A new lipid formulation of low dose ibuprofen shows non-inferiority to high dose standard ibuprofen: the FLARE study (flaring arthralgia relief evaluation in episodic flaring knee pain) - a randomised double-blind study.

OBJECTIVE: To investigate short-term efficacy and safety of a novel lipid ibuprofen formulation 1200 mg/day compared with standard ibuprofen 1200 mg/day and 2400 mg/day in episodic knee arthralgia/flaring pain. DESIGN: Multicentre, randomised, double-blind, 3-arm, non-inferiority trial conducted at 27 primary care centres. Adults with ≥1 knee flare episode within 12 months were recruited within 24 h of new flare with pain severity ≥5 on a 0-10 numerical rating scale (NRS). Primary outcome was change from baseline in WOMAC pain subscale over 5 days. Main secondary outcome was Gastrointestinal Symptom Rating Scale (GSRS) change from baseline. Other endpoints included assessment of WOMAC total subscale scores and self-reported NRS for pain, subject nominated activity, stiffness and swelling. RESULTS: 462 patients were enrolled (58.9% males; mean age 52.2 years). Treatment allocation comprised 148 lipid 1200 mg, 155 soft-gel 1200 mg, 159 soft-gel 2400 mg. WOMAC pain subscale scores decreased in all groups, with lipid 1200 mg being non-inferior to soft-gel 1200 mg (adjusted mean difference -0.26 [95% confidence interval [CI] -0.69, 0.17]) and to soft-gel 2400 mg (difference 0.19 [95% CI -0.24, 0.62]). No differences were seen in mean GSRS total scores. NRS secondary endpoints suggested greater improvements in the lipid 1200 mg group compared to soft-gel 1200 mg, with similar results to soft-gel 2400 mg. The most frequent drug-related adverse events (AEs) were gastrointestinal (GI) disorders, with statistically fewer events for lipid 1200 mg vs soft-gel 2400 mg (P = 0.01, post-hoc analysis). CONCLUSIONS: Ibuprofen 1200 mg/day lipid formulation was non-inferior to standard ibuprofen soft-gel capsules 1200 mg and 2400 mg/day in relieving flaring knee pain. NRS endpoints showed lipid 1200 mg was numerically similar to soft-gel 2400 mg. TRIAL REGISTRATION NUMBER: EudraCT number: 2014-004254-33.

Rococo study: a real-world evaluation of an over-the-counter medicine in acute cough (a multicentre, randomised, controlled study).

OBJECTIVES: To investigate the efficacy and safety of CS1002, an over-the-counter cough treatment containing diphenhydramine, ammonium chloride and levomenthol in a cocoa-based demulcent. DESIGN: A multicentre, randomised, parallel group, controlled, single-blinded study in participants with acute upper respiratory tract infection-associated cough. SETTING: 4 general practitioner (GP) surgeries and 14 pharmacies in the UK. PARTICIPANTS: Participants aged ≥18 years who self-referred to a GP or pharmacist with acute cough of <7 days' duration. Participant inclusion criterion was cough severity ≥60 mm on a 0-100 mm visual analogue scale (VAS). Exclusion criteria included current smokers or history of smoking within the past 12 months (including e-cigarettes). 163 participants were randomised to the study (mean participant age 38 years, 57% females). INTERVENTIONS: Participants were randomised to CS1002 (Unicough) or simple linctus (SL), a widely used cough treatment, and treatment duration was 7 days or until resolution of cough. MAIN OUTCOME MEASURES: The primary analysis was intention-to-treat (157 participants) and comprised cough severity assessed using a VAS after 3 days' treatment (prespecified primary end point at day 4). Cough frequency, sleep disruption, health status (Leicester Cough Questionnaire (LCQ-acute)) and cough resolution were also assessed. RESULTS: At day 4 (primary end point), the adjusted mean difference (95% CI) in cough severity VAS between CS1002 and SL was -5.9 mm (-14.4 to 2.7), p=0.18. At the end of the study (day 7) the mean difference in cough severity VAS was -4.2 mm (-12.2 to 3.9), p=0.31. CS1002 was associated with a greater reduction in cough sleep disruption (mean difference -11.6 mm (-20.6 to 2.7), p=0.01) and cough frequency (mean difference -8.1 mm (-16.2 to 0.1), p=0.05) compared with SL. There was greater improvement in LCQ-acute quality of life scores with CS1002 compared with SL: mean difference (95% CI) 1.2 (0.05 to 2.36), p=0.04 after 5 days' treatment. More participants prematurely stopped treatment due to cough improvement in the CS1002 group (24.4%) compared with SL (10.7%; p=0.02). Adverse events (AEs) were comparable between CS1002 (20.5%) and SL (27.6%) and largely related to the study indication. 6 participants (7%) in the CS1002 group reduced the dose of medication due to drowsiness/tiredness, which subsequently resolved. These events were not reported by participants as AEs. CONCLUSIONS: Although the primary end point was not achieved, CS1002 was associated with greater reductions in cough frequency, sleep disruption and improved health status compared with SL. TRIAL REGISTRATION NUMBER: EudraCT number 2014-004255-31.

Diisopropylfluorophosphate alters retinal neurotransmitter levels and reduces experimentally-induced myopia.

The excessive enlargement of the eye seen in myopia is known to be regulated, in part, by retinal neurotransmitters. One excitatory retinal neurotransmitter, acetylcholine, has been implicated in the signal cascade through the effectiveness of the muscarinic antagonist, atropine, in preventing myopia development. The present study therefore examined whether an indirect cholinomimetic, diisopropylfluorophosphate (DFP), could increase the level of experimental myopia, induced by the deprivation of pattern vision. Injections of either phosphate-buffered DFP or phosphate-buffered saline were made every 48 h into the vitreous chamber of one eye of chicks. The injected eye was then deprived of pattern vision by a translucent occluder. The fellow eye remained untreated and acted as a genetic control. At the end of the treatment period (8 days) axial ocular dimensions and cycloplegic refractive error were measured. To investigate the effects of DFP on retinal neurotransmitter levels, measurements of acetylcholine and dopamine contents were made on retinal tissue following either a single or multiple DFP injections, using reverse phase high performance liquid chromatography (HPLC). Rather than potentiating myopia and vitreous chamber elongation, a significant reduction in myopia (58%) was observed in DFP-injected deprived eyes, compared to saline controls. However, open eyes injected with DFP showed no difference in refraction or vitreous chamber depth compared to contralateral control eyes or saline controls. HPLC analysis revealed increased steady-state content of acetylcholine (+34 +/- 6 ng/mg protein, mean +/- SEM, P<0.01, equivalent to a 54% increase) and dopamine (+377 +/- 83 pg/mg protein, P<0.01, a 36% increase) in DFP-treated eyes compared to contralateral control eyes following a single DFP injection. No changes in either acetylcholine or dopamine content were found in saline-treated control animals. Injection of dopamine antagonists, in combination with DFP, indicated that the DFP-induced reduction in myopia is mediated, at least in part, through a D2 receptor mechanism. Findings argue against a direct cholinergic 'stop-go' pathway controlling ocular growth. Instead the reduction of induced myopia could be related to the action of DFP (directly or indirectly) on dopamine levels in the retina.

Managing shoulder dystocia.

PIP: In midwifery textbooks not much has been written about the management of shoulder dystocia, although it sometimes occurs, and midwives conducting the delivery have to know how to manage it. Should dystocia occurs when the shoulders are stuck in the antero-posterior diameter of the outlet. Sometimes the shoulders fail to rotate into the antero-posterior diameter; in this situation the shoulders are in the oblique diameter of the outlet. This usually happens when the baby is big, weighing more than 4 kilograms. In such cases, the head is big, and it is difficult to deliver the face and the chin. The woman should be in lithotomy position, with the buttocks slightly beyond the end of the bed. The baby's air passages should be sucked of mucus and liquid, so that respiration is initiated. A wide episiotomy should be performed to enlarge the outlet. If the shoulders are in the oblique diameter of the outlet, the midwife should correct the position by hooking a finger into the anterior axilla and rotate the shoulders forward to the antero-posterior diameter of the outlet, before attempting to deliver the shoulders. The next step is the delivery of the posterior shoulder. The midwife puts a finger into the axilla of the posterior shoulder, and by gentle traction downwards, the posterior shoulder is freed. After this, the anterior shoulder is delivered the normal way. This can be aided by applying pressure on the anterior shoulder above the pubic. If the above management fails, then the assistance of the obstetrician must be sought. It is important to recognize large babies before birth in order to initiate appropriate measures before the woman goes into labor. During delivery, the shoulders must be rotated into the antero-posterior diameter of the outlet before attempting to deliver them.^ieng

The concept of deadspace with special reference to the single breath test for carbon dioxide.

We present a review and a theoretical analysis of factors determining airway deadspace (VDaw) and alveolar deadspace (VDalv), the two constituents of physiological deadspace (VDphys). VDaw if the volume of gas between the lips and the alveolar/fresh gas interface, the location of which is determined by inspiratory flow pattern and airway geometry. VDalv can be caused by incomplete alveolar gas mixing and associated V/Q mismatching within the terminal respiratory units, temporal V/Q mismatching within units, spatial V/Q mismatching between units, and venous admixture. Most causes of VDphys are influenced by inspiratory flow pattern and the time available for gas diffusion and distribution. Analysis can be made from the single breath test for carbon dioxide (SBT--CO2) which is the plot of fraction of carbon dioxide in expired gas against expired volume. The common causes of VDalv are associated with a sloping SBT-CO2 phase III. Combination of SBT-CO2 with PaCO2 yields VDphys and VDalv. A sloping phase III with a negative arterial-end-tidal PCO2 gradient implies compensation by perfusion for early emptying, overventilated alveoli.