Summary goodness-of-fit statistics for binary generalized linear models with noncanonical link functions.

Generalized linear models (GLM) with a canonical logit link function are the primary modeling technique used to relate a binary outcome to predictor variables. However, noncanonical links can offer more flexibility, producing convenient analytical quantities (e.g., probit GLMs in toxicology) and desired measures of effect (e.g., relative risk from log GLMs). Many summary goodness-of-fit (GOF) statistics exist for logistic GLM. Their properties make the development of GOF statistics relatively straightforward, but it can be more difficult under noncanonical links. Although GOF tests for logistic GLM with continuous covariates (GLMCC) have been applied to GLMCCs with log links, we know of no GOF tests in the literature specifically developed for GLMCCs that can be applied regardless of link function chosen. We generalize the Tsiatis GOF statistic originally developed for logistic GLMCCs, (TG), so that it can be applied under any link function. Further, we show that the algebraically related Hosmer-Lemeshow (HL) and Pigeon-Heyse (J(2) ) statistics can be applied directly. In a simulation study, TG, HL, and J(2) were used to evaluate the fit of probit, log-log, complementary log-log, and log models, all calculated with a common grouping method. The TG statistic consistently maintained Type I error rates, while those of HL and J(2) were often lower than expected if terms with little influence were included. Generally, the statistics had similar power to detect an incorrect model. An exception occurred when a log GLMCC was incorrectly fit to data generated from a logistic GLMCC. In this case, TG had more power than HL or J(2) .

Supports for medical students during rural clinical placements: factors associated with intention to practise in rural locations.

INTRODUCTION: Through rural clinical schools (RCSs), medical students may undertake an extended block of clinical training in rural Australia. The premise of these placements is that meaningful rural exposure will facilitate rural career uptake. RCSs offer a range of supports to facilitate student engagement in the program. This study aims to analyse RCS students' perceptions of these supports and impact on intentions to work rurally. METHODS: Between September 2012 and January 2013 RCS students were invited to complete questions regarding perceptions of student support, as a part of the annual Federation of Australian Medical Educators survey. Multivariable logistic regression was used to identify associations between supports and intentions for rural internship or career. RESULTS: There were 454 participants. A majority of students (n=349, 79.1%) felt well supported by their RCS. Students from a rural background (odds ratio (OR)=1.64 (95% confidence interval (CI):1.13-2.38)), or who indicated that their placement had a positive impact on their wellbeing (OR=1.38 (95%CI:1.07-1.80)), were more likely to intend to complete a rural internship. Those who felt socially isolated were less likely to elect this (OR=0.82 (0.70-0.97)). Outcomes were similar for those indicating a preference for rural or remote practice after completing training. CONCLUSIONS: Student perceptions of supports offered by RCSs were generally very positive. Perceptions of financial support were not predictive of rural career intent. Although this does not negate the importance of providing appropriate financial supports, it does demonstrate that student wellbeing is a more important recruitment factor for rural practice.

Routine prescribing of gabapentin or pregabalin in supportive and palliative care: what are the comparative performances of the medications in a palliative care population?

Neuropathic pain is a prevalent and distressing problem faced by people with life-limiting illness that is often difficult to palliate. Gabapentin and pregabalin are widely prescribed as part of the routine approach to palliating neuropathic pain. Although they are often viewed as interchangeable agents, very little comparative data of their benefits and harms exists in clinical practice. Two previously reported pharmacovigilance studies that had used the same methodology for gabapentin and pregabalin were compared. These studies examined the benefits and harms of gabapentin and pregabalin after the medications had been routinely prescribed by clinicians working in a network of palliative care services using the same data collection tools with the same definitions and the same time points. Data were collected over 21 days from 282 patients prescribed either gabapentin or pregabalin for pain. Items included medication doses, pain scores, and adverse effects. In order to compare the medication responses, the final doses of pregabalin were converted to gabapentin does equivalents using previously published recommendations. The final pain scores were similar for both groups, and the reduction in pain were similar (OR = 11.2; 95 % CI 3.9, 32.7, p < 0.001). However, this was achieved at lower doses of gabapentin compared to pregabalin. Those receiving gabapentin were more likely to experience harms (OR = 3.5; 95 % CI 1.4, 9.1, p = 0.009) with the reported harms including somnolence, ataxia, nausea, tremor and nystagmus This hypothesis-generating work strongly supports the need for further trials to best delineate clinical differences in the GABA analogues.

Comparative Effectiveness of Supine Avoidance versus Continuous Positive Airway Pressure for Treating Supine-isolated Sleep Apnea: A Clinical Trial.

Rationale: About 20-35% of patients with obstructive sleep apnea (OSA) have supine-isolated OSA, for which supine sleep avoidance could be an effective therapy. However, traditional supine discomfort-based methods show poor tolerance and compliance to treatment and so cannot be recommended. Supine alarm devices show promise, but evidence to support favorable adherence to treatment and effectiveness at reducing excessive daytime sleepiness compared with continuous positive airway pressure (CPAP) remains limited. Objectives: To establish if alarm-based supine-avoidance treatment in patients with supine-isolated OSA is noninferior to CPAP in reducing daytime sleepiness. Methods: After baseline questionnaire administration and in-home supine-time and polysomnography assessments, patients with supine-isolated OSA and Epworth Sleepiness Scale scores ⩾8 were randomized to ⩾6 weeks of supine-avoidance or CPAP treatment, followed by crossover to the remaining treatment with repeat assessments. Noninferiority was assessed from change in Epworth Sleepiness Scale with supine avoidance compared with CPAP using a prespecified noninferiority margin of 1.5. Average nightly treatment use over all nights and treatment efficacy and effectiveness at reducing respiratory disturbances were also compared between treatments. Results: The reduction in sleepiness score with supine avoidance (mean [95% confidence interval], -1.9 [-2.8 to -1.0]) was noninferior to that with CPAP (-2.4 [-3.3 to -1.4]) (supine avoidance-CPAP difference, -0.4 [-1.3 to 0.6]), and the lower confidence limit did not cross the noninferiority margin of 1.5 (P = 0.021). Average treatment use was higher with supine avoidance compared with CPAP (mean ± standard deviation, 5.7 ± 2.4 vs. 3.9 ± 2.7 h/night; P < 0.001). Conclusions: In patients with supine-isolated OSA, vibrotactile supine alarm device therapy is noninferior to CPAP for reducing sleepiness and shows superior treatment adherence. Clinical trial registered with www.anzctr.org.au (ACTRN 12613001242718).

CaSR-mediated interactions between calcium and magnesium homeostasis in mice.

Calcium (Ca) and magnesium (Mg) homeostasis are interrelated and share common regulatory hormones, including parathyroid hormone (PTH) and vitamin D. However, the role of the calcium-sensing receptor (CaSR) in Mg homeostasis in vivo is not well understood. We sought to investigate the interactions between Mg and Ca homeostasis using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR) (double knockout, DKO). Serum Mg is lower in PTH KO and DKO mice than in WT mice on standard chow, whereas supplemental dietary Ca leads to equivalent Mg levels for all three genotypes. Mg loading increases serum Mg in all genotypes; however, the increase in serum Mg is most pronounced in the DKO mice. Serum Ca is increased with Mg loading in the PTH KO and DKO mice but not in the WT mice. Here, too, the hypercalcemia is much greater in the DKO mice. Serum and especially urinary phosphate are reduced during Mg loading, which is likely due to intestinal chelation of phosphate by Mg. Mg loading decreases serum PTH in WT mice and increases serum calcitonin in both WT and PTH KO mice but not DKO mice. Furthermore, Mg loading elevates serum 1,25-dihydroxyvitamin D in all genotypes, with greater effects in PTH KO and DKO mice, possibly due to reduced levels of serum phosphorus and FGF23. These hormonal responses to Mg loading and the CaSR's role in regulating renal function may help to explain changes in serum Mg and Ca found during Mg loading.

Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo.

Calcium and phosphorus homeostasis are highly interrelated and share common regulatory hormones, including FGF23. However, little is known about calcium's role in the regulation of FGF23. We sought to investigate the regulatory roles of calcium and phosphorus in FGF23 production using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR; PTH-CaSR DKO). In wild-type, PTH KO, and PTH-CaSR DKO mice, elevation of either serum calcium or phosphorus by intraperitoneal injection increased serum FGF23 levels. In PTH KO and PTH-CaSR DKO mice, however, increases in serum phosphorus by dietary manipulation were accompanied by severe hypocalcemia, which appeared to blunt stimulation of FGF23 release. Increases in dietary phosphorus in PTH-CaSR DKO mice markedly decreased serum 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] despite no change in FGF23, suggesting direct regulation of 1,25(OH)(2)D(3) synthesis by serum phosphorus. Calcium-mediated increases in serum FGF23 required a threshold level of serum phosphorus of about 5 mg/dl. Analogously, phosphorus-elicited increases in FGF23 were markedly blunted if serum calcium was less than 8 mg/dl. The best correlation between calcium and phosphorus and serum FGF23 was found between FGF23 and the calcium × phosphorus product. Since calcium stimulated FGF23 production in the PTH-CaSR DKO mice, this effect cannot be mediated by the full-length CaSR. Thus the regulation of FGF23 by both calcium and phosphorus appears to be fundamentally important in coordinating the serum levels of both mineral ions and ensuring that the calcium × phosphorus product remains within a physiological range.

Deficiency of the calcium-sensing receptor in the kidney causes parathyroid hormone-independent hypocalciuria.

Rare loss-of-function mutations in the calcium-sensing receptor (Casr) gene lead to decreased urinary calcium excretion in the context of parathyroid hormone (PTH)-dependent hypercalcemia, but the role of Casr in the kidney is unknown. Using animals expressing Cre recombinase driven by the Six2 promoter, we generated mice that appeared grossly normal but had undetectable levels of Casr mRNA and protein in the kidney. Baseline serum calcium, phosphorus, magnesium, and PTH levels were similar to control mice. When challenged with dietary calcium supplementation, however, these mice had significantly lower urinary calcium excretion than controls (urinary calcium to creatinine, 0.31±0.03 versus 0.63±0.14; P=0.001). Western blot analysis on whole-kidney lysates suggested an approximately four-fold increase in activated Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). In addition, experimental animals exhibited significant downregulation of Claudin14, a negative regulator of paracellular cation permeability in the thick ascending limb, and small but significant upregulation of Claudin16, a positive regulator of paracellular cation permeability. Taken together, these data suggest that renal Casr regulates calcium reabsorption in the thick ascending limb, independent of any change in PTH, by increasing the lumen-positive driving force for paracellular Ca(2+) transport.

Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells.

Several proteins implicated in the pathogenesis of polycystic kidney disease (PKD) localize to cilia. Furthermore, cilia are malformed in mice with PKD with mutations in TgN737Rpw (encoding polaris). It is not known, however, whether ciliary dysfunction occurs or is relevant to cyst formation in PKD. Here, we show that polycystin-1 (PC1) and polycystin-2 (PC2), proteins respectively encoded by Pkd1 and Pkd2, mouse orthologs of genes mutated in human autosomal dominant PKD, co-distribute in the primary cilia of kidney epithelium. Cells isolated from transgenic mice that lack functional PC1 formed cilia but did not increase Ca(2+) influx in response to physiological fluid flow. Blocking antibodies directed against PC2 similarly abolished the flow response in wild-type cells as did inhibitors of the ryanodine receptor, whereas inhibitors of G-proteins, phospholipase C and InsP(3) receptors had no effect. These data suggest that PC1 and PC2 contribute to fluid-flow sensation by the primary cilium in renal epithelium and that they both function in the same mechanotransduction pathway. Loss or dysfunction of PC1 or PC2 may therefore lead to PKD owing to the inability of cells to sense mechanical cues that normally regulate tissue morphogenesis.

Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial.

OBJECTIVES: To compare the effect of a single infusion of zoledronic acid (ZA) with placebo on knee pain and bone marrow lesions (BMLs). METHODS: Adults aged 50-80 years (n=59) with clinical knee osteoarthritis and knee BMLs were randomised to receive either ZA (5 mg/100 ml) or placebo. BMLs were determined using proton density-weighted fat saturation MR images at baseline, 6 and 12 months. Pain and function were measured using a visual analogue scale (VAS) and the knee injury and osteoarthritis outcome score (KOOS) scale. RESULTS: At baseline, mean VAS score was 54 mm and mean total BML area was 468 mm(2). VAS pain scores were significantly reduced in the ZA group compared with placebo after 6 months (-14.5 mm, 95% CI -28.1 to -0.9) but not after 3 or 12 months. Changes on the KOOS scales were not significant at any time point. Reduction in total BML area was greater in the ZA group compared with placebo after 6 months (-175.7 mm(2), 95% CI -327.2 to -24.3) with a trend after 12 months (-146.5 mm(2), 95% CI -307.5 to +14.5). A greater proportion of those in the ZA group achieved a clinically significant reduction in BML size at 6 months (39% vs 18%, p=0.044). Toxicity was as expected apart from a high rate of acute phase reactions in treatment and placebo arms. CONCLUSIONS: ZA reduces knee pain and areal BML size and increases the proportion improving over 6 months. Treatment of osteoarthritis may benefit from a lesion specific therapeutic approach. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN 12609000399291.

A prospective study of the impact of musculoskeletal pain and radiographic osteoarthritis on health related quality of life in community dwelling older people.

BACKGROUND: Pain and radiographic changes are common in persons with osteoarthritis, but their relative contributions to quality of life are unknown. METHODS: Prospective cohort study of 1098 men and women aged 50-80 years, randomly selected from the electoral roll. Participants were interviewed at baseline and approximately 2.6 and five years later. Participants self-reported prior diagnosis of arthritis and presence of joint pain. Joint space narrowing (JSN) and osteophytes at the hip and knee were assessed by X-ray. Quality of life (QoL) was assessed using the Assessment of QoL (AQoL) instrument. Data was analysed using linear regression and mixed modelling. RESULTS: The median AQoL score at baseline was 7.0, indicating very good QoL. Prevalence of pain ranged from 38-62%. Over five years of observation, pain in the neck, shoulders, back, hips, hands, knees and feet were all independently and negatively associated with QoL, in a dose-response relationship. Diagnosed osteoarthritis at all sites was associated with poorer QoL but after adjustment for pain, this only remained significant at the back. Radiographic OA was not associated with QoL. While AQoL scores declined over five years, there was no evidence of an interaction between pain and time. CONCLUSIONS: Pain is common in older adults, is stable over time, and the strongest musculoskeletal correlate of QoL. It also mediates the association between diagnosed OA and QoL. Since the same factors were associated with quality of life over time as at baseline, this suggests that quality of life tracks over a five year period.

Blood Pressure, Aortic Stiffness, Hemodynamics, and Cognition in Twin Pairs Discordant for Type 2 Diabetes.

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of cognitive impairment and dementia with poorly understood underlying mechanisms. OBJECTIVE: We examined the role of blood pressure (BP), aortic stiffness, and hemodynamics in this association. METHODS: Cross-sectional sample of late middle-aged twins discordant for T2D from the Australian Twin Registry. Measurements included neuropsychological battery and brain MRI including arterial spin labelling (ASL) to measure cerebral perfusion. Mobil-o-Graph devices were used to non-invasively obtain 24-hour BP, aortic stiffness, and hemodynamic measures. Using mixed modelling, we studied associations of T2D with cognition, MRI measures, BP, aortic stiffness, and hemodynamics. RESULTS: There were 23 twin pairs with mean age 63.7 (SD = 6.1) years. T2D (ß=-0.45, p < 0.001) and age (ß=-0.05, p = 0.022) were independently associated with poorer attention but not with memory or perceptual speed. T2D was associated with reduced nocturnal central systolic BP dipping (ß=-3.79, p = 0.027), but not with BP, aortic stiffness, cerebral perfusion, or other hemodynamic measures. There was a statistically significant interaction between T2D and central systolic BP dipping in predicting attention scores (both p < 0.05 for the interaction term) whereby there was a positive association between BP dipping and attention scores in those with T2D, but not in those without T2D. CONCLUSION: We found an association between T2D and reduced nocturnal central systolic dipping, but not with any other measures of BP, stiffness or hemodynamic measures. Further study of the role of nocturnal central BP dipping in the association between T2D and cognitive impairment may help identify potential mechanisms.

Assessment of cellular immune responses of healthy and diseased Tasmanian devils (Sarcophilus harrisii).

The Tasmanian devil (TD) (Sarcophilus harrisii) is under threat from devil facial tumour disease (DFTD), a cancer that is transmitted between devils by direct cell implantation. As no devil is known to have rejected the tumour allograft, an understanding of the immune status of this species is essential to help explain the unique infectious nature of this cancer. We analysed differential white blood cell counts, the phagocytic response of neutrophils as well as mitogen-induced lymphocyte proliferation. Devils analysed included healthy TDs kept in captivity, healthy devils from disease-free and diseased areas as well as diseased devils. Neutrophils isolated from the peripheral blood of healthy devils showed competent phagocytosis and peripheral blood mononuclear cells from healthy and diseased devils proliferated in response to Con A, PHA and PWM stimulation. Although a wide range of responses was observed and relatively high doses of mitogens were required, there was no significant difference between males and females, adults and juveniles or between normal and diseased animals, suggesting that transmission of DFTD is not a consequence of a severely impaired immune system. As lymphocytes from all TDs appear to require strong stimulation for activation, this threshold may contribute to all devils being susceptible to DFTD.

Fat mass, but not fat-free mass, predicts increased foot pain with obesity, independent of bariatric surgery.

BACKGROUND: Foot pain is a common manifestation of obesity. OBJECTIVE: To determine if bariatric surgery is associated with a reduction in foot pain and if body mass index (BMI) or body composition predict a change in foot pain. SETTING: University hospital. METHODS: Participants with foot pain awaiting bariatric surgery were recruited for this prospective study. Multivariable linear regression was used to determine predictors of change in foot pain between baseline and 6-month follow-up using body composition (fat mass index and fat-free mass index) or BMI, adjusting for, depression, age, sex, and group (surgery versus control). RESULTS: Forty-five participants (38 female), mean ± standard deviation age of 45.7 ± 9.4 years, were recruited for this study. Twenty-nine participants mean ± standard deviation BMI of 44.8 ± 7.0 kg underwent bariatric surgery, while 16 participants mean ± standard deviation BMI of 47.9 ± 5.2 kg were on the waiting list (control). One participant was lost to follow-up. The treatment group lost a mean of 24.3 kg (95% confidence interval [CI] 21.1-27.5), while the control group gained 1.2 kg (95% CI -2.5 to 4.9), respectively. In multivariable analysis, bariatric surgery was significantly associated with reduced foot pain at 6-month follow-up -32.6 points (95% CI -43.8 to -21.4, P < .001), while fat mass index was significantly associated with increased pain at follow-up 1.5 points (95% CI .2 to 2.8, P = .027), after controlling for fat-free mass index, age, sex, and depression. CONCLUSIONS: Bariatric surgery was significantly associated with reduced foot pain. Higher baseline fat mass index, but not fat-free mass index or BMI, was predictive of increased foot pain at follow-up. Foot pain may be mediated by metabolic, rather than mechanical, factors in bariatric surgery candidates.

The calcium-sensing receptor (CaR) is involved in strontium ranelate-induced osteoblast proliferation.

Strontium ranelate has several beneficial effects on bone and reduces the risk of vertebral and hip fractures in women with postmenopausal osteoporosis. We investigated whether Sr(2+) acts via a cell surface calcium-sensing receptor (CaR) in HEK293 cells stably transfected with the bovine CaR (HEK-CaR) and rat primary osteoblasts (POBs) expressing the CaR endogenously. Elevating Ca(o)(2+) or Sr(2+) concentration-dependently activated the CaR in HEK-CaR but not in non-transfected cells, but the potency of Sr(2+) varied depending on the biological response tested. Sr(2+) was less potent than Ca(o)(2+) in stimulating inositol phosphate accumulation and in increasing Ca(i)(2+), but was comparable to Ca(o)(2+) in stimulating ERK phosphorylation and a non-selective cation channel, suggesting that Ca(2+) and Sr(2+) have differential effects on specific cellular processes. With physiological concentrations of Ca(o)(2+), Sr(2+)-induced further CaR activation. Neither Sr(2+) nor Ca(o)(2+) affected the four parameters just described in non-transfected cells. In POB, Sr(2+) stimulated cellular proliferation. This effect was CaR-mediated, as transfecting the cells with a dominant negative bovine CaR significantly attenuated Ca(o)(2+)-stimulated POB proliferation. Finally, Sr(2+) significantly increased the mRNA levels of the immediate early genes, c-fos and egr-1, which are involved in POB proliferation, and this effect was attenuated by overexpressing the dominant negative CaR. In conclusion, Sr(2+) is a full CaR agonist in HEK-CaR and POB, and, therefore, the anabolic effect of Sr(2+) on bone in vivo could be mediated, in part, by the CaR.

The Tasmanian Epilepsy Register--a community-based cohort. Background and methodology for patient recruitment from the Australian national prescription database.

BACKGROUND/AIMS: Centralized prescription databases may provide an efficient mechanism for recruitment of community-treated disease. METHODS: The Australian federal government agency, the Health Insurance Commission (HIC), invited patients to participate in the Tasmanian Epilepsy Register (TER). Eligible patients included those who received at least one anticonvulsant above a 'reportable' price threshold between July 1, 2001 and June 30, 2002. Patients were asked to disclose their medical indication for anticonvulsant treatment with additional demographic and prescription information obtained from the HIC. RESULTS: 7,541 were eligible for recruitment. After two mail invitations over 6 months, 3,375 (46.6%) had responded, but TER enrollment amongst those indicating treatment for epilepsy was 1,180 (78.3%). TER participants were more likely to obtain their prescriptions exclusively from their general practitioner (70.9%) or from combined sources (19.1%) rather than from pediatrician (4.2%), neurologist (1.4%) or general physician (1.0%) sources. Patients were more likely to respond with increasing age (linear trend p < 0.001), when from a higher socioeconomic area (linear trend p < 0.001), or if their prescription was obtained from a neurologist (p < 0.001). CONCLUSION: The national Australian prescription database represents community-treated epilepsy and provides an effective and efficient method for patient recruitment for clinical epidemiological research.

Mid-term migration of a cementless, porous acetabular cup: A 5 year Radiostereometric analysis.

PURPOSE: The aim of the study was to determine the 5 year migratory and wear patterns, adverse events and clinical outcomes of a cementless, porous acetabular cup. METHODS: RSA imaging of a cohort of 11 patients was retrospective analysed at 5 years post Total Hip Arthroplasty (THA). Changes in pain, function and symptoms of the hip at 5 years post-THA were compared to preoperative and 2 year postoperative assessments on the Harris Hip Score (HHS) and Hip dysfunction and Osteoarthritis Outcome Score (HOOS). RESULTS: The majority of cup migration occurred up to 6 months and stabilised thereafter (6 months to 5 years, p = 0.091-0.866, Wilcoxon Signed Rank test). The direction of rotation around the 3 axes was evenly distributed among the cups between anterior-posterior rotation, internal-external rotation and increased-decreased inclination. The majority of the cups translated proximally, at an average migration of 0.36 mm (±95%CI 0.17) at 5-years post-THA. Following initial bedding in, up to 6 months, there was no detectable polyethylene wear between 6 months and 5 years. At 5 years postoperatively, a statistically significant difference was observed across all HOOS subscales in comparison to preoperative values, with higher means reported at 5 years (p < 0.001). The total mean HHS displayed a statistically significant improvement, increasing from 'poor' preoperatively to 'good' at 5 years post-THA. CONCLUSION: Following initial migration between discharge and 6 months, the cementless porous acetabular cup demonstrated a tendency for stabilisation from 6 months up to 5 years post-THA, suggesting good mid-term fixation. Additionally, improvements in clinical outcome measures of pain, function and quality-of-life remained high following THA at 5 years post-surgery.

Long-term cognitive transitions, rates of cognitive change, and predictors of incident dementia in a population-based first-ever stroke cohort.

BACKGROUND AND PURPOSE: There are few data on long-term cognitive outcomes after first-ever stroke. We aimed to study long-term cognitive transitions, rates of cognitive change, and factors associated with incident dementia and cognitive impairment-no dementia (CIND) 2 years after first-ever stroke. METHODS: A population-based cohort of incident first-ever stroke cases (n=99; mean age, 69.9 years) and an age- and sex-matched comparison group (nonstrokes, n=99) were followed up for 2 years by 3 serial examinations. Rates of cognitive change were compared by repeated-measures analyses. Factors associated with incident dementia and CIND at 2 years were determined by multinomial logistic regression. RESULTS: Significant stroke x time interactions were present for all cognitive domains, with stroke cases showing a greater rate of decline compared with nonstrokes. Stroke recurrence during follow-up was responsible for significantly greater global decline. Strokes with recurrence (P=0.02), age (P=0.004), and baseline cognitive impairment (P<0.001) were independently associated with incident dementia at 2 years. Strokes without recurrence (P=0.008), age (P=0.001), and baseline cognitive impairment (P<0.001) were independently associated with CIND at 2 years. CONCLUSIONS: Recurrent stroke contributes importantly to global cognitive decline after a first-ever stroke. Secondary stroke prevention will be important in ameliorating dementia related to stroke. Mechanisms underlying the progression of early cognitive impairment to dementia in stroke patients need further investigation.

Pharmacovigilance in hospice/palliative care: net effect of pregabalin for neuropathic pain.

INTRODUCTION: Real-world effectiveness of many medications has been poorly researched, including in hospice/palliative care. Directly extrapolating findings from other clinical settings may not yield robust clinical advice. Pharmacovigilance studies provide an opportunity to understand better the net impact of medications. The study aimed to examine immediate and short-term benefits and harms of pregabalin in routine practice for neuropathic pain in hospice/palliative care. METHODS: A consecutive cohort of 155 patients from 62 centres in 5 countries was started on pregabalin and studied prospectively. Data were collected at three time points: baseline; day 7 (immediate, short-term harms); ad hoc reports of any harms ≤21 days; and day 21 (short-term benefits). RESULTS: Median dose for 155 patients at day 21 was 150 mg/24 h. Benefits were reported by 61 patients (39%), of whom 11 (7%) experienced complete pain resolution. Harms were reported by 51 (35%) patients at or before 7 days, the most frequent of which were somnolence, fatigue, cognitive disturbance and dizziness. 10 patients (6%) ceased pregabalin due to harms, but 82 patients (53%) were being treated at 21 days. In regression modelling, people with worse baseline pain derived more benefit (OR=8.5 (95% CI 2.5 to 28.68). CONCLUSIONS: Pregabalin delivered benefit to many patients, with 4 of 10 experiencing pain reductions by 21 days. Harms, occurring in 1 in 3 patients, may be difficult to detect in clinical practice, as they mostly involve worsening of symptoms prevalent at baseline.

Predictors of Mortality for Delirium in Palliative Care.

INTRODUCTION: Delirium has a high mortality rate. Understanding predictors of prognosis in patients with delirium will aid treatment decisions and communication. This study aimed to explore variables associated with death during an established episode of delirium in palliative care when haloperidol treatment had been commenced. METHODS: A consecutive cohort of palliative care patients, from 14 centers across four countries, is reported. The outcome of interest was death within 14 days from commencement of haloperidol treatment for delirium. Clinicodemographic variables explored were delirium severity, age, gender, primary life limiting illness, body mass index (BMI), total daily haloperidol dose at baseline (mg), functional status, and comorbidities. RESULTS: One hundred and sixteen palliative care patients where vital status was known were included in the analysis; 45% (n = 52) died within 10 days, and 56% (n = 65) died within 14 days. In multivariate analyses no clinical or demographic variables predicted death, apart from lower BMI in noncancer patients. CONCLUSION: This study has shown a very high mortality rate within two weeks of commencing haloperidol for delirium in palliative care, with no clear clinical predictors for those with a higher chance of dying. Having a higher BMI offered some benefit in survival, but only in noncancer patients. When delirium occurs in advanced illness, discussion should be initiated about the gravity of the clinical situation.