Serious infections in patients with myasthenia gravis: population-based cohort study.

BACKGROUND AND PURPOSE: To characterize the frequency and risk of serious infections in patients with myasthenia gravis (MG) relative to age/sex/area-matched comparators. METHODS: This was a population-based cohort study in Ontario, Canada of patients with newly-diagnosed MG and 1:4 age/sex/area-matched general population comparators accrued from 1 April 2002 to 31 December 2015. The main outcome was a serious infection, defined by a primary diagnosis code on a hospitalization or emergency department record. We computed crude overall and sex-specific rates of infection among patients with MG and comparators, and the frequency of specific types of infection. Adjusted hazard ratios and 95% confidence intervals were estimated using Cox regression. RESULTS: Among 3823 patients with MG, 1275 (33.4%) experienced a serious infection compared with 2973/15 292 (19.4%) of comparators over a mean follow-up of over 5 years. Crude infection rates among patients with MG were twice those in comparators (72.5 vs. 35.0 per 1000 person-years, respectively). The most common infection types were respiratory infections, particularly bacterial pneumonia. After adjustment for potential confounders, MG was associated with a 39% increased infection risk (adjusted hazard ratio, 1.39; 95% confidence intervals, 1.28-1.51). CONCLUSIONS: Patients with MG are at a significantly higher absolute and relative risk of serious infections compared with age/sex/area-matched comparators. This needs to be considered when selecting MG treatments and when planning vaccination/prophylaxis. Determining whether this risk is due to the use of immunosuppressive medications (vs. MG itself) is an important area for future research.

Proximal femoral resection without post-operative traction for the painful dislocated hip in young patients with cerebral palsy: a review of 79 cases.

Proximal femoral resection (PFR) is a proven pain-relieving procedure for the management of patients with severe cerebral palsy and a painful displaced hip. Previous authors have recommended post-operative traction or immobilisation to prevent a recurrence of pain due to proximal migration of the femoral stump. We present a series of 79 PFRs in 63 patients, age 14.7 years (10 to 26; 35 male, 28 female), none of whom had post-operative traction or immobilisation. A total of 71 hips (89.6%) were reported to be pain free or to have mild pain following surgery. Four children underwent further resection for persistent pain; of these, three had successful resolution of pain and one had no benefit. A total of 16 hips (20.2%) showed radiographic evidence of heterotopic ossification, all of which had formed within one year of surgery. Four patients had a wound infection, one of which needed debridement; all recovered fully. A total of 59 patients (94%) reported improvements in seating and hygiene. The results are as good as or better than the historical results of using traction or immobilisation. We recommend that following PFR, children can be managed without traction or immobilisation, and can be discharged earlier and with fewer complications. However, care should be taken with severely dystonic patients, in whom more extensive femoral resection should be considered in combination with management of the increased tone.

Trends in selection and timing of first-line pharmacotherapy in older patients with type 2 diabetes diagnosed between 1994 and 2006.

AIMS: To characterize temporal trends in the selection and timing of first-line pharmacotherapy among older patients with Type 2 diabetes. DESIGN AND METHODS: We studied five population-based cohorts every 3 years, from 1994 to 2006. In each of those years, we identified all subjects aged 66 years or older newly diagnosed with diabetes and determined the initial glucose-lowering drug and the time between diagnosis and drug initiation. We calculated the proportion of patients prescribed each agent and estimated time from diagnosis to initiation using Kaplan-Meier survival analysis. RESULTS: We identified a total of 64 368 eligible people who initiated drug therapy during the study period. From 1994 to 2006, first-line metformin use increased from 20.1 to 79.0%. Glyburide (glibenclamide) decreased from 71.1% of all first-line therapies in 1994 to 9.8% in 2006, while first-line use of insulin or combination therapy have changed little at approximately 5% each. No other medication exceeded 2% of first-line therapies. The median time from diagnosis to initiation of pharmacotherapy increased dramatically during the study period, from 1.8 years in 1994 to 4.6 years in 2006. CONCLUSIONS: Metformin has become the most commonly used initial medication for the treatment of diabetes. Although guidelines have evolved to recommend more aggressive initiation and intensification of pharmacotherapy, our results suggest that the time from diagnosis to initiation has increased substantially.

Progression through diabetes therapies among new elderly users of metformin: a population-based study.

AIMS: To examine temporal changes in progression to second-line therapies among older patients with diabetes newly treated with metformin. METHODS: We conducted a population-based study among residents of Ontario, Canada aged 66 years and older with diabetes newly treated with metformin monotherapy in 1997, 2000, 2003 or 2006. Each annual cohort was followed until progression to a second oral hypoglycaemic agent, insulin or until 31 December 2010. Time to progression to a second oral hypoglycaemic agent or insulin was compared across the cohorts. RESULTS: In the four annual cohorts, we identified a total of 46 104 people newly treated with metformin monotherapy. The median time to progression to any second diabetes therapy lengthened significantly over time, from 5.0 years in 1997 to 6.1 years in 2003 (P < 0.0001). Similarly, the time to progression to insulin lengthened over the study period (P = 0.03). Furthermore, the choice of second-line therapy changed over time. While 80.7% of new metformin users in 1997 progressed to glyburide therapy as second-line treatment, the corresponding figure by 2006 was only 45.1% as newer treatment options emerged. CONCLUSIONS: Although recent guidelines recommend aggressive intensification of oral therapy for patients with Type 2 diabetes, older Ontarians with diabetes who started metformin in 2006 remained on monotherapy for longer than those who started in 1997. Furthermore, although there is no consensus regarding a preferred second-line therapy, the introduction of new alternatives has led to greater variation in the selection of second-line therapies in this population.

A population-based assessment of the drug interaction between levothyroxine and warfarin.

Most drug interaction resources suggest that levothyroxine can dramatically potentiate the effect of warfarin. However, the mechanistic basis of the interaction is speculative, and little evidence supports a meaningful drug interaction. We conducted a population-based nested case-control study to examine the risk of hospitalization for hemorrhage following the initiation of levothyroxine in a cohort of 260,076 older patients receiving warfarin. In this group, we identified 10,532 case subjects hospitalized for hemorrhage and 40,595 controls. In the primary analysis, we found no association between hospitalization for hemorrhage during warfarin therapy and initiation of levothyroxine in the preceding 30 days (adjusted odds ratio 1.11, 95% confidence interval 0.67-1.86). Secondary analyses using more remote initiation of levothyroxine also found no association. These findings suggest that concerns about a clinically meaningful levothyroxine-warfarin drug interaction are not justified. Drug interaction resources that presently characterize this interaction as important should reevaluate this classification.

Bisphosphonate prescribing, persistence and cumulative exposure in Ontario, Canada.

UNLABELLED: We studied new users of oral bisphosphonates and found that less than half persisted with therapy for 2 years, and interruptions in use were common. During a median observation period of 4.7 years, 10% of patients filled only a single prescription, 37% switched therapies and median cumulative exposure was 2.2 years. INTRODUCTION: We sought to describe bisphosphonate prescribing, persistence and cumulative exposure among seniors in Ontario, Canada. METHODS: We used Ontario Drug Benefit pharmacy claims to identify residents aged ≥ 66 years who initiated oral bisphosphonate therapy between April 1996 and March 2009. The first date of bisphosphonate dispensing was considered the index date. Persistence with therapy was defined as continuous treatment with no interruption exceeding 60 days. We examined persistence with therapy and the number of extended gaps (>60 days) between prescriptions over time periods ranging from 1 to 9 years. We also identified the proportion of patients filling only a single prescription and switching to a different bisphosphonate, and calculated the median days of exposure irrespective of gaps in therapy. RESULTS: A total of 451,113 eligible new bisphosphonate users were identified: mean age = 75.6 years (SD = 6.9), 84% female, and median follow-up length = 4.7 years. Persistence with therapy declined from 63% at 1 year to 46% at 2 years and 12% at 9 years. Among those with at least 5 years of follow-up (n = 213,029), 61% had one or more extended gaps in bisphosphonate therapy. Overall, 10% of patients filled only a single prescription, 37% switched to a different bisphosphonate and the median exposure was 2.2 years. CONCLUSION: Less than half of patients persisted with bisphosphonate therapy for 2 years and interruptions in therapy were common, with most patients experiencing two or more >60-day gaps in therapy. Interventions are needed to improve persistence with bisphosphonate therapy and reduce the frequency of gaps in treatment.

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.

Elastic intramedullary nailing of paediatric fractures of the forearm: a decade of experience in a teaching hospital in the United Kingdom.

We present the results of 90 consecutive children with displaced fractures of the forearm treated by elastic stable intramedullary nailing with a mean follow-up of 6.6 months (2.0 to 17.6). Eight (9%) had open fractures and 77 (86%) had sustained a fracture of both bones. The operations were performed by orthopaedic trainees in 78 patients (86%). All fractures healed at a mean of 2.9 months (1.1 to 8.7). There was one case of delayed union of an ulnar fracture. An excellent or good functional outcome was achieved in 76 patients (84%). There was no statistical difference detected when the grade of operating surgeon, age of the patient and the diaphyseal level of the fracture were correlated with the outcome. A limited open reduction was required in 40 fractures (44%). Complications included seven cases of problematic wounds, two transient palsies of the superficial radial nerve and one case each of malunion and a post-operative compartment syndrome. At final follow-up, all children were pain-free and without limitation of sport and play activities. Our findings indicate that the functional outcome following paediatric fractures of the forearm treated by elastic stable intramedullary nailing is good, without the need for anatomical restoration of the radial bow.

Osteoporosis quality indicators using healthcare utilization data.

SUMMARY: Healthcare utilization data may be used to examine the quality of osteoporosis management by identifying dual-energy X-ray absorptiometry (DXA) testing (sensitivity = 98%, specificity = 93%) and osteoporosis pharmacotherapy (κ = 0.81) with minimal measurement error. INTRODUCTION: In osteoporosis, key quality indicators among older women include risk assessment by DXA and/or pharmacotherapy within 6 months following fracture. METHODS: The purpose of this study was to examine healthcare utilization data for use as quality indicators of osteoporosis management. We linked data from 858 community-dwelling women aged over 65 years who completed a standardized telephone interview about osteoporosis management to their healthcare utilization (medical and pharmacy claims) data. Agreement between self-report of osteoporosis pharmacotherapy and pharmacy claims was examined using kappa statistics. We examined the sensitivity and specificity of medical claims to identify DXA testing as well as the sensitivity and specificity of medical and pharmacy claims to identify those with DXA-documented osteoporosis (T-score ≤ -2.5). RESULTS: Participants were aged 75 (SD = 6) years on average; 96% were Caucasian. Agreement between self-report and claims-based osteoporosis pharmacotherapy was very good (κ = 0.81; 95% CI = 0.76, 0.86). The sensitivity of medical claims to identify DXA testing was 98% (95% CI = 95.9, 99.1), with estimated specificity of 93% (95% CI = 89.8, 95.4). We abstracted DXA results from test reports of 359 women, of whom 114 (32%) were identified with osteoporosis. Medical (osteoporosis diagnosis) and pharmacy (osteoporosis pharmacotherapy) claims within a year after DXA testing had a sensitivity of 80% (95% CI = 71.3, 86.8) and specificity of 72% (95% CI = 66.2, 77.8) to identify DXA-documented osteoporosis. CONCLUSION: Healthcare utilization data may be used to examine the quality of osteoporosis management by identifying DXA testing and osteoporosis pharmacotherapy (care processes) with minimal measurement error. However, medical and pharmacy claims alone do not provide a good means for identifying women with underlying osteoporosis.

Structural characterisation of ligand-binding determinants in human lung surfactant protein D: influence of Asp325.

The crystal structures of a biologically and therapeutically active recombinant homotrimeric fragment of human lung surfactant protein D with a series of bound ligands have been determined. While the structures reveal various different binding modes, all utilise a similarly positioned pair of mannose-type O3' and O4' hydroxyls with no direct interaction between any non-terminal sugar and protein. The orientation, position, and interactions of the bound terminal sugar depend on the sugar itself, the presence and form of glycosidic linkage, and the environment in the crystal, which, via Asp325, places stereochemical and electronic constraints, different for the three different subunits in the homotrimer, on the ligand-binding site. As a direct consequence of this influence, the other binding-pocket flanking residue, Arg343, exhibits variable conformation and variable interactions with bound ligand and leaves open to question which orientation of terminal mannobiose, and of other terminal disaccharides, may be present in extended physiological ligands. The combined structural evidence shows that there is significant flexibility in recognition; that Asp325, in addition to Arg343, is an important determinant of ligand selectivity, recognition, and binding; and that differences in crystal contact interfaces exert, through Asp325, significant influence on preferred binding modes.

The management of septic arthritis in children: systematic review of the English language literature.

We performed a systematic review of the optimal management of septic arthritis in children as recommended in the current English literature using MEDLINE, EMBASE, CINAHL, the Cochrane Library and reference lists of retrieved articles without date restrictions up to 31 January 2009. From 2236 citations, 227 relevant full-text articles were screened in detail; 154 papers fulfilled the inclusion criteria, from which conclusions were drawn on the management of infected joints in children. Our review showed that no single investigation, including joint aspiration, is sufficiently reliable to diagnose conclusively joint infection. The roles of aspiration, arthrotomy and arthroscopy in treatment are not clear cut, and the ideal duration of antibiotic therapy is not yet fully defined. These issues are discussed. Further large-scale, multi-centre studies are needed to delineate the optimal management of paediatric septic arthritis.

Hypothalamic-pituitary-adrenal axis abnormalities in response to deletion of 11beta-HSD1 is strain-dependent.

Inter-individual differences in hypothalamic-pituitary-adrenal (HPA) axis activity underlie differential vulnerability to neuropsychiatric and metabolic disorders, although the basis of this variation is poorly understood. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has previously been shown to influence HPA axis activity. 129/MF1 mice null for 11beta-HSD1 (129/MF1 HSD1(-/-)) have greatly increased adrenal gland size and altered HPA activity, consistent with reduced glucocorticoid negative feedback. On this background, concentrations of plasma corticosterone and adrenocorticotrophic hormone (ACTH) were elevated in unstressed mice, and showed a delayed return to baseline after stress in HSD1-null mice with reduced sensitivity to exogenous glucocorticoid feedback compared to same-background genetic controls. In the present study, we report that the genetic background can dramatically alter this pattern. By contrast to HSD1(-/-) mice on a 129/MF1 background, HSD1(-/-) mice congenic on a C57Bl/6J background have normal basal plasma corticosterone and ACTH concentrations and exhibit normal return to baseline of plasma corticosterone and ACTH concentrations after stress. Furthermore, in contrast to 129/MF1 HSD1(-/-) mice, C57Bl/6J HSD1(-/-) mice have increased glucocorticoid receptor expression in areas of the brain involved in glucocorticoid negative feedback (hippocampus and paraventricular nucleus), suggesting this may be a compensatory response to normalise feedback control of the HPA axis. In support of this hypothesis, C57Bl/6J HSD1(-/-) mice show increased sensitivity to dexamethasone-mediated suppression of peak corticosterone. Thus, although 11beta-HSD1 appears to contribute to regulation of the HPA axis, the genetic background is crucial in governing the response to (and hence the consequences of) its loss. Similar variations in plasticity may underpin inter-individual differences in vulnerability to disorders associated with HPA axis dysregulation. They also indicate that 11beta-HSD1 inhibition does not inevitably activate the HPA axis.

Supracondylar humeral fractures in children: ten years' experience in a teaching hospital.

Although supracondylar fracture is a very common elbow injury in childhood, there is no consensus on the timing of surgery, approach for open reduction and positioning of fixation wires. We report our ten-year experience between 1993 and 2003 in 291 children. Most fractures (285; 98%) were extension injuries, mainly Gartland types II (73; 25%) and III (163; 56%). Six (2%) were open fractures and a neurovascular deficit was seen in 12 (4%) patients. Of the 236 children (81%) who required an operation, 181 (77%) were taken to theatre on the day of admission. Most (177; 75%) of the operations were performed by specialist registrars. Fixation was by crossed Kirschner wires in 158 of 186 (85%) patients and open reduction was necessary in 52 (22%). A post-operative neurological deficit was seen in nine patients (4%) and three (1%) required exploration of the ulnar nerve. Only 22 (4%) patients had a long-term deformity, nine (3%) from malreduction and three (1%) because of growth arrest, but corrective surgery for functional limitation was required in only three (1%) patients.

Traumatic hip dislocation in a 21-month-old child.

Traumatic hip dislocation in the paediatric population is a relatively rare occurrence and constitutes an orthopaedic emergency. A trivial force is all that is required and non-accidental injury should not be necessarily suspected. A case report involving a hip dislocation in a 21-month-old child, the youngest in the recent English literature is detailed.

Future possibilities of the Linac Coherent Light Source.

A study of the potential for the development of the Linac Coherent Light Source (LCLS) beyond the specifications of the baseline design is presented. These future developments include delivery of X-ray pulses in the 1 fs regime, extension of the spectral range, increase of the FEL power, exploitation of the spontaneous emission, and a more flexible time structure. As this potential is exploited, the LCLS can maintain its role as a world-leading instrument for many years beyond its commissioning in 2008 and initial operation as the world's first X-ray free-electron laser.

Role of family physicians in hospitals. Did it change between 1977 and 1997?

OBJECTIVE: To investigate whether hospital activities and attitudes toward hospitals of members of an urban family medicine department changed between 1977 and 1997. To explore whether these activities and attitudes are different among fee-for-service (FFS) and non-FFS physicians in 1997. DESIGN: Cross-sectional surveys by interview (1977) and self-administered questionnaire (1997). SETTING: Community-based family practices in Hamilton, Ont. PARTICIPANTS: In 1977, 88 of 89 (98.9%) and, in 1997, 66 of 88 (75.0%) members of the Department of Family Medicine at St Joseph's Hospital in Hamilton. MAIN OUTCOME MEASURES: Perceived reasons for involvement in hospital work; time spent and main activities in hospital; use of hospital privileges; attitudes toward family physicians' role in hospital, hospital work, and the Department of Family Medicine; perceptions of patients', consultants', and hospital administrators' attitudes toward family physicians' role in hospitals. RESULTS: In 1977 and 1997, patient care and continuing education remained key reasons for doing hospital work. In 1997, however, respondents spent a mean of 3 hours less per week in hospital; used the hospital less often for procedures, meetings, and teaching; and assumed less responsibility for their patients' in-hospital care. While perceptions of hospital work changed over the years, most physicians continued to see a need and have a desire to remain involved in hospitals. Fee-for-service and non-FFS physicians held different opinions on the needs of both hospitalized patients and family physicians. CONCLUSION: Although physicians' hospital activities and attitudes changed between 1997 and 1997, most continued to see a need and have a desire to remain involved in hospitals.

Characterisation of human adenylyl cyclase IX reveals inhibition by Ca(2+)/Calcineurin and differential mRNA plyadenylation.

The functional diversity of adenylyl cyclases provides for different modes of cyclic AMP signalling in mammals. This study reports the cloning and functional characterisation of a cDNA encoding human adenylyl cyclase IX (ACIX). The data show that human ACIX is a Ca(2+)/calcineurin-inhibited adenylyl cyclase prominently expressed in vital organs, including brain, heart, and pancreas. ACIX mRNA was detected in several brain regions, including neocortex, hippocampus, striatum, and cerebellum. By in situ hybridisation, ACIX mRNA was localised to pyramidal and granule cells of the hippocampus, indicating that it is expressed predominantly in nerve cells. Further analysis of ACIX mRNA expression revealed two major forms of ACIX mRNA that arose through tissue-specific differential mRNA polyadenylation. Taken together, the data show that (a) human ACIX is under inhibitory control by Ca(2+) through calcineurin, (b) ACIX may be involved in higher brain functions, and (c) post-transcriptional regulation of ACIX gene expression is a species-specific control mechanism that may enhance the versatility of cyclic AMP signalling in humans.