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Ethnopharmacological Relevance: Indigenous use communities in the Western Cape (South Africa) where Aspalathus linearis (Brum.f) R.Dahlgren - or rooibos - grows naturally, has a long history of using rooibos for medicinal purposes. Apart from its well-known antioxidant effect, the Cederberg community in particular has been using rooibos as a treatment for high blood pressure. Given the detrimental effects of high blood pressure on endothelial cells, rooibos may either directly or indirectly affect vascular health. This, together with more recent reports of neuroprotective effects, may position rooibos as complementary medicine in related vascular conditions such as ischaemic stroke., Aims of the Study: The study aimed to evaluate the potential benefit of acute administration of unfermented rooibos, on vascular health in a larval zebrafish model of stroke., Materials and Methods: Stroke was induced via 24-h ponatinib exposure, in the presence or absence of an aqueous solution of an ethanolic extract of unfermented Rooibos (GreenOxithin™). The magnitude of stroke was assessed by monitoring larval locomotion and thrombus formation. In terms of specific mechanisms probed, changes in redox status (MDA and TEAC), neurological markers (TH and NeuroD1) and endothelial health (tight/adhesion junction protein expression) were assessed., Results: Rooibos treatment limited thrombus formation and prevented stroke-induced deficits on larval motility. In terms of redox status, rooibos treatment prevented lipid peroxidation 3 days after initial stroke induction, reducing the need for significant upregulation of endogenous antioxidant mechanisms. Stroke-induced changes in neuronal (NeuroD1 and TH) protein expression were normalized in the presence of rooibos, suggesting a neuroprotective role. In terms of tight junction proteins, stroke-related decreases in ZO-1 expression were again prevented by rooibos treatment. In addition, rooibos treatment may beneficially modulate levels of claudin-5 and VE-cadherin, to indirectly limit stroke-associated vascular dysfunction., Conclusions: Taken together, activity data and physiological assessments suggest that unfermented rooibos may indeed have benefit in the context of stroke, via action at multiple targets. Thus, current data further our understanding of the mechanisms of actions of rooibos and warrant future research to confirm sufficient bioavailability of rooibos in target tissues, in mammalian systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Anxiety disorders are the most prevalent psychiatric disorders, exhibiting strong female bias. Clinical studies implicate declining estradiol levels in the exacerbation of anxiety symptoms in the premenstrual phase of the menstrual cycle. This study aimed to simulate estradiol fluctuation-linked anxiety behavior in larval zebrafish, using an estradiol treatment withdrawal model. Contrary to model aims, estradiol treatment withdrawal decreased both basal activity and anxiety-like hyperlocomotion (ANOVA main effect of dose, P  < 0.0001 and P  < 0.01, respectively) in the light/dark transition test. The accuracy of the estradiol washout model was not improved by longer durations of treatment or withdrawal. Basal activity was slightly altered by supraphysiological concentrations of WAY-200070 in the absence of added estradiol. Estrogen receptor (ER) β expression was not upregulated in larvae exposed to physiologically relevant, low concentrations of estradiol. Longer exposure to low concentrations of estradiol increased antioxidant capacity ( P  < 0.01). In addition, acute exposure to low concentrations of estradiol increased basal activity. Data suggest that in the current models, estradiol-associated altered activity levels were linked to more favorable redox status, rather than reflecting altered anxiety levels. As such, it is recommended that zebrafish larval behavioral analysis be conducted in parallel with mechanistic studies such as redox indicators, for investigations focused on ER signaling., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Objectives: To determine the impact of telementoring on caregiver performance during a high-fidelity medical simulation model (HFMSM) of a critically ill patient in a resource-limited setting., Design: A two-center, randomized, controlled study using a HFMSM of a patient with community-acquired pneumonia complicated by acute respiratory distress syndrome., Setting: A notional clinic in a remote location staffed by a single clinician and nonmedical assistant., Participants: Clinicians with limited experience managing critically ill patients., Interventions: Telemedicine (TM) support., Measurements: The primary outcome was clinical performance as measured by accuracy, reliability, and efficiency of care. Secondary outcomes were patient survival, procedural quality, subjective assessment of the HFMSM, and perceived workload., Main Results: TM participants ( N = 11) performed better than non-TM (NTM, N = 12) in providing expected care (accuracy), delivering care more consistently (reliability), and without consistent differences in efficiency (timeliness of care). Accuracy: TM completed 91% and NTM 42% of expected tasks and procedures. Efficiency: groups did not differ in the mean (± sd) minutes it took to obtain an advanced airway successfully (TM 15.2 ± 10.5 vs. NTM 22.8 ± 8.4, p = 0.10) or decompress a tension pneumothorax with a needle (TM 0.7 ± 0.5 vs. NTM 0.6 ± 0.9, p = 0.65). TM was slower than NTM in completing thoracostomy (22.3 ± 10.2 vs. 12.3 ± 4.8, p = 0.03). Reliability: TM performed 13 of 17 (76%) tasks with more consistent timing than NTM. TM completed 68% and NTM 29% of procedural quality metrics. Eighty-two percent of the TM participants versus 17% of the NTM participants simulated patients survived ( p = 0.003). The groups similarly perceived the HFMSM as realistic, managed their patients with personal ownership, and experienced comparable workload and stress., Conclusions: Remote expertise provided with TM to caregivers in resource-limited settings improves caregiver performance, quality of care, and potentially real patient survival. HFMSM can be used to study interventions in ways not possible with real patients.

Background: Disparities in physical and mental health among Black, Indigenous, and People of Color (BIPOC) are well-documented and mirrored in the Veteran population. Chronic stress due to racism and discrimination is one possible mechanism driving these negative health outcomes. The Race-Based Stress and Trauma Empowerment (RBSTE) group is a novel, manualized, health promotion intervention designed to address the direct and indirect impacts of racism among Veterans of Color. This paper describes the protocol of the first pilot randomized controlled trial (RCT) of RBSTE. This study will examine the feasibility, acceptability, and appropriateness of RBSTE compared to an active control (an adaptation of Present-Centered Therapy; PCT) in a Veterans Affairs (VA) healthcare setting. A secondary aim is to identify and optimize strategies for holistic evaluation., Methods: Veterans of Color (N = 48) endorsing perceived discrimination and stress will be randomized to RBSTE or PCT; both groups will be delivered in 8 weekly, 90-min virtual group sessions. Outcomes will include measures of psychological distress, discrimination and ethnoracial identity, holistic wellness, and allostatic load. Measures will be administered at baseline and post-intervention., Conclusion: This study will inform future interventions targeting identity-based stressors and represents an important step in advancing equity for BIPOC in medicine and research., Clinical Trial Registration Number: NCT05422638., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Emtricitabine/tenofovir disoproxil fumarate [FTC-TDF] is a daily oral medication taken by HIV-negative individuals for pre-exposure prophylaxis (PrEP) to prevent human immunodeficiency virus (HIV) infection. A higher incidence of sexually transmitted infections (STIs) among PrEP users has been reported compared to STI incidence before PrEP use. Asymptomatic incident STI rates were investigated among 78 patients presenting for PrEP in Honolulu, Hawai'i, from April 2018 to May 2019. Testing for oropharyngeal gonorrhea, urethral gonorrhea and chlamydia, rectal gonorrhea and chlamydia, and syphilis was performed. Incident STI percentages were calculated at each follow-up visit. Ninety-seven percent of patients were men who have sex with men (MSM). Forty-seven percent of patients had follow-up data 6 months after initiation and 28% after 1 year. Thirty-two percent of patients self-reported an STI before initiating PrEP. More than half reported anonymous partners. There were 35 positive STI tests during the study period, and 25% of patients had one or more positive tests during this time. At initiation, 17% of patients were found to have an STI, followed by 16% at 3 months, 14% at 6 months, 8% at 9 months, and 5% at 12 months. At all visits, chlamydia was the most common STI detected; at 6 months, 18% of all rectal tests were positive for chlamydia. There were inconsistent condom use and high STI rates from screening during PrEP initiation and follow-up, offering an opportunity to identify asymptomatic STIs in this population. This study is the first report in Hawai'i of STI rates among PrEP users., (©Copyright 2021 by University Health Partners of Hawai‘i (UHP Hawai‘i).)

Considering that the phenomenon of accelerated ageing contributes to early onset of various chronic diseases, modelling of the relevant dysregulated systems or responses is vital for research aimed at identification of potential therapeutic targets. Here, we aimed to establish a model capable of simulating the redox and inflammatory changes of accelerated ageing-specifically, the aim was early phase accelerated ageing, which would allow therapeutic intervention in a preventative approach prior to clinical disease manifestation. A secondary aim was to evaluate the sensitivity of the model to reflect preventative treatment efficacy. Daily D-galactose injections (250 mg/kg body mass/day) for 8 weeks in 9-week-old male Wistar rats induced a model of early accelerated ageing (decreased plasma FRAP; P < 0.05 and altered inflammatory signalling) and an aged profile in lymph node ultrastructure, but did not yet result in telomere shortening. Preventative daily oral antioxidant administration (grape seed-derived polyphenol, 100 mg/kg body mass) prevented tissue ageing, beneficially modulated the inflammatory response, including neutrophil chemokinetic capacity, and tended to increase absolute telomere length. Data suggests that using a mild model of D-galactose administration than those employed to induce neurodegeneration, simulated the point where oxidative stress starts to overwhelm the endogenous antioxidant response and where a pro-inflammatory phenotype switch manifests. Furthermore, despite the expected small effect size, the model was sufficiently sensitive to reflect benefits of preventative antioxidant treatment in the context of ageing. This model presents a practical model for use in drug discovery, particularly in the context of preventative medicine aimed at limiting oxidative stress-associated ageing. Since this starting point of accelerated ageing as illustrated by current data, is not expected to reflect major ageing-associated changes yet, we recommend that future preventative drug discovery studies employ a longitudinal study design in order to clearly demonstrate the delay of this starting point by preventative strategies.

Rheumatoid arthritis is prevalent in more than 1% of the global population, with the highest occurrence between ages 35 and 50, which places a huge burden on the economy. Drug discovery for the prevention of this chronic disease is; therefore, a priority. It is known that subclinical progression of many chronic non-communicable diseases is exacerbated via accelerated ageing, a pro-inflammatory phenotype shift. However, rheumatoid arthritis additionally has significant humoral immune activation, inflammatory signalling-and thus the accelerated ageing profile-may differ from other chronic inflammatory diseases. The current study simulated inflammatory arthritis onset in a collagen-induced arthritis (CIA) rodent model, to characterise the redox and inflammatory profile at the onset of clinical symptoms, in different tissues, in the presence and absence of preventative antioxidant treatment. The data illustrate that an increased free radical level are evident already very early on in RA disease progression. Furthermore, oxidative stress seems to somewhat precede a significant pro-inflammatory state, perhaps due to humoral immune activation. Our data across different compartments further suggest that the compensatory increase in endogenous antioxidant activity is gradually exhausted at a different pace, with the liver showing the first signs of oxidant damage, even before significant evidence exist in circulation. The current data further suggest that preventative antioxidant intervention may have a sparing effect on endogenous antioxidant mechanisms and preserve telomere length to delay disease progression-or at least the accelerated ageing known to exacerbate RA symptoms-although it did not seem to have a significant direct effect on the autoimmune activity.

The unique species specificity of the bacterial cytolysin intermedilysin is explained by its requirement for the human complement regulator CD59 as the primary receptor. Binding studies using individual domains of intermedilysin mapped the CD59-binding site to domain 4 and swap mutants between human and rabbit (non-intermedilysin-binding) CD59 implicated a short sequence (residues 42-59) in human CD59 in binding intermedilysin. We set out to map more closely the CD59 binding site in intermedilysin. We first looked for regions of homology between domain 4 in intermedilysin and the terminal complement components that bind CD59, C8 and C9. A nine amino acid sequence immediately adjacent the undecapeptide segment in intermedilysin domain 4 matched (5 of 9 identical, 3 of 9 conserved) a sequence in C9. A peptide containing this sequence caused dose-dependent inhibition of intermedilysin-mediated lysis of human erythrocytes and rendered erythrocytes more susceptible to complement lysis. Surface plasmon resonance analysis of intermedilysin binding to immobilized CD59 revealed saturable fast-on, fast-off binding and a calculated affinity of 4.9 nM. Substitution of three residues from the putative binding site caused a 5-fold reduction in lytic potency of intermedilysin and reduced affinity for immobilized CD59 by 2.5-fold. The demonstration that a peptide modeled on the CD59-binding site inhibits intermedilysin-mediated haemolysis leads us to suggest that such peptides might be useful in treating infections caused by intermedilysin-producing bacteria.

Pneumolysin is an important virulence factor of the human pathogen Streptococcus pneumoniae. Sequence analysis of the ply gene from 121 clinical isolates of S. pneumoniae uncovered a number of alleles. Twenty-two strains were chosen for further analysis, and 14 protein alleles were discovered. Five of these had been reported previously, and the remaining 9 were novel. Cell lysates were used to determine the specific hemolytic activities of the pneumolysin proteins. Six strains showed no hemolytic activity, and the remaining 16 were hemolytic, to varying degrees. We report that the nonhemolytic allele reported previously in serotype 1, sequence type (ST) 306 isolates is also present in a number of pneumococcal isolates of serotype 8 that belong to the ST53 lineage. Serotype 1 and 8 pneumococci are known to be associated with outbreaks of invasive disease. The nonhemolytic pneumolysin allele is therefore associated with the dominant clones of outbreak-associated serotypes of S. pneumoniae.

Objectives: To estimate the declining benefits of screening for prostate cancer as patient age at screening increases. The benefits of prostate cancer screening decline with age because of the long natural history of prostate cancer and competing causes of death among older men., Methods: We used a previously described Monte Carlo simulation based on a Markov model of prostate cancer detection in men aged 40 to 90 years and simulated prostate cancer screening in 1000 populations of 1,000,000 men each. The age at the final prostate-specific antigen test in the model was varied to simulate the discontinuation of screening from age 50 to 80 years. The model outputs were the number of men treated, the number of prostate cancer deaths prevented by treatment, and person-years of life saved., Results: The relationship between treatments required to prevent a death was not constant but widened with age. Compared with screening to age 65 years, screening to age 75 and 80 years required twice and three times, respectively, the number of treatments per person-year of life saved., Conclusions: Our results have helped to quantify the declining treatment benefit as the patient age at screening and treatment for prostate cancer increases. We believe that men older than 70 years should be carefully counseled about the declining benefits of prostate cancer detection with screening.

Context: Despite widespread use of serum prostate-specific antigen (PSA) testing to detect prostate cancer, the relative effectiveness of different PSA screening strategies is unknown., Objective: To compare prostate cancer mortality, PSA testing rates, and biopsy rates using various PSA screening strategies, including the standard strategy of annually testing men aged 50 through 75 years., Design and Setting: A Monte-Carlo simulation based on a Markov model was used to simulate the natural history of prostate cancer using different starting ages, testing intervals, and PSA thresholds for prostate biopsy. Age-specific PSA levels and prostate biopsy detection probabilities were determined from population data and surgical series., Main Outcome Measures: Numbers of prevented prostate cancer deaths, PSA tests, and prostate biopsies per 1000 men aged 40 through 80 years, compared among 7 different strategies vs no screening., Results: Compared with annual PSA testing beginning at age 50 years, the strategy of PSA testing at ages 40 and 45 years followed by biennial testing beginning at age 50 years was estimated to simultaneously reduce prostate cancer mortality and number of PSA tests and biopsies performed per 1000 men. Specifically, compared with no screening, the standard strategy prevents 3.2 deaths, with an additional 10,500 PSA tests and 600 prostate biopsies, while the earlier but less frequent strategy prevents 3.3 deaths, with an additional 7500 PSA tests and 450 prostate biopsies. Strategies that lowered the PSA threshold for prostate biopsy to below 4.0 ng/mL or strategies that used age-specific PSA levels were not more efficient than use of a PSA threshold of 4.0 ng/mL. These 2 findings remained true under all sensitivity analyses performed to test assumptions of the model., Conclusion: Recognizing that the efficacy of PSA screening is unproved, the standard strategy of annual PSA screening beginning at age 50 years appears to be less effective and more resource intensive compared with a strategy that begins earlier but screens biennially instead of annually. JAMA. 2000;284:1399-1405.

Objective: To compare the effects of in vivo and in vitro maturation of human oocytes., Design: Women (n = 60) undergoing follicular stimulation for in vitro fertilization, using long-course analog therapy to suppress endogenous luteinizing hormone (LH), were randomly allocated to a short (34 hour) or long (39 hour) delay between human chorionic gonadotropin (hCG) administration and oocyte retrieval. Each patient's oocytes were divided into two groups that were either inseminated immediately or after 5 hours., Results: The incidence of polyspermic fertilization was highest in oocytes inseminated immediately after a short hCG/oocyte retrieval interval (17/100) and was significantly (P less than 0.05) reduced by preincubation and/or a long hGG/oocyte retrieval interval. Fertilization rates were higher with 39 hours than with 34 hours in vivo maturation (84.2% versus 76.8%; P less than 0.05). The incidence of delayed fertilization was reduced by extending the hCG/oocyte retrieval interval (short, 12.9%; long, 3.9%; P less than 0.001)., Conclusions: Extension of the in vivo maturation time increased fertilization rates and eliminated the requirement for preinsemination incubation, allowing simplification of laboratory procedures.

The possibility of DNA degradation is of concern to all involved in the storage of DNA, whether for diagnostic or research purposes. Many DNA banks are at present maintained at low temperatures, but optimum conditions for storage and handling have yet to be fully assessed. Both DNA and fresh blood have been subjected to repeated cycles of freezing and thawing and DNA extracted from the blood. DNA yield has been established and integrity examined by digestion, electrophoresis, and Southern blot analysis using DNA fingerprinting techniques. No degradation of DNA could be detected using these techniques; however, DNA yield was shown to be adversely affected by freezing, with yield reduced by more than 25% in blood samples frozen only once.

The ascorbic acid concentration in the posterior and anterior chambers of the rhesus monkey (Macaca mulatta) eye was determined, and found to be significantly higher in the posterior chamber. Monkeys anesthetized with pentobarbital sodium had a higher posterior chamber ascorbic acid concentration than monkeys sedated with phencyclidine. The ascorbic acid diffusion coefficient, calculated from the posterior and anterior chamber data, was 0.0012 min.-1 for monkeys given phencyclidine and 0.0010 min.-1 for pentobarbital-anesthetized monkeys.