Optimization of iron oxide nanoparticles for MRI-guided magnetic hyperthermia tumor therapy: reassessing the role of shape in their magnetocaloric effect.

Superparamagnetic iron oxide nanoparticles have hogged the limelight in different fields of nanotechnology. Surprisingly, notwithstanding the prominent role played as agents in magnetic hyperthermia treatments, the effects of nanoparticle size and shape on the magnetic hyperthermia performance have not been entirely elucidated yet. Here, spherical or cubical magnetic nanoparticles synthesized by a thermal decomposition method with the same magnetic and hyperthermia properties are evaluated. Interestingly, spherical nanoparticles displayed significantly higher magnetic relaxivity than cubic nanoparticles; however, comparable differences were not observed in specific absorption rate (SAR), pointing out the need for additional research to better understand the connection between these two parameters. Additionally, the as-synthetized spherical nanoparticles showed negligible cytotoxicity and, therefore, were tested in vivo in tumor-bearing mice. Following intratumoral administration of these spherical nanoparticles and a single exposure to alternating magnetic fields (AMF) closely mimicking clinical conditions, a significant delay in tumor growth was observed. Although further in vivo experiments are warranted to optimize the magnetic hyperthermia conditions, our findings support the great potential of these nanoparticles as magnetic hyperthermia mediators for tumor therapy.

Characterization of Latin American migrants at risk for Trypanosoma cruzi infection in a non-endemic setting. Insights into initial evaluation of cardiac and digestive involvement.

BACKGROUND: Trypanosoma cruzi causes Chagas disease (CD), a potentially fatal disease characterized by cardiac disorders and digestive, neurological or mixed alterations. T. cruzi is transmitted to humans by the bite of triatomine vectors; both the parasite and disease are endemic in Latin America and the United States. In the last decades, population migration has changed the classic epidemiology of T. cruzi, contributing to its global spread to traditionally non-endemic countries. Screening is recommended for Latin American populations residing in non-endemic countries. METHODS: The present study analyzes the epidemiological characteristics of 2,820 Latin American individuals who attended the International Health Service (IHS) of the Hospital Clinic de Barcelona between 2002 and 2019. The initial assessment of organ damage among positive cases of T. cruzi infection was analyzed, including the results of electrocardiogram (ECG), echocardiogram, barium enema and esophagogram. RESULTS: Among all the screened individuals attending the clinic, 2,441 (86.6%) were born in Bolivia and 1,993 (70.7%) were female. Of individuals, 1,517 (81.5%) reported previous exposure to the vector, which is a strong risk factor associated with T. cruzi infection; 1,382 individuals were positive for T. cruzi infection. The first evaluation of individuals with confirmed T. cruzi infection, showed 148 (17.1%) individuals with Chagasic cardiomyopathy, the main diagnostic method being an ECG and the right bundle branch block (RBBB) for the most frequent disorder; 16 (10.8%) individuals had a normal ECG and were diagnosed of Chagasic cardiomyopathy by echocardiogram. CONCLUSIONS: We still observe many Latin American individuals who were at risk of T. cruzi infection in highly endemic areas in their countries of origin, and who have not been previously tested for T. cruzi infection. In fact, even in Spain, a country with one of the highest proportion of diagnosis of Latin American populations, T. cruzi infection remains underdiagnosed. The screening of Latin American populations presenting with a similar profile as reported here should be promoted. ECG is considered necessary to assess Chagasic cardiomyopathy in positive individuals, but echocardiograms should also be considered as a diagnostic approach given that it can detect cardiac abnormalities when the ECG is normal.

Hippocampal neurogenesis and Arc expression are enhanced in high-fat fed prepubertal female pigs by a diet including omega-3 fatty acids and Bifidobacterium breve CECT8242.

PURPOSE: Obesity during childhood has become a pandemic disease, mainly caused by a diet rich in sugars and fatty acids. Among other negative effects, these diets can induce cognitive impairment and reduce neuroplasticity. It is well known that omega-3 and probiotics have a beneficial impact on health and cognition, and we have hypothesized that a diet enriched with Bifidobacterium breve and omega-3 could potentiate neuroplasticity in prepubertal pigs on a high-fat diet. METHODS: Young female piglets were fed during 10 weeks with: standard diet (T1), high-fat (HF) diet (T2), HF diet including B. breve CECT8242 (T3) and HF diet including the probiotic and omega-3 fatty acids (T4). Using hippocampal sections, we analyzed by immunocytochemistry the levels of doublecortin (DCX) to study neurogenesis, and activity-regulated cytoskeleton-associated protein (Arc) as a synaptic plasticity related protein. RESULTS: No effect of T2 or T3 was observed, whereas T4 increased both DCX+ cells and Arc expression. Therefore, a diet enriched with supplements of B. breve and omega-3 increases neurogenesis and synaptic plasticity in prepubertal females on a HF diet from nine weeks of age to sexual maturity. Furthermore, the analysis of serum cholesterol and HDL indicate that neurogenesis was related to lipidic demand in piglets fed with control or HF diets, but the neurogenic effect induced by the T4 diet was exerted by mechanisms independent of this lipidic demand. CONCLUSION: Our results show that the T4 dietary treatment is effective in potentiating neural plasticity in the dorsal hippocampus of prepubertal females on a HF diet.

Effects of Creatine Supplementation after 20 Minutes of Recovery in a Bench Press Exercise Protocol in Moderately Physically Trained Men.

BACKGROUND: The aims of this study were to analyse the effect of creatine supplementation on the performance improvement in a bench pressing (BP) strength test of muscle failure and to evaluate muscle fatigue and metabolic stress 20 min after the exercise. METHODS: Fifty young and healthy individuals were randomly assigned to a creatine group (n = 25) or a placebo group (n = 25). Three exercise sessions were carried out, with one week of rest between them. In the first week, a progressive load BP test was performed until the individuals reached the one repetition maximum (1RM) in order to for us obtain the load-to-velocity ratio of each participant. In the second week, the participants conducted a three-set BP exercise protocol against 70% 1RM, where they performed the maximum number of repetitions (MNR) until muscle failure occurred, with two minutes of rest between the sets. After one week, and following a supplementation period of 7 days, where half of the participants consumed 0.3 g·kg-1·day-1 of creatine monohydrate (CR) and the other half consumed 0.3 g·kg-1·day-1 of placebo (PLA, maltodextrin), the protocol from the second week was repeated. After each set, and up to 20 min after finishing the exercise, the blood lactate concentrations and mean propulsive velocity (MPV) at 1 m·s-1 were measured. RESULTS: The CR group performed a significantly higher number of repetitions in Set 1 (CR = 14.8 repetitions, PLA = 13.6 repetitions, p = 0.006) and Set 2 (CR = 8 repetitions, PLA = 6.7 repetitions, p = 0.006) after supplementation, whereas no significant differences were seen in Set 3 (CR = 5.3 repetitions, PLA = 4.7 repetitions, p = 0.176). However, there was a significant increase in blood lactate at minute 10 (p = 0.003), minute 15 (p = 0.020), and minute 20 (p = 0.015) after the exercise in the post-supplementation period. Similarly, a significant increase was observed in the MPV at 1 m·s-1 in the CR group with respect to the PLA group at 10, 15, and 20 min after the exercise. CONCLUSIONS: Although the creatine supplementation improved the performance in the strength test of muscle failure, the metabolic stress and muscle fatigue values were greater during the 20 min of recovery.

Milk fat globule membrane plus milk fat increase docosahexaenoic acid availability in infant formulas.

PURPOSE: Milk fat globule membrane (MFGM) has components with emulsifier properties that could affect the provision of substrates to the brain. We evaluated the effects of MFGM plus milk fat addition to infant formulas on docosahexaenoic acid (DHA) availability and gut development. METHODS: In Experiment 1, suckling piglets were divided into 3 groups: Group L1 (n = 8): fed with a vegetal fat formula with palm oil; L2 (n = 8): canola oil formula and L3 (n = 8): milk fat + canola oil + 1% Lacprodan (3% MFGM of total protein content). In Experiment 2, Group L4 (n = 7): fed with canola oil + 1% Lacprodan (3% MFGM) and Group L5 (n = 5): milk fat + canola oil + 2% Lacprodan (6% MFGM). All formulas contained 0.2% DHA and 0.2% arachidonic acid. RESULTS: In Experiment 1, DHA was similar among the groups in both total fatty acids and plasma phospholipids (PL). However, 3% MFGM (L3) increased significantly the proportion of DHA and LC-PUFA n-3 in liver total fatty acids, jejunum, and also in jejunum PL respect to the other formulas. There were no changes in gut histology, cell proliferation, apoptosis, or brain DHA content. In Experiment 2, higher MFGM dose was used. Then, higher DHA was not only found in peripheral tissues of 6% MFGM (L5) piglets but also in plasma PL, while a similar trend was observed in cortex PL (p = 0.123). CONCLUSION: In conclusion, MFGM plus milk fat may increase DHA availability of infant formulas which could contribute to their beneficial health effects.

Effects of Capacitive-Resistive Electric Transfer on Sports Performance in Paralympic Swimmers: A Stopped Randomized Clinical Trial.

Throughout history a variety of therapeutic tools have been studied as possible enhancers of sports activities. This study proposes the use of Capacitive-Resistive Electric Transfer (CRET) as a performance booster to paralympic athletes, specifically those belonging to the Spanish Paralympic swimming committee. The study was a randomized, single-blind, and observer-blind, crossover clinical trial. Six athletes were randomly assigned to three groups: one treated with CRET (A); a placebo group (B) and a control group (C). The CRET group attended a twenty-minute session before being subjected to pool trials at distances of 50 and 100 m at maximum performance. Measurements were in two dimensions: time in seconds and the Borg scale for perceived exertion. Comparisons between groups were made with respect to distance and the main variables. In the case of perceived exertion, no significant changes were observed in any of the distances; however, in the case of the time variable, a significant difference was observed between Group A vs. Personal Record at 100 m distance (76.3 ± 6.8 vs. 68.4 ± 3.3). The proposed protocol and level of hyperthermia applied suggest refusal of CRET use for the 100-m distance a few minutes before sports practice. Our analysis suggests the need to modify the presented protocol. ClinicalTrials.gov identifier under NCT number: NCT04336007.

Effectiveness of Dry Needling of Myofascial Trigger Points in the Triceps Surae Muscles: Systematic Review.

This study aims to analyze the effects of Dry Needling (DN) for the release of myofascial trigger points (MTrPs) in the triceps surae muscles (TSM). A systematic review was performed up to February 2022 in PubMed, PEDro, Scopus, CENTRAL, and Web of Science. Selection criteria were studies involving subjects older than 18 years presenting MTrPs in the TSM, without any concomitant acute or chronic musculoskeletal conditions; DN interventions applied to the MTrPs of the TSM; and results on pain, range of motion (ROM), muscle strength, muscle stiffness, and functional outcomes. The PEDro scale was used to assess the methodological quality of the studies, and the Risk of Bias Tool 2.0 to assess risk of bias. A total of 12 studies were included in the systematic review, involving 426 participants. These results suggest that DN of MTrPs in TSM could have a positive impact on muscle stiffness and functional outcomes. There are inconclusive findings on musculoskeletal pain, ROM, and muscle strength. Significant results were obtained in favor of the control groups on pressure pain thresholds. Despite the benefits obtained on muscle stiffness and functional performance, the evidence for the use of DN of MTrPs in the TSM remains inconclusive.

A synbiotics, long chain polyunsaturated fatty acids, and milk fat globule membranes supplemented formula modulates microbiota maturation and neurodevelopment.

BACKGROUND & AIMS: The critical window of concurrent developmental paths of the nervous system and gut microbiota in infancy provides an opportunity for nutritional interventions with potential health benefits later in life. METHODS: We compared the dynamics of gut microbiota maturation and explored its association with neurodevelopment at 12 months and 4 years of age in 170 full-term healthy infants fed a standard formula (SF) or a new formula (EF) based on standard formula supplemented with synbiotics, long chain polyunsaturated fatty acids (LC-PUFA) and bovine milk fat globule membranes (MFGM), including a breastfed reference group (BF). RESULTS: Using Dirichlet Multinomial Modelling, we characterized three microbial enterotypes (Mixed, anaerobic and aerobic profile; Bact, Bacteroides-dominant; Firm, Firmicutes-enriched) and identified a new enterotype dominated by an unidentified genus within Lachnospiraceae (U_Lach). Enterotypes were associated with age (Mixed with baseline, U_Lach with month 6, Bact and Firm with months 12 and 18). Trajectories or timely enterotype shifts in each infant were not random but strongly associated with type of feeding. Trajectories in SF shifted from initial Mixed to U_Lach, Bact or Firm at month. Microbiota maturation in EF split into a fast trajectory as in SF, and a slow trajectory with Mixed to U_Lach, Bact or Firm transitions at months 12 or 18, as in BF. EF infants with slow trajectories were more often in-home reared and born by vaginal delivery to mothers with pre-pregnancy lean BMI. At 12 months of age, language and expressive language scores were significantly higher in EF infants with fast trajectories than in BF. Neurodevelopmental outcomes were similar between EF infants with slow trajectories and BF at 12 months and 4 years of age. CONCLUSIONS: Feeding a synbiotics, LC-PUFA and MFGM supplemented formula in a specific infant environment promoted probiotic growth and retarded gut microbiota maturation with similar neurodevelopment outcomes to breastfed infants. CLINICAL TRIAL REGISTRY NUMBER: NCT02094547.

At the beginnings of the funerary Megalithism in Iberia at Campo de Hockey necropolis.

The excavations undertaken at the Campo de Hockey site in 2008 led to the identification of a major Neolithic necropolis in the former Island of San Fernando (Bay of Cádiz). This work presents the results of the latest studies, which indicate that the site stands as one of the oldest megalithic necropolises in the Iberian Peninsula. The main aim of this work is to present with precision the chronology of this necropolis through a Bayesian statistical model that confirms that the necropolis was in use from c. 4300 to 3800 cal BC. The presence of prestige grave goods in the earliest and most monumental graves suggest that the Megalithism phenomenon emerged in relation to maritime routes linked to the distribution of exotic products. We also aim to examine funerary practices in these early megalithic communities, and especially their way of life and the social reproduction system. As such, in addition to the chronological information and the Bayesian statistics, we provide the results of a comprehensive interdisciplinary study, including anthropological, archaeometric and genetic data.

Circulating nitrate-nitrite reduces oxygen uptake for improving resistance exercise performance after rest time in well-trained CrossFit athletes.

This study aimed to determine the effects of circulating nitrate plus nitrite (NOx) concentrations on resistance exercise performance, VO2 and biomarkers of muscle damage. Eleven well-trained male CrossFit athletes (29.2 ± 3.7 years, 78.9 ± 5.4 kg, 175.1 ± 6.3 cm) carried out a resistance exercise test after drinking 140 mL of beetroot juice (BJ) or placebo. The test consisted of repeating the same resistance exercise routine twice: wall ball shots plus full back squat with 3-min rest (1st routine) or without rest (2nd routine) between the two exercises. Higher NOx plasma levels were verified after BJ than placebo in the pretest and post-test (p < 0.001). A higher number of repetitions was observed after BJ intake compared to placebo in the full back squat exercise during the first routine (p = 0.004). A significantly reduced VO2 was detected after BJ intake compared to placebo during rest and full back squat execution in the first routine (p < 0.05). Plasma myoglobin concentrations were significantly increased with BJ compared to placebo (p = 0.036). These results showed that plasma NOx levels reduced VO2 after BJ intake during rest time. These reduced VO2 was a key factor for improving full back squat performance during the first routine.

Ethanolic extract from Lepidium virginicum L. ameliorates DNBS-induced colitis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Lepidium virginicum L. (Brassicaceae) is a plant widely used in traditional Mexican medicine as an expectorant, diuretic, and as a remedy to treat diarrhea and dysentery, infection-derived gastroenteritis. However, there is no scientific study that validates its clinical use as an anti-inflammatory in the intestine. AIM OF THE STUDY: This study aimed to investigate the anti-inflammatory properties of the ethanolic extract of Lepidium virginicum L. (ELv) in an animal model of inflammatory bowel disease (IBD)-like colitis. MATERIALS AND METHODS: The 2,4-dinitrobenzene sulfonic acid (DNBS) animal model of IBD was used. Colitis was induced by intrarectal instillation of 200 mg/kg of DNBS dissolved vehicle, 50% ethanol. Control rats only received the vehicle. Six hours posterior to DNBS administration, ELv (3, 30, or 100 mg/kg) was administered daily by gavage or intraperitoneal injection. The onset and course of the inflammatory response were monitored by assessing weight loss, stool consistency, and fecal blood. Colonic damage was evaluated by colon weight/length ratio, histopathology, colonic myeloperoxidase (MPO) activity, and gene expression of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), chemokine C-X-C motif ligand 1 (CXCL-1), and interleukin-6 (IL-6). RESULTS: Rats treated with DNBS displayed significant weight loss, diarrhea, fecal blood, colon shortening, a significant increase in immune cell infiltration and MPO activity, as well as increased proinflammatory cytokine expression. Intraperitoneal administration of ELv significantly reduced colon inflammation, whereas oral treatment proved to be ineffective. In fact, intraperitoneal ELv significantly attenuated the clinical manifestations of colitis, immune cell infiltration, MPO activity, and pro-inflammatory (CXCL-1, TNF-α, and IL-1ß) gene expression in a dose-dependent manner. CONCLUSION: Traditional medicine has employed ELv as a remedy for common infection-derived gastrointestinal symptoms; however, we hereby present the first published study validating its anti-inflammatory properties in the mitigation of DNBS-induced colitis.

In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris.

OBJECTIVE: Candida auris has emerged as a health-care-associated and multidrug-resistant fungal pathogen of great clinical concern. As many as 50% of C. auris clinical isolates are reported to be resistant to amphotericin B, but no mechanisms contributing to this resistance have been identified. Here we describe a clinical case in which high-level amphotericin B resistance was acquired in vivo during therapy and undertake molecular and genetic studies to identify and characterize the genetic determinant of resistance. METHODS: Whole-genome sequencing was performed on four C. auris isolates obtained from a single patient case. Cas9-mediated genetic manipulations were then used to generate mutant strains harbouring mutations of interest, and these strains were subsequently subjected to amphotericin B susceptibility testing and comprehensive sterol profiling. RESULTS: A novel mutation in the C. auris sterol-methyltransferase gene ERG6 was found to be associated with amphotericin B resistance, and this mutation alone conferred a >32-fold increase in amphotericin B resistance. Comprehensive sterol profiling revealed an abrogation of ergosterol biosynthesis and a corresponding accumulation of cholesta-type sterols in isolates and strains harbouring the clinically derived ERG6 mutation. CONCLUSIONS: Together these findings definitively demonstrate mutations in C. auris ERG6 as the first identified mechanism of clinical amphotericin B resistance in C. auris and represent a significant step forward in the understanding of antifungal resistance in this emerging public health threat.

Elaboration and characterization of nanoemulsion with orange essential oil and pectin.

BACKGROUND: Nanoemulsions formulated with citric essential oils are currently of interest because of their physical and chemical properties and multiple applications in areas such as the food industry or agrochemicals. These are thermodynamically unstable and have almost Newtonian flow behaviour, but a suitable formulation allows systems to be obtained with good physical stability and rheological properties. The addition of pectin makes this possible. In this work, food nanoemulsions formulated with pectin, orange essential oil (5 wt%), and Tween 80 were obtained by microfluidization. First, the effect of Tween 80 concentration from 1 to 5 wt% on emulsions without pectin was evaluated. Then, pectin was added to the most stable nanoemulsion obtained and two variables were studied: the pectin solution concentration (from 2 to 6 wt%) and the pectin/emulsion ratio (1:1 or 2:1) at a fixed pectin concentration. RESULTS: Rheological, laser diffraction, and multiple light scattering techniques were employed to determine the content of Tween 80 that results in the most stable nanoemulsion without pectin, which was 3 wt%. In addition, these techniques were used to determine the structure and physical stability of the nanoemulsions containing orange essential oil and pectin. The results obtained showed that the emulsions containing 2 wt% pectin were destabilized before 24 h. Furthermore, the emulsion with 6 wt% pectin and a 2:1 pectin/emulsion ratio showed the highest viscosity and the lowest mean diameters, and therefore the greatest stability. CONCLUSION: This work extends the knowledge of formulation of nanoemulsions and using essential oils. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Mechanistic Insight from Preclinical Models of Parkinson's Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy.

Parkinson's disease (PD) is characterized by four pathognomonic hallmarks: (1) motor and non-motor deficits; (2) neuroinflammation and oxidative stress; (3) pathological aggregates of the α-synuclein (α-syn) protein; (4) neurodegeneration of the nigrostriatal system. Recent evidence sustains that the aggregation of pathological α-syn occurs in the early stages of the disease, becoming the first trigger of neuroinflammation and subsequent neurodegeneration. Thus, a therapeutic line aims at striking back α-synucleinopathy and neuroinflammation to impede neurodegeneration. Another therapeutic line is restoring the compromised dopaminergic system using neurotrophic factors, particularly the glial cell-derived neurotrophic factor (GDNF). Preclinical studies with GDNF have provided encouraging results but often lack evaluation of anti-α-syn and anti-inflammatory effects. In contrast, clinical trials have yielded imprecise results and have reported the emergence of severe side effects. Here, we analyze the discrepancy between preclinical and clinical outcomes, review the mechanisms of the aggregation of pathological α-syn, including neuroinflammation, and evaluate the neurorestorative properties of GDNF, emphasizing its anti-α-syn and anti-inflammatory effects in preclinical and clinical trials.

Impact of Fall Risk and Direct Oral Anticoagulant Treatment on Quality-Adjusted Life-Years in Older Adults with Atrial Fibrillation: A Markov Decision Analysis.

BACKGROUND AND OBJECTIVE: The decision to initiate anticoagulation in older adults with atrial fibrillation is complicated by the benefit of ischemic stroke prevention vs the risk of falls resulting in major bleeds. The objective of this study was to assess the impact of different treatments including direct oral anticoagulants on quality-adjusted life-years (QALYs) in patients aged 75 years and older with atrial fibrillation in the context of falls. METHODS: A Markov decision process was constructed for older patients with atrial fibrillation taking no anti-thrombotic, aspirin, warfarin, rivaroxaban, and apixaban. Input probabilities for clinical events were estimated from the available literature. One-way and two-way sensitivity analyses were performed by measuring the impact of varying input probabilities of clinical events on QALY outcomes. RESULTS: The base-case scenario estimated that older adults treated with no anti-thrombotic, aspirin, warfarin, rivaroxaban, and apixaban had QALYs of 8.03, 8.69, 10.38, 11.02, and 11.56, respectively. The sensitivity analysis estimated that an older adult would need to fall over 45 (rivaroxaban) and 458 (apixaban) times per year for the QALY of a direct oral anticoagulant to be lower than that of aspirin. CONCLUSIONS: Older adults with atrial fibrillation benefit from stroke protection of anticoagulants, especially direct oral anticoagulants, even if they are at high risk of falls. Clinicians should not consider fall risk as a deciding factor for withholding anticoagulation in this population of patients.

Effectiveness of Motor Imagery on Motor Recovery in Patients with Multiple Sclerosis: Systematic Review.

The effects of motor imagery (MI) on functional recovery of patients with neurological pathologies, such as stroke, has been recently proven. The aim of this study is to evaluate the effectiveness of MI on motor recovery and quality of life (QOL) in patients with multiple sclerosis (pwMS). A search was carried out in the following scientific databases: PubMed, CINAHL, PEDro, Scopus, Cochrane and Web of Science, up to November 2020. The grey literature and reference lists of potentially relevant articles were also searched. The Checklist for Measuring Quality and The Cochrane collaboration's tool were used to assess the methodological quality and risk of bias of the studies. Five studies were included in the systematic review. Findings showed that pwMS using MI had significant improvements in walking speed and distance, fatigue and QOL. In addition, several benefits were also found in dynamic balance and perceived walking ability. Although the evidence is limited, rehabilitation using MI with the application of musical and verbal guides (compared to non-intervention or other interventions), can produce benefits on gait, fatigue and QOL in pwMS with a low score in the Expanded Disability Status Scale.

Mirror therapy simultaneously combined with electrical stimulation for upper limb motor function recovery after stroke: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the current evidence on the effectiveness of simultaneous combination of mirror therapy and electrical stimulation in the recovery of upper limb motor function after stroke, compared with conventional therapy, mirror therapy or electrical stimulation isolated. DATA SOURCES: Articles published in PubMed, Web of Science, Scopus, Physiotherapy Evidence Database (PEDro), Cochrane Central register of controlled trials and ScienceDirect up to July 2020. REVIEW METHODS: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. Methodological quality was assessed using the PEDro tool. The RevMan 5.4 statistical software was used to obtain the meta-analysis, through the standardized mean difference and 95% confidence intervals (CI), and to evaluate the risk of bias. The GRADE approach was employed to assess the certainty of evidence. RESULTS: Eight articles were included in this systematic review, seven were included in the meta-analysis. A total of 314 participants were analyzed. The overall quality of the articles included in this review was good. There was no overall significant mean difference on upper limb motor function after stroke using the Upper-Extremity Fugl-Meyer Assessment by 1.56 (95% CI = -2.08, 5.20; P = 0.40; moderate-certainty evidence) and the Box and Block Test results by 1.39 (95% CI = -2.14, 4.92; P = 0.44; high-certainty evidence). There was overall significant difference in the Action Research Arm Test by 3.54 (95% CI = 0.18, 6.90; P = 0.04; high-certainty evidence). CONCLUSION: Direct scientific evidence about the effectiveness of the combined therapy of mirror therapy and electrical stimulation simultaneously for the improvement of the upper limb motor function after stroke is lacking. Further high-quality and well-designed research is needed.

An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris.

Candida auris is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a bis-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against C. auris. Azoffluxin enhances fluconazole activity through the inhibition of efflux pump Cdr1, thus increasing intracellular fluconazole levels. This activity is conserved across most C. auris clades, with the exception of clade III. Azoffluxin also inhibits efflux in highly azole-resistant strains of Candida albicans, another human fungal pathogen, increasing their susceptibility to fluconazole. Furthermore, azoffluxin enhances fluconazole activity in mice infected with C. auris, reducing fungal burden. Our findings suggest that pharmacologically targeting Cdr1 in combination with azoles may be an effective strategy to control infection caused by azole-resistant isolates of C. auris.