is a natural phenomenon, its presence at some stage in childhood being a normal finding. Notwithstanding this, some children with OME may go on to develop chronic otitis media with structural changes (tympanic membrane retraction pockets, erosion of portions of the ossicular chain and cholesteatoma), language delays and behavioural problems. It remains uncertain whether or not any of these findings are direct consequences of OME. The most common medical treatment options include the use of decongestants, mucolytics, steroids, antihistamines and antibiotics. The effectiveness of these therapies has not been established. Surgical treatment options include grommet (ventilation or tympanostomy tube) insertion, adenoidectomy or both. Opinions regarding the risks and benefits of grommet insertion vary greatly. The management of OME therefore remains controversial. OBJECTIVES: To assess the effectiveness of grommet insertion compared with myringotomy or non-surgical treatment in children with OME. The outcomes studied were (i) hearing level, (ii) duration of middle ear effusion, (iii) well-being (quality of life) and (iv) prevention of developmental sequelae possibly attributable to the hearing loss (for example, impairment in impressive and expressive language development (measured using standardised tests), verbal intelligence, and behaviour). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2003), MEDLINE (1966 to 2003), EMBASE (1973 to 2003) and reference lists of all identified studies. The date of the last systematic search was March 2003, and personal non-systematic searches have been performed up to August 2004. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the effect of grommets on hearing, duration of effusion, development of language, cognition, behaviour or quality of life. Only studies using common types of grommets (mean function time of 6 to 12 months) were included. DATA COLLECTION AND ANALYSIS: Data from studies were extracted by two reviewers and checked by the other reviewers. MAIN RESULTS: Children treated with grommets spent 32% less time (95% confidence interval (CI) 17% to 48%) with effusion during the first year of follow-up. Treatment with grommets improved hearing levels, especially during the first six months. In the randomised controlled trials that studied the effect of grommet insertion alone, the mean hearing levels improved by around 9 dB (95% CI 4 dB to 14 dB) after the first six months, and 6 dB (95% CI 3 dB to 9 dB) after 12 months. In the randomised controlled trials that studied the combined effect of grommets and adenoidectomy, the additional effect of the grommets on hearing levels was improvement by 3 to 4 dB (95% CI 2 dB to 5 dB) at six months and about 1 to 2 dB (95% CI 0 dB to 3 dB) at 12 months. Ears treated with grommets had an additional risk for tympanosclerosis of 0.33 (95% CI 0.21 to 0.45) one to five years later. In otherwise healthy children with long-standing OME and hearing loss, early insertion of grommets had no effect on language development or cognition. One randomised controlled trial in children with OME more than nine months, hearing loss and disruptions to speech, language, learning or behaviour showed a very marginal effect of grommets on comprehensive language. AUTHORS' CONCLUSIONS: The benefits of grommets in children appear small. The effect of grommets on hearing diminished during the first year. Potentially adverse effects on the tympanic membrane are common after grommet insertion. Therefore an initial period of watchful waiting seems to be an appropriate management strategy for most children with OME. As no evidence is yet available for the subgroups of children with speech or language delays, behavioural and learning problems or children with defined clinical syndromes (generally excluded from the primary studies included in this review), the clinician will need to make decisions regarding treatment for such children based on other evidence and indications of disability related to hearing impairment. This review does not resolve the discrepancy between parental and clinical observation of a beneficial treatment effect and the results in the reviewed RCT showing only a short-term effect on hearing and virtually no effect on development. Is the perceived, often dramatic, effect of grommets only a short-term one? Are some children more sensitive to OME-related hearing loss than others? If so, how do we identify them?Further research should focus upon indications. Studies should use sufficiently large sample sizes to show significant interactions. There is a need to determine the most suitable variables and appropriate "softer" outcomes to be the subject of these interaction tests. Interesting options include measures of speech-in-noise and binaural hearing. The generally modest results in the trials which are included in this review should make it easier to justify randomisation of more severely affected and higher-risk children in appropriately constructed trials. Randomised controlled trials are necessary in these children before more detailed conclusions about the effectiveness of grommets can be drawn.

CYP1A2 activity is an important determinant of clozapine dosage in schizophrenic patients.

Clozapine is an effective atypical antipsychotic drug applied in the treatment of resistant schizophrenia. The drug is mainly metabolized by cytochrome P-450 (CYP) enzymes especially the isozyme CYP1A2. Remarkably, the effective dosage varies widely among patients, making it necessary to individualize drug therapy with clozapine. The explanation for dosage variation may be differences in drug metabolism, and more specifically of CYP1A2 activity. This study is aimed at determining to what extent variability in clozapine dose can be explained by pharmacokinetic (PK) factors and more specifically by CYP1A2 activity in effectively treated psychiatric patients. In 22 evaluable patients with a schizophrenic disorder chronically using clozapine, the CYP1A2 activity and the clozapine clearance were estimated. For calculation of the pharmacokinetic parameters of clozapine, population PK software based upon Bayesian analysis was used. Caffeine clearance was estimated with the paraxanthine/caffeine ratio and served as estimate of CYP1A2 activity.A significant linear relationship was found between the clozapine dose and clozapine clearance (R: 0.71; P<0.05), whereas no relationship was found between clozapine dosage and clozapine serum trough concentration. Moreover, individual caffeine and clozapine clearances were found to be significantly related (R: 0.62; P<0.05) as were clozapine dose per kg body weight and P/C mol ratio (R: 0.44; P<0.05). We conclude that CYP1A2 activity is an important determinant of the variability of effective clozapine doses in psychiatric patients.

Health technology assessment in clinical biochemistry. Methylmalonic acid: a Danish showcase.

In 1992 plasma methylmalonic acid (MMA) was introduced in Denmark for diagnosing vitamin B-12 deficiency. Now, 10 years later, we report on a health technology assessment (HTA) suggesting that the clinical usefulness of MMA is uncertain. MMA is an obvious component for measurement in the diagnosis of vitamin B-12 deficiency because MMA accumulates when there is a lack of vitamin B-12, and technologically the analysis is of high quality. The diagnostic sensitivity of MMA is high, whereas the diagnostic specificity is debatable, and our results suggest it to be relatively low. The organizational aspect implies that both MMA and P-cobalamins have been increasingly employed, though no consensus on the use of the analyses has emerged. The benefit to the patient is not obvious. An increased level of MMA does not predict further increases over time, and vitamin B-12 treatment shows limited clinical benefit in individuals with a moderately increased MMA. The economic consequences of introducing MMA were an increase in the costs of MMA and P-cobalamins of 12% per year during 1992-2000 and an increase in the turnover of vitamin B-12 preparations of 9% per year. In conclusion, MMA was introduced on sound grounds for both pathophysiological considerations and analytical quality. Our HTA shows that the resources employed to diagnose and to treat vitamin B-12 deficiency have increased considerably, but yet we have no evidence to suggest the clinical benefit.

Two novel methods for the determination of CYP1A2 activity using the paraxanthine/caffeine ratio.

Cytochrome P450 1A2 (CYP1A2) plays an important role in drug metabolism. Provocation with caffeine is used to estimate CYP1A2 activity, but in most tests a long period of caffeine abstinence has to be taken into account. We compared two novel methods with the currently applied test. The pharmacokinetic (PK) parameters of caffeine and paraxanthine were estimated in eight caffeine-taking healthy volunteers by fitting serum concentration-time data to a two-compartment PK model. Then a three-step approach was followed. Step 1: The caffeine administration regimens of three provocation methods, which differ by their periods of abstinence, together with the PK parameters of each volunteer, were entered in a PK simulation program and the molecular ratio of the paraxanthine/caffeine concentration (P/C molratio) of each method was estimated for the individual volunteers. Step 2: For each method a relationship for the population between the caffeine clearance (Clc) and the corresponding P/C molratio was empirically established. Step 3: The true caffeine clearance (Clc tr) of each volunteer, as found by fitting the individual PK curve, was compared for all three methods with the clearance estimated from the individual P/C molratio using the relationship of step 2. The predictive values for Clc of the three methods did not differ significantly from Clc tr. For the three methods the values for bias were 6.7, 4.3 and 3.1%, respectively and for precision they were 12.3, 20.6 and 17.8%. We conclude that the two novel methods of caffeine provocation show good predictive performance for Clc when compared with the conventional method. Abstaining from caffeine for a long period is not necessary to estimate CYP1A2 activity (using the P/C molratio) accurately.

[MEDLINE in the age of Internet]. / MEDLINE i Internettets tidsalder.

The use MEDLINE and related resources of literature information has increased significantly with the increased availability and speed of the Internet. However, literature information is presented in many different ways via the Internet and search facilities and web addresses are frequently changed. Many physicians and medical researchers find it difficult to keep track of what is available and many lack skills in effective searching. The present paper presents an overview of the MEDLINE database and related databases available from the National Library of Medicine and searchable through PubMed and Internet Greatfull Med. We discuss strategies for searching MEDLINE and the coverage of MEDLINE related to that of related databases from the NLM and other sources.

[Online publishing in the Internet age]. / Online-publicering i Internettets tidsalder.

The availability of full text medical journal articles is rapidly increasing with the increased availability of the Internet. The potentials of the new technology present researchers, publishers, and librarians with new problems and challenges. Some resources are made available free of charge, whereas others are distributed as parts of large licences negotiated between publishers and consortia of research libraries. How can researchers maintain an overview of the constantly changing resources? How can libraries cope with tasks rapidly redefined by the technology? And how can publishers survive when production and distribution of literature information, including the handling of peer reviewing, might just as well be performed by the researchers themselves or their organisations? The present paper presents some of the resources available and discusses both national and international projects and activities that deal with these questions.

Regional variations in the use of diagnostic coronary angiography. A one-year population-based study of all diagnostic coronary angiographies performed in a rural and an urban Danish county.

The aim of this study was to monitor coronary angiography activity and results, and to evaluate indications and treatment consequences using regional hospital registers and case records in the rural county of Ringkjøbing and urban county of Aarhus The study included all patients who had undergone a coronary angiography during 1996. For women, there were 606 (rural) and 1296 (urban) coronary angiographies per one million inhabitants (p < 0.0001) and for men, 1884 (rural) and 3051 (urban) coronary angiographies per one million inhabitants (p < 0.0001). In both counties the age distribution of the women examined was the same as that for the men. The angiographic rates were the same in the two counties for patients examined for valvular heart disease and severe arrhythmias. For patients with ischaemic heart disease, the angiographic rate for rural patients was two to three times lower than that for urban patients (p < 0.01). Revascularization procedures were performed in 39% (rural) and 40% (urban) of the examined women (NS) and 66% (rural) and 59% (urban) of the examined men (p < 0.05). Despite wide regional differences in coronary angiography activity, angiography was deployed to the same extent for examination of patients with valvular and severe arrhythmia heart disease. For patients examined for ischaemic heart disease, angiography activity was considerably lower in the rural area. The female patients had a higher frequency of normal coronary angiograms than the male patients.

[Tympanometry]. / Tympanometri.

A flat tympanogram predicts a middle ear effusion in about 90% of cases. This paper describes how to perform tympanometry, some common problems when doing it and how to classify the curves in normal (type A), middle ear effusion (type B) or negative pressure (type C). The theoretical background of impedance audiometry is outlined. The stapedius reflex, pneumatic otoscopy, reflexometry and otomicroscopy are described as supplements or alternatives in diagnosing fluid in the middle ear. Tympanometry is recommended as a diagnostic modality for general practitioners.

[Acute otitis media and antibiotics. Evidence-based guidelines for antibiotic therapy?]. / Akut otitis media og antibiotika. Evidensbaserede retningslinjer for antibiotisk behandling?

Antibiotic treatment of acute otitis media is controversial. The questions are when to treat, with which antibiotic, and for how long? Within the last years three reviews attempting to discuss these questions have been published. All three found only a marginal effect of antibiotic treatment. The effect was less earache after the first day. The meta-analyses showed that between eight and 22 children had to be treated before one had any benefit of the treatment. The randomized studies did not find a greater effect of amoxicillin than of penicillin. The marginal effect of antibiotics on acute otitis media supports watchful waiting and individualized care and follow-up. There is a need for well-organized, randomized, placebo-controlled trials including the youngest children and the more severe cases of acute otitis media where the effect of antibiotic treatment may turn out to be most beneficial.

A video-based performance in noise test for measuring audio-visual disability in young school children: test development, with validation by trained teachers, parents and audiometry as relative standards for disability.

BACKGROUND: impaired ability to detect target sounds in noisy surroundings is a particular feature of children with a history of otitis media with effusion (OME). Children with current OME are also likely to experience difficulty in speech reception in classrooms where a high level of background noise has been recorded. No tests are currently available which are feasible in primary care and which objectively measure school-related disabilities. The effects of speech in noise and the extent to which this is offset by speech reading contribute important dimensions to disability. METHODS: a video-based speech reception test has been developed using the same principles in 227 English and 182 Danish 4-8 year-old children. Distribution data was collected for both language versions of the test. The test has been compared with audiometry and teacher and parents assessments to establish its validity. INTERPRETATION: there are no gold standards for audio-visual disability in current clinical use. The poor positive predictive value of audiometry for likely classroom functioning is a cause for concern, particularly in relation to inappropriate referral of children by primary care physicians.