Inter-laboratory comparison of routine autoantibody detection methods for autoimmune neuropathies and myasthenia gravis.

Serological tests are important to detect autoantibodies (autoAbs) in patients with autoimmune neuropathies (AN) and myasthenia gravis (MG) as they are biomarkers for diagnosis, stratification, treatment selection, and monitoring. However, tests to detect autoAbs frequently lack proper standardization and results differ across diagnostic laboratories. We compared results for tests routinely performed in Spanish diagnostic laboratories to detect AN and MG autoAbs. In the Spanish Society of Immunology Autoimmunity Group national workshop, serum samples from 13 patients with AN or MG were tested for anti-ganglioside, anti-myelin-associated glycoprotein (MAG), anti-nicotinic acetylcholine receptor (AChR), and anti-muscle-specific kinase (MuSK) autoAbs using reference methods and were distributed for analysis to 27 participating laboratories using their routine methods. Overserved were inter-laboratory variability and worryingly low sensitivity, especially for anti-ganglioside immunoglobulin G and anti-MAG autoAb detection. This pilot study reflects autoAbs detection state of the art in AN and MG testing in leading diagnostic laboratories in Spain, highlighting the need for standardization prior to clinical use.

Co-crystal of tramadol-celecoxib (CTC) for acute moderate-to-severe pain.

OBJECTIVE: This narrative review aims to provide a clinical perspective on the potential role of co-crystal of tramadol-celecoxib (CTC) in the management of acute moderate-to-severe pain by synthesizing the available preclinical and clinical data, with emphasis on phase 3 trials. METHODS: A non-systematic literature review was performed using a targeted PubMed search for articles published between January 1, 2000, and May 2, 2023; all publication types were permitted, and selected articles were limited to those published in English. Search results were manually reviewed to identify references based on their preclinical and clinical relevance to CTC and management of acute moderate-to-severe pain. RESULTS: The crystalline structure of CTC alters the physicochemical properties of tramadol and celecoxib, modifying their pharmacokinetics. If taken in a free combination, tramadol reduces absorption of celecoxib. Conversely, administration of CTC slows tramadol absorption and lowers its maximum plasma concentration, while increasing celecoxib plasma concentration through its enhanced release. In clinical studies across models of acute moderate-to-severe pain, CTC demonstrated an early onset of analgesia, with improved efficacy and lower rescue medication use, compared with either agent alone. CTC's safety profile was in line with that expected for the individual components; no additive effects were observed. CTC exhibited tramadol-sparing effects, with efficacy seen at lower daily/cumulative opioid doses vs. tramadol alone. CONCLUSIONS: Results from phase 3 trials suggest that the modified physicochemical properties of tramadol and celecoxib in CTC translate into an improved clinical benefit-risk profile, including fewer opioid-related adverse effects due to lower overall opioid dosing.

Co-crystal of Tramadol-Celecoxib Versus Tramadol or Placebo for Acute Moderate-to-Severe Pain After Oral Surgery: Randomized, Double-Blind, Phase 3 Trial (STARDOM1).

INTRODUCTION: Co-crystal of tramadol-celecoxib (CTC) is the first analgesic co-crystal for acute pain. This completed phase 3 multicenter, double-blind trial assessed the efficacy and safety/tolerability of CTC in comparison with that of tramadol in the setting of moderate-to-severe pain up to 72 h after elective third molar extraction requiring bone removal. METHODS: Adults (n = 726) were assigned randomly to five groups (2:2:2:2:1): orally administered twice-daily CTC 100 mg (44 mg rac-tramadol hydrochloride/56 mg celecoxib; n = 164), 150 mg (66/84 mg; n = 160) or 200 mg (88/112 mg; n = 160); tramadol 100 mg four times daily (n = 159); or placebo four times daily (n = 83). Participants in CTC groups also received twice-daily placebo. The full analysis set included all participants who underwent randomization. The primary endpoint was the sum of pain intensity differences over 0 to 4 h (SPID0-4; visual analog scale). Key secondary endpoints included 4-h 50% responder and rescue medication use rates. Safety endpoints included adverse events (AEs), laboratory measures, and Opioid-Related Symptom Distress Scale (OR-SDS) score. RESULTS: All CTC doses were superior to placebo (P < 0.001) for primary and key secondary endpoints. All were superior to tramadol for SPID0-4 (analysis of covariance least squares mean differences [95% confidence interval]: - 37.1 [- 56.5, - 17.6], - 40.2 [- 59.7, - 20.6], and - 41.7 [- 61.2, - 22.2] for 100, 150, and 200 mg CTC, respectively; P < 0.001) and 4-h 50% responder rate. Four-hour 50% responder rates were 32.9% (CTC 100 mg), 33.8% (CTC 150 mg), 40.6% (CTC 200 mg), 20.1% (tramadol), and 7.2% (placebo). Rescue medication use was lower in the 100-mg (P = 0.013) and 200-mg (P = 0.003) CTC groups versus tramadol group. AE incidence and OR-SDS scores were highest for tramadol alone. CONCLUSIONS: CTC demonstrated superior pain relief compared with tramadol or placebo, as well as an improved benefit/risk profile versus tramadol. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02982161; EudraCT number, 2016-000592-24.

Lower fatigue and faster recovery of ultra-short race pace swimming training sessions.

Ultra-short race-pace training (USRPT) is a high-intensity training modality used in swimming for the development of specific race-technique. However, there is little information about the fatigue associated to this modality. In a crossover design, acute responses of two volume-equated sessions (1000-m) were compared on 14 national swimmers: i) USRPT: 20×50-m; ii) RPT: 10×100-m. Both protocols followed an equivalent work-recovery ratio (1:1) based on individual 200-m race-pace. The swimming times and the arm-strokes count were monitored on each set and compared by mixed-models. Blood lactate [La-] and countermovement jump-height (CMJ) were compared within and between conditions 2 and 5 min after the protocols. The last bouts in RPT were 1.5-3% slower than the target pace, entailing an arm-strokes increase of ~0.22 for every second increase in swimming time. USRPT produced lower [La-] ([Mean ± standard deviation], 2 min: 8.2±2.4 [p = 0.021]; 5 min: 6.9±2.8 mM/L [p = 0.008]), than RPT (2 min: 10.9±2.3; 5 min: 9.9±2.4 mM/L). CMJ was lowered at min 2 after RPT (-11.09%) and USRPT (-5.89%), but returned to baseline in USRPT at min 5 of recovery (4.07%). In conclusion, lower fatigue and better recovery were achieved during USRPT compared to traditional high-volume set.

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.

Efficacy and safety of co-crystal of tramadol-celecoxib (CTC) in acute moderate-to-severe pain after abdominal hysterectomy: A randomized, double-blind, phase 3 trial (STARDOM2).

BACKGROUND: STARDOM2 is a randomized, double-blind, phase 3 trial evaluating the efficacy and safety of co-crystal of tramadol-celecoxib (CTC)-a first-in-class analgesic co-crystal comprising racemic tramadol hydrochloride and celecoxib in a supramolecular network that modifies their pharmacokinetic properties-for the management of acute postoperative pain (NCT03062644; EudraCT:2016-000593-38). METHODS: Patients with moderate-to-severe pain following abdominal hysterectomy were randomized 2:2:2:2:2:1 to oral CTC 100 mg (rac-tramadol hydrochloride 44 mg/celecoxib 56 mg) twice daily (BID); CTC 150 mg (66/84 mg) BID; CTC 200 mg (88/112 mg) BID; immediate-release tramadol 100 mg four times daily (QID); celecoxib 100 mg BID; or placebo, for 5 days. The primary endpoint was the sum of pain intensity differences over 0-4 h (SPID0-4 ). Key secondary endpoints were rescue medication use within 4 h, 50% response rate at 4 h, and safety/tolerability. RESULTS: Of 1355 patients enrolled, 1138 were randomized (full analysis set) and 1136 treated (safety analysis set). In the prespecified gatekeeping analysis of SPID0-4 , CTC 200 mg was not superior to tramadol but showed non-inferior efficacy (p < 0.001) that was sustained throughout the 120-h period, despite a 5-day cumulative tramadol administration of 880 mg with CTC 200 mg BID versus 2000 mg with tramadol 100 mg QID. Treatment-emergent adverse events (TEAEs) and severe TEAEs were less common with CTC 200 mg versus tramadol. Treatment-related TEAEs were 14.4% with CTC 200 mg and 23.6% with tramadol. CONCLUSIONS: Although the study did not meet its primary endpoint, CTC 200 mg showed a clinically relevant improvement in overall benefit/risk profile versus tramadol alone, with considerably lower cumulative opioid exposure. SIGNIFICANCE: In the randomized, double-blind, phase 3 STARDOM2 trial-in acute moderate-to-severe pain after abdominal hysterectomy-the novel co-crystal of tramadol-celecoxib (CTC) 200 mg BID was superior to placebo and non-inferior to tramadol 100 mg QID. Although superiority to tramadol was not reached, CTC 200 mg BID exposed patients to lower cumulative opioid (tramadol) doses than tramadol (100 mg QID) alone, with fewer treatment-emergent adverse events. CTC 200 mg thus has a clinically relevant improved benefit/risk profile compared with tramadol alone.

Are the 50 m Race Segments Changed From Heats to Finals at the 2021 European Swimming Championships?

This study explored in the 50 m races of the four swimming strokes the performance parameters and/or technical variables that determined the differences between swimmers who reach the finals and those who do not. A total of 322 performances retrieved from the 2021 Budapest European championships were the focus of this study. The results of the performances achieved during the finals compared to the heats showed that the best swimmers did not excel during the heats, as a significant progression of performance was observed in most of the strokes as the competition progressed. Specifically, combining men and women, the swimmers had in freestyle a mean coefficient of variation (CV) of ∼0.6%, with a mean range of performance improvement (∆%) of ∆ = ∼0.7%; in breaststroke a mean CV of ∼0.5% and ∆ = -0.2%; in backstroke a mean CV of ∼0.5% and ∆ = -0.6%, and; in butterfly a mean CV of ∼0.7% and ∆ = -0.9%. For all strokes, it was a reduction of the underwater phase with the aim of increasing its speed. However, this result was not always transferred to the final performance. In any case, most of the swimmers tried to make improvements from the start of the race up to 15 m. Furthermore, the swimmers generated an overall increase in stroke rate as the rounds progressed. However, a decrease in stroke length resulted and, this balance appeared to be of little benefit to performance.

Biophysical Impact of 5-Week Training Cessation on Sprint Swimming Performance.

PURPOSE: To assess changes in swimming performance, anthropometrics, kinematics, energetics, and strength after 5-week training cessation. METHODS: Twenty-one trained and highly trained swimmers (13 males: 17.4 [3.1] y; 50-m front crawl 463 [77] FINA points; 8 females: 16.7 [1.7] y; 50-m front crawl 535 [48] FINA points) performed a 50-m front-crawl all-out swim test, dryland and pool-based strength tests, and 10-, 15-, 20-, and 25-m front-crawl all-out efforts for anaerobic critical velocity assessment before and after a 5-week training cessation. Heart rate and oxygen uptake (V˙O2) were continuously measured before and after the 50-m swim test (off-kinetics). RESULTS: Performance was impaired 1.9% (0.54 s) for males (P = .007, d = 0.91) and 2.9% (0.89 s) for females (P = .033, d = 0.93). Neither the anthropometrical changes (males: r2 = .516, P = .077; females: r2 = .096, P = .930) nor the physical activities that each participant performed during the off-season (males: r2 = .060, P = .900; females: r2 = .250, P = .734) attenuated performance impairments. Stroke rate and clean swimming speed decreased (P < .05), despite similar stroke length and stroke index (P > .05). Blood lactate concentrations remained similar (P > .05), but V˙O2 peak decreased in females (P = .04, d = 0.85). Both sexes showed higher heart rate before and after the 50-m swim test after 5 weeks (P < .05). Anaerobic metabolic power deterioration was only observed in males (P = .035, d = 0.65). Lower in-water force during tethered swimming at zero speed was observed in males (P = .033, d = 0.69). Regarding dryland strength, lower-body impairments were observed for males, while females showed upper-body impairments (P < .05). CONCLUSIONS: A 5-week training cessation yielded higher heart rate in the 50-m front crawl, anaerobic pathways, and dryland strength impairments. Coaches should find alternatives to minimize detraining effects during the off-season.

Growth Differentiation Factor 15 (GDF-15): A Novel Biomarker Associated with Poorer Respiratory Function in COVID-19.

It is essential to find new biomarkers for severity stratification of patients with coronavirus disease (COVID-19). Growth differentiation factor 15 (GDF-15) is upregulated in pathological conditions that involve inflammation and/or oxidative stress. We determined circulating levels of GDF-15 and correlated them with clinical and laboratory parameters reflecting severity in 84 patients with COVID-19, finding that GDF-15 levels were higher in both patients than in 20 healthy controls and were higher in patients with poorer respiratory function. GDF-15 levels also correlated with interleukin-6, C-reactive protein, ferritin and D-dimer levels and with neutrophilia and lymphopenia. Of all the analysed biomarkers, GDF-15 showed the best area under the receiver operating characteristics curve in identifying patients with poor respiratory function. In conclusion, our data support GDF-15 as a biomarker associated with pulmonary impairment in COVID-19 and so can potentially be useful in stratifying COVID-19 cases by severity.

Swimming with Swimsuit and Wetsuit at Typical vs. Cold-water Temperatures (26 vs. 18 ℃).

This study aimed to compare three swimming conditions in a swimming flume with water at 26 ℃ (using swimsuit) and 18 ℃ (randomly with swimsuit and wetsuit). Seventeen swimmers (32.4±14.7 years old, 175.6±0.06 cm height, and 70.4±9.8 kg body mass) performed three bouts until exhaustion at a 400-m front crawl pace (24 h intervals). ANOVA repeated measures compared the experimental conditions. Swimming at 26 ℃ with swimsuit evidenced a higher metabolic demand (total energy expenditure; (E)), comparing to 18 ℃ swimsuit (p=0.05) and with 18 ℃ wetsuit (p=0.04). The 26 ℃ swimsuit condition presented higher peak oxygen uptake (VO2peak), blood lactate concentrations ([La-]peak), rate of perceived exertion (RPE), maximal heart rate (HRmax), anaerobic lactic energy (AnL), E, energy cost (C), V̇O2 amplitude (Ap), and stroke rate (SR), but lower stroke length (SL) and stroke index (SI) than 18 ℃ wetsuit. The 18 ℃ swimsuit condition (comparing to wetsuit) lead to higher V̇O2peak, [La-]peak, HRmax, E, C, Ap, and SR but lower SL and SI. Swimming at aerobic power intensity with swim and wetsuit at 18 ℃ does not induce physiologic and biomechanical disadvantages compared to 26 ℃. The results suggested that the use of wetsuit might increase performance at 18 ℃ water temperature for competitive master swimmers. Its use is thus recommended in open water swimming competitions when the water temperature is 18-20 ℃.

Protocolización de la post-activación potenciación estimulada en natación y su relación con la fuerza relativa / Protocolization of post-activation performance enhancements in swimming and its relationship with the relative strength

OBJETIVO: Este estudio experimentó un protocolo de post-activación potenciación estimulada en 16 nadadores de competición. MÉTODO: En primer lugar, se aplicaron ejercicios de acondicionamiento para extremidades superiores e inferiores y se exploraron los efectos producidos tras 5, 8, 12 y 20 minutos de descanso en un test que implicaba tres saltos verticales y tres flexiones explosivas. En una sesión posterior, se aplicaron ejercicios de acondicionamiento específico en ambas extremidades proporcionando el mismo tiempo de descanso que había inducido los mejores resultados en la evaluación exploratoria (8 min), y sus efectos se evaluaron en una prueba de natación sprint (50 m). Finalmente, también se obtuvo el índice de fuerza relativa de los participantes y se estudió su relación con el rendimiento. RESULTADOS: Las variables relacionadas con la salida de natación mejoraron. La velocidad en el despegue fue mayor debido al incremento de las fuerzas desarrolladas en el poyete. El tiempo de nado en la prueba de 50-m se mantuvo igual a la situación estándar aunque la velocidad fue mayor en los primeros metros. CONCLUSIONES: Los sujetos con mayor índice de fuerza obtuvieron mejores resultados y reaccionaron mejor a la post-activación potenciación estimulada posiblemente porque sus efectos son más efectivos en las fibras tipo II y estas, son más comunes en sujetos entrenados

OBJETIVO: Este estudo tentou um protocolo de aprimoramento de desempenho pós-ativação (PAPE) em 16 nadadores treinados. MÉTODO: Primeiro, exercícios de condicionamento máximo para membros superiores e inferiores foram aplicados e testados após 5, 8, 12 e 20 minutos de descanso através do teste de contrações voluntárias máximas (3 repetições de salto vertical e 3 repetições de flexão voadora). Em uma sessão subsequente, exercícios específicos de condicionamento foram aplicados novamente em ambos os membros e seus efeitos foram avaliados em uma corrida de natação de 50 m após proporcionar o mesmo tempo de descanso em que o melhor desempenho foi detectado (8 min). Por fim, o índice de força relativa foi obtido em todos os participantes para estudar a relação com as variáveis de desempenho na natação. RESULTADOS: Todas as variáveis relacionadas à natação iniciaram o desempenho. A velocidade durante o vôo foi maior devido ao aumento das forças produzidas contra o bloco. O tempo de natação para 50-m foi semelhante ao obtido após a condição padrão, embora as velocidades de natação fossem maiores no início da corrida. CONCLUSÕES: Os indivíduos com maior índice de força relativa obtiveram melhores resultados e reagiram melhor ao aprimoramento de desempenho pós-ativação, possivelmente por seus efeitos serem maiores nas fibras do tipo II e serem mais frequentes em indivíduos treinados

Post high intensity pull-over semi-tethered swimming potentiation in national competitive swimmers.

BACKGROUND: The swimming community has shown considerable interest in using dry-land warm-ups as a method of impacting performance. This study compared the effects of high-resistance pull-over and swimming warm-up in semi-tethered resisted swimming. METHODS: An incremental-load semi-tethered swimming test was individually administered in 20 national-competitive swimmers to determine the load maximizing swimming power. In different sessions, participants tested such a load 6 min after a swimming warm-up (SWU) or a dry-land warm-up (DLWU: 3 pull-over reps at 85% of the one-repetition maximum). Kinetic variables (velocity, force, acceleration, impulse, power rate of force development [RFD] and intra-cycle variation), were obtained with a linear encoder through trapezoidal integration regarding time. Kinematic variables (distance, time, stroke-rate and stroke-length), were obtained by video recordings. The differences between protocols were observed by paired-samples t-test (ANOVA). Pearson's coefficient explored correlations between kinetics and kinematics variables; significance was set at P<0.05. RESULTS: DLWU increased RFD (34.52±16.55 vs. 31.29±13.70 N/s; Δ=9.35%) and stroke-rate (64.70±9.84 vs. 61.56±7.07 Hz; Δ=5.10%) compared to SWU, but decreased velocity, force, acceleration, impulse and power. During the incremental-load test velocity and power were higher than obtained after SWU (1.21±0.14 vs. 1.17±0.12 m/s; Δ=3.06%), (51.38±14.93 vs. 49.98±15.40 W; Δ=2.72%), suggesting enhancements prompted by the test itself. Correlations between stroke-length with impulse (r=0.76) and power (r=0.75) associated kinetics with kinematics. CONCLUSIONS: Potentiation responses were present after the dry-land warm-up. However, swimmers may benefit more from submaximal prolonged conditioning activities such as resisted swimming rather than high-resistance dry-land sets to obtain performance enhancements.

Anticuerpos anti-GQ1b: utilidad de su determinación en el diagnóstico del síndrome de Miller-Fisher / Anti-GQ1b antibodies: usefulness of its detection for the diagnosis of Miller-Fisher syndrome

FUNDAMENTO: Estudiar la presencia de anticuerpos anti-GQ1b como herramienta para el diagnóstico del síndrome de Miller-Fisher (SMF). PACIENTES Y MÉTODO: Se estudiaron 54 pacientes con sospecha de SMF y 10 pacientes con diagnóstico cierto de síndrome de Guillain-Barré con oftalmoplejía (un caso), encefalitis de Bickerstaff (un caso), oftalmoplejía recidivante (7 casos) y diplopía recidivante (un caso). Los resultados se compararon con 130 pacientes con otras neuropatías disinmunes. Se realizó determinación de anticuerpos anti-GQ1b mediante ensayo enzimático de inmunoabsorción (ELISA) y posterior comprobación por cromatografía en capa fina (CCF), así como serología de Campylobacter jejuni mediante test de fijación de complemento. RESULTADOS: Se confirmó el diagnóstico de SMF en 38 pacientes. En un 97,3 por ciento de ellos se detectaron anticuerpos anti-GQ1b, siendo todos negativos para serología de Campylobacter jejuni. Ningún paciente con sintomatología aguda troncoencefálica resultó positivo. Sólo un 1,8 por ciento de pacientes con otras neuropatías presentaron anticuerpos anti-GQ1b. Un 84,2 por ciento (16/19) de enfermos a los que se les realizó una segunda determinación a las 4-5 semanas negativizaron los anticuerpos, coincidiendo además con una mejoría clínica. CONCLUSIONES: Los anticuerpos anti-GQ1b son indicadores del SMF y sirven para su diagnóstico diferencial, sobre todo con otras enfermedades agudas cerebelosas y de tronco cerebral. Su positividad depende del momento en que se realiza el estudio, por lo que se recomienda su investigación dentro de las primeras 4 semanas de curso clínico. La correlación entre la tríada de ataxia, arreflexia y oftalmoplejía y títulos positivos de anticuerpos anti-GQ1b confirma su especificidad para el diagnóstico del SMF (AU)