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•Celecoxib-tramadol co-crystal (CTC) is a first-in-class API-API co-crystal.•Celecoxib absorption is inhibited when co-administered with tramadol.•Celecoxib absorption interference is minimized with CTC.•CTC do not result in higher systemic exposure compared to tramadol or celecoxib.•This study validates the dosing regimen for a subsequent factorial Phase 3 study. Celecoxib-tramadol co-crystal (CTC) is a first-in-class co-crystal of celecoxib and racemic tramadol. This Phase 1 bioavailability study compared single-dose pharmacokinetic (PK) parameters of CTC with those of the individual reference products from the United States, immediate-release celecoxib and tramadol, taken alone and simultaneously to determine their systemic exposure. This was a single-center, randomized, single-dose, open-label, 4-period, 4-sequence, crossover study conducted in healthy subjects between October and December 2016. Study treatments included 200-mg CTC (equivalent to 112-mg celecoxib and 88-mg tramadol; Treatment-1); 100-mg tramadol (Treatment-2); 100-mg celecoxib (Treatment-3); and 100-mg celecoxib plus 100-mg tramadol (Treatment-4). The PK parameters of interest were Cmax, AUC0–T, and AUC0–∞, which were also calculated normalized to the dose. Tmax was only considered as supportive. The statistical analysis was based on a parametric analysis of variance model of the PK parameters; the two-sided 90% CI of the ratio of geometric mean values for the Cmax, AUC0–T, and AUC0–∞ was based on ln-transformed data, and Tmax was rank-transformed. Thirty-six subjects aged 18 to 55 years (21 male subjects, 15 female subjects; mean age, 35 years) participated in the study. Celecoxib from CTC presented a lower Cmax, reduced AUCs, and a faster Tmax. The interference in celecoxib absorption when celecoxib and tramadol are administered together was minimized with the CTC. For Treatment-1, -3, and -4, celecoxib PK parameters were 259, 318, and 165 ng/mL (Cmax), respectively; 1930, 2348, and 1929 ng • h/mL (AUC0–T); and 1.5, 3.0, and 2.5 hours (Tmax). Tramadol and its active metabolite O-desmethyl tramadol from CTC presented lower Cmax and AUCs as well as a longer Tmax. Tramadol/O-desmethyl tramadol PK parameters for Treatment-1, -2, and -4 were 214/55, 305/78, and 312/78 ng/mL for Cmax; 2507/846, 2709/965, and 2888/1010 ng • h/mL for AUC0–T; and 3.0/4.0, 2.0/2.5, and 1.9/2.5 hours for Tmax. Reported adverse events (none unexpected) occurred more frequently with Treatment-2 and Treatment-4. The aim of this study was to compare the PK profile of the US-marketed tramadol and celecoxib products with CTC to determine their systemic exposure and to validate the dosing regimen for a subsequent pivotal factorial Phase 3study. PK parameters of each active component in CTC were favorably modified by co-crystallization and did not result in higher systemic exposure compared with US-marketed celecoxib, tramadol, and their concomitant administration. © 2021 Elsevier HS Journals, Inc.

This trial assessed the efficacy of MR309 (a novel selective sigma-1 receptor ligand previously developed as E-52862) in ameliorating oxaliplatin-induced peripheral neuropathy (oxaipn). A discontinuous regimen of MR309 (400 mg/day, 5 days per cycle) was tested in patients with colorectal cancer receiving FOLFOX in a phase II, randomized, double-blind, placebo-controlled, multicenter clinical trial. Outcome measures included changes in 24-week quantitative measures of thermal sensitivity and total neuropathy score. In total, 124 patients were randomized (1:1) to MR309 or placebo. Sixty-three (50.8%) patients withdrew prematurely before completing 12 planned oxaliplatin cycles. Premature withdrawal because of cancer progression was less frequent in the MR309 group (7.4% vs 25.0% with placebo; p = 0.054). MR309 significantly reduced cold pain threshold temperature [mean treatment effect difference (SE) vs placebo: 5.29 (1.60)°C; p = 0.001] and suprathreshold cold stimulus-evoked pain intensity [mean treatment effect difference: 1.24 (0.57) points; p = 0.032]. Total neuropathy score, health-related quality-of-life measures, and nerve-conduction parameters changed similarly in both arms, whereas the proportion of patients with severe chronic neuropathy (National Cancer Institute Common Terminology Criteria for Adverse Events ≥ 3) was significantly lower in the MR309 group (3.0% vs 18.2% with placebo; p = 0.046). The total amount of oxaliplatin delivered was greater in the active arm (1618.9 mg vs 1453.8 mg with placebo; p = 0.049). Overall, 19.0% of patients experienced at least 1 treatment-related adverse event (25.8% and 11.9% with MR309 and placebo, respectively). Intermittent treatment with MR309 was associated with reduced acute oxaipn and higher oxaliplatin exposure, and showed a potential neuroprotective role for chronic cumulative oxaipn. Furthermore, MR309 showed an acceptable safety profile.

Background Co-crystal of tramadol–celecoxib (CTC), containing equimolar quantities of the active pharmaceutical ingredients (APIs) tramadol and celecoxib (100 mg CTC = 44 mg rac –tramadol hydrochloride and 56 mg celecoxib), is a novel API-API co-crystal for the treatment of pain. We aimed to establish the effective dose of CTC for treating acute pain following oral surgery. Methods A dose-finding, double-blind, randomised, placebo- and active-controlled, multicentre (nine Spanish hospitals), phase II study (EudraCT number: 2011-002778-21) was performed in male and female patients aged ≥ 18 years experiencing moderate to severe pain following extraction of two or more impacted third molars requiring bone removal. Eligible patients were randomised via a computer-generated list to receive one of six single-dose treatments (CTC 50, 100, 150, 200 mg; tramadol 100 mg; and placebo). The primary efficacy endpoint was the sum of pain intensity difference (SPID) over 8 h assessed in the per-protocol population. Results Between 10 February 2012 and 13 February 2013, 334 patients were randomised and received study treatment: 50 mg ( n  = 55), 100 mg ( n  = 53), 150 mg ( n  = 57), or 200 mg ( n  = 57) of CTC, 100 mg tramadol ( n  = 58), or placebo ( n  = 54). CTC 100, 150, and 200 mg showed significantly higher efficacy compared with placebo and/or tramadol in all measures: SPID (0–8 h) (mean [standard deviation]): − 90 (234), − 139 (227), − 173 (224), 71 (213), and 22 (228), respectively. The proportion of patients experiencing treatment-emergent adverse events was lower in the 50 (12.7% [ n  = 7]), 100 (11.3% [ n  = 6]), and 150 (15.8% [ n  = 9]) mg CTC groups, and similar in the 200 mg (29.8% [ n  = 17]) CTC group, compared with the tramadol group (29.3% [ n  = 17]), with nausea, dizziness, and vomiting the most frequent events. Conclusion Significant improvement in the benefit–risk ratio was observed for CTC (doses ≥ 100 mg) over tramadol and placebo in the treatment of acute pain following oral surgery. Funding Laboratorios del Dr. Esteve, S.A.U.

Background A new paradigm of hybrid working exists, with most office workers sharing their work between the office and home office environment. Working from home increases time spent or prolonged sitting, which is associated with an increased risk of chronic disease. Interventions to reduce sitting time, specifically designed for both the office and home-office environments, are required to address this growing public health issue. This study presents a protocol to evaluate the effectiveness of a digital intervention (Click2Move) to reduce sitting time and improve employees’ health and occupational wellbeing among hybrid office workers. Methods A two-arm cluster randomised controlled trial will be undertaken among hybrid office employees. In total, 200 employees will be recruited across four companies across Europe (The Netherlands, Spain, Ireland, and Slovenia). Participants within each company will be randomly allocated to the intervention or control group at the unit/cluster level. The intervention group will receive the novel multicomponent Click2Move intervention (including environmental, organisational, and individual strategies) for 12 months, and the control groups will maintain their usual work practices. The primary outcome will be occupational sedentary time measured via activPAL 3TM at baseline and at 3, 6 and 12 months follow-up. Secondary outcomes will include device-based (activPAL 3TM ) and self-reported (Global Physical Activity Questionnaire and Workforce Sitting Questionnaire) physical activity and sedentary behaviour; self-reported musculoskeletal disorders (Standardised Nordic Questionnaire) and pain (Numeric Rating Scale); self-reported presenteeism and absenteeism (Health and Work Performance Questionnaire), job satisfaction (Need for Recovery scale) and fatigue (single-item 5-point Likert scale). Focus groups will be conducted with employees post-intervention. Linear mixed models, accounting for covariates, will be employed to determine the effects of the intervention. Additionally, we will perform a full process evaluation analysis. Discussion The proposed study will offer a comprehensive evaluation of a digital intervention aimed at reducing sedentary behaviour among hybrid office workers, offering practical solutions to enhance the health, wellbeing and productivity of a growing segment of the workplace. Trial registration ClinicalTrials.gov NCT06247228. Registered 30 January 2024.

Background Office workers have the highest estimated daily sedentary time (ST). The Covid-19 pandemic resulted in a switch from office-based work to home-office work or a hybrid of both. Home-office work has been shown to increase ST compared to the office, which may have deleterious health consequences. Objective This study explored managers perspectives on the factors influencing their employee’s ability to reduce ST in a home-office context. Design A descriptive qualitative study. Methods Semi-structured interviews ( n  = 20), which were mapped to the COM-B model, were conducted with managers from Ireland, Spain and The Netherlands. Interviews were conducted through Zoom, recorded and transcribed verbatim. A reflexive thematic analysis approach was used. Results Organisational support, management engaging in physical activity (PA) during work and a social element were seen as key to increasing engagement in interventions. Creating opportunities for employees to engage in PA during work was seen as another key element. Leveraging infrastructure put in place during the Covid-19 pandemic was identified as a feasible approach to providing education and encouragement to employees. Lastly, managers feared the impact reducing ST may have on the performance of both employees and the organisation, yet, managers felt an increase in employee well-being would benefit their company long-term. Conclusion These results highlight the need to include organisational support and leadership from management, ensuring a top-down approach. These changes may create opportunities for employees to reduce their ST while working from home, which may benefit both the employees’ and organisations.

Evidence suggests that working from home increases the sedentary behaviours of desk-based workers, which may have deleterious health consequences. Owing to the unique nature of working from home, it is important to understand employees’ perspectives on the factors influencing their ability to reduce their sedentary behaviours. This qualitative study employed semi-structured focus groups and interviews with desk-based employees to investigate perspectives on the factors influencing their ability to reduce their sedentary behaviours in a home-office context. Reflexive thematic analysis was used to analyse the data. Employees want the autonomy to choose when and how they reduce their sedentary behaviours. They want organisations to support them and incorporate a social element into interventions. Employees do not feel trusted whilst working from home, which creates a reluctancy to leave their desk. There is a need for education on the negative health outcomes associated with high levels of sedentary behaviours, while employees want to be held accountable for changing their behaviour and for their efforts in reducing their sedentary behaviours to be rewarded. These results highlight the need for multi-component interventions to reduce sitting in the home-office context. Organisations should provide employees autonomy over how they reduce their siting time and work to reduce the stigma of working from home. Interventions must also educate staff on the health consequences associated with higher levels of sedentary time.

We compared hospital-acquired catheter-related bacteremia (CRB) episodes diagnosed at acute care hospitals in Catalonia, Spain, during the COVID-19 pandemic in 2020 with those detected during 2007-2019. We compared the annual observed and predicted CRB rates by using the negative binomial regression model and calculated stratified annual root mean squared errors. A total of 10,030 episodes were diagnosed during 2007-2020. During 2020, the observed CRB incidence rate was 0.29/10 patient-days, whereas the predicted CRB rate was 0.14/10 patient-days. The root mean squared error was 0.153. Thus, a substantial increase in hospital-acquired CRB cases was observed during the COVID-19 pandemic in 2020 compared with the rate predicted from 2007-2019. The incidence rate was expected to increase by 1.07 (95% CI 1-1.15) for every 1,000 COVID-19-related hospital admissions. We recommend maintaining all CRB prevention efforts regardless of the coexistence of other challenges, such as the COVID-19 pandemic.

INTRODUCTION Cut‐offs derived from baseline cognitive assessments, stratified by intellectual disability (ID) level, have been proposed to diagnose symptomatic Alzheimer's disease (AD) in Down syndrome (DS). However, discrepancies in ID classification risk misclassification when applying cut‐offs across sites. METHODS This dual‐center cohort study included 673 adults with mild to moderate ID at different AD stages. We assessed ID classification discrepancies across sites and the impact on Cambridge Cognitive Examination for Older Adults with Down's Syndrome (CAMCOG‐DS) cut‐offs for AD dementia diagnosis derived from receiver operating characteristic analysis. RESULTS Inter‐rater agreement for ID level classification was 95% within sites but 60% between sites. While CAMCOG‐DS score distributions in the whole cohort were similar across sites, ID classification discrepancies caused higher cut‐offs in Barcelona for mild and moderate ID compared to Munich. Applying site‐specific cut‐offs to another cohort reduced sensitivity and specificity. DISCUSSION Standardizing ID classification is critical for generalizable cut‐offs to accurately diagnose AD dementia based on neuropsychological assessments in DS. Highlights CAMCOG‐DS cut‐offs by intellectual disability level classify dementia in Down syndrome. ID classification discrepancies between sites impact CAMCOG‐DS diagnostic cut‐offs. Applying site‐specific cut‐offs to other cohorts reduces sensitivity and specificity. Standardized ID classification is essential for generalizable cognitive cut‐offs. Use site‐specific cut‐offs until ID classification is standardized.

Hybrid work is the new modus operandi for many office workers, leading to more sedentary behavior than office-only working. Given the potential of digital interventions to reduce sedentary behavior and the current lack of studies evaluating these interventions for home office settings, it is crucial to develop digital interventions for such contexts involving all stakeholders. This study aimed to reach expert consensus on the most feasible work strategies and the most usable digital elements as a delivery method to reduce sedentary behavior in the home office context. A modified Delphi study including 3 survey rounds and focus groups was conducted to achieve consensus. The first Delphi round consisted of two 9-point Likert scales for assessing the feasibility of work strategies and the potential usefulness of digital elements to deliver the strategies. The work strategies were identified and selected from a scoping review, a systematic review, and 2 qualitative studies involving managers and employees. The median and mean absolute deviation from the median for each item are reported. The second round involved 2 ranking lists with the highly feasible strategies and highly useful digital elements based on round 1 responses to order the list according to experts' preferences. The weighted average ranking for each item was calculated to determine the most highly ranked work strategies and digital elements. The third round encompassed work strategies with a weight above the median from round 2 to be matched with the most useful digital elements to implement each strategy. In total, 4 focus groups were additionally conducted to gain a greater understanding of the findings from the Delphi phase. Focus groups were analyzed using the principles of reflexive thematic analysis. A total of 27 international experts in the field of occupational health participated in the first round, with response rates of 86% (25/29) and 66% (19/29) in rounds 2 and 3, respectively, and 52% (15/29) in the focus groups. Consensus was achieved on 18 work strategies and 16 digital elements. Feedback on activity progress and goal achievement; creating an action plan; and standing while reading, answering phone calls, or conducting videoconferences were the most feasible work strategies, whereas wrist-based activity trackers, a combination of media, and app interfaces in smartphones were the most useful digital elements. Moreover, experts highlighted the requirement of combining multiple levels of strategies, such as social support, physical environment, and individual strategies, to enhance their implementation and effectiveness in reducing sedentary behavior when working from home. This expert consensus provided a foundation for developing digital interventions for sedentary behavior in home office workers. Ongoing interventions should enable the evaluation of feasible strategies delivered via useful digital elements in home office or hybrid contexts.

L265P is an early mutation in IgM monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic Waldenström macroglobulinemia (WM). Given the high prevalence of the mutation observed in epidemiological studies, its presence is not sufficient to drive disease progression. In fact, a recent risk model of progression reported that the impact of other laboratory biomarkers was superior to the mutation's presence. Due to the low incidence of these clinicopathological entities, there is a need for a better characterization of tumor and immune cells that can help to identify novel biomarkers. We hypothesize that the characterization of the risk groups in asymptomatic patients could improve the discovery of drivers of disease progression. We characterized the genomic and immune landscape of the most recent prognostic risk categories in 19 IgM MGUS and 17 asymptomatic WM patients. We performed targeted next generation sequencing (NGS) on CD19+ cells from bone marrow samples at diagnosis using a panel of 54 lymphoma-driver genes. Whole bone marrow samples were also used to measure mRNA gene expression in tumor and immune cells using the PanCancer ImmuneProfiling panel on the nCounter platform (NanoString). We observed that low-risk patients were only characterized by the presence of L265P, while intermediate- and high-risk groups harbored additional mutations on , , and . Regarding the mRNA expression analyses, we found an increased proportion of myeloid cells in the low-risk group, with monocytes having a significant decrease in low versus high-risk patients. The high-risk group also upregulated genes involved in the activation of NF-κB and B-cell receptor (BCR) signaling, while low-risk patients upregulated genes associated with an alternative activation of B cells or a decrease of the BCR signaling, such as TOLLIP, CEACAM1 and CR1. Beyond the mutation, we described novel molecular mechanisms associated with high-risk patients, as an effort moving towards easy-to use new biomarkers in IgM gammopathy.