Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: Secondary analyses by baseline pain intensity and use of rescue medication of a phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial.

BACKGROUND: In the randomized, phase 3, SUSA-301 trial, celecoxib-tramadol co-crystal (CTC) provided significantly greater analgesia compared with celecoxib, tramadol, or placebo in adults with acute, moderate-to-severe, postoperative pain. This post hoc, secondary analysis further evaluated the use of rescue medication and the incidence of treatment-emergent adverse events (TEAEs). METHODS: Patients (N = 637) were randomized 2:2:2:1 to receive oral CTC 200 mg twice daily (BID; n = 184), tramadol 50 mg four times daily (QID; n = 183), celecoxib 100 mg BID (n = 181), or placebo QID (n = 89). Post hoc analyses were conducted on the use of rescue medications up to 4 and 48 h post-study drug dose, stratified by baseline pain intensity (moderate/severe), and on the incidence of TEAEs, stratified by rescue medication use. RESULTS: A significantly lower proportion of patients received any rescue medication within 4 h post-study dose with CTC (49.5%) versus tramadol (61.7%, p = 0.0178), celecoxib (65.2%, p = 0.0024), and placebo (75.3%, p = 0.0001); this was also seen for oxycodone use. Fewer patients in the CTC group received ≥3 doses of rescue medication compared with the other groups, irrespective of baseline pain intensity. In patients who did not receive opioid rescue medication, CTC was associated with a lower incidence of nausea and vomiting TEAEs versus tramadol alone. In patients who received rescue oxycodone, the incidence of nausea was similar in the CTC and tramadol groups, and higher versus celecoxib and placebo. CONCLUSION: Celecoxib-tramadol co-crystal was associated with reduced rescue medication use and an acceptable tolerability profile compared with tramadol or celecoxib alone in adults with acute, moderate-to-severe, postoperative pain.

Radiculopathy with motor deficit: a cross-sectional study of the impact of the surgeon's experience on the indication and timing of surgical treatment.

PURPOSE: The optimal management of patients with compressive radiculopathy with motor deficit (CRMD) is controversial. Our goal was to provide evidence on the impact of the spine surgeons' experience on surgical planning and timing. METHODS: Spine surgeons were invited to participate in a 5-item online survey. A literature review was carried out. RESULTS: Of the 94 spine surgeons who responded to the survey, 70% would operate early on a patient with acute CRMD, but only 48% would do so if the radicular pain had resolved. Surgeons with more than 15 years of experience chose more conservative options. Twenty published studies were selected in the literature review. CONCLUSION: The optimal management of patients with compressive radiculopathy associated with a non-progressive motor loss remains unknown. The results of our survey show that surgeons with extensive surgical experience take a more conservative and cautious approach.

Three-Day Icatibant on Top of Standard Care in Patients With Coronavirus Disease 2019 Pneumonia: A Randomized, Open-Label, Phase 2, Proof-of-Concept Trial.

BACKGROUND: We aimed to evaluate icatibant, a competitive antagonist of the bradykinin B2 receptors, for the treatment of inpatients with coronavirus disease 2019 (COVID-19) pneumonia admitted in the early hypoxemic stage. METHODS: The randomized, open-label clinical trial of icatibant for COVID-19 pneumonia (ICAT·COVID, registered as NCT04978051 at ClinicalTrials.gov) was conducted in Barcelona. Inpatients requiring supplemental but not high-flow oxygen or mechanical ventilation were allocated (1:1) to treatment with either three 30-mg icatibant doses/d for 3 consecutive days plus standard care or standard care alone, and followed for up to 28 days after initial discharge. The primary and key secondary outcomes were clinical response on study day 10/discharge and clinical efficacy at 28 days from initial discharge, respectively. RESULTS: Clinical response occurred in 27 of 37 patients (73.0%) in the icatibant group and 20 of 36 patients (55.6%) in the control group (rate difference, 17.42; 95% confidence interval [CI], -4.22 to 39.06; P = .115). Clinical efficacy ensued in 37 patients (100.0%) in the icatibant group and 30 patients (83.3%) in the control group (rate difference, 16.67; 95% CI, 4.49-28.84; P = .011). No patient died in the icatibant group, compared with 6 patients (16.7%) in the control group (P = .011). All patients but 1 had adverse events, which were evenly distributed between study arms. No patient withdrew because of adverse events. CONCLUSIONS: Adding icatibant to standard care was safe and improved both COVID-19 pneumonia and mortality in this proof-of-concept study. A larger, phase 3 trial is warranted to establish the clinical value of this treatment. CLINICAL TRIALS REGISTRATION: NCT04978051.

Usefulness of ICG Angiography-Guided Thyroidectomy for Preserving Parathyroid Function.

INTRODUCTION: Hypoparathyroidism is the most frequent complication after total thyroidectomy and, when permanent, it becomes a severe chronic disease. We assessed the usefulness of indocyanine green (ICG) angiography-guided thyroidectomy to reduce the postoperative hypocalcemia. METHODS: Prospective study with two consecutive cohorts of patients who underwent total thyroidectomy: historical control group (CG) and angiography-guided thyroidectomy group (AG). In all patients, ICG-angiography was performed at the end of the surgery to predict immediate parathyroid gland (PG) function. In the AG, ICG-angiography was also done after PG identification to show their vascular supply. We compared the rate of postoperative hypocalcemia (calcium supplementation needed due to hypocalcemia symptoms or calcium levels < 1.8 mmol/L on the first postoperative day) and permanent hypocalcemia (need of calcium ± vitamin D supplementation 12 months after thyroidectomy). RESULTS: We included 120 consecutive patients (84 CG; 36 AG). Thyroid cancer was the most common diagnostic (63.1% CG-69.4% AG; p = 0.646) and central neck dissection was also frequent (54.8% CG-64.3% AG; p = 0.468). The AG developed a lower rate of postoperative (26.2-5.6%; p = 0.011) and permanent hypocalcemia (11.9-0%; p = 0.032). The OR for permanent hypocalcemia was 0.673 (95% CI 0.591-0.766). A significant higher rate of well vascularized PG at the end of the surgery (score 2) in the AG (39.2-52.9%; p = 0.018) was also seen. CONCLUSION: ICG angiography-guided thyroidectomy is a useful tool to identify PG vascularization, allowing a better PG preservation and a significant decrease in hypocalcemia rates.

Feasibility of a multidisciplinary group videoconferencing approach for chronic low back pain: a randomized, open-label, controlled, pilot clinical trial (EN-FORMA).

BACKGROUND: Low back pain is a common condition that becomes even more prevalent with aging. A non-pharmacological multidisciplinary approach for chronic non-specific low back pain (CNSLBP) has been recommended, but integrating different healthcare professionals is challenging. A multidisciplinary group videoconferencing approach (MGVA) can be helpful. Our aim was to provide evidence on MGVA's feasibility in managing CNSLBP and its impact on clinical practice. METHODS: We conducted an open-label, randomized, controlled, parallel-group pilot clinical trial with CNSLBP patients irresponsive to conservative treatment. Patients between 18 and 67 years of age were randomly assigned (1:1) to either Standard-of-Care + MGVA (experimental group) or Standard-of-Care alone (control group). MGVA consisted of integrated sessions for physical rehabilitation/physiotherapy, psychology, and social work treatments. The control group received standard clinical practice treatment. The feasibility was assessed by the number of study procedures completed to at least 80% as planned. The impact on clinical practice was evaluated by the number of patients who changed their status from "candidate" to "non-candidate" to low back surgery as the treatment of choice for CNSLBP. The SF-36, Oswestry Disability Index, and TMMS-24 questionnaires were used. We performed a whole population-based descriptive analysis. RESULTS: We included 20 patients, but only 18 were randomized (2 withdrew consent before randomization). The mean (SD) age was 53.1 (5.9) years, and mostly women (13/18); 7 were actively employed. In the experimental group, 6/9 (67%, 95%CI:35-88%) patients attended at least 80% of the scheduled procedures, while in the control group, 8/9 (89%, 95%CI:57-98%) did. Additionally, 1 out of 4 (25%) patients in the experimental group changed their status from "candidate" for low back surgery to "non-candidate". None of the 2 patients in the control group did so. We found differences between groups in the SF-36 mental health component (p-value:0.061), Oswestry Disability Index (p-value:0.032), and TMMS-24 Repair component (p-value:0.014) at the end of the trial favoring MGVA. CONCLUSIONS: The multidisciplinary group videoconferencing approach to managing chronic non-specific low back pain was feasible, suggesting overall beneficial effects on patients' health and could play a role in changing a patient's status from "candidate" to "non-candidate" for surgery. TRIAL REGISTRATION: NCT05093543 (ClinicalTrials.gov), first registered in 26/10/2021.

Lessons learned in aortoenteric fistula repair: a multidisciplinary team approach and diagnostic-therapeutic algorithm matter.

Aortoenteric fistula (AEF) is a low-prevalence, life-threatening condition regardless of treatment, with a 30-50% postoperative (≤60 days) mortality. This study aimed to estimate our postoperative cumulative mortality incidence and assess the feasibility of the diagnostic-therapeutic algorithm used in our clinical practice. We performed a retrospective cohort study of patients treated for AEF at a fully-equipped tertiary healthcare center between January 2008 and December 2020.

Effectiveness of a high fiber diet in improving constipation in patients with defecatory dyssynergy under treatment with anorrectal biofeedback. Exploratory, randomized clinical trial. / Eficacia de la dieta alta en fibra en la mejora del estreñimiento en pacientes con disinergia defecatoria en tratamiento con biofeedback anorrectal. Ensayo clínico exploratorio, aleatorizado.

INTRODUCTION: Fiber is the initial treatment in chronic functional constipation. However, its role in the group of patients with defecatory dyssynergy is not well established. The objective of the study is to evaluate the efficacy and safety of a high fiber diet in patients with defecatory dyssynergy in the treatment with anorectal biofeedback. PATIENTS AND METHODS: An exploratory, randomized (1:1), double-blind, controlled «add-on¼ clinical trial was carried out in a reference center in Spain in patients with functional constipation and defecatory dyssynergy according to the ROMEIV criteria. CONTROL GROUP: treatment with biofeedback and low-fiber diet (15-20g/day). Experimental group: treatment with biofeedback and high fiber diet (25-30g/day). Analyzed: responder (primary endpoint), patient whose defecatory dyssynergy had been corrected (>20% reduction in anal pressure during the defecation maneuver and normal balloon expulsion test); anorectal parameters (anal relaxation, reduced straining); safety (abdominal symptoms: flatulence, pain, borborygmus, bloating). RESULTS: A total of 44 patients were randomized: 22 per group. The percentage of responders was 75% (15/20; 95%CI: 53 89%) control group and 70% (14/20; 95%CI: 48-85%) experimental group, P=.225. Differences in favor of the control group were only observed in abdominal symptoms: flatulence (P=.028), abdominal distension (P=.041) and digestive comfort (P=.043). CONCLUSIONS: In patients with defecatory dyssynergy, a high-fiber diet not only does not improve the efficacy of anorectal biofeedback but is associated with a loss of improvement in abdominal symptoms.

Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: A phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial.

BACKGROUND: Celecoxib-tramadol co-crystal (CTC) is a first-in-class analgesic co-crystal of celecoxib and racemic tramadol with an improved pharmacologic profile, conferred by the co-crystal structure, compared with its active constituents administered alone/concomitantly. AIM: We evaluated CTC in moderate-to-severe acute postoperative pain. MATERIALS AND METHODS: This randomized, double-blind, factorial, active- and placebo-controlled phase 3 trial (NCT03108482) was conducted at 6 US clinical research centers. Adults with moderate-to-severe acute pain following bunionectomy with osteotomy were randomized to oral CTC (200 mg [112 mg celecoxib/88 mg rac-tramadol hydrochloride] every 12 h), tramadol (50 mg every 6 h), celecoxib (100 mg every 12 h), or placebo for 48 h. Patients, investigators, and personnel were blinded to assignment. The primary endpoint was the 0-48 h sum of pain intensity differences (SPID0-48) in all randomized patients. Pain intensity was assessed on a 0-10 numerical rating scale (NRS). Safety was analyzed in patients who received study medication. Funded by ESTEVE Pharmaceuticals. RESULTS: In 2017 (March to November), 1323 patients were screened and 637 randomized to CTC (n = 184), tramadol (n = 183), celecoxib (n = 181), or placebo (n = 89). Mean baseline NRS was 6.7 in all active groups. CTC had a significantly greater effect on SPID0-48 (least-squares mean: -139.1 [95% confidence interval: -151.8, -126.5]) than tramadol (-109.1 [-121.7, -96.4]; p < 0.001), celecoxib (-103.7 [-116.4, -91.0]; p < 0.001), or placebo (-74.6 [-92.5, -56.6]; p < 0.001). Total treatment-emergent adverse events (TEAEs) were 358 for CTC and 394 for tramadol. Drug-related TEAEs occurred in 37.7% patients in the CTC group, compared with 48.6% in the tramadol group. There were no serious TEAEs/deaths. CONCLUSION: CTC provided greater analgesia than comparable daily doses of tramadol and celecoxib, with similar tolerability to tramadol. CTC is approved in the United States.

Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial.

BACKGROUND: We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis. METHODS: A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy. RESULTS: Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93-1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018). CONCLUSIONS: Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events. CLINICAL TRIALS REGISTRATION: NCT01898338.

Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study.

BACKGROUND: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome. METHODS: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid ß peptides 1-42 and 1-40 and their ratio (Aß1-42/1-40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate. FINDINGS: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aß1-42/1-40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life. INTERPRETATION: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments. FUNDING: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.

Comparison of two sample collection devices for anal cytology in HIV-positive men who have sex with men: Cytology brush and Dacron swab.

OBJECTIVE: HIV-positive men who have sex with men (MSM) are a vulnerable group for anal cancer (AC), a cancer with a well-described precursor lesion, which can be detected early in screening programs using anal liquid-based cytology (aLBC). We aim to compare two aLBC sample collection devices: cytology brush (CB) and Dacron swab (DS). METHODS: Retrospective analysis of two consecutive study periods, the first using CB and the second DS. Participants underwent an aLBC, a human papillomavirus (HPV) DNA test and a high-resolution anoscopy (HRA), and a biopsy was performed for suspicious lesions. The sensitivity and specificity of aLBC, area under the receiver operating characteristic (ROC) curve (AUC), and concordance between cytology and HRA were assessed using Cohen's kappa coefficient. RESULTS: A total of 239 participants were enrolled (CB group, 120; DS group, 119). aLBC was benign in 46% of samples, and high-grade squamous intraepithelial lesion (HSIL) was detected in 11.7%. Prevalence of biopsy-proven HSIL was 15.3%. No differences in cytological and histological results were observed between the groups. aLBC-HRA concordance was weak for benign results (CB group, k = 0.309; DS group, k = 0.350) as well as for HSIL (k = 0.321 and 0.387, respectively). Sensitivity and specificity were 100% and 51.4%, respectively, in the CB group and 88% and 54.3% in the DS group (AUC = 0.711 and 0.759, respectively, P-value = .514). Representation of the transformation zone (TZ) was adequate in 83.3% of samples in the CB group and 50.4% in the DS group (P-value <.001). CONCLUSION: Our data suggest that both devices had similar accuracy to detect anal HSIL, although samples collected with CB are more likely to have an adequate TZ representation, the presence of which could be an indicator of sample quality.

Total and Unbound Bictegravir Concentrations and Viral Suppression in Cerebrospinal Fluid of Human Immunodeficiency Virus-Infected Patients (Spanish HIV/AIDS Research Network, PreEC/RIS 56).

We determined total and unbound concentrations of bictegravir (BIC) in cerebrospinal fluid (CSF) in 15 asymptomatic, virologically suppressed patients. The median plasma and CSF total BIC concentrations were 1837.1 ng/mL (interquartile range [IQR], 1237.2-2586.7) and 6.9 (IQR, 4.8-10.9), respectively. Median unbound BIC concentration was 2.48 ng/mL (IQR, 1.6-3.7). Total and unbound BIC CSF concentrations were above the half-maximal effective concentration value in all patients, and all subjects had human immunodeficiency virus viral suppression in plasma and CSF. Bictegravir may contribute to inhibit viral replication in this compartment.

Routine Screening of Anal Cytology in Persons With Human Immunodeficiency Virus and the Impact on Invasive Anal Cancer: A Prospective Cohort Study.

BACKGROUND: The efficacy of screening programs to prevent anal cancer in persons with human immunodeficiency virus 1 (HIV-1) is unclear. METHODS: To examine the impact of a screening program to detect anal cancer precursors on the incidence of cases of invasive anal squamous-cell carcinoma (IASCC) in persons with HIV-1, we performed a single-center, retrospective analysis of a prospective cohort of outpatients with HIV-1 attending a reference HIV unit from January 2005 onward. All participants were invited to participate in a continued structured screening program for anal cancer prevention. We estimated the incidence of IASCC and performed a comparative analysis between subjects enrolled in the screening program (screening group) and those who declined to participate (nonscreening group). To reduce any selection bias, a propensity score analysis was applied. RESULTS: We included 3111 persons with HIV-1 (1596 men-who-have-sex-with-men [MSM], 888 men-who-have-sex-with-women [MSW], 627 women; mean age, 41 years), with a median follow-up of 4.7 years (14 595 patient-years of follow-up); 1691 (54%) participated in the screening program. Ten patients were diagnosed with IASCC: 2 (MSM) in the screening group and 8 (4 MSM, 2 MSW, and 2 women) in the nonscreening group. The incidence rates of IASCC were 21.9 (95% confidence interval [CI], 2.7-70.3) and 107.0 (95% CI, 46.2-202.0) per 100 000 person-years, respectively. After a propensity score adjustment, the difference was significant in favor of the screening group (hazard ratio, 0.17; 95% CI, .03-.86). CONCLUSIONS: The number of cases of IASCC was significantly lower in persons with HIV engaged in an anal cytology screening program. These results should be validated in a randomized clinical trial.

Inter-implant fractures: an unmet medical need-a preventive approach proposal.

Inter-implant fractures are associated with reduced quality of life and increased 1-year mortality. For that reason, we propose, instead of treating, a novel, preventative surgical approach that involves splinting the inter-implant femoral shaft interval. In patients with a previous femoral implant in whom a second surgery for new material implantation was necessary (including knee or hip arthroplasty, plate or femoral nailing), an overlapping technique using the minimally invasive plate osteosynthesis technique was performed during the second surgery. Nine patients were included, all females with median (range) age of 78 (55-88) years. No surgery-related complications or mortality occurred. Two patients suffered fractures from a casual fall postoperatively with no implant failure or hospital admission required. In conclusion, instead of treating such fractures after they occur, we propose an effective, safe and reproducible preventative surgical approach, not previously reported, which involves internal femoral splinting, a plate and the minimally invasive plate osteosynthesis technique.

Acute Achilles Tendon Ruptures: Efficacy of Conservative and Surgical (Percutaneous, Open) Treatment-A Randomized, Controlled, Clinical Trial.

There is controversy regarding the best treatment for acute ruptures of the Achilles tendon. Multiple treatments present good results in the short and long term, none being superior to the other if a protocol of rehabilitation with full early weightbearing rehabilitation is followed. The objective of this study was to provide evidence on the efficacy and safety of conservative or surgical (percutaneous or open) treatment for acute Achilles tendon rupture. A randomized, controlled, parallel-groups, pilot clinical trial was performed in patients aged ≥18 years who arrived at the emergency room of our center experiencing acute Achilles tendon rupture. Patients were randomized via a computer-generated list to receive 1 of 3 treatments (conservative, percutaneous surgery, or open surgery). All patients followed the same protocol of rehabilitation with early weightbearing. A responder (i.e., successful treatment) was defined as capable of standing heelrise mono- and bipodally for 3 seconds, having a pain score ≤2 (verbal numerical rating scale) after walking, and having returned to active previous life (sport) at 1-year follow-up. From 2014 to 2017, 34 consecutive patients (median age, 41 years [range 18 to 59]; 32 male [94%]) were included: 11 conservative treatment, 11 percutaneous surgery, and 12 open surgery. At 1-year follow-up, the proportion of responders was 100% (11/11, 95% confidence interval [CI] 74% to 100%), 82% (9/11, 95% CI 52% to 95%), and 83% (10/12, 95% CI 55% to 95%), respectively. There was no case of total rerupture. Similar efficacy was found for conservative, percutaneous, and open surgery treatments for acute Achilles tendon rupture at 1-year follow-up with an early weightbearing rehabilitation program.

Pharmacokinetics of multiple doses of co-crystal of tramadol-celecoxib: findings from a four-way randomized open-label phase I clinical trial.

AIM: We compared the pharmacokinetic (PK) profiles of co-crystal of tramadol-celecoxib (CTC) vs. each reference product (alone and in open combination) after single (first dose) and multiple dosing. METHODS: Healthy adults aged 18-50 years received, under fasted conditions, 15 twice-daily doses of the following treatments (separated by ≥14-day washout): 200 mg immediate-release (IR) CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; treatment 1); 100 mg IR tramadol (treatment 2), 100 mg celecoxib (treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (treatment 4). The treatment sequence was assigned by computer-generated randomization. PK parameters were calculated using non-compartmental analysis. Parameters for CTC were adjusted according to reference product dose. RESULTS: A total of 30 subjects (20 males, mean age 35 years) were included. Multiple-dose tramadol PK parameters for treatments 1, 2 and 4, respectively, were 551, 632 and 661 ng ml-1 [mean maximum plasma concentration (Cmax )]; 4796, 4990 and 5284 ng h ml-1 (area under the plasma concentration-time curve over the dosing interval at steady state); and 3.0, 2.0 and 2.0 h (median time to Cmax at steady state). For treatments 1, 3 and 4, multiple-dose celecoxib PK parameters were 445, 536 and 396 ng ml-1 ; 2803, 3366 and 2897 ng h ml-1 ; and 2.0, 2.0 and 3.0 h. Single-dose findings were consistent with multiple-dose data. Types of adverse events were consistent with known reference product safety profiles. CONCLUSION: After single (first dose) and multiple dosing, PK parameters for each active pharmaceutical ingredient in CTC were modified by co-crystallization compared with reference products alone or in open combination.

Single-dose pharmacokinetics of co-crystal of tramadol-celecoxib: Results of a four-way randomized open-label phase I clinical trial in healthy subjects.

AIMS: Co-crystal of tramadol-celecoxib (CTC) is a novel co-crystal molecule containing two active pharmaceutical ingredients under development by Esteve (E-58425) and Mundipharma Research (MR308). This Phase I study compared single-dose pharmacokinetics (PK) of CTC with those of the individual reference products [immediate-release (IR) tramadol and celecoxib] alone and in open combination. METHODS: Healthy adults aged 18-55 years were orally administered four treatments under fasted conditions (separated by 7-day wash-out period): 200 mg IR CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; Treatment 1); 100 mg IR tramadol (Treatment 2); 100 mg celecoxib (Treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (Treatment 4). Treatment sequence was assigned using computer-generated randomization. PK parameters were calculated using noncompartmental analysis with parameters for CTC adjusted according to reference product dose (100 mg). RESULTS: Thirty-six subjects (28 male, mean age 36 years) participated. Tramadol PK parameters for Treatments-1, -2 and -4, respectively, were 263, 346 and 349 ng ml-1 (mean maximum plasma concentration); 3039, 2979 and 3119 ng h ml-1 (mean cumulative area under the plasma concentration-time curve); and 2.7, 1.8 and 1.8 h (median time to maximum plasma concentration). For Treatments 1, 3 and 4, the respective celecoxib PK parameters were 313, 449 and 284 ng ml-1 ; 2183, 3093 and 2856 ng h ml-1 ; and 1.5, 2.3 and 3.0 h. No unexpected adverse events were reported. CONCLUSION: PK parameters of each API in CTC were modified by co-crystallization compared with marketed formulations of tramadol, celecoxib, and their open combination.

Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease.

INTRODUCTION: We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). METHODS: Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid ß (Aß) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). RESULTS: CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aß040 levels between groups or between subjects with and without CAA. DISCUSSION: CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aß40 levels are not a useful biomarker for CAA in AD.

Acute Pain and Analgesic Requirements After Pulmonary Endarterectomy With Deep Hypothermic Circulatory Arrest.

OBJECTIVES: To assess postoperative pain intensity and the analgesic requirements in the postoperative period in patients undergoing sternotomy for pulmonary endarterectomy involving deep hypothermic circulatory arrest. DESIGN: Retrospective cohort study. SETTING: Single-center hospital study. PARTICIPANTS: Patients 18 years and older undergoing sternotomy for cardiac surgery between August 2012 and August 2014. INTERVENTIONS: No modification to usual clinical practice. MEASUREMENTS AND MAIN RESULTS: Intraoperative opioid and steroid administration, referral to the chronic pain unit, intensive care unit pain scores, and analgesic administration in the first 48 hours after the admission to the intensive care unit were recorded. Postoperative pain was evaluated by means of a categoric verbal scale from no pain (0) to severe pain (3); this is the routine analgesic scale used in the authors' intensive care unit. A total of 200 consecutive patients undergoing pulmonary endarterectomy (PEA group) were included in the study. No patient in the PEA group received morphine during surgery. The mean (standard deviation) postoperative pain intensity score at 24 hours was 0.30 (0.54) in the PEA group. Postoperative morphine was administered in 39% of patients. No PEA patient was referred to the chronic pain unit after hospital discharge. CONCLUSION: The total analgesic requirements and pain score of patients undergoing sternotomy for pulmonary endarterectomy with deep hypothermic circulatory arrest seemed to be low.