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To the Editor: Acute kidney injury (AKI) is a lesser-known complication of hip fracture that may come about owing to decreased kidney perfusion and heightened inflammation from trauma, pain, bleeding, and fasting. Approximately 15%-20% of patients undergoing surgery for a hip fracture develop AKI, with 0.5%-1.8% receiving dialysis. [...]

Objective To determine whether 3% w/w levomenthol added to ibuprofen gel (5% w/w) improves its efficacy compared with ibuprofen gel alone or diclofenac gel (1.16%) for the treatment of soft-tissue injuries. Methods A total of 182 patients with acute soft-tissue injuries participated in a randomised, single-blind, single-dose study to assess the efficacy and safety of three topical analgesic gels. Efficacy was assessed as the score change in a numeric rating scale for pain. Results The median time to significant pain relief was 20 minutes for the ibuprofen/levomenthol and diclofenac gels but 25 minutes for ibuprofen gel. At 2 hours, significantly more patients treated with ibuprofen/levomenthol gel reported a cooling sensation (45.8%) compared with diclofenac (16.4%) or ibuprofen (14.7%) gels, and both ibuprofen/levomenthol and diclofenac gels provided significantly more effective global pain relief compared with ibuprofen gel. Few adverse events and no serious adverse events related to study medication were recorded. Conclusions Although all gels effectively relieved pain, both ibuprofen/levomenthol and diclofenac gels provided superior global pain relief compared with ibuprofen gel, with a shorter median time to significant pain relief. Only ibuprofen/levomenthol gel provided cooling for up to 2 hours. None of the gels were associated with serious safety concerns. EudraCT No 2015-005240-33 EU Clinical Trials Register URL: https://www.clinicaltrialsregister.eu/ctr-search/search

© 2020 Elsevier Ltd Background: Observational studies have suggested that accelerated surgery is associated with improved outcomes in patients with a hip fracture. The HIP ATTACK trial assessed whether accelerated surgery could reduce mortality and major complications. Methods: HIP ATTACK was an international, randomised, controlled trial done at 69 hospitals in 17 countries. Patients with a hip fracture that required surgery and were aged 45 years or older were eligible. Research personnel randomly assigned patients (1:1) through a central computerised randomisation system using randomly varying block sizes to either accelerated surgery (goal of surgery within 6 h of diagnosis) or standard care. The coprimary outcomes were mortality and a composite of major complications (ie, mortality and non-fatal myocardial infarction, stroke, venous thromboembolism, sepsis, pneumonia, life-threatening bleeding, and major bleeding) at 90 days after randomisation. Patients, health-care providers, and study staff were aware of treatment assignment, but outcome adjudicators were masked to treatment allocation. Patients were analysed according to the intention-to-treat principle. This study is registered at ClinicalTrials.gov (NCT02027896). Findings: Between March 14, 2014, and May 24, 2019, 27 701 patients were screened, of whom 7780 were eligible. 2970 of these were enrolled and randomly assigned to receive accelerated surgery (n=1487) or standard care (n=1483). The median time from hip fracture diagnosis to surgery was 6 h (IQR 4–9) in the accelerated-surgery group and 24 h (10–42) in the standard-care group (p

Background: Scottish Intercollegiate Guidelines Network and National Institute of Health and Care Excellence guidelines stress the importance of assessing patients with psoriasis for psoriatic arthritis, comorbidities associated with severe disease and quality of life (QoL). The purpose of the study was to evaluate the primary care management of psoriasis in relation to disease severity and QoL from apatient's perspective. Methods: A cross-sectional survey of adults (≥18 years) with psoriasis managed in primary care was conducted in Scotland over 1-year (2012-2013). Patients with psoriasis were identified and invited to participate in the online/telephone survey. The questionnaires included; Dermatology Life Quality Index (DLQI), Self-Administered Psoriasis Area and Severity Index (SAPASI), Psoriasis Epidemiology Screening Tool (PEST). The primary outcome measure was DLQI. Secondary outcomes included; demographics; comorbidities; involvement of different body sites; SAPASI and PEST scores. Relationships between measures were analysed using univariate analysis. Results: The mean age of patients (n = 905) was 54.5 years (SD = 16.1), 436 (48.2 %) were men, and median DLQI and SAPASI scores were 4.0 and 6.0, respectively. Current psoriasis treatments were topical only (587, 64.9 %), oral medications or phototherapy (122, 13.5%), biologics (26, 3 %) and none (156, 17.2 %). Despite SIGN recommendations,256 of 391 patients (65.5 %) with a DLQI >5 (at least a moderate effect on QoL) had not seen a specialist during the past year. According to PEST scores, 259 patients (28.6 %) had symptoms suggestive of psoriatic arthritis requiring rheumatology referral. Conclusion: National recommendations are not being fully implemented in primary care in patients with psoriasis or psoriatic arthritis.

Objectives The authors recently reported on efficacy and safety of prolonged-release melatonin formulation (PRM; Circadin 2 mg) in elderly insomnia patients. The age cut-off for response to PRM and the long-term maintenance of efficacy and safety were further evaluated by looking at the total cohort (age 18-80 years) from that study and subsets of patients aged 18-54 and 55-80 years (for whom the drug is currently indicated). Design Randomised, double-blind, placebo controlled trial. Setting Multicentre, outpatients, primary care setting. Methods A total of 930 males and females aged 18-80 years with primary insomnia who reported mean nightly sleep latency (SL) >20 min were enrolled and 791 entered the active phase of the study. The study comprised a 2-week, single-blind placebo run-in period followed by 3 week's double-blind treatment with PRM or placebo, one tablet per day at 2 hours before bedtime. PRM patients continued whereas placebo completers were re-randomised 1:1 to PRM or placebo for 26 weeks followed by 2-weeks run-out on placebo. Main outcome measures SL and other sleep variables derived from sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of life (WHO-5), Clinical Global Impression of Improvement (CGI-I) and adverse effects, recorded each visit, withdrawal and rebound effects during run-out. Results In all, 746 patients completed the 3-week and 555 (421 PRM, 134 placebo) completed the 6-month period. The principal reason for drop-out was patient decision. At 3 weeks, significant differences in SL (diary, primary variable) in favour of PRM vs. placebo treatment were found for the 55-80-year group (-15.4 vs. -5.5 min, p = 0.014) but not the 18-80-year cut-off which included younger patients. Other variables (SL-PSQI, PSQI, WHO-5, CGI-I scores) improved significantly with PRM in the 18-80-year population, more so than in the 55-80-year age group. Improvements were maintained or enhanced over the 6-month period with no signs of tolerance. No withdrawal symptoms or rebound insomnia were detected. Most adverse events were mild with no significant differences between PRM and placebo groups in any safety outcome. Conclusions The results demonstrate short- and long-term efficacy of PRM in insomnia patients aged 18-80 years, particularly those aged 55 and over. PRM was well-tolerated over the entire 6-month period with no rebound or withdrawal symptoms following discontinuation. Study Registry No: ClinicalTrials.gov ID: NCT00397189.

Primary care patients with a major depressive disorder and 17-item Hamilton Rating Scale for Depression (17-HAM-D) score >18 were randomized to 24 weeks of treatment with mirtazapine 30-45 mg/day (n=99) or paroxetine 20-30 mg/day (n=98). Both treatments were efficacious in improving depressive symptomatology, as assessed by group mean 17-HAM-D scores, percentages of HAM-D responders and remitters and Clinical Global Improvement responders. The mirtazapine group showed statistically significantly larger decreases from baseline in group mean 17-HAM-D scores at weeks 1, 2 and 4, and the difference with the paroxetine group reached the level of clinical relevance at weeks 2 and 4. Antidepressant efficacy was maintained throughout both the acute and continuation phase of treatment. Both treatments were well tolerated. The only adverse event with a statistically significantly higher incidence in the mirtazapine group was fatigue. Statistically significantly more paroxetine-treated patients complained of increased sweating, headache and nausea. The results demonstrate that both mirtazapine and paroxetine were efficacious and well tolerated when used for 24 weeks in depressed patients treated in primary care. An observed difference in efficacy favouring mirtazapine between weeks 1 and 4 indicates that mirtazapine patients had improved earlier compared to those on paroxetine, and corroborates similar findings in other comparisons of mirtazapine versus selective serotonin reuptake inhibitors.

This paper extends options-based mortgage default theory to include transaction costs. When transaction costs are considered, the rational borrower will default only when the value of the collateral falls below the mortage value by an amount equal to the net transaction costs. Since, for most borrowers, net transaction costs are positive, standard measures of equity may be significantly negative by the time the rational borrower exercises the default option. This research shows theoretically and empirically the effects of frictions on the individual strike price. The addition of transaction costs to the theory provides several testable implications for equity loss severity. First, the longer the foreclosure process and the period of free rent to the borrower, the lower the severity. Second, severity will be smaller when bankruptcy has been declared. Third, severity is decreasing in the contract decreasing function of the probability of a deficiency judgment. The empirical results, using servicing and foreclosure data from a large northeastern thrift, support the theoretical model.

Alan G Wade1, Gordon M Crawford1, David Young21CPS Research, Glasgow, UK; 2Department of Mathematics and Statistics, University of Strathclyde, Glasgow, Scotland, UKAim: To assess the attitudes and preferences of patients currently being treated for depression or anxiety disorders with traditional oral antidepressants relative to a placebo orodispersible (ODT) formulation of escitalopram.Methods: This was an open study collecting patient-reported outcome data from patients with anxiety or depression that were treated with oral antidepressant medication on Day 0 before and after receiving a single placebo ODT, and on Day 3 or 4 after receiving two further daily doses of placebo ODT. Patients aged 18–80 years who were currently receiving treatment with oral antidepressants were recruited from general practice and by advertising. Patients with significant symptoms of anxiety or depression (scoring ≥9 on either the depression or anxiety subscales of the Hospital Anxiety and Depression Scale) were included in the study.Results: A total of 150 patients were enrolled in and completed the study. About 37% of the patients had had trouble with swallowing tablets, and patients with higher depression scores reported more general swallowing problems than those with lower scores (P = 0.002). Most patients (75.3%) believed that an ODT might work faster but that it would make no difference to the effectiveness of the medication (63.1%) or the number of side effects (81.3%). About 96% of the patients reported experiencing a pleasant taste following the placebo ODT, although seven patients did not like its taste or aftertaste. This study found that 80.7% of patients reported that the tablets were easy or very easy to get out of the packaging.Conclusion: Based on the results of the placebo version of escitalopram ODT, the escitalopram ODT is likely to be well accepted by patients suffering from anxiety or depressive symptoms.Keywords: ODT, swallowing difficulties, antidepressant, depression, anxiety

Alan G Wade1, Gordon M Crawford1, Neil Pumford1, Alex McConnachie21Patients Direct, 3 Todd Campus, Glasgow, UK; 2Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UKBackground: There has been worldwide interest in the safety of the pandemic influenza A (H1N1p) vaccines, although limited data are available from the vaccine recipients’ perspective. This evaluation was designed to collect data from people who had received an influenza vaccination during the 2009–2010 season using a web-based data collection tool supplemented by telephone reporting (PROBE).Methods: People scheduled to receive the influenza A (H1N1p) or seasonal influenza vaccines were recruited through media advertising and campaigns throughout the West of Scotland. Vaccine recipients participated in the evaluation by answering demographic and side effect questions using PROBE methodology on the day of the immunization, after 3 days, 8 days, 6 weeks, 12 weeks, and 26 weeks.Results: A total of 1103 vaccine recipients including 134 young children (0–4 years) participated in the evaluation; 694 (63%) received H1N1p vaccine only, 135 (12%) seasonal vaccine only, 224 (20%) both H1N1p and seasonal vaccines, and 50 (5%) received H1N1p or seasonal vaccine with a non-influenza vaccine (eg, travel or pneumococcal). Overall, 42% of recipients reported experiencing a side effect after their baseline vaccination; the most commonly reported were general and arm side effects (>20%). Injection site discomfort/pain and flu-like symptoms were reported by 57% and 24% of recipients, respectively. A significantly higher proportion of the 960 H1N1p vaccine recipients experienced a side effect (44% vs 27%, P < 0.001) or injection site discomfort/pain (61% vs 26%, P < 0.001) than those receiving seasonal influenza vaccines. Female sex and H1N1p vaccination were associated with a significantly higher risk of injection site discomfort/pain, whereas the 70+ age group was associated with a significantly lower risk. H1N1p vaccine was well tolerated by children under 5 years with side effects reported at a similar frequency to that found in the total population.Conclusions: Safety and tolerability data from influenza vaccine recipients including young children (via parents/carers) can be effectively collected using an online questionnaire with a telephone option (PROBE). The influenza A (H1N1p) vaccine was well tolerated, but was associated with more local short-term reactions than the seasonal influenza vaccine.Keywords: safety, influenza, vaccination, H1N1, patient reported outcomes, side effects

Background Escitalopram is licensed for use at doses up to 20 mg but is used clinically at higher doses. There is limited published data at higher doses and none in the treatment of Major Depressive Disorder (MDD). Methods This open-label, pilot study was designed to investigate the efficacy, safety and tolerability of escitalopram in doses up to 50 mg in MDD. It was conducted in 60 primary care patients with MDD who had not responded to adequate treatment with citalopram. Patients were treated with escalating doses of escitalopram up to 50 mg for up to 32 weeks until they achieved remission (Montgomery-Asberg Depression Rating Scale [MADRS] ≤8) or failed to tolerate the dose. Results Forty-two patients (70%) completed the study. Twenty-one patients (35%) achieved remission with 8 of the 21 patients (38%) needing the 50 mg dose to achieve remission. Median time to remission was 24 weeks and median dose in remission was 30 mg. No significant safety issues were identified although tolerability appeared to decline above a dose of 40 mg with 26% of patients unable to tolerate 50 mg. Twelve (20%) patients had adverse events leading to discontinuation. The most common adverse events were headache (35%), nausea, diarrhoea and nasopharyngitis (all 25%). Minor mean weight gain was found during the study, which did not appear to be dose-related. Half of the patients who completed the study chose to continue treatment with escitalopram rather than taper down the dose at 32 weeks. Conclusions Dose escalation with escitalopram above 20 mg may have a useful role in the management of patients with MDD, although further studies are needed to confirm this finding. Trial Registration ClinicalTrials.gov: NCT00785434

Background: Melatonin is extensively used in the USA in a non-regulated manner for sleep disorders. Prolonged release melatonin (PRM) is licensed in Europe and other countries for the short term treatment of primary insomnia in patients aged 55 years and over. However, a clear definition of the target patient population and well-controlled studies of long-term efficacy and safety are lacking. It is known that melatonin production declines with age. Some young insomnia patients also may have low melatonin levels. The study investigated whether older age or low melatonin excretion is a better predictor of response to PRM, whether the efficacy observed in short-term studies is sustained during continued treatment and the long term safety of such treatment.\ud \ud Methods: Adult outpatients (791, aged 18-80 years) with primary insomnia, were treated with placebo (2 weeks) and then randomized, double-blind to 3 weeks with PRM or placebo nightly. PRM patients continued whereas placebo completers were re-randomized 1:1 to PRM or placebo for 26 weeks with 2 weeks of single-blind placebo run-out. Main outcome measures were sleep latency derived from a sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of Life (World Health Organzaton-5) Clinical Global Impression of Improvement (CGI-I) and adverse effects and vital signs recorded at each visit.\ud \ud Results: On the primary efficacy variable, sleep latency, the effects of PRM (3 weeks) in patients with low endogenous melatonin (6-sulphatoxymelatonin [6-SMT] ≤8 μg/night) regardless of age did not differ from the placebo, whereas PRM significantly reduced sleep latency compared to the placebo in elderly patients regardless of melatonin levels (-19.1 versus -1.7 min; P = 0.002). The effects on sleep latency and additional sleep and daytime parameters that improved with PRM were maintained or enhanced over the 6-month period with no signs of tolerance. Most adverse events were mild in severity with no clinically relevant differences between PRM and placebo for any safety outcome.\ud \ud Conclusions: The results demonstrate short- and long-term efficacy and safety of PRM in elderly insomnia patients. Low melatonin production regardless of age is not useful in predicting responses to melatonin therapy in insomnia. The age cut-off for response warrants further investigation.

To profile the effects of escitalopram with duloxetine on urinary flow rate and symptoms in elderly males aged 55-75 years.This was an open, randomised pilot study. A total of 34 male volunteers with no existing urinary symptoms were randomised: 17 to escitalopram 10 mg once daily and 17 to duloxetine 60 mg once daily for 16 days. Doses were then tapered to 5 mg and 30 mg, respectively for 14 days. Subjects measured their urinary flow at home using a Urospec device for 48 hours pre-dose, immediately after the first dose, at 2 weeks and 5 days after stopping treatment.The primary variable was the maximum urinary flow rate (Q(max)). Secondary variables were time to maximum flow rate (TQ(max)) and mean flow rate (Q(m)). The percentage of voided volume voided when the maximum flow was reached (VQ(max)), average voided volume (V(v)) and urinary symptoms assessed using the American Urological Association symptom index were also measured.Mean Q(max) values increased from baseline in escitalopram-treated subjects and decreased in duloxetine-treated subjects. The maximum difference in treatment effect was observed after 2 days of treatment and was statistically significant (4.27 mL/sec, 95% CI 1.14-7.39, p = 0.009). Similar results were obtained with TQ(max). There were no significant differences between treatments in other urinary flow measures or urinary symptoms. Urinary flow measures reverted towards baseline values after stopping treatment. There were no treatment-related adverse events.The results of this small, pilot study suggest that duloxetine may cause a decline in urinary flow in elderly men. A larger study in patients with urinary flow symptoms would be required to determine the clinical relevance of these findings.

Melatonin, the hormone produced nocturnally by the pineal gland, serves as a circadian time cue and sleep-anticipating signal in humans. With age, melatonin production declines and the prevalence of sleep disorders, particularly insomnia, increases. The efficacy and safety of a prolonged release melatonin formulation (PR-melatonin; Circadin* 2 mg) were examined in insomnia patients aged 55 years and older.Randomised, double blind, placebo-controlled.Primary care.From 1248 patients pre-screened and 523 attending visit 1, 354 males and females aged 55-80 years were admitted to the study, 177 to active medication and 177 to placebo. The study was conducted by primary care physicians in the West of Scotland and consisted of a 2-week, single blind, placebo run-in period followed by a 3-week double blind treatment period with PR-melatonin or placebo, one tablet per day at 2 hours before bedtime.Responder rate (concomitant improvement in sleep quality and morning alertness on Leeds Sleep Evaluation Questionnaire [LSEQ]), other LSEQ assessments, Pittsburgh Sleep Quality Index (PSQI) global score, other PSQI assessments, Quality of Night and Quality of Day derived from a diary, Clinical Global Improvement scale (CGI) score and quality of life (WHO-5 well being index).Of the 354 patients entering the active phase of the study, 20 failed to complete visit 3 (eight PR-melatonin; 12 Placebo). The principal reasons for drop-out were patient decision and lost to follow-up. Significant differences in favour of PR-melatonin vs. placebo treatment were found in concomitant and clinically relevant improvements in quality of sleep and morning alertness, demonstrated by responder analysis (26% vs. 15%; p = 0.014) as well as on each of these parameters separately. A significant and clinically relevant shortening of sleep latency to the same extent as most frequently used sleep medications was also found (-24.3 vs.-12.9 minutes; p = 0.028). Quality of life also improved significantly (p = 0.034).PR-melatonin results in significant and clinically meaningful improvements in sleep quality, morning alertness, sleep onset latency and quality of life in primary insomnia patients aged 55 years and over.The trial was conducted prior to registration being introduced.

Background Clinically proven over-the-counter (OTC) treatment options are becoming increasingly important in the self-management of acute sore throat. The aim of this study was to determine the analgesic and sensorial benefits of two different amylmetacresol/2,4-dichlorobenzyl alcohol (AMC/DCBA) throat lozenge formulation variants, AMC/DCBA Warm lozenge and AMC/DCBA Cool lozenge, compared with an unflavoured, non-medicated placebo lozenge in the relief of acute sore throat due to upper respiratory tract infections. Methods In this multicentre, randomised, double-blind, single-dose study, 225 adult patients with acute sore throat were randomly assigned to receive either one AMC/DCBA Warm lozenge (n = 77), one AMC/DCBA Cool lozenge (n = 74) or one unflavoured, non-medicated lozenge (matched for size, shape and demulcency; n = 74). After baseline assessments, patients received their assigned lozenge and completed four rating assessments at 11 timepoints from 1 to 120 minutes post dose. Analgesic properties were assessed by comparing severity of throat soreness and sore throat relief ratings. Difficulty in swallowing, throat numbness, functional, sensorial and emotional benefits were also assessed. Results Both the AMC/DCBA Warm and AMC/DCBA Cool lozenge induced significant analgesic, functional, sensorial and emotional effects compared with the unflavoured, non-medicated lozenge. Sore throat relief, improvements in throat soreness and difficulty in swallowing, and throat numbness were observed as early as 1-5 minutes, and lasted up to 2 hours post dose. Sensorial benefits of warming and cooling associated with the AMC/DCBA Warm and AMC/DCBA Cool lozenge, respectively, were experienced soon after first dose, and in the case of the latter, it lasted long after the lozenge had dissolved. Emotional benefits of feeling better, happier, less distracted and less frustrated were reported in those taking either of the AMC/DCBA throat lozenge variants, with no differences in adverse events compared with the unflavoured, non-medicated lozenge. Conclusions AMC/DCBA Warm and AMC/DCBA Cool lozenges are well-tolerated and effective OTC treatment options, offering functional, sensorial and emotional benefits to patients with acute sore throat, over and above that of the rapid efficacy effects provided. Trial registration ISRCTN: ISRCTN00003567

The report is prompted by the rash of good mathematical research on the problem of the moments of the number of crossings of a curve by a stochastic process. It is felt that this problem is important to some engineers and designers who may find a brief introduction to these recent publications useful.

Sufficient conditions for consistency of a nonparametric maximum likelihood estimate are given which are applicable to those problems where a class of distribution functions is specified only in terms of its graphs. Consistency is proven and applications are given.

The authors present an iteration procedure to locate the minimum of a continuously differentiable strictly convex function over the unbounded simplex in Euclidean n-space, and prove that the procedure converges to the unique minimum. This procedure is constructed to facilitate its adaptation to machine programming. Applications of this procedure to maximum likelihood estimation in certain non-parametric cases are mentioned.

A formula is derived for the expected number of crossings of an arbitrary, possibly discontinuous, curve in a time interval (O, T) by a continuous non-stationary normal process. It is shown that a formula analogous to that of M. R. Leadbetter and J. D. Cryer holds under conditions more general than they considered.

Background: The anti-TNF inhibitor, etanercept is administered as a once or twice weekly subcutaneous injection for the treatment of rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis (JIA). Limited data from the patients' perspective are available on the use of biologics in the treatment of these chronic conditions and this evaluation was designed to collect data from patients who had been prescribed etanercept for the first time. This manuscript describes the self-reported baseline characteristics and health-related quality of life of patients prior to treatment. Follow-up data will be reported separately.\ud \ud Methods: Patients throughout the United Kingdom prescribed etanercept were invited to participate in an evaluation of their condition and treatment using a data collection tool consisting of a web-based system supplemented by telephone reporting (PROBE). Outcome measures reported at baseline included demographic data, the condition being treated, previous treatment with biologic agents and current and previous medications. Questions modified from standard, validated quality of life questionnaires such as EQ-5D were incorporated and patients made a global assessment of the severity of their own illness using the CGI-S scale.\ud \ud Results: A total of 344 patients/carers/parents participated in the evaluation at baseline, 290 (84%) by online questionnaire and 54 (16%) by telephone. Overall, the study population had a mean age of 53 years, was predominantly female (62%) and 20% had been previously treated with a biologic agent. A total of 191 (56%) patients were receiving treatment with etanercept for rheumatoid arthritis, 44 (13%) for psoriatic arthritis, 43 (13%) for ankylosing spondylitis, 35 (10%) for psoriasis, 9 (3%) for known juvenile idiopathic arthritis (JIA) and 22 (6%) for another condition/patient unsure/missing response. All patients were prescribed the 50 mg weekly dose of etanercept except for 1 patient with JIA (40 mg) dose and 2 patients with psoriasis (100 mg). Thirty-eight percent of patients with rheumatoid arthritis were not receiving treatment with methotrexate.\ud \ud Conclusions: The baseline characteristics and health-related quality of life of first time users of etanercept can be adequately described using self-reported patient data collected using an online questionnaire with a telephone option (PROBE).