Higher Unilateral Muscle Imbalance at the Contralateral Knee 6 Months after Anterior Cruciate Ligament Reconstruction.

There are a considerable number of patients who, after anterior cruciate ligament reconstruction (ACL), suffer from relapses or reduced performance. Data collected from isokinetic dynamometry can provide useful information on the condition of the knee during rehabilitation. Seventy-one young sports patients with ACL reconstruction performed concentric (CON) isokinetic dynamometry (CON/CON 90°/s and CON/CON 240°/s) to assess the muscle strength of the quadriceps (Q) and hamstrings (H) in both knees at 6 months after ACL reconstruction. Limb symmetry index (LSI) and the H/Q ratio were calculated. Comparative statistical tests and multivariate regression were performed. At 90°/s, 57 patients (80.3%) had an LSI below 90% for quadriceps and 28 (60.6%) for hamstring. The number of imbalanced patients according to H/Q ratio was higher in the non-operated knee (n = 56, 78.9%) (p < 0.001). At 240°/s, 49 cases (69.1%) had LSI values above 90% for quadriceps and 37 (52.1%) for hamstrings. Regarding H/Q, imbalanced cases were higher in the non-operated limb (n = 60, 84.5%) (p < 0.001). Strength data at 6 months after ACL reconstruction and post-operative rehabilitation indicated greater unilateral (H/Q) muscle imbalance in the non-operated knee than in the operated knee. Most patients did not achieve the adequate LSI values.

Current Challenges in the Development of Platelet-Rich Plasma-Based Therapies.

Nowadays, biological therapies are booming and more of these formulations are coming to the market. Platelet-rich plasma, or PRP, is one of the most widely used biological therapies due to its ease of obtention and autologous character. Most of the techniques to obtain PRP are focusing on new processes and methods of optimization. However, not enough consideration is being given to modify the molecular components of PRP to generate more effective formulations with the aim of improving PRP treatments. Therefore, this review covers different novel PRP-obtaining methods that attempt to modify the molecular composition of the plasma.

Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy.

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this double-blind, randomized trial, we assigned patients with ATTR-CM in a 1:1 ratio to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically. RESULTS: A total of 655 patients underwent randomization; 326 were assigned to receive vutrisiran and 329 to receive placebo. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P = 0.02) and a lower risk of death from any cause through 42 months (hazard ratio, 0.65; 95% CI, 0.46 to 0.90; P = 0.01). A primary end-point event occurred in 163 patients in the vutrisiran group and in 202 in the placebo group. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group. CONCLUSIONS: Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.).

Validation of a rapid collagenase activity detection technique based on fluorescent quenched gelatin with synovial fluid samples.

BACKGROUND: Measuring collagenase activity is crucial in the field of joint health and disease management. Collagenases, enzymes responsible for collagen degradation, play a vital role in maintaining the balance between collagen synthesis and breakdown in joints. Dysregulation of collagenase activity leads to joint tissue degradation and diseases such as rheumatoid arthritis and osteoarthritis. The development of methods to measure collagenase activity is essential for diagnosis, disease severity assessment, treatment monitoring, and identification of therapeutic targets. RESULTS: This study aimed to validate a rapid collagenase activity detection technique using synovial fluid samples. Antibody microarray analysis was initially performed to quantify the levels of matrix metalloproteinase-9 (MMP-9), a major collagenase in joints. Subsequently, the developed gelatin-based test utilizing fluorescence measurement was used to determine collagenase activity. There was a significant correlation between the presence of MMP-9 and collagenase activity. In addition, Lower Limit of Detection and Upper Limit of Detection can be preliminary estimated as 8 ng/mL and 48 ng/mL respectively. CONCLUSIONS: The developed technique offers a potential point-of-care assessment of collagenase activity, providing real-time information for clinicians and researchers. By accurately quantifying collagenase activity, healthcare professionals can optimize patient care, improve treatment outcomes, and contribute to the understanding and management of joint-related disorders. Further research and validation are necessary to establish the full potential of this rapid collagenase activity detection method in clinical practice.

Tree demographic strategies largely overlap across succession in Neotropical wet and dry forest communities.

Secondary tropical forests play an increasingly important role in carbon budgets and biodiversity conservation. Understanding successional trajectories is therefore imperative for guiding forest restoration and climate change mitigation efforts. Forest succession is driven by the demographic strategies-combinations of growth, mortality and recruitment rates-of the tree species in the community. However, our understanding of demographic diversity in tropical tree species stems almost exclusively from old-growth forests. Here, we assembled demographic information from repeated forest inventories along chronosequences in two wet (Costa Rica, Panama) and two dry (Mexico) Neotropical forests to assess whether the ranges of demographic strategies present in a community shift across succession. We calculated demographic rates for >500 tree species while controlling for canopy status to compare demographic diversity (i.e., the ranges of demographic strategies) in early successional (0-30 years), late successional (30-120 years) and old-growth forests using two-dimensional hypervolumes of pairs of demographic rates. Ranges of demographic strategies largely overlapped across successional stages, and early successional stages already covered the full spectrum of demographic strategies found in old-growth forests. An exception was a group of species characterized by exceptionally high mortality rates that was confined to early successional stages in the two wet forests. The range of demographic strategies did not expand with succession. Our results suggest that studies of long-term forest monitoring plots in old-growth forests, from which most of our current understanding of demographic strategies of tropical tree species is derived, are surprisingly representative of demographic diversity in general, but do not replace the need for further studies in secondary forests.

Factores asociados con la fragilidad en un servicio ambulatorio de geriatría de un hospital universitario en Bogotá (Colombia) / Factors Associated with Frailty in the Geriatric Outpatient Service of a University Hospital in Bogotá (Colombia) / Fatores associados à fragilidade no ambulatório de geriatria de um hospital universitário de Bogotá (Colômbia)

Introducción: la fragilidad, entendida como un estado previo a la discapacidad, confiere mayor vulnerabi-lidad a estresores externos y contribuye a desenlaces negativos como caídas, hospitalización, discapacidad y mortalidad. El objetivo de este estudio fue identificar su prevalencia y evaluar los factores asociados en los pacientes del Servicio Ambulatorio de Geriatría del Hospital Universitario San Ignacio (husi) en Bogotá (Colombia). Materiales y métodos: estudio de corte transversal con 689 pacientes atendidos en la consulta externa de geriatría del husi entre agosto de 2016 y marzo de 2020. Mediante regresiones logísticas se iden-tificaron los factores relacionados con la fragilidad. Resultados: la prevalencia fue del 35.4 %. En el análisis bivariado, las variables asociadas con la fragilidad fueron edad mayor de 80 años (or: 2.07; ic95 %: 1.40-3.20; p = 0.001), sexo femenino (or: 1.40; ic95 %: 0.99-2.02; p = 0.03), multimorbilidad (or: 2.13; ic95 %: 1.40-2.90; p < 0.001) y malnutrición (or: 2.23; ic95 %: 1.22-4.07; p = 0.009). En el análisis multivariado, la multimor-bilidad (or: 2.46; ic95 %: 1.62-3.75; p = 0.001), la velocidad de la marcha lenta (or: 5.15; ic95 %: 3.0-8.60; p = 0.001) y el perímetro de pantorrilla bajo (or: 1.60; ic95 %: 1.03-2.50; p = 0.06) se vincularon con la fragilidad. Conclusión: la prevalencia de fragilidad en el servicio de geriatría del husies mayor a la de los referentes nacionales; adicionalmente, las variables analizadas coinciden con las encontradas en la literatura; todo esto respecto a la gran complejidad clínica de los pacientes. Es clave la detección de los factores que se asocian con fragilidad, a fin de intervenirlos y prevenir desenlaces adversos

Introduction: Frailty, understood as a pre-disability state, increases vulnerability to external stressors and contributes to negative outcomes such as falls, hospitalization, disability, and mortality. This study aims to identify the prevalence of frailty and assess the associated factors in patients attending the geriatric outpatient service of the Hospital Universitario San Ignacio (husi). Materials and methods: A cross-sectional study involving 689 patients treated at the husigeriatric outpatient clinic between August 2016 and March 2020. Logistic regressions were conducted to identify factors associated with frailty. Results: The prevalence of frailty was 35.4 %. In bivariate analysis, variables associated with frailty included age over 80 years (or: 2.07; ci95 %: 1.40-3.20; p = 0.001), female sex (or: 1.40; ci95 %:0.99-2.02; p= 0.03), multimorbidity (or: 2.13; ci95 %:1.40-2.90; p < 0.001) and malnutrition (or: 2.23; ci95 %: 1.22-4.07; p = 0.009). In multivariate analysis, multimorbidity (or: 2.46; ci95 %: 1.62-3.75; p = 0.001), slow walking speed (or: 5.15; ci95 %: 3.0-8.60; p = 0.001) and low calf perimeter (or: 1.60; ci95 %: 1.03-2.50; p = 0.06) were associated with frailty. Conclusion: The prevalence of frailty in our center exceeds national references; and the identified variables align with those reported in the literature; reflecting the considerable clin-ical complexity of our patients. Detecting factors associated with frailty is crucial for intervention and prevention of adverse outcomes

ntrodução: a fragilidade, entendida como um estado anterior à incapacidade, confere maior vulnerabi-lidade a estressores externos e contribui para desfechos negativos como quedas, hospitalização, incapa-cidade e mortalidade. O objetivo deste estudo foi identificar a prevalência e avaliar os fatores associados à fragilidade em pacientes do ambulatório de geriatria do Hospital Universitário San Ignacio (husi) de Bogotá, Colômbia. Materiais e métodos: estudo transversal com 689 pacientes atendidos no ambulatório de geriatria do husi entre agosto de 2016 e março de 2020. Foram realizadas regressões logísticas para identificar fatores associados à fragilidade. Resultados: a prevalência de fragilidade foi de 35.4 %. Na análise bivariada, as variáveis associadas à fragilidade foram: idade acima de 80 anos (or:2.07; ic95 %:1.40-3,20; p = 0.001), gênero feminino (or:1.40; ic95 %:0.99-2.02; p = 0.03), multimorbidade (or: 2.13; ic95 %: 1.40-2.90; p < 0.001) e desnutrição (or:2.23; ic95 %:1.22-4.07; p = 0.009). Na análise multivariada, multimorbidade (or:2.46; ic95 %: 1.62-3.75; p = 0.001), velocidade lenta de caminhada (or:5.15; ic95 %:3.0-8.60; p = 0.001) e baixa circunferência da panturrilha (or: 1.60; ic95 %: 1.03-2.50; p = 0.06) foram associados à fragilidade. Conclusão: a prevalência de fragilidade no husi é superior à das referências nacionais; adicionalmente, as variáveis associadas coincidem com as encontradas na literatura; tudo isso em relação à grande complexidade clínica dos nossos pacientes. É fundamental detectar os fatores associados à fragilidade para intervir e prevenir resultados adversos

A Novel Fibrin Matrix Derived from Platelet-Rich Plasma: Protocol and Characterization.

Although fibrin matrices derived from Platelet-Rich Plasma (PRP) are widely used in regenerative medicine, they have some limitations that can hinder their application. Modifying the composition of the PRP-derived fibrin matrix may improve its properties, making it suitable for certain medical uses. Three types of fibrin matrices were obtained: a PRP-derived fibrin matrix (FM), a PRP-derived fibrin matrix with a high fibrinogen content and platelets (FM-HFP) and a PRP-derived fibrin matrix with a high fibrinogen content (FM-HF). The fibrinogen levels, biomechanical properties and cell behavior were analyzed. The presence of platelets in the FM-HFP generated an inconsistent fibrin matrix that was discarded for the rest of the analysis. The fibrinogen levels in the FM-FH were higher than those in the FM (p < 0.0001), with a concentration factor of 6.86 ± 1.81. The values of clotting and swelling achieved using the FM-HF were higher (p < 0.0001), with less clot shrinkage (p < 0.0001). The FM had a significantly higher stiffness and turned out to be the most adherent composition (p = 0.027). In terms of cell viability, the FM-HF showed less cell proliferation but higher live/dead ratio values (p < 0.01). The increased fibrinogen and platelet removal in the FM-HF improved its adhesion and other biomechanical properties without affecting cell viability.

Derotational high tibial osteotomy in cases of anterior knee pain and/or patellofemoral instability: a systematic review.

IMPORTANCE: Derotational high tibial osteotomy (HTO) is a surgical intervention for correcting rotational malalignments in the lower limb, which may contribute to anterior knee pain (AKP) and/or patellofemoral instability (PFI). This surgical technique is not yet widely implemented and requires a systematic evaluation of its outcomes. AIM: To assess the effectiveness of derotational HTO in correcting rotational malalignments of the lower limb in patients with AKP and/or PFI through radiological, clinical, and patient-reported outcome measures. EVIDENCE REVIEW: Searches were conducted in the PubMed, Embase, and Web of Science databases up to March 3, 2023, to identify studies utilizing derotational HTO in patients with AKP and/or PFI. The primary outcome measures of interest were measurements of lower limb angular correction. Other radiological, clinical, and patient-reported outcome measures were also analyzed. The risk of bias was judged with the RoBANS tool. FINDINGS: A total of 8 studies were included, comprising 215 patients (27.0 â€‹± â€‹3.9 years) and 245 knees. The most reported angle was tibial torsion (k â€‹= â€‹6 studies, n â€‹= â€‹173 knees), with a mean difference between postoperative and preoperative values (postsurgical correction) ranging from -37.8° to -10.8°. Patient-reported outcome measures showed significant improvements in the postoperative moment, exceeding the minimal clinically important difference in almost all cases, and with high patient satisfaction (93.6%). CONCLUSIONS AND RELEVANCE: Derotational HTO allows the correction of rotational malalignments of the lower limb (tibial torsion) and promotes patient satisfaction. LEVEL OF EVIDENCE: Level IV.

Adaptive servo-ventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF): a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial

BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely.

Derotational distal femoral osteotomy corrects excessive femoral anteversion in patients with patellofemoral instability: A systematic review.

PURPOSE: Patellofemoral instability (PFI) is a common condition that can be caused from multiple factors, including lower limb rotational malalignments. Determining precise criteria for performing corrective torsional osteotomy can be a daunting task due to the lack of consensus on normal and excessive values and the limited evidence-based data in the postoperative results. The purpose was to assess the clinical, functional and imaging outcomes following derotational distal femoral osteotomy (DDFO) in patients with PFI and/or anterior knee pain (AKP) associated with lower limb rotational malalignments. METHODS: Searches were conducted on PubMed, EMBASE and Web of Science databases up to October 2023. Studies reporting outcomes after DDFO in patients with PFI and/or AKP were eligible for the systematic review. The primary outcome was imaging metrics, especially femoral anteversion. Secondary outcomes included the patient-reported outcome measures (PROMs) (clinical and functional). Quantitative synthesis involved the use of weighted averages to calculate pre- to postoperative mean differences (MD) and compare them against the minimal clinically important difference (MCID). RESULTS: Ten studies (309 knees) were included with a mean follow-up of 36.1 ± 11.7 months. Imaging outcomes consistently indicated the correction of femoral anteversion (MD = -19.4 degrees, 95% confidence interval: -20.1 to -18.7) following DDFO. PROMs showed significant improvements in most studies, exceeding the MCID. Patient satisfaction with the DDFO was high (93.3%). CONCLUSIONS: The DDFO was an effective treatment option for correcting excessive femoral anteversion in patients with PFI associated with clinically relevant functional and clinical improvement and a high satisfaction rate. LEVEL OF EVIDENCE: Level IV, systematic review of level II-IV studies.

Women show a positive response to platelet-rich plasma despite presenting more painful knee osteoarthritis than men.

PURPOSE: The purpose of this study was to evaluate the impact of gender on the efficacy of platelet-rich plasma (PRP) in patients with knee osteoarthritis (KOA), comparing their short-term response between men and women. METHODS: Four hundred-eighteen patients (529 knees) were included. Patients were treated with three injections of PRP on a weekly basis. Blood and PRP samples were randomly tested. Patients were asked to complete the knee injury and osteoarthritis outcome score (KOOS) and 12-item short form survey (SF-12), at baseline and 6 months. Success rates were calculated according to a reduction in the pain score of at least 9.3 points [minimal clinically important improvement (MCII)]. Comparative tests and multivariate regression were performed. RESULTS: The PRP had a platelet concentration factor of 2.0X compared to blood levels, with no leucocytes or erythrocytes. KOOS scores showed an increase from baseline to 6 months (p < 0.0001). There was an increase in the physical component summary (PCS) (p < 0.0001) and mental component summary (MCS) (p < 0.01) of the SF-12. The number of knees of women with MCII was 156 out of 262 (59.6%), whereas the number of knees of men was 136 out of 267 (50.9%) (p = 0.0468). Women had worse baseline scores on pain (p = 0.009), PCS (p < 0.0001) and MCS (p < 0.0001). CONCLUSION: Although the symptomatology generated by KOA was worse in women when compared to men, treatment with repeated injections of PRP was effective, ultimately achieving a higher improvement in women providing comparable final follow-up outcomes between men and women. LEVEL OF EVIDENCE: Level IV.

Method to obtain a plasma rich in platelet- and plasma-growth factors based on water evaporation.

Platelet-Rich Plasma, also known as PRP, is an autologous biologic product used in medicine as a treatment for tissue repair. Nowadays, the majority of PRP obtention methods enrich only platelets, not considering extraplatelet biomolecules, which take part in several cell processes. In the present work, a novel PRP preparation method was developed to obtain a PRP rich in both platelet and plasma extraplatelet molecules. The method is based on the evaporation of the water of the plasma using a rotary evaporator. With this new methodology an increase in plasmatic growth factors and, as a consequence, a better dermal fibroblast cell viability was achieved, compared to a standard PRP formulation. This novel PRP product obtained with this new methodology showed promising results in vitro as an improved PRP treatment in future application.

Adaptive servo-ventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF): a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial.

BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely. FUNDING: Canadian Institutes of Health Research and Philips RS North America.

Estrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice.

Menopause is associated with cognitive deficits and brain atrophy, but the brain region and cell-specific mechanisms are not fully understood. Here, we identify a sex hormone by age interaction whereby loss of ovarian hormones in female mice at midlife, but not young age, induced hippocampal-dependent cognitive impairment, dorsal hippocampal atrophy, and astrocyte and microglia activation with synaptic loss. Selective deletion of estrogen receptor beta (ERß) in astrocytes, but not neurons, in gonadally intact female mice induced the same brain effects. RNA sequencing and pathway analyses of gene expression in hippocampal astrocytes from midlife female astrocyte-ERß conditional knock out (cKO) mice revealed Gluconeogenesis I and Glycolysis I as the most differentially expressed pathways. Enolase 1 gene expression was increased in hippocampi from both astrocyte-ERß cKO female mice at midlife and from postmenopausal women. Gain of function studies showed that ERß ligand treatment of midlife female mice reversed dorsal hippocampal neuropathology.

New Formulation of Platelet-Rich Plasma Enriched in Platelet and Extraplatelet Biomolecules Using Hydrogels.

Platelet-rich plasma (PRP) is an autologous biologic product used in several fields of medicine for tissue repair due to the regenerative capacity of the biomolecules of its formulation. PRP consists of a plasma with a platelet concentration higher than basal levels but with basal levels of any biomolecules present out of the platelets. Plasma contains extraplatelet biomolecules known to enhance its regenerative properties. Therefore, a PRP containing not only a higher concentration of platelets but also a higher concentration of extraplatelet biomolecules that could have a stronger regenerative performance than a standard PRP. Considering this, the aim of this work is to develop a new method to obtain PRP enriched in both platelet and extraplatelet molecules. The method is based on the absorption of the water of the plasma using hydroxyethyl acrylamide (HEAA)-based hydrogels. A plasma fraction obtained from blood, containing the basal levels of platelets and proteins, was placed in contact with the HEAA hydrogel powder to absorb half the volume of the water. The resulting plasma was characterized, and its bioactivity was analyzed in vitro. The novel PRP (nPRP) showed a platelet concentration and platelet derived growth factor (PDGF) levels similar to the standard PRP (sPRP), but the concentration of the extraplatelet growth factors IGF-1 (p < 0.0001) and HGF (p < 0.001) were significantly increased. Additionally, the cells exposed to the nPRP showed increased cell viability than those exposed to a sPRP in human dermal fibroblasts (p < 0.001) and primary chondrocytes (p < 0.01). In conclusion, this novel absorption-based method produces a PRP with novel characteristics compared to the standard PRPs, with promising in vitro results that could potentially trigger improved tissue regeneration capacity.

Method Based on Ultrafiltration to Obtain a Plasma Rich in Platelet and Plasma Growth Factors.

Platelet-Rich Plasma (PRP) is an autologous biological product which, due to its regenerative capacity, is currently used in different fields of medicine. This biological treatment has proven to be effective in numerous research studies due to its high content of growth factors released by platelets. However, the current systems used to obtain PRP do not enrich the growth factors and cytokines outside platelets. Considering this, the present work aims to develop a new technique by which all the biomolecules present in plasma are enriched. Thus, a new method based on ultrafiltration has been developed for the obtaining of the novel PRP. By this method, ultrafiltration of the plasma water is carried out using a 3KDa filtering unit. The results showed that the technique was able to concentrate extraplatelet factors, such as IGF-1 and HGF, in contrast with conventional plasmas. Thus, the cultured cells responded with increased viability to this new PRP. These results could provide a new approach to the treatment of injuries requiring regenerative medicine, potentially improving the outcomes of the conventional PRPs.

High sensitivity c-reactive protein and circulating biomarkers of endothelial dysfunction in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) have revolutionized the management of patients with chronic myelogenous leukemia (CML); however, they may cause cardiovascular (CV) toxicities. In this cross-sectional study, we explored whether high-sensitivity C-reactive protein (hsCRP) and novel markers of vascular dysfunction were associated with exposure to specific TKIs, in 262 CML patients. Hs-CRP level was not associated with CML disease activity or treatment with a specific TKI. Body mass index (OR: 1.15, 95% CI: 1.108-1.246; p < 0.001) and CML duration (OR: 1.004, 95% CI: 1.001-1.008; p = 0.024) were independently associated with higher hs-CRP. In exploratory analyses, novel endothelial-centric markers (e.g. ET-1 and VCAM-1) were differential across the various TKIs, particularly amongst nilotinib- and ponatinib-treated patients. While Levels of hs-CRP do not appear to be correlated with specific TKIs, circulating markers of vascular dysfunction were altered in patients treated with specific TKIs and should be explored as potential markers of TKI-associated CV risk.