Osteoporosis medication prescribing in British Columbia and Ontario: impact of public drug coverage.

UNLABELLED: We compared the patterns of osteoporosis medication prescribing between two provinces in Canada with different public drug coverage policies. Oral bisphosphonates were the primary drugs used, yet access to the second-generation oral bisphosphonates (alendronate, risedronate) was limited in one region. Implications of differential access to oral bisphosphonates warrants further study. INTRODUCTION: Approved therapies for treating osteoporosis in Canada include bisphosphonates, calcitonin, denosumab, raloxifene, and teriparatide. However, significant variation in access to these medications through public drug coverage exists across Canada. We sought to compare patterns of osteoporosis medication prescribing between British Columbia (BC) and Ontario. METHODS: Using dispensing data from BC (PharmaNet) and Ontario (Ontario Drug Benefits), we identified all new users of osteoporosis medications aged 66 or more years from 1995/1996 to 2008/2009. We summarized the number of new users by fiscal year, sex, and index drug for each province. BC data were also stratified by whether drugs were dispensed within or outside public PharmaCare. RESULTS: We identified 578,254 (n = 122,653 BC) eligible new users. Overall patterns were similar between provinces: (1) most patients received an oral bisphosphonate (93% in BC and 99% in Ontario); (2) etidronate prescribing declined after 2001/2002, reaching a low of 41% in BC and 10% in Ontario in 2008/2009; and (3) the proportion of males treated increased over time, from 7% in 1996/1997 to 25% in 2008/2009. However, we note major differences within versus outside the BC PharmaCare system. In particular, <2% of drugs dispensed within PharmaCare compared to 79% of drugs dispensed outside PharmaCare were for a second-generation bisphosphonate (alendronate or risedronate). CONCLUSIONS: Oral bisphosphonates are the primary drugs used to treat osteoporosis in Canada. Prescribing practices changed over time as newer medications came to market, yet access to second-generation bisphosphonates through BC PharmaCare was limited. Implications of differential access to oral bisphosphonates warrants further study.

Individualized prescribing portraits to reduce inappropriate initiation of opioid analgesics to opioid naïve patients in primary care: Protocol for a randomized controlled trial.

Background Opioid analgesics are frequently initiated for chronic and acute pain despite weak evidence of benefit, although prescribing rates of some analgesics decreased in the context of the epidemic. In some populations, up to a quarter of opioid naïve persons prescribed opioids for non-cancer pain develop prescription opioid use disorder (OUD). Audit and feedback interventions rely on constructive use of routinely collected data to align professional behaviours and clinical practice with best evidence. These interventions have been shown to help reduce inappropriate initiation. However, effectiveness and acceptability of individualized "portraits" of physicians' prescribing patterns, to reduce inappropriate initiation of opioid analgesics to opioid naïve persons, have not been evaluated. Methods REDONNA is a mixed-methods randomized study testing the effectiveness of individualized prescribing Portraits to reduce inappropriate initiation of opioid analgesics. This intervention to improve safety of opioid prescribing in primary care in British Columbia (BC), Canada involves mailing individual prescribing portraits to an 'early group' of 2604 family physicians, followed in 6 months by a mailing to 2553 family physicians in the 'delayed group'. Primary outcome is number of new opioid prescriptions initiated in opioid naïve people, measured using administrative data from a centralized medication monitoring database covering all prescription opioids dispensed from BC community pharmacies. Secondary endpoints will compare prescribing impact between the two groups. A qualitative sub-study will examine feasibility among a purposive sample of physicians and patients. Discussion This trial provides important evidence on the intervention's potential to steer policy and practice on inappropriate opioid analgesics initiation. Trial registration: The study was registered prospectively on 30 March 2020 at the ISRCTN Register (https://www.isrctn.com/ISRCTN34246811).

Managing organ transplantation, the ultimate public resource.

Public awareness campaigns have minimal impact on transplant waiting lists. Why? There is no substantial Australian-based research on the attitudes of stakeholders, or the public. An explanation is awareness groups may have a negative impact either by promoting public fatigue about organ donation or, for want of professionalism and training, lack the tact to convey a balanced message. The nascent Australian Organ and Tissue, Donation and Transplantation Authority is a welcome influence to the administration of transplantation, with a promise of an evidence-based approach to tackle a pragmatic appraisal of the problem and implementing practical methodologies to increase transplantation.

Drosophila melanogaster males respond differently at the behavioural and genome-wide levels to Drosophila melanogaster and Drosophila simulans females.

Drosophila melanogaster are found in sympatry with Drosophila simulans, and matings between the species produce nonfertile hybrid offspring at low frequency. Evolutionary theory predicts that females choose mates, so males should alter their behaviour in response to female cues. We show that D. melanogaster males quickly decrease courtship towards D. simulans females. Courtship levels are reduced within 5 min of exposure to a heterospecific female, and overall courtship is significantly lower than courtship towards conspecific females. To understand changes at the molecular level during mate choice, we performed microarray analysis on D. melanogaster males that courted heterospecific D. simulans females and found nine genes have altered expression compared with controls. In contrast, males that court conspecific females alter expression of at least 35 loci. The changes elicited by conspecific courtship likely modulate nervous system function to reinforce positive conspecific signals and dampen the response to heterospecific signals.

The Drosophila ecdysone receptor (EcR) gene is required maternally for normal oogenesis.

Oogenesis in Drosophila is regulated by the steroid hormone ecdysone and the sesquiterpenoid juvenile hormone. Response to ecdysone is mediated by a heteromeric receptor composed of the EcR and USP proteins. We have identified a temperature-sensitive EcR mutation, EcR(A483T), from a previously isolated collection of EcR mutations. EcR(A483T) is predicted to affect all EcR protein products (EcR-A, EcR-B1, and EcR-B2) since it maps to a common exon encoding the ligand-binding domain. In wild-type females, we find that both EcR-A and EcR-B1 are expressed in nurse cells and follicle cells throughout oogenesis. EcR mutant females raised at permissive temperature and then shifted to restrictive temperature exhibit severe reductions in fecundity. Oogenesis in EcR mutant females is defective, and the spectrum of oogenic defects includes the presence of abnormal egg chambers and loss of vitellogenic egg stages. Our results demonstrate a requirement for EcR during female reproduction and suggest that EcR is required for normal oogenesis.

Sjögren-Larsson syndrome is caused by a common mutation in northern European and Swedish patients.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. Patients with SLS have deficient activity of fatty aldehyde dehydrogenase (FALDH), an enzyme involved in long-chain fatty alcohol oxidation. The cDNA encoding FALDH has recently been cloned and several different mutations have been found in SLS patients. We have now identified a point mutation (C943 --> T) in 7 of 19 kindreds of European descent, accounting for 24% of the SLS alleles. The C943T mutation was only found in patients of northern European ancestry from Sweden, the Netherlands, Germany, and Belgium. Haplotype analysis suggested that the patients carrying the C943T allele were distantly related. All four Swedish patients were homozygous for C943T, indicating that this mutation is probably the major cause of SLS in the inbred Swedish families. The mutation leads to the substitution of serine for the highly conserved proline 315 in the FALDH protein, and expression studies confirm that it destroys enzymatic activity. The mutation was readily detected with an MnlI restriction enzyme digestion test. The finding that C943T is a common SLS mutation in northern European and Swedish patients affords a rapid simple method for diagnosing SLS by screening patients for this mutation with DNA-based methods.

Involvement of microsomal fatty aldehyde dehydrogenase in the alpha-oxidation of phytanic acid.

We investigated the role of microsomal fatty aldehyde dehydrogenase (FALDH) in the conversion of pristanal into pristanic acid. Cultured skin fibroblasts from controls and patients with Sjögren-Larsson syndrome (SLS) who are genetically deficient in FALDH activity were incubated with [2,3-(3)H]phytanic acid. The release of aqueous-soluble radioactivity by the SLS cells was decreased to 25% of normal, consistent with an intact formation of pristanal but a deficiency of further oxidation. SLS cells also accumulated four-fold more radioactivity in N-alkyl-phosphatidyl ethanolamine, which arises from incorporation of free aldehyde into phosphatidyl ethanolamine. Recombinant human FALDH expressed in Chinese hamster ovary cells readily oxidized pristanal and cultured fibroblasts from SLS patients showed a severe deficiency in FALDH activity (13% of normal) when pristanal was used as substrate. Nevertheless, SLS patients did not accumulate phytanic acid in their plasma. We conclude that FALDH is involved in the oxidation of pristanal to pristanic acid and that this reaction is deficient in patients with SLS.

Characteristics and distribution of nuclear medicine physicians.

OBJECTIVES: The authors examined the characteristics and distribution of physicians certified by The American Board of Nuclear Medicine (ABNM). METHODS: Three thousand seven hundred twenty-nine physicians were certified by the ABNM by 1989, and information on 3,389 physicians was obtained for this study from available databases. RESULTS: The age distribution shows 24% (793) of patients were 60 years of age or older; 17% (560) were 55 to 59 years of age; and 21% (714) were 50 to 54 years of age. The average rate of physicians certified by the ABNM was 67.8 annually over the most recent 5 years. Those physicians with additional board certification in radiology, internal medicine, and pathology also were examined. The radiology/nuclear medicine group demonstrated the largest change, with 56.7% having dual certification in the initial 6 years of the ABNM and only 26.4% in the most recent 6 years. The ratio of state population to the number of certified nuclear medicine physicians within the state was found to vary from 30,000:1 in the District of Columbia to 370,000:1 in New Hampshire. CONCLUSIONS: There will be a decline, and possibly a shortage, of comprehensively trained nuclear medicine physicians over the next 10 to 20 years. There is also a decreasing trend of American Board of Radiology (ABR) certification associated with ABNM certification. In addition, there is an uneven distribution of ABNM-certified physicians.

Evaluating the performance of detection algorithms in digital mammography.

The initial and relative evaluation of computer methodologies developed for assisting diagnosis in mammography is usually done by comparing the computer output to ground truth data provided by experts and/or biopsy. Reported studies, however, give little information on how the performance indices of computer assisted diagnosis (CAD) algorithms are determined in this initial stage of evaluation. Several strategies exist in the estimation of the true positive (TP) and false positive (FP) rates with respect to ground truth. Adopting one strategy over another yields different performance rates that can be over- or underestimates of the true performance. Furthermore, the estimation of pairs of TP and FP rates gives a partial picture of the performance of an algorithm. It is shown in this work that new performance indices are needed to fully describe the degree of detection (part or whole) and the type of detection (single calcification, cluster of calcifications, mass, or artifact). Several evaluation strategies were tested. The one that yielded the most realistic performances included the following criteria: The detected area should be at least 50% of the true area and no more than four times the true area in order to be considered TP. At least three true calcifications should be detected to within 1 cm2 with nearest neighbor distances of less than square root(2) cm for a cluster to be considered TP. Separate detection measures should be established and used for artifacts and naturally occurring structures to maximize the benefits of the evaluation. Finally, it is critical that CAD investigators provide information on the tested image set as well as the criteria used for the evaluation of the algorithms to allow comparisons and better understanding of their methodologies.

Fatty aldehyde dehydrogenase: genomic structure, expression and mutation analysis in Sjögren-Larsson syndrome.

Fatty aldehyde dehydrogenase (FALDH) is a microsomal enzyme that catalyzes the oxidation of medium- and long-chain aliphatic aldehydes derived from metabolism of fatty alcohol, phytanic acid, ether glycerolipids and leukotriene B4. The FALDH gene (ALDH3A2) in man and mouse consists of 11 exons and is closely linked to the gene for ALDH3. In both species, alternative splicing results in formation of a second minor protein, FALDHv, that has a unique carboxy-terminal end. The functional significance of this alternate protein is not known. In humans, mutations in the FALDH gene cause Sjögren-Larsson syndrome (SLS), which is characterized by ichthyosis, mental retardation and spasticity. Missense mutations involving 24 amino acid positions in FALDH have been identified. These amino acids are more highly conserved among related class 3 aldehyde dehydrogenase enzymes than expected, suggesting that they are critically important for protein folding, catalysis or stability. Studies of mutations in SLS should prove useful for understanding structure-function correlations in FALDH and other aldehyde dehydrogenase proteins.

The molecular basis of Sjögren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity, and deficient activity of fatty aldehyde dehydrogenase (FALDH). To define the molecular defects causing SLS, we performed mutation analysis of the FALDH gene in probands from 63 kindreds with SLS. Among these patients, 49 different mutations-including 10 deletions, 2 insertions, 22 amino acid substitutions, 3 nonsense mutations, 9 splice-site defects, and 3 complex mutations-were found. All of the patients with SLS were found to carry mutations. Nineteen of the missense mutations resulted in a severe reduction of FALDH enzyme catalytic activity when expressed in mammalian cells, but one mutation (798G-->C [K266N]) seemed to have a greater effect on mRNA stability. The splice-site mutations led to exon skipping or utilization of cryptic acceptor-splice sites. Thirty-seven mutations were private, and 12 mutations were seen in two or more probands of European or Middle Eastern descent. Four single-nucleotide polymorphisms (SNPs) were found in the FALDH gene. At least four of the common mutations (551C-->T, 682C-->T, 733G-->A, and 798+1delG) were associated with multiple SNP haplotypes, suggesting that these mutations originated independently on more than one occasion or were ancient SLS genes that had undergone intragenic recombination. Our results demonstrate that SLS is caused by a strikingly heterogeneous group of mutations in the FALDH gene and provide a framework for understanding the genetic basis of SLS and the development of DNA-based diagnostic tests.

Malakoplakia. A case report and review of the renal manifestations and immunopathology.

A case of renal malakoplakia associated with prednisone therapy is reported; clinical recovery had taken place 6 months later, after nephrectomy and cessation of corticosteroid administration.

A common deletion mutation in European patients with Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder characterized by ichthyosis, mental retardation, spasticity, and deficient activity of fatty aldehyde dehydrogenase (FALDH). We identified a frequent FALDH mutation in exon 9 among SLS probands of European descent. This mutation is a 2-bp deletion of nucleotides GA 1297-1298 and results in premature termination of translation at codon 435 along with substitution of Arg and Cys for Glu433 and Gly434 respectively. The GA del1297-8 mutation was found in 10 of 21 European SLS probands and could be readily detected using an allele-specific PCR method. This GA deletion mutation or a previously identified common point mutation 9C943Y) was present in 66% of the European SLS probands, and the two mutations together accounted for 48% of the SLS alleles. Screening European patients for these two common mutations should be useful for DNA-based diagnosis of SLS and genetic counseling.

The uptake of cadmium from a dietary and soluble source by the crustacean Daphnia magna.

Daphnia were exposed to radioactively labeled cadmium in solution and in the presence of Chlorella which had been preloaded with the metal to varying extents. Illuminated algal cells retained the cadmium and greatly reduced its availability to the daphnids. Autoradiographic evidence was obtained which implicated the exoskeleton as a major sink for the cadmium taken up from solution. Cadmium in solution at a concentration close to the 48 hr LC50 level did not affect respiration during the first 6 hr of exposure. Retention patterns were similar, regardless of the source of cadmium, but ecdysis resulted in a considerable loss of body burden provided that this had been acquired via a predominantly soluble route.

Rheumatoid arthritis and hereditary angioedema.

We describe a case in which rheumatoid arthritis (RA) developed in a patient with hereditary angioedema. Hereditary angioedema, one of the inherited complement deficiencies, has been reported in association with a number of autoimmune disorders, but there has been only 1 report of an association between RA and hereditary angioedema.