OBJECTIVE: The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5-HT in the antidepressant effects of ketamine remains unclear.
METHODS: The chronic restraint stress procedure was performed to induce depression-like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant-like effects of ketamine. Tph2 knockout or depletion of 5-HT by PCPA and 5,7-DHT were used to manipulate the brain 5-HT system. ELISA and fibre photometry recordings were used to measure extracellular 5-HT levels in the brain.
RESULTS: 60 min after injection, ketamine (10 mg·kg-1, i.p.) produced rapid antidepressant-like effects and increased brain 5-HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5-HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant-like effects of ketamine were abrogated by PCPA and 5,7-DHT, or by Tph2 knockout. Importantly, NBQX (10 mg·kg-1, i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5-HT levels and abolished the sustained antidepressant-like effects of ketamine in naïve or CRS-treated mice.
CONCLUSIONS: This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant-like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets.

Herein, we synthesized hydrogel films from crosslinked polyethylene oxide (PEO) and guar gum (GG) which can offer hydrophilicity, antibacterial efficacy, and neovascularization. This study focuses on synthesis and material/biological characterization of rosemary (RM) and citric acid (CA) loaded PEO/GG hydrogel films. Scanning Electron Microscopy images confirmed the porous structure of the developed hydrogel film matrix (PEO/GG) and the dispersion of RM and CA within it. This porous structure promotes moisture adsorption, cell attachment, proliferation, and tissue layer formation. Fourier Transform Infrared Spectroscopy (FTIR) further validated the crosslinking of the PEO/GG matrix, as confirmed by the appearance of C-O-C linkage in the FTIR spectrum. PEO/GG and PEO/GG/RM/CA revealed similar degradation and release kinetics in Dulbecco\'s Modified Eagle Medium, Simulated Body Fluid, and Phosphate Buffer Saline (degradation of ∼55 % and release of ∼60 % RM in 168 h.). The developed hydrogel film exhibited a zone of inhibition against Escherichia. coli (2 mm) and Staphylococcus. aureus (9 mm), which can be attributed to the presence of RM in the hydrogel film. Furthermore, incorporating CA in the hydrogel film promoted neovascularization, as confirmed by the Chorioallantoic Membrane Assay. The developed RM and CA-loaded PEO/GG-based hydrogel films offered suitable in-vitro properties that may aid in potential wound healing applications.

The development of smart systems for pesticidal delivery presents a significant advancement in enhancing the utilization efficiency of pesticides and mitigating environmental risks. Here an acid-responsive pesticidal delivery system using microspheres formed by the self-assembly of halloysite clay nanotubes (HNTs) is proposed. Insecticide avermectin (AVM) and herbicide prometryn (PMT) are used as two models of hydrophobic pesticide and encapsulated within the porous microspheres, followed by a coating of tannic acid/iron (TA/FeIII) complex films to generate two controlled-release pesticides, named as HCEAT and HCEPT, resulting in the loading capacity of AVM and PMT being 113.3 and 120.3 mg g-1, respectively. Both HCEAT and HCEPT exhibit responsiveness to weak acid, achieving 24 h-release ratios of 85.8% and 80.5% at a pH of 5.5. The experiment and simulation results indicate that the coordination interaction between EDTA2- and Ca2+ facilitates the spherical aggregation of HNTs. Furthermore, these novel pesticide formulations demonstrate better resistance against ultraviolet (UV) irradiation, higher foliar affinity, and less leaching effect, with negligible impact of the carrier material on plants and terrestrial organisms. This work presents a promising approach toward the development of efficient and eco-friendly pesticide formulations, greatly contributing to the sustainable advancement of agriculture.

UNASSIGNED: Untreated ocular infections can damage the unique fine structures of the eye with possible visual impairments and blindness. Ciprofloxacin (CIP) ophthalmic solution is prescribed as first-line therapy in ocular bacterial infections. Natamycin (NT) ophthalmic suspension is one of the progenitors in ocular antifungal therapy. Nanostructured lipid carriers (NLCs) have been widely examined for ocular penetration enhancement and distribution to deeper ocular tissues. The objective of the current study was to prepare NLCs loaded with a combination of CIP and NT (CIP-NT-NLCs) and embed them in an in-situ gelling system (CIP-NT-NLCs-IG). This novel formulation will target the co-delivery of CIP and NT for the treatment of mixed ocular infections or as empirical treatment in case of limited access to healthcare diagnostic services.
UNASSIGNED: CIP-NT-NLC and CIP-NT-NLC-IG formulations were evaluated based on physicochemical characteristics, in vitro release, and ex vivo transcorneal permeation studies and compared against commercial CIP and NT ophthalmic eye drops.
UNASSIGNED: NLCs formulation (0.1% CIP and 0.3% NT) showed particle size, polydispersity index, and zeta potential of 196.2 ± 1.2 nm, 0.43 ± 0.06, and -28.1 ± 1.4 mV, respectively. Moreover, CIP-NT-NLCs showed entrapment efficiency of 80.9 ± 2.9 and 98.7 ± 1.9% for CIP and NT, respectively. CIP-NT-NLCs-IGformulation with 0.2% w/v gellan gum demonstrated the most favorable viscoelastic characteristics for ocular application. CIP-NT-NLCs and CIP-NT-NLCs-IG formulations exhibited a sustained release pattern for both drugs over 24 h. Moreover, CIP-NT-NLCs and CIP-NT-NLC-IG formulations showed 4.0- and 2.2-folds, and 5.0- and 2.5-folds enhancement in ex vivo transcorneal permeability of CIP and NT, respectively, compared to the control formulations.
UNASSIGNED: The results suggest that this dual nanoparticulate-based in-situ gelling drug delivery system can serve as a promising topical delivery platform for the treatment of ocular infections.

The study\'s objective was to examine variations in viral load (VL) suppression definitions among clients in the Ryan White Program (RWP). Data from clients enrolled in the RWP during 2017 were examined to calculate the proportion of virally suppressed clients using three definitions: recent viral suppression, defined as having a suppressed VL (< 200 copies/mL) in the last test in 2017; maintained viral suppression, having a suppressed VL for both the first and last tests in 2017; and sustained viral suppression, having all tests in 2017 showing suppression. Relative differences across all three definitions were computed. Recent viral suppression measures were higher than maintained and sustained viral suppression measures by 7.0% and 10.1%, respectively. Significant relative differences in definitions by demographic, socioeconomic and clinical status were observed. It may be beneficial for care planning to report not only estimates of recent viral suppression but maintained and sustained viral suppression as well.

Cortical processing of binocular disparity is believed to begin in V1 where cells are sensitive to absolute disparity, followed by the extraction of relative disparity in higher visual areas. While much is known about the cortical distribution and spatial tuning of disparity-selective neurons, the relationship between their spatial and temporal properties is less well understood. Here, we use steady-state Visual Evoked Potentials and dynamic random dot stereograms to characterize the temporal dynamics of spatial mechanisms in human visual cortex that are primarily sensitive to either absolute or relative disparity. Stereograms alternated between disparate and non-disparate states at 2 Hz. By varying the disparity-defined spatial frequency content of the stereograms from a planar surface to corrugated ones, we biased responses towards absolute vs. relative disparities. Reliable Components Analysis was used to derive two dominant sources from the 128 channel EEG records. The first component (RC1) was maximal over the occipital pole. In RC1, first harmonic responses were sustained, tuned for corrugation frequency, and sensitive to the presence of disparity references, consistent with prior psychophysical sensitivity measurements. By contrast, the second harmonic, associated with transient processing, was not spatially tuned and was indifferent to references, consistent with it being generated by an absolute disparity mechanism. Thus, our results reveal a duplex coding strategy in the disparity domain, where relative disparities are computed via sustained mechanisms and absolute disparities are computed via transient mechanisms.

South Africa is an upper middle-income country with wide wealth inequality. It faces a quadruple burden of disease and poor health outcomes, with access to appropriate and adequate health care a challenge for millions of South Africans. The introduction of large-scale, comprehensive community health worker (CHW) programs in the country, within the context of implementing universal health coverage, was anticipated to improve population health outcomes. However, there is inadequate local (or global) evidence on whether such programs are effective, especially in urban settings.
This study is part of a multi-method, quasi-experimental intervention study measuring effectiveness of a large-scale CHW program in a health district in an urban province of South Africa, where CHWs now support approximately one million people in 280,000 households. Using interviewer administered questionnaires, a 2019 cross-sectional survey of 417 vulnerable households with long-term CHW support (intervention households) are compared to 417 households with no CHW support (control households). Households were selected from similar vulnerable areas from all sub-levels of the Ekurhuleni health district.
The 417 intervention and control households each had good health knowledge. Compared to controls, intervention households with long-term comprehensive CHW support were more likely to access early care, get diagnosed for a chronic condition, be put on treatment and be well controlled on chronic treatment. They were also more likely to receive a social grant, and have a birth certificate or identity document. The differences were statistically significant for social support, health seeking behavior, and health outcomes for maternal, child health and chronic care.
A large-scale and sustained comprehensive CHW program in an urban setting improved access to social support, chronic and minor acute health services at household and population level through better health-seeking behavior and adherence to treatment. Direct evidence from households illustrated that such community health worker programs are therefore effective and should be part of health systems in low- and middle-income countries.

The three-compartment controller with enhanced recovery (3CC-r) model of muscle fatigue has previously been validated separately for both sustained (SIC) and intermittent isometric contractions (IIC) using different objective functions, but its performance has not yet been tested against both contraction types simultaneously using a common objective function. Additionally, prior validation has been performed using common parameters at the joint level, whereas applications to many real-world tasks will require the model to be applied to agonistic and synergistic muscle groups. Lastly, parameters for the model have previously been derived for a mixed-sex cohort not considering the differece in fatigabilities between the sexes. In this work we validate the 3CC-r model using a comprehensive isometric contraction database drawn from 172 publications segregated by functional muscle group (FMG) and sex. We find that prediction errors are reduced by 19% on average when segregating the dataset by FMG alone, and by 34% when segregating by both sex and FMG. However, minimum prediction errors are found to be higher when validated against both SIC and IIC data together using torque decline as the outcome variable than when validated sequentially against hypothesized SIC intensity-endurance time curves with endurance time as the outcome variable and against raw IIC data with torque decline as the outcome variable.

We conducted a randomized trial among emergency department patients with migraine to determine the relative impact on migraine-associated symptoms of hydromorphone, an opioid, versus prochlorperazine, an antidopaminergic antiemetic.
This was a post hoc analysis of data from a double-blind study registered at http://clinicaltrials.gov (NCT02389829). Patients who met International Classification of Headache Disorders, 3rd edition criteria for migraine without aura or for probable migraine without aura were eligible for participation. Participants received either hydromorphone 1 mg IV or prochlorperazine 10 mg IV plus diphenhydramine 25 mg IV and could receive a second dose of the same medication 1 h later if needed. The outcomes were sustained relief of nausea, photophobia, and phonophobia.
A total of 127 patients were enrolled, of whom 63 received prochlorperazine and 64 received hydromorphone. Of 49 patients in the prochlorperazine arm who reported nausea at baseline, 34 (69.4%) reported complete resolution without relapse versus 15/49 (30.6%) in the hydromorphone arm (absolute risk reduction [ARR] = 38.8%, 95% CI: 20.5%-57.0%, p < 0.001). Of 55 patients in the prochlorperazine arm who reported photophobia at baseline, 23 (41.8%) reported complete resolution without relapse versus 13/62 (20.9%) patients treated with hydromorphone (ARR = 20.8%, 95% CI: 4.3%-37.3%, p = 0.014). Of 56 patients in the prochlorperazine arm who reported phonophobia at baseline, 25 (44.6%) reported complete resolution without relapse versus 16/59 (27.1%) in the hydromorphone arm (ARR = 17.5%, 95% CI: 0.3%-34.8%, p = 0.049). For adverse events, three patients in the prochlorperazine arm reported anxiety or restlessness, and nine patients in the hydromorphone arm reported dizziness or weakness.
Prochlorperazine plus diphenhydramine is more efficacious than hydromorphone for the treatment of migraine-associated symptoms.

Previous studies have shown that lifestyle changes, such as diet and exercise, can lead to weight loss, resulting in dramatic improvements in overall health and chronic disease risk. However, while many traditional dieting, food tracking and weight loss coaching programs result in short-term weight loss, there is less evidence of their effectiveness on sustaining weight loss over time.
We conducted a retrospective analysis of 1,740 adults with obesity who used Foodsmart, a digital personalized dietary assessment, meal planning and food purchasing platform. Participants reported age, gender, at least three measures of weight, and their diet using a food frequency questionnaire. We defined sustained weight loss as participants who lost 5 % of initial weight between their first and second reported weights and lost weight or maintained weight between second and third reported weights. A healthy eating score, Nutriscore, was calculated to assess overall diet quality. We used multivariate logistic regression models to examine the association between user characteristics and odds of sustained weight loss.
Over a median of 25 months, the mean (standard deviation) change in weight among participants was - 6.2 (19.8) pounds. In total, 39.3 % (684/1,740) of participants lost at least 5 % of their initial weight, and 22.4 % percent (389/1,740) of participants sustained weight loss. In the fully-adjusted logistic regression model, we found that obesity class 2 (odds ratio, OR: 1.69, 95 % confidence interval, CI: 1.27-2.24, P < 0.001), obesity class 3 (OR: 2.23, 95 % CI: 1.68-2.97, P < 0.001), baseline diet quality (OR: 1.06, 95 % CI: 1.02-1.09, P < 0.001), and greater change in diet quality (OR: 1.10, 95 % CI: 1.07-1.14, P < 0.001) were significantly associated with sustained weight loss.
This study characterized and demonstrated the utility of Foodsmart, a digital platform that gives personalized nutrition recommendations and meal planning tools, in sustained weight reduction among users with obesity.