Integrative non-pharmacological care for individuals at risk of rheumatoid arthritis.

There is increasing knowledge in the recognition of individuals at risk for progression to rheumatoid arthritis (RA) before the clinical manifestation of the disease. This prodromal phase preceding the manifestation of RA may represent a "window of opportunity" for preventive interventions that may transform the clinical approach to this disease. However, limited evidence exists in support of effective interventions to delay the onset or even halt the manifestation of RA. Given the multifactorial nature of RA development and disease progression, the latest guidelines for established RA stress the use of integrative interventions and multidisciplinary care strategies, combining pharmacologic treatment with non-pharmacological approaches. Accordingly, individuals at risk of RA could be offered an integrative, multifactorial intervention approach. Current data point toward pharmacological intervention reverting the subclinical inflammation and delay in the disease onset. In addition, targeting life style modifiable factors (smoking cessation, dental health, physical activity, and diet) may presumably improve RA prognosis in individuals at risk, mainly by changes in epigenetics, autoantibodies, cytokines profiles, and microbiome. Nonetheless, the benefits of multidisciplinary interventions to halt the manifestation of RA in at-risk individuals remain unknown. As there is a growing knowledge of possible pharmacological intervention in the preclinical phase, this narrative review aims to provide a comprehensive overview of non-pharmacological treatments in individuals at risk of RA. Considering the mechanisms preceding the clinical manifestation of RA we explored all aspects that would be worth modifying and that would represent an integrative non-pharmacological care for individuals at risk of RA.

Effects of a concurrent training, respiratory muscle exercise, and self-management recommendations on recovery from post-COVID-19 conditions: the RECOVE trial.

The aim of this study was to determine the effectiveness of physical exercise, respiratory muscle training, and the self-management World Health Organization (WHO) recommendations leaflet on the recovery of physical fitness, quality of life, and symptom status in people with post-COVID-19 conditions. Eighty nonhospitalized adults with a post-COVID-19 condition were randomly assigned to one of four 8-wk parallel intervention groups: 1) multicomponent exercise program based on concurrent training (CT, number of subjects (n) = 20; 3 resistance and endurance supervised sessions per week at low-moderate intensity); 2) inspiratory muscle training (RM, n = 17; 2 standardized daily sessions); 3) a combination of both of the above (CTRM, n = 23); and 4) control group (CON, n = 20; following the WHO guidelines for post-COVID-19-related illness rehabilitation). No significant differences between groups were detected at baseline. Although no significant differences between interventions were detected in the V̇o2max, significant individual improvements were identified in the CT (7.5%; effect size, ES = 0.28) and CTRM (7.8%; ES = 0.36) groups. Lower body muscle strength significantly improved in the CT and CTRM (14.5%-32.6%; ES = 0.27-1.13) groups compared with RM and CON (-0.3% to 11.3%; ES = 0.10-0.19). The CT and CTRM groups improved significantly for dyspnea and fatigue, as did the health status. In addition, significant differences between interventions were described in fatigue and depression scales favoring CT and CTRM interventions. An individualized and supervised concurrent training with or without inspiratory muscle training was safe and more effective than self-care recommendations and inspiratory muscle training alone, to regain cardiovascular and muscular fitness, improve symptom severity, and health status in outpatients with post-COVID-19 conditions.NEW & NOTEWORTHY Eight weeks of concurrent training, with or without inspiratory muscle exercise, was better than WHO "Support for Rehabilitation: Self-Management after COVID-19-Related Illness" recommendations or inspiratory muscle training alone to improve cardiopulmonary fitness, strength, and symptom severity, in a safe and effective manner. The RECOVE trial proved the benefits and utility of a supervised exercise program in people with post-COVID-19 conditions after mild COVID-19 in an ambulatory setting.

Acute Beetroot Juice Supplementation Does Not Improve Match-Play Activity in Professional Tennis Players.

ObjectiveBeetroot juice is a source of dietary nitrate (NO3-) recognized as a potential ergogenic aid to enhance tolerance during endurance exercise of submaximal-to-maximal intensity. However, little is known about the effects of beetroot juice on exercise performance in intermittent sports such as tennis. The present study aimed to determine the effect of acute beetroot juice supplementation on movement patterns during a competitive tennis match in professional players.MethodsIn a double-blind and randomized experiment, nine professional tennis players performed two experimental trials 3 h after ingesting either 70 mL of a commercially-available concentrated beetroot juice (6.4 mmol NO3-) or placebo (0.005 mmol NO3-). In each experimental trial, players completed a 3-set tennis match and two performance tests (i.e., serve speed and isometric handgrip strength) before and after the match. Match-play running performance was recorded using wearable GPS and accelerometer units.ResultsIn comparison to the placebo trial, the acute beetroot juice supplementation did not modify any match-play running performance (p = 0.178 to 0.997, d = 0.01 to 0.42). Furthermore, beetroot juice supplementation did not alter the pre-to-post match change in serve speed (p = 0.663, ηp2 = 0.03) or isometric handgrip strength (p = 0.219, ηp2 = 0.18).Conclusions: The current results indicated that acute ingestion of a commercialized shot of nitrate-rich beetroot juice (70 mL containing 6.4 mmol of NO3-) did not produce any performance benefit on tennis matchplay. Thus, acute beetroot juice supplementation seems an ergogenic aid with little value to enhance physical performance in professional tennis players.

Does Acute Beetroot Juice Supplementation Improve Neuromuscular Performance and Match Activity in Young Basketball Players? A Randomized, Placebo-Controlled Study.

Whereas beetroot juice (BJ) supplementation is shown to increase physical performance in endurance activities, its benefits in team sports has been barely studied. In this randomized placebo-controlled study, we investigated the effects of BJ acute supplementation in improving neuromuscular performance and physical match activity in basketball. Ten young male competitive basketball players aged 15-16 years received 140 mL of BJ or placebo (PLA) on two separated days in a balanced cross-over design. Testing sessions comprised a neuromuscular test battery consisting of a countermovement jump (CMJ), isometric handgrip strength, 10-m/20-m sprint and agility T-test, followed by a 40-minute simulated basketball match. Physical match activity (distances, speeds, accelerations, and decelerations) was monitored using an inertial tracking system (Wimu ProTM) Results revealed no significant effects of BJ on CMJ (p = 0.304, ES = 0.13), isometric handgrip strength (p = 0.777, ES = 0.06), 10-m (p = 0.820, ES = 0.10), and 20-m sprint (p = 0.540, ES = 0.13), agility T-test (p = 0.979, ES ≤ 0.01) and any physical match demands (p > 0.151, ES = 0.13-0.48). Acute moderate doses of BJ (12.8 mmol of NO3-) was not effective in improving neuromuscular performance (jump height, isometric handgrip strength, sprint, and agility) or physical match requirements in young trained basketball players the day of the competition.

Health Benefits of ß-Hydroxy-ß-Methylbutyrate (HMB) Supplementation in Addition to Physical Exercise in Older Adults: A Systematic Review with Meta-Analysis.

Both regular exercise training and beta-hydroxy-beta-methylbutyrate (HMB) supplementation are shown as effective treatments to delay or reverse frailty and reduce cognitive impairment in older people. However, there is very little evidence on the true benefits of combining both strategies. The aim of this meta-analysis was to quantify the effects of exercise in addition to HMB supplementation, on physical and cognitive health in older adults. Data from 10 randomized controlled trials (RCTs) investigating the effect of HMB supplementation and physical function in adults aged 50 years or older were analyzed, involving 384 participants. Results showed that HMB supplementation in addition to physical exercise has no or fairly low impact in improving body composition, muscle strength, or physical performance in adults aged 50 to 80 years, compared to exercise alone. There is a gap of knowledge on the beneficial effects of HMB combined with exercise to preserve cognitive functions in aging and age-related neurodegenerative diseases. Future RCTs are needed to refine treatment choices combining HMB and exercises for older people in particular populations, ages, and health status. Specifically, interventions in older adults aged 80 years or older, with cognitive impairment, frailty, or limited mobility are required.

Effects of ß-hydroxy-ß-methylbutyrate (HMB) supplementation in addition to multicomponent exercise in adults older than 70 years living in nursing homes, a cluster randomized placebo-controlled trial: the HEAL study protocol.

BACKGROUND: Evidence supports the fact that multicomponent exercise and HMB supplementation are, separately, effective in improving older adult's health and palliate functional metabolic diseases in older people. However, the true effect of HMB supplementation combined with a tailored exercise program in frail older adults is still unknown. Thus, the aim of the HEAL (HMB + Exercise = Adults Living longer) study is to assess the effects of the combination of a daily multicomponent exercise and resistance training (VIVIFRAIL program) intervention in addition to HMB supplementation on older adults' health. METHODS/DESIGN: A 24-week cluster randomized, double-blind, placebo-controlled study will be conducted on 104 adults ≥70 years. Nursing homes will be randomized to either of four groups: Ex-HMB (exercise intervention with HMB), Ex-Plac (exercise intervention with placebo), NoEx-HMB (no exercise intervention with HMB), and Controls (No exercise and no HMB). Intervention groups which include exercise will complete the individualized multicomponent (strength, balance and cardiovascular exercises) training program VIVIFRAIL. Intervention groups which include HMB supplementation will receive a 3 g/daily dose of free acid HMB in powder form. The primary outcome measure is the functional capacity. Secondary outcome measures are muscle strength and power, frailty and fall risk, body composition, biochemical analyses and cardiometabolic risk factor, disability and comorbidity, cognitive function and depression. DISCUSSION: The findings of the HEAL study will help professionals from public health systems to identify cost-effective and innovative actions to improve older people's health and quality of life, and endorse exercise practice in older adults and people living in nursing homes. TRIAL REGISTRATION: NCT03827499 ; Date of registration: 01/02/2019.

Janus Gold Nanostars-Mesoporous Silica Nanoparticles for NIR-Light-Triggered Drug Delivery.

Janus gold nanostar-mesoporous silica nanoparticle (AuNSt-MSNP) nanodevices able to release an entrapped payload upon irradiation with near infrared (NIR) light were prepared and characterized. The AuNSt surface was functionalized with a thiolated photolabile molecule (5), whereas the mesoporous silica face was loaded with a model drug (doxorubicin) and capped with proton-responsive benzimidazole-ß-cyclodextrin supramolecular gatekeepers (N 1). Upon irradiation with NIR-light, the photolabile compound 5 photodissociated, resulting in the formation of succinic acid, which induced the opening of the gatekeeper and cargo delivery. In the overall mechanism, the gold surface acts as a photochemical transducer capable of transforming the NIR-light input into a chemical messenger (succinic acid) that opens the supramolecular nanovalve. The prepared hybrid nanoparticles were non-cytotoxic to HeLa cells, until they were irradiated with a NIR laser, which led to intracellular doxorubicin release and hyperthermia. This induced a remarkable reduction in HeLa cells viability.

First-in-human, Randomized, Double-blind Clinical Trial of Differentially Adjuvanted PAMVAC, A Vaccine Candidate to Prevent Pregnancy-associated Malaria.

BACKGROUND: Malaria in pregnancy has major impacts on mother and child health. To complement existing interventions, such as intermittent preventive treatment and use of impregnated bed nets, we developed a malaria vaccine candidate with the aim of reducing sequestration of asexual "blood-stage" parasites in the placenta, the major virulence mechanism. METHODS: The vaccine candidate PAMVAC is based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A (CSA). Healthy, adult malaria-naive volunteers were immunized with 3 intramuscular injections of 20 µg (n = 9) or 50 µg (n = 27) PAMVAC, adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Allocation was random and double blind. The vaccine was given every 4 weeks. Volunteers were observed for 6 months following last immunization. RESULTS: All PAMVAC formulations were safe and well tolerated. A total of 262 adverse events (AEs) occurred, 94 (10 grade 2 and 2 grade 3) at least possibly related to the vaccine. No serious AEs occurred. Distribution and severity of AEs were similar in all arms. PAMVAC was immunogenic in all participants. PAMVAC-specific antibody levels were highest with PAMVAC-GLA-SE. The antibodies inhibited binding of VAR2CSA expressing P. falciparum-infected erythrocytes to CSA in a standardized functional assay. CONCLUSIONS: PAMVAC formulated with Alhydrogel or GLA-based adjuvants was safe, well tolerated, and induced functionally active antibodies. Next, PAMVAC will be assessed in women before first pregnancies in an endemic area. CLINICAL TRIALS REGISTRATION: EudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489.

Relationships among gene expression and anthocyanin composition of Malbec grapevine clones.

Anthocyanin profiles are commonly used for grapevine cultivar identification because it is currently accepted that this trait is closely related to their genetic characteristics. Nevertheless, the extent of the variation for the anthocyanin profiles among clones of the same cultivar has not yet been studied in depth. The relative concentration of anthocyanins of 131 Malbec clones grown in the same vineyard was investigated by HPLC-DAD and the use of comprehensive statistic procedures. Complementarily, the expression level of structural and regulatory genes was studied via real time polymerase chain reaction. Significant variation was identified among the profiles of the clones, mainly due to variations in the amounts of malvidin derivatives. Finally, the differential expression in F3'5'H, OMT1 and AM2 genes seems to be related to the malvidin content variation. This work shows the existence of variation for the anthocyanin profiles among clones from the same grapevine cultivar and the putative involvement of genes related to hydroxylation, methylation, and transport of anthocyanins on the basis of such variation.

Tratamiento con estimulación del nervio vago en pacientes con epilepsia resistente a los fármacos: experiencia en el Hospital Universitario Son Espases / Vagal nerve stimulation treatment in patients with drug resistant epilepsy: Son Espases University Hospital experience

Objetivo Presentar la experiencia en el tratamiento de la epilepsia resistente a los fármacos mediante estimulación del nervio vago (ENV) en nuestro centro, valorando el impacto de este tratamiento sobre el control de la enfermedad, así como sobre aspectos relacionados con la calidad de vida de los pacientes y de sus cuidadores principales. Material y métodos Se realizó un análisis retrospectivo de los pacientes implantados desde enero de 2004 hasta diciembre de 2012. Se evaluaron los resultados de encuestas y test completados por los pacientes y sus cuidadores principales. Resultados Se incluyeron 15 pacientes con un seguimiento medio tras la cirugía de 4,41 (0,5-8) años. La edad media en el momento de la cirugía fue de 25 (10-50) años. Más del 66% de los pacientes experimentaron una disminución en la intensidad de las crisis > 25%. El 47% presentó una reducción > 50% en la frecuencia de las mismas. Como efectos adversos indeseables un paciente presentó disfonía persistente, otro tos y molestias cervicales autolimitados, y otro molestias cervicales. En 2 pacientes fue necesaria la explantación por cefalea refractaria al tratamiento médico. No hubo complicaciones derivadas del acto (AU)

OBJECTIVE: To present our experience in treating drug-resistant epilepsy with vagal nerve stimulation in our centre, evaluating its impact on disease control and on different aspects related to the patients and main caretakers' quality of life. MATERIALS AND METHODS: This was a retrospective analysis of patients operated from January 2004 until December 2012. Interviews and tests completed by outpatients and principle caretakers were evaluated. RESULTS: Fifteen patients were included, with a mean postoperative follow-up of 4.41 (0.5-8) years. Mean age at implantation was 25 (10-50) years. Over 66% of the patients perceived a reduction greater than 25% of their crisis intensity. Forty-seven percent of the patients experienced a decrease greater than 50% in the number of crises. As undesired adverse events, one patient presented persistent dysphonia, another self-limited cough and cervical discomfort and another, persistent cervical discomfort. The device had to be removed in 2 patients due to refractory headaches. There were no complications derived from the surgical procedure. CONCLUSIONS: Vagal nerve stimulation is an effective treatment for reducing crisis frequency and intensity. The patients as well as their caretakers experience a subjective improvement in their quality of life. Despite its economic cost, it seems to reduce their care needs to a certain degree and its use may therefore be justified (AU)

A new in vivo screening paradigm to accelerate antimalarial drug discovery.

The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task.

[Mucinous adenocarcinoma on chronic perianal fistula treated by neoadjuvant chemoradiotherapy and laparoscopy-assisted abdominoperineal amputation]. / Adenocarcinoma mucinoso en fístula perianal de largo tiempo de evolución tratado mediante QT-RT neoadyuvante y amputación abdominoperineal laparoscópica.

We present a male patient with a perianal fistula of 30 years' duration that had been treated on several occasions. The patient presented with mucoid anal adenocarcinoma. He was treated with preoperative neoadjuvant chemotherapy (5-FU and leucovorin) and external radiation therapy plus laparoscopy-assisted abdominoperineal amputation. Mucoid adenocarcinoma on chronic perianal fistula is an infrequent process. Late diagnosis is associated with a poor prognosis.

Effects of creatine supplementation on muscle power, endurance, and sprint performance.

PURPOSE: To determine the effects of creatine (Cr) supplementation (20 g x d(-1) during 5 d) on maximal strength, muscle power production during repetitive high-power-output exercise bouts (MRPB), repeated running sprints, and endurance in handball players. METHODS: Nineteen trained male handball players were randomly assigned in a double-blind fashion to either creatine (N = 9) or placebo (N = 10) group. Before and after supplementation, subjects performed one-repetition maximum half-squat (1RM(HS) and bench press (1RM(BP)), 2 sets of MRPB consisting of one set of 10 continuous repetitions (R10) followed by 1 set until exhaustion (R(max)), with exactly 2-min rest periods between each set, during bench-press and half-squat protocols with a resistance equal to 60 and 70% of the subjects' 1RM, respectively. In addition, a countermovement jumping test (CMJ) interspersed before and after the MRPB half-squat exercise bouts and a repeated sprint running test and a maximal multistage discontinuous incremental running test (MDRT) were performed. RESULTS: Cr supplementation significantly increased body mass (from 79.4 +/- 8 to 80 +/- 8 kg; P < 0.05), number of repetitions performed to fatigue, and total average power output values in the R(max) set of MRPB during bench press (21% and 17%, respectively) and half-squat (33% and 20%, respectively), the 1RM(HS) (11%), as well as the CMJ values after the MRPB half-squat (5%), and the average running times during the first 5 m of the six repeated 15-m sprints (3%). No changes were observed in the strength, running velocity, or body mass measures in the placebo group during the experimental period. CONCLUSION: Short-term Cr supplementation leads to significant improvements in lower-body maximal strength, maximal repetitive upper- and lower-body high-power exercise bouts, and total repetitions performed to fatigue in the R(max) set of MRPB, as well as enhanced repeated sprint performance and attenuated decline in jumping ability after MRPB in highly trained handball players. Cr supplementation did not result in any improvement in upper-body maximal strength and in endurance running performance.