Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer.

BACKGROUND: Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy. METHODS: At a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes). RESULTS: Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P = 0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis. CONCLUSIONS: After 15 years of follow-up, prostate cancer-specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.).

L1CAM immunocapture generates a unique extracellular vesicle population with a reproducible miRNA fingerprint.

Micro RNAs (miRNAs) are short, non-coding RNAs with significant potential as diagnostic and prognostic biomarkers. However, a lack of reproducibility across studies has hindered their introduction into clinical settings. Inconsistencies between studies include a lack of consensus on the miRNAs associated with a specific disease and the direction of regulation. These differences may reflect the heterogenous nature of pathologies with multiple phenotypes, such as amyotrophic lateral sclerosis (ALS). It is also possible that discrepancies are due to different sampling, processing, and analysis protocols across labs. Using miRNA extracted from L1CAM immunoaffinity purified extracellular vesicles (neural-enriched extracellular vesicles or NEE), we thrice replicated an 8-miRNA fingerprint diagnostic of ALS, which includes the miRNA species and direction of regulation. We aimed to determine if the extra purification steps required to generate NEE created a unique extracellular vesicle (EV) fraction that might contribute to the robustness and replicability of our assay. We compared three fractions from control human plasma: 1) total heterogenous EVs (T), 2) L1CAM/neural enriched EVs (NEE), and 3) the remaining total-minus-NEE fraction (T-N). Each fraction was characterized for size, total protein content, and protein markers, then total RNA was extracted, and qPCR was run on 20 miRNAs. We report that the miRNA expression within NEE was different enough compared to T and T-N to justify the extra steps required to generate this fraction. We conclude that L1CAM immunocapture generates a unique fraction of EVs that consistently and robustly replicates a miRNA fingerprint which differentiates ALS patients from controls.

Functional and quality of life outcomes of localised prostate cancer treatments (Prostate Testing for Cancer and Treatment [ProtecT] study).

OBJECTIVE: To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. PATIENTS AND METHODS: Men aged 50-69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. RESULTS: Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. CONCLUSION: Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes.

Cyclotides Chemosensitize Glioblastoma Cells to Temozolomide.

Glioblastoma multiforme (GBM) is the most aggressive cancer originating in the brain, with a median survival of 12 months. Most patients do not respond to or develop resistance to the only effective chemotherapeutic drug, temozolomide (TMZ), used to treat gliomas. Novel treatment methods are critically needed. Cyclotides are plant peptides that may be promising adjuvants to TMZ chemotherapy. They exhibit antitumor activity and chemosensitize cells to doxorubicin in breast cancer studies. During this research, we optimized cyclotide isolation techniques, and several cyclotides (CyO2, CyO13, kalata B1, and varv peptide A) exhibited dose-dependent cytotoxicity in MTT assays with IC50 values of 2.15-7.92 µM against human brain astrocytoma cells (U-87 MG) and human bone marrow derived neuroblastoma cells (SH-SY5Y). CyO2 and varv peptide A increased TMZ-induced cell death in U-87 MG cultures alone and when coexposed with CyO2 or varv peptide A plus TMZ. Phase contrast microscopy of glioblastoma cells exposed to cyclotides alone and coexposed to TMZ indicated shrunken, granular cells with blebbing, and the most pronounced effects were observed with coexposure treatments of cyclotides and TMZ. Cumulative results provide the proof-of-concept that cyclotides may enhance TMZ chemotherapy, and in vivo pharmacokinetic investigations of cyclotides are warranted with respect to GBM.

Evaluation of the Melbourne Rapid Fields Test Procedure.

SIGNIFICANCE: Both the Melbourne Rapid Fields (MRF) tablet and home versions are easy-to-use, portable, and low-cost and accurate methods of evaluating visual fields. PURPOSE: This study aimed to investigate the clinical capabilities of the MRF perimetry test by comparing it with the Humphrey Field Analyzer (HFA), determine MRF consistency, assess the influence of refractive error, ascertain ambient illumination effects, and evaluate the consistency between the tablet and Internet Web site versions of the MRF. METHODS: Forty healthy young participants with normal visual function (33 female, 7 male; average age, 24 years) underwent two MRF office-based tablet, two HFA tests, and two MRF Web site-based tests, one in our laboratory and one at home on their own computer using the 24-2 test pattern each time. An additional six healthy participants with normal visual function performed the 24-2 test with varying amounts of blur. RESULTS: The average individual sensitivity values of MRF and HFA were within 4.02 dB (right eye) and 4.15 dB (left eye). The dynamic range of the MRF was smaller (30 dB) than that of the HFA. When sensitivity values greater than 30 dB were excluded, the sensitivity differences were within 2.2 dB (right eye) and 2.46 dB (left eye) of each other. Only a small number of cases produced reliability values (false positives, false negatives, fixation losses) that were outside of normal limits. There was a high correlation between test results obtained with the tablet version of the MRF test when compared with the Internet-based Web site version. CONCLUSIONS: Quantitative visual field testing and perimetric screening procedures can be performed effectively and can provide results that are comparable with bowl perimeter test results.

FTIR Characterization of Sulfated Polysaccharides Obtained from Macrocystis integrifolia Algae and Verification of Their Antiangiogenic and Immunomodulatory Potency In Vitro and In Vivo.

The aim of this study was to evaluate the antiangiogenic and immunomodulatory potential of sulfated polysaccharides from the marine algae Macrocystis integrifolia characterized by FTIR. The cytotoxicity of sulfated polysaccharides was evaluated using the 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) assay. Antiangiogenic activity was evaluated using the chicken chorioallantoic membrane (CAM) assay. Immunomodulatory activity was determined on macrophage functionality and allergic response. The results showed that sulfated polysaccharides significantly decreased angiogenesis in chicken chorioallantoic membranes (p < 0.05). Likewise, they inhibited in vivo chemotaxis and in vitro phagocytosis, the transcription process of genes that code the enzymes cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and nitric oxide synthase-2 (NOS-2) and the nuclear factor kappa-light chain enhancer of activated B cells (NF-κB), showing immunomodulatory properties on the allergic response, as well as an in vivo inhibitory effect in the ovalbumin-induced inflammatory allergy model (OVA) and inhibited lymphocyte proliferation specific to the OVA antigen in immunized mice. Finally, these compounds inhibited the histamine-induced skin reaction in rats, the production of immunoglobulin E (IgE) in mice, and the passive response to skin anaphylaxis in rats. Therefore, the results of this research showed the potential of these compounds to be a promising source for the development of antiangiogenic and immunomodulatory drugs.

Interpreting magnitude of change in strength and conditioning: Effect size selection, threshold values and Bayesian updating.

The magnitude of change following strength and conditioning (S&C) training can be evaluated comparing effect sizes to thresholds. This study conducted a series of meta-analyses and compiled results to identify thresholds specific to S&C, and create prior distributions for Bayesian updating. Pre- and post-training data from S&C interventions were translated into standardised mean difference (SMDpre) and percentage improvement (%Improve) effect sizes. Bayesian hierarchical meta-analysis models were conducted to compare effect sizes, develop prior distributions, and estimate 0.25-, 0.5-, and 0.75-quantiles to determine small, medium, and large thresholds, respectively. Data from 643 studies comprising 6574 effect sizes were included in the analyses. Large differences in distributions for both SMDpre and %Improve were identified across outcome domains (strength, power, jump and sprint performance), with analyses of the tails of the distributions indicating potential large overestimations of SMDpre values. Future evaluations of S&C training will be improved using Bayesian approaches featuring the information and priors developed in this study. To facilitate an uptake of Bayesian methods within S&C, an easily accessible tool employing intuitive Bayesian updating was created. It is recommended that the tool and specific thresholds be used instead of isolated effect size calculations and Cohen's generic values when evaluating S&C training.

The ProtecT randomised trial cost-effectiveness analysis comparing active monitoring, surgery, or radiotherapy for prostate cancer.

BACKGROUND: There is limited evidence relating to the cost-effectiveness of treatments for localised prostate cancer. METHODS: The cost-effectiveness of active monitoring, surgery, and radiotherapy was evaluated within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial from a UK NHS perspective at 10 years' median follow-up. Prostate cancer resource-use collected from hospital records and trial participants was valued using UK reference-costs. QALYs (quality-adjusted-life-years) were calculated from patient-reported EQ-5D-3L measurements. Adjusted mean costs, QALYs, and incremental cost-effectiveness ratios were calculated; cost-effectiveness acceptability curves and sensitivity analyses addressed uncertainty; subgroup analyses considered age and disease-risk. RESULTS: Adjusted mean QALYs were similar between groups: 6.89 (active monitoring), 7.09 (radiotherapy), and 6.91 (surgery). Active monitoring had lower adjusted mean costs (£5913) than radiotherapy (£7361) and surgery (£7519). Radiotherapy was the most likely (58% probability) cost-effective option at the UK NICE willingness-to-pay threshold (£20,000 per QALY). Subgroup analyses confirmed radiotherapy was cost-effective for older men and intermediate/high-risk disease groups; active monitoring was more likely to be the cost-effective option for younger men and low-risk groups. CONCLUSIONS: Longer follow-up and modelling are required to determine the most cost-effective treatment for localised prostate cancer over a man's lifetime. TRIAL REGISTRATION: Current Controlled Trials number, ISRCTN20141297: http://isrctn.org (14/10/2002); ClinicalTrials.gov number, NCT02044172: http://www.clinicaltrials.gov (23/01/2014).

Negative Food Effect of Danirixin: Use of PBPK Modelling to Explore the Effect of Formulation and Meal Type on Clinical PK.

PURPOSE: To use physiologically-based pharmacokinetic (PBPK) modelling to explore the food effect of different DNX hydrobromide (HBr) hemihydrate salt tablet formulations using biorelevant dissolution. METHODS: Compendial dissolution using a paddle method and TIM-1 biorelevant dissolution were performed and incorporated into a previously reported PBPK model. A two-part clinical study evaluated tablet formulations in the fasted/fed (high fat) state (Part A), and the impact of food (fasted/normal/high fat) and Proton Pump Inhibitor (PPI) co-administration for a selected formulation; as well as a formulation containing DNX HBr in the monohydrate state (Part B). RESULTS: TIM-1 data showed that the fed state bioaccessibility of DNX was significantly decreased compared to the fasted state with no significant differences between formulations. Dosed with normal/high fat food the selected formulation showed comparable exposure and a modest increase in DNX systemic PK was observed with PPI dependent on meal type. Under fed conditions DNX systemic exposure was comparable for the monohydrate and hemihydrate formulations. The integration of biorelevant TIM-1 data into the PBPK model led to the successful simulation of a DNX negative food effect. CONCLUSIONS: Interactions between DNX and food components are the likely the source of the negative food effect via micellar entrapment, ion pairing and/or meal induced viscosity changes.

Hypertensive Response to Ischemic Stroke in the Normotensive Wistar Rat.

Background and Purpose- Over 80% of ischemic stroke patients show an abrupt increase in arterial blood pressure in the hours and days following ischemic stroke. Whether this poststroke hypertension is beneficial or harmful remains controversial and the underlying physiological basis is unclear. Methods- To investigate the dynamic cardiovascular response to stroke, adult Wistar rats (n=5-8 per group, 393±34 g) were instrumented with telemeters to blood pressure, intracranial pressure, renal sympathetic nerve activity, and brain tissue oxygen in the predicted penumbra (Po2). After 2 weeks of recovery, cardiovascular signals were recorded for a 3-day baseline period, then ischemic stroke was induced via transient middle cerebral artery occlusion, or sham surgery. Cardiovascular signals were then recorded for a further 10 days, and the functional sensorimotor recovery assessed using the cylinder and sticky dot tests. Results- Baseline values of all variables were similar between groups. Compared to sham, in the 2 days following stroke middle cerebral artery occlusion produced an immediate, transient rise above baseline in mean blood pressure (21±3 versus 2±4 mm Hg; P<0.001), renal sympathetic nerve activity (54±11% versus 7±4%; P=0.006), and cerebral perfusion pressure (12±5 versus 1±4; P≤0.001). Intracranial pressure increased more slowly, peaking 3 days after middle cerebral artery occlusion (14±6 versus -1±1 mm Hg; P<0.001). Treating with the antihypertensive agent nifedipine after stroke (1.5-0.75 mg/kg per hour SC) ameliorated poststroke hypertension (12±3 mm Hg on day 1; P=0.041), abolished the intracranial pressure increase (3±1; P<0.001) and reduced cerebral perfusion pressure (10±3 mm Hg; P=0.017). Preventing poststroke hypertension affected neither the recovery of sensorimotor function nor infarct size. Conclusions- These findings suggest that poststroke hypertension is immediate, temporally matched to an increase in sympathetic outflow, and elevates cerebral perfusion pressure for several days after stroke, which may enhance cerebral perfusion. Preventing poststroke hypertension does not appear to worsen prognosis after stroke in young, normotensive, and otherwise healthy rats. Visual Overview- An online visual overview is available for this article.

10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer.

BACKGROUND: The comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen (PSA) testing remains uncertain. METHODS: We compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths. RESULTS: There were 17 prostate-cancer-specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P=0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P=0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P=0.004 for the overall comparison). Higher rates of disease progression were seen in the active-monitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison). CONCLUSIONS: At a median of 10 years, prostate-cancer-specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

Analysis of BMAA enantiomers in cycads, cyanobacteria, and mammals: in vivo formation and toxicity of D-BMAA.

Chronic dietary exposure to the cyanobacterial toxin ß-N-methylamino-L-alanine (BMAA) triggers neuropathology in non-human primates, providing support for the theory that BMAA causes a fatal neurodegenerative illness among the indigenous Chamorro people of Guam. However, since there are two stereoisomers of BMAA, it is important to know if both can occur in nature, and if so, what role they might play in disease causation. As a first step, we analysed both BMAA enantiomers in cyanobacteria, cycads, and in mammals orally dosed with L-BMAA, to determine if enantiomeric changes could occur in vivo. BMAA in cyanobacteria and cycads was found only as the L-enantiomer. However, while the L-enantiomer in mammals was little changed after digestion, we detected a small pool of D-BMAA in the liver (12.5%) of mice and in the blood plasma of vervets (3.6%). Chiral analysis of cerebrospinal fluid of vervets and hindbrain of mice showed that the free BMAA in the central nervous system was the D-enantiomer. In vitro toxicity investigations with D-BMAA showed toxicity, mediated through AMPA rather than NMDA receptors. These findings raise important considerations concerning the neurotoxicity of BMAA and its relationship to neurodegenerative disease.

Workplace interventions to improve sitting posture: A systematic review.

PURPOSE: Evaluate the effectiveness of workplace interventions to improve sitting posture of workers that spend long periods of time seated at a visual display terminal. METHODS: A systematic review of randomised controlled trials, non-randomised controlled trials and single-group intervention trials featuring workplace interventions with pre- and follow-up measurements of sitting posture was conducted (registered in PROSPERO, CRD#42015027648). Nine databases were searched for studies available between January 2005 and February 2016. RESULTS: 2519 articles were screened with 12 studies meeting the inclusion criteria. The included studies featured various ergonomic workplace interventions and comprised 4 randomised controlled trial (n=457), 2 non-randomised controlled trials (n=416) and 6 single-group intervention trials (n=328). Due to clinical and methodological heterogeneity, pooling of data was not completed and a narrative summary of findings was developed using the Grading of Recommendations Assessment Development and Evaluation (GRADE) framework. The evidence for four review outcomes was assessed with medium to large positive improvements obtained for the majority of studies investigating changes to gross sitting posture, whereas mixed findings were obtained for more specific local segment assessments of sitting posture. The overall evidence quality for all review outcomes were identified as either 'low' or 'very low'. CONCLUSION: There is evidence which is limited in quality to indicate that ergonomic workplace interventions can improve gross sitting posture. More high quality research across a range of intervention types is required with longer follow-up durations and more advanced methods to assess sitting posture with greater frequency and less bias.

Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain.

Neurofibrillary tangles (NFT) and ß-amyloid plaques are the neurological hallmarks of both Alzheimer's disease and an unusual paralytic illness suffered by Chamorro villagers on the Pacific island of Guam. Many Chamorros with the disease suffer dementia, and in some villages one-quarter of the adults perished from the disease. Like Alzheimer's, the causal factors of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) are poorly understood. In replicated experiments, we found that chronic dietary exposure to a cyanobacterial toxin present in the traditional Chamorro diet, ß-N-methylamino-l-alanine (BMAA), triggers the formation of both NFT and ß-amyloid deposits similar in structure and density to those found in brain tissues of Chamorros who died with ALS/PDC. Vervets (Chlorocebus sabaeus) fed for 140 days with BMAA-dosed fruit developed NFT and sparse ß-amyloid deposits in the brain. Co-administration of the dietary amino acid l-serine with l-BMAA significantly reduced the density of NFT. These findings indicate that while chronic exposure to the environmental toxin BMAA can trigger neurodegeneration in vulnerable individuals, increasing the amount of l-serine in the diet can reduce the risk.

Evolutionary trajectories explain the diversified evolution of isogamy and anisogamy in marine green algae.

The evolution of anisogamy (the production of gametes of different size) is the first step in the establishment of sexual dimorphism, and it is a fundamental phenomenon underlying sexual selection. It is believed that anisogamy originated from isogamy (production of gametes of equal size), which is considered by most theorists to be the ancestral condition. Although nearly all plant and animal species are anisogamous, extant species of marine green algae exhibit a diversity of mating systems including both isogamy and anisogamy. Isogamy in marine green algae is of two forms: isogamy with extremely small gametes and isogamy with larger gametes. Based on disruptive selection for fertilization success and zygote survival (theory of Parker, Baker, and Smith), we explored how environmental changes can contribute to the evolution of such complex mating systems by analyzing the stochastic process in the invasion simulations of populations of differing gamete sizes. We find that both forms of isogamy can evolve from other isogamous ancestors through anisogamy. The resulting dimensionless analysis accounts for the evolutionary stability of all types of mating systems in marine green algae, even in the same environment. These results imply that evolutionary trajectories as well as the optimality of gametes/zygotes played an important role in the evolution of gamete size.

Dose-Response Modelling of Resistance Exercise Across Outcome Domains in Strength and Conditioning: A Meta-analysis.

BACKGROUND: Resistance exercise is the most common training modality included within strength and conditioning (S&C) practice. Understanding dose-response relationships between resistance training and a range of outcomes relevant to physical and sporting performance is of primary importance for quality S&C prescription. OBJECTIVES: The aim of this meta-analysis was to use contemporary modelling techniques to investigate resistance-only and resistance-dominant training interventions, and explore relationships between training variables (frequency, volume, intensity), participant characteristics (training status, sex), and improvements across a range of outcome domains including maximum strength, power, vertical jump, change of direction, and sprinting performance. METHODS: Data were obtained from a database of training studies conducted between 1962 and 2018, which comprised healthy trained or untrained adults engaged in resistance-only or resistance-dominant interventions. Studies were not required to include a control group. Standardized mean difference effect sizes were calculated and interventions categorized according to a range of training variables describing frequency (number of sessions per week), volume (number of sets and repetitions performed), overall intensity (intensity of effort and load, categorised as low, medium or high), and intensity of load (represented as % of one-repetition maximum [1RM] prescribed). Contemporary modelling techniques including Bayesian mixed-effects meta-analytic models were fitted to investigate linear and non-linear dose-responses with models compared based on predictive accuracy. RESULTS: Data from a total of 295 studies comprising 535 groups and 6,710 participants were included with analyses conducted on time points ≤ 26 weeks. The best performing model included: duration from baseline, average number of sets, and the main and interaction effects between outcome domain and intensity of load (% 1RM) expressed non-linearly. Model performance was not improved by the inclusion of participant training status or sex. CONCLUSIONS: The current meta-analysis represents the most comprehensive investigation of dose-response relationships across a range of outcome domains commonly targeted within strength and conditioning to date. Results demonstrate the magnitude of improvements is predominantly influenced by training intensity of load and the outcome measured. When considering the effects of intensity as a % 1RM, profiles differ across outcome domains with maximum strength likely to be maximised with the heaviest loads, vertical jump performance likely to be maximised with relatively light loads (~ 30% 1RM), and power likely to be maximised with low to moderate loads (40-70% 1RM).

Biological ammonium transporters: evolution and diversification.

Although ammonium is the preferred nitrogen source for microbes and plants, in animal cells it is a toxic product of nitrogen metabolism that needs to be excreted. Thus, ammonium movement across biological membranes, whether for uptake or excretion, is a fundamental and ubiquitous biological process catalysed by the superfamily of the Amt/Mep/Rh transporters. A remarkable feature of the Amt/Mep/Rh family is that they are ubiquitous and, despite sharing low amino acid sequence identity, are highly structurally conserved. Despite sharing a common structure, these proteins have become involved in a diverse range of physiological process spanning all domains of life, with reports describing their involvement in diverse biological processes being published regularly. In this context, we exhaustively present their range of biological roles across the domains of life and after explore current hypotheses concerning their evolution to help to understand how and why the conserved structure fulfils diverse physiological functions.

Reliability of spatial-temporal metrics used to assess collective behaviours in football: an in-silico experiment.

BACKGROUND: The purpose of this study was to investigate the reliability of spatio-temporal measurements applied within collective behaviour research in football. METHODS: In silico experiments were conducted introducing positional errors (0.5, 2 and 4 m) representative of commercial tracking systems to match data from the 2020 European Championship qualifiers. Ratios of the natural variance ('signal') of spatio-temporal metrics obtained throughout sections of each game relative to the variance created by positional errors ('noise') were taken to calculate reliability. The effects of error magnitude and time of analysis (1, 5 and 15 mins; length of attack: <10, 10-20, >20 s) were assessed and compared using Cohen's f2 effect size. RESULTS: Error magnitude was found to exert greater influence on reliability (f2 = 0.15 to 0.81) compared with both standard time of analysis (f2 = 0.03 to 0.08) and length of attacks (f2 = 0.15 to 0.32). DISCUSSION: The results demonstrate that technologies generating positional errors of 0.5 m or less should be expected to produce spatio-temporal metrics with high reliability. However, technologies that generate errors of 2 m or greater may produce unreliable values, particularly when analyses are conducted over discrete events such as attacks, which although critical, are often short in duration.

Cyanotoxin Analysis of Air Samples from the Great Salt Lake.

The Great Salt Lake in Utah is the largest saline lake in the Western hemisphere and one of the largest terminal lakes in the world. Situated at the eastern edge of the Great Basin, it is a remnant of the freshwater Lake Bonneville whose water level precipitously lowered about 12,000 years ago due to a natural break in Red Rock pass to the north. It contains a diverse assemblage of cyanobacteria which vary spatially dependent on salinity. In 1984, the waters of the Great Salt Lake occupied 8500 km2. Nearly four decades later, the waters occupy 2500 km2-a reduction in surface area of 71%. With predominantly westerly winds, there is a potential for the adjacent metropolitan residents to the east to be exposed to airborne cyanobacteria- and cyanotoxin-containing dust. During the summer and fall months of 2022, air and dried sediment samples were collected and assessed for the presence of BMAA which has been identified as a risk factor for ALS. Collection of air samples equivalent to a person breathing for 1 h resulted in BMAA and isomers being found in some air samples, along with their presence in exposed lakebed samples. There was no clear relationship between the presence of these toxins in airborne and adjacent lakebed samples, suggesting that airborne toxins may originate from diffuse rather than point sources. These findings confirm that continued low water levels in the Great Salt Lake may constitute an increasing health hazard for the 2.5 million inhabitants of communities along the Wasatch Front.

Antileishmanial Activity of Clinanthus milagroanthus S. Leiva & Meerow (Amaryllidaceae) Collected in Peru.

Leishmaniasis is a worldwide infectious parasitic disease caused by different species of protozoa of the genus Leishmania, which are transmitted to animals and humans through the bite of insects of the Psychodidae family. In the present work, the antileishmanial activity of an alkaloid extract of the bulbs of Clinanthus milagroanthus S. Leiva & Meerow (Amaryllidaceae) was evaluated in vitro, in vivo, and in silico against the parasite Leishmania braziliensis, and the chemical profile of the sample was determined by GC-MS analysis. At concentrations of 1, 10, and 100 µg·mL−1, the alkaloid extract presented inhibition percentages of 8.7%, 23.1%, and 98.8%, respectively, against L. braziliensis with a p < 0.05, and IC50 values of 18.5 ± 0.3 µg·mL−1. Furthermore, at a dose of 1.0 mg·kg−1, a greater decrease in lesion size was observed (90%) for in vivo assays, as well as a decrease in infection (96%), finding no significant differences (p > 0.05) in comparison with amphotericin B (92% and 98%, respectively). Eleven alkaloids were identified in C. milagroanthus bulbs: galanthamine, vittatine/crinine, 8-O-demethylmaritidine, anhydrolycorine, 11,12-dehydroanhydrolycorine, hippamine, lycorine, 2-hydroxyanhydrolycorine, 7-hydroxyclivonine, 2α-hydroxyhomolycorine, and 7-hydroxyclivonine isomer. A molecular model of Leishmania braziliensis trypanothione reductase (TRLb) was built using computational experiments to evaluate in silico the potential of the Amaryllidaceae alkaloid identified in C. milagroanthus toward this enzyme. The structures galanthamine, 7-hydroxyclivonine isomer, and crinine showed better estimated free energy of binding than the reference compound, amphotericin B. In conclusion, this is the first in vitro, in vivo, and in silico report about the antileishmanial potential and alkaloid profiling of the extract of C. milagroanthus bulbs, which could become an interesting source of bioactive molecules.