Evaluating the safety and short-term equivalence of colchicine versus prednisone in older patients with acute calcium pyrophosphate crystal arthritis (COLCHICORT): an open-label, multicentre, randomised trial.

BACKGROUND: Acute calcium pyrophosphate crystal arthritis causes intense joint pain mainly affecting older people. Because guidance and evidence remain scarce, management of this disease relies on expert opinion. We therefore aimed to compare the safety and short-term equivalence of low-dose colchicine with oral prednisone in older patients with acute calcium pyrophosphate crystal arthritis. METHODS: We did an open-label, multicentre, randomised, trial (COLCHICORT) at six hospitals in Paris and northern France. We enrolled patients who were admitted to hospital who were 65 years or older and who presented with acute calcium pyrophosphate crystal arthritis with a symptom duration of less than 36 h. Diagnosis of calcium pyrophosphate crystal arthritis was made by the identification of calcium pyrophosphate crystals on synovial fluid analysis or typical clinical presentation (onset of joint pain and swelling). Key exclusion criteria included absence of calcium pyrophosphate crystals on synovial fluid analysis or a history of gout. Participants were randomly allocated (1:1), using a centralised electronic treatment group allocation module, to receive either colchicine 1·5 mg on day 1 and 1 mg on day 2 (ie, the colchicine group) or oral prednisone 30 mg on days 1 and 2 (ie, the prednisone group). The primary outcome was change in joint pain (measured by visual analogue scale [VAS] from 0 mm to 100 mm) at 24 h. Equivalence was determined whether the 95% CI of the between-group difference at 24 h was within the -13 mm to +13 mm margin in the per-protocol analysis. Adverse events were recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). This trial is completed and is registered with ClinicalTrials.gov, NCT03128905. FINDINGS: Between Feb 5, 2018, and May 7, 2022, 111 patients who were admitted to hospital were randomly assigned (57 [51%] to the colchicine group and 54 [49%] to the prednisone group). 95 (86%) of 111 patients were included in the per-protocol analysis (49 [52%] in the colchicine group and 46 [48%] in the prednisone group). The median age was 88·0 years (IQR 82·0-91·0) and 69 (73%) of 95 participants were women and 26 (27%) were men. Acute calcium pyrophosphate crystal arthritis affected mainly the knee in 46 (48%) of 95 participants, the wrist in 19 (20%), and the ankle in 12 (13%). Pain VAS at baseline was 68 mm (SD 17). At 24 h, change in pain VAS was -36 mm (SD 32) in the colchicine group and -38 mm (SD 23) in the prednisone group. The between-group difference in change in pain VAS at 24 h was -1 mm (95% CI -12 to 10), showing equivalence between the two drugs. In the colchicine group, 12 (22%) of 55 patients had diarrhoea, one (2%) had hypertension, and none had hyperglycaemia. In the prednisone group, three (6%) of 54 had diarrhoea, six (11%) had hypertension, and three (6%) had hyperglycaemia. No deaths occurred in the colchicine group; two deaths occurred in the prednisone group, which were deemed unrelated to prednisone (one due to infectious valvular endocarditis leading to heart failure, and one due to a stroke). INTERPRETATION: Colchicine and prednisone exhibit equivalent short-term efficacy for the treatment of acute calcium pyrophosphate crystal arthritis, with different safety profiles in the older population. FUNDING: French Inter-regional Hospital Program of Clinical Research.

Proposition of a structured list of information items to be transmitted to primary caregivers after in-hospital medication optimization: a qualitative study.

Background and objective: Defective transmission of drug information during the transition from hospital to home care are causes of adverse drug reactions in older patients. We aimed to reach a consensus concerning information about changes in treatment to be transmitted to primary caregivers when an older patient is discharged from hospital.Methods: A qualitative focus group study was conducted with general practitioners, geriatricians, community pharmacists, and hospital pharmacists providing care for older patients. Four steps were used to reach a focus group consensus: 1) presentation of the purpose of the focus group; 2) generation and enumeration of ideas; 3) sharing opinions about these ideas; 4) voting to create a list of ranked items. The process involved three focus groups.Results: A consensus was reached on ten items: indication for continued, discontinued, newly introduced or changed treatments and their duration; reasons for discontinuing drugs or introducing new drugs; information about re-evaluating treatments; reasons for hospital stay, significant elements and diagnosis at discharge; administrative information concerning the patient; the name of the primary care physician, and the discharging hospital unit and the physician(s) in charge; known allergies, information about liver and kidney failure; main adverse effects to monitor; date of latest blood tests; hospital admission/discharge dates.Conclusion: The consensus on the list of information items concerning changes in the treatment should be used by hospital physicians and pharmacists to ensure safe patient discharge.

Type I Phosphatidylinositol-4-Phosphate 5-Kinases α and γ Play a Key Role in Targeting HIV-1 Pr55Gag to the Plasma Membrane.

HIV-1 assembly occurs principally at the plasma membrane (PM) of infected cells. Gag polyprotein precursors (Pr55Gag) are targeted to the PM, and their binding is mediated by the interaction of myristoylated matrix domain and a PM-specific phosphoinositide, the phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2]. The major synthesis pathway of PI(4,5)P2 involves the activity of phosphatidylinositol-4-phosphate 5-kinase family type 1 composed of three isoforms (PIP5K1α, PIP5K1ß, and PIP5K1γ). To examine whether the activity of a specific PIP5K1 isoform determines proper Pr55Gag localization at the PM, we compared the cellular behavior of Pr55Gag in the context of PIP5K1 inhibition using siRNAs that individually targeted each of the three isoforms in TZM-bl HeLa cells. We found that downregulation of PIP5K1α and PIP5K1γ strongly impaired the targeting of Pr55Gag to the PM with a rerouting of the polyprotein within intracellular compartments. The efficiency of Pr55Gag release was thus impaired through the silencing of these two isoforms, while PIP5K1ß is dispensable for Pr55Gag targeting to the PM. The PM mistargeting due to the silencing of PIP5K1α leads to Pr55Gag hydrolysis through lysosome and proteasome pathways, while the silencing of PIP5K1γ leads to Pr55Gag accumulation in late endosomes. Our findings demonstrated that, within the PIP5K1 family, only the PI(4,5)P2 pools produced by PIP5K1α and PIP5K1γ are involved in the Pr55Gag PM targeting process.IMPORTANCE PM specificity of Pr55Gag membrane binding is mediated through the interaction of PI(4,5)P2 with the matrix (MA) basic residues. It was shown that overexpression of a PI(4,5)P2-depleting enzyme strongly impaired PM localization of Pr55Gag However, cellular factors that control PI(4,5)P2 production required for Pr55Gag-PM targeting have not yet been characterized. In this study, by individually inhibiting PIP5K1 isoforms, we elucidated a correlation between PI(4,5)P2 metabolism pathways mediated by PIP5K1 isoforms and the targeting of Pr55Gag to the PM of TZM-bl HeLa cells. Confocal microscopy analyses of cells depleted from PIP5K1α and PIP5K1γ show a rerouting of Pr55Gag to various intracellular compartments. Notably, Pr55Gag is degraded by the proteasome and/or by the lysosomes in PIP5K1α-depleted cells, while Pr55Gag is targeted to endosomal vesicles in PIP5K1γ-depleted cells. Thus, our results highlight, for the first time, the roles of PIP5K1α and PIP5K1γ as determinants of Pr55Gag targeting to the PM.

Usefulness of a Visual Analog Scale for Measuring Anxiety in Hospitalized Patients Experiencing Pain: A Multicenter Cross-Sectional Study.

BACKGROUND: Anxiety is common in hospitalized patients and can worsen pain or lead to unsuccessful pain relief. AIMS: The purpose of this study was to evaluate the usefulness of measuring anxiety with a visual analog scale (VAS) in the hospitalized patient experiencing pain. DESIGN: We conducted a multiple-center cross-sectional study. PARTICIPANTS/SUBJECTS: Adult inpatients experiencing moderate to severe pain defined by a pain VAS score ≥40 of 100 were included. METHODS: Pain and anxiety data were collected using the following instruments: pain VAS, anxiety VAS, State Anxiety Scale of the Spielberger State-Trait Anxiety Inventory (STAI-YA) and Anxiety Subscale of the Hospital Anxiety and Depression Scale (HAD-A). RESULTS: Data were collected from 394 patients. Of those patients, 43.6% (171 of 392) and 36.6% (143 of 391) had significant anxiety according to STAI-Ya and HAD-A, respectively. Correlation was good between anxiety-VAS and STAI-YA (ρ = 0.67 [95% confidence interval 0.61-0.72]) and moderate between anxiety VAS and HAD-D (ρ = 0.48 [0.39-0.56]). The main factor predictive of situational anxiety was history of anxiety-depression symptoms (odds ratio = 2.95 [1.93-4.56]). For anxiety VAS score ≥ 40 of 100, the sensitivity for detecting anxiety was 81% with 70% specificity. CONCLUSION: This study confirmed the high prevalence of anxiety among inpatients experiencing pain, demonstrated the capacity of a VAS to assess this anxiety, determined an anxiety VAS cutoff level to screen for significant anxiety, and identified risk factors of anxiety in this population. Anxiety VAS has been found to be an easy-to-use method familiar to caregivers, with all the advantages needed for an effective screening instrument. An anxiety VAS score ≥40 of 100 would thus warrant particular attention to adapt care to the patient's anxiety-related pain and initiate specific therapeutic interventions.

Characterization of woodwind instrument toneholes with the finite element method.

A method is proposed to determine the transfer matrix parameters of a discontinuity in a waveguide with the finite element method (FEM). This is used to characterize open and closed woodwind instrument toneholes and develop expressions for the shunt and series equivalent lengths. Two types of toneholes are characterized: Unflanged toneholes made of thin material, such as found on saxophones and concert flutes, and toneholes drilled through a thick material, such as found on most instruments made of wood. The results are compared with previous tonehole models from the literature. In general, the proposed expressions provide a better fit across a wide range of frequencies and tonehole sizes than previous results. For tall toneholes, the results are in general agreement with previous models. For shorter tonehole heights, some discrepancies from previous results are found that are most important for larger diameter toneholes. Finally, the impact of a main bore taper (conicity) on the characterization of toneholes was investigated and found to be negligible for taper angles common in musical instruments.

Measurement of vocal-tract influence during saxophone performance.

This paper presents experimental results that quantify the range of influence of vocal tract manipulations used in saxophone performance. The experiments utilized a measurement system that provides a relative comparison of the upstream windway and downstream air column impedances under normal playing conditions, allowing researchers and players to investigate the effect of vocal-tract manipulations in real time. Playing experiments explored vocal-tract influence over the full range of the saxophone, as well as when performing special effects such as pitch bending, multiphonics, and "bugling." The results show that, under certain conditions, players can create an upstream windway resonance that is strong enough to override the downstream system in controlling reed vibrations. This can occur when the downstream air column provides only weak support of a given note or effect, especially for notes with fundamental frequencies an octave below the air column cutoff frequency and higher. Vocal-tract influence is clearly demonstrated when pitch bending notes high in the traditional range of the alto saxophone and when playing in the saxophone's extended register. Subtle timbre variations via tongue position changes are possible for most notes in the saxophone's traditional range and can affect spectral content from at least 800-2000 Hz.