"Anxiety is not cute" analysis of twitter users' discourses on romanticizing mental illness.

BACKGROUND: The proliferation of social media platforms has provided a unique space for discourse on mental health, originally intended to destigmatize mental illness. However, recent discourses on these platforms have shown a concerning shift towards the romanticization of mental health issues. This research focuses on Twitter (now called X) users' authentic discussions on the phenomenon of romanticizing mental health, aiming to uncover unique perspectives, themes, and language used by users when engaging with this complex topic. METHODS: A comprehensive content analysis was conducted on 600 relevant tweets, with the application of topic modeling techniques. This methodology allowed for the identification and exploration of six primary themes that emerged from Twitter users' discussions. Statistical tests were not applied in this qualitative analysis. RESULTS: The study identified six primary themes resulting from Twitter users' discussions on the romanticization of mental health. These themes include rejecting/critiquing the glamorization of mental health, monetization of mental health by corporate organizations, societal misconceptions of mental health, the role of traditional media and social media, unfiltered realities of depression, and the emphasis on not romanticizing mental health. CONCLUSIONS: This study provides valuable insights into the multifaceted discourses surrounding the romanticization of mental health on Twitter. It highlights users' critiques, concerns, and calls for change, emphasizing the potential harm caused by romanticizing mental illness. The findings underscore the importance of fostering responsible and empathetic discussions about mental health on social media platforms. By examining how Twitter users interact with and respond to the romanticization of mental health, this research advances our understanding of emerging perspectives on mental health issues among social media users, particularly young adolescents. The study also underscores the effects of this phenomenon on individuals, society, and the mental health community. Overall, this research emphasizes the need for more responsible and knowledgeable discussions around mental health in the digital age.

Neutralization Activity of Anti-drug Antibodies Against a Biotherapeutic Can Be Predicted from a Comprehensive Pharmacokinetics, Pharmacodynamics, and Anti-drug Antibody Data Analysis.

Historically, a neutralization antibody (NAb) assay is considered critical in immunogenicity assessment of biologic therapeutics, even with low anti-drug antibody (ADA) positive rates. In 2019, FDA new guidelines issued on immunogenicity testing acknowledged the possibility of using "a highly sensitive PD marker or an appropriately designed PK assay or both that generate data that inform clinical activity" to replace a NAb assay. In the current manuscript, we present data for PK, PD, and ADA assays which collectively succeed to replace the standalone NAb assay. The data include a total LC/MS-based PK assay, a serum neutralization antibody (SNA) assay that essentially measures pharmacodynamically functional PK and can detect NAb activity in the presence of 1:1 ratio of drug, and a highly drug-tolerant ADA assay. In addition, a model-based meta-analysis (MBMA) demonstrated that the ability of SNA assay to detect NAb at 1:1 ratio of drug is sensitive enough to monitor clinically meaningful efficacy change, which is 50% reduction of SNA titer. Our strategy of preparing a holistic data package discussed here may provide a roadmap to the community for alternatives in assaying neutralizing activity of ADA.

SANRA-a scale for the quality assessment of narrative review articles.

BACKGROUND: Narrative reviews are the commonest type of articles in the medical literature. However, unlike systematic reviews and randomized controlled trials (RCT) articles, for which formal instruments exist to evaluate quality, there is currently no instrument available to assess the quality of narrative reviews. In response to this gap, we developed SANRA, the Scale for the Assessment of Narrative Review Articles. METHODS: A team of three experienced journal editors modified or deleted items in an earlier SANRA version based on face validity, item-total correlations, and reliability scores from previous tests. We deleted an item which addressed a manuscript's writing and accessibility due to poor inter-rater reliability. The six items which form the revised scale are rated from 0 (low standard) to 2 (high standard) and cover the following topics: explanation of (1) the importance and (2) the aims of the review, (3) literature search and (4) referencing and presentation of (5) evidence level and (6) relevant endpoint data. For all items, we developed anchor definitions and examples to guide users in filling out the form. The revised scale was tested by the same editors (blinded to each other's ratings) in a group of 30 consecutive non-systematic review manuscripts submitted to a general medical journal. RESULTS: Raters confirmed that completing the scale is feasible in everyday editorial work. The mean sum score across all 30 manuscripts was 6.0 out of 12 possible points (SD 2.6, range 1-12). Corrected item-total correlations ranged from 0.33 (item 3) to 0.58 (item 6), and Cronbach's alpha was 0.68 (internal consistency). The intra-class correlation coefficient (average measure) was 0.77 [95% CI 0.57, 0.88] (inter-rater reliability). Raters often disagreed on items 1 and 4. CONCLUSIONS: SANRA's feasibility, inter-rater reliability, homogeneity of items, and internal consistency are sufficient for a scale of six items. Further field testing, particularly of validity, is desirable. We recommend rater training based on the "explanations and instructions" document provided with SANRA. In editorial decision-making, SANRA may complement journal-specific evaluation of manuscripts-pertaining to, e.g., audience, originality or difficulty-and may contribute to improving the standard of non-systematic reviews.

Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention.

Regimen adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of human immunodeficiency virus (HIV) infection. Long-acting drug formulations requiring less-frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses. The administration of long-acting formulations in a clinical setting enables health care providers to directly track adherence. MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) drug candidate under investigation as part of a regimen for HIV treatment, with potential utility as a single agent for preexposure prophylaxis (PrEP). The active triphosphate of MK-8591 (MK-8591-TP) exhibits protracted intracellular persistence and, together with the potency of MK-8591, supports its consideration for extended-duration dosing. Toward this end, drug-eluting implant devices were designed to provide prolonged MK-8591 release in vitro and in vivo Implants, administered subcutaneously, were studied in rodents and nonhuman primates to establish MK-8591 pharmacokinetics and intracellular levels of MK-8591-TP. These data were evaluated against pharmacokinetic and pharmacodynamic models, as well as data generated in phase 1a (Ph1a) and Ph1b clinical studies with once-weekly oral administration of MK-8591. After a single administration in animals, MK-8591 implants achieved clinically relevant drug exposures and sustained drug release, with plasma levels maintained for greater than 6 months that correspond to efficacious MK-8591-TP levels, resulting in a 1.6-log reduction in viral load. Additional studies of MK-8591 implants for HIV treatment and prevention are warranted.

Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects.

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies.

Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects.

Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo-fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings. Manifestation of EFDT in either one or both species was demonstrated for 282 compounds (74%). EFDT was detected in only one species (rat or rabbit) in almost a third (31%, 118 compounds), with 58% (68 compounds) of rat studies and 42% (50 compounds) of rabbit studies identifying an EFDT signal. For 24 compounds (6%), fetal malformations were observed in one species (rat or rabbit) in the absence of any EFDT in the second species. In general, growth retardation, fetal variations, and malformations were more prominent in the rat, whereas embryo-fetal death was observed more often in the rabbit. Discordance across species may be attributed to factors such as maternal toxicity, study design differences, pharmacokinetic differences, and pharmacologic relevance of species. The current analysis suggests that in general both species are equally sensitive on the basis of an overall EFDT LOAEL comparison, but selective EFDT toxicity in one species is not uncommon. Also, there appear to be species differences in the prevalence of various EFDT manifestations (i.e. embryo-fetal death, growth retardation, and dysmorphogenesis) between rat and rabbit, suggesting that the use of both species has a higher probability of detecting developmental toxicants than either one alone.

Micro-CT imaging: Developing criteria for examining fetal skeletons in regulatory developmental toxicology studies - A workshop report.

During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies. Implementing these technologies into the Good Laboratory Practice environment requires rigorous testing, validation, and documentation to ensure the reproducibility of data. A workshop on current practices and regulatory requirements was held with the goal of defining minimal criteria for the proper implementation of these technologies and subsequent submission to regulatory agencies. Micro-computed tomography (micro-CT) is especially well suited for high-throughput evaluations, and is gaining popularity to evaluate fetal skeletons to assess the potential developmental toxicity of test agents. This workshop was convened to help scientists in the developmental toxicology field understand and apply micro-CT technology to nonclinical toxicology studies and facilitate the regulatory acceptance of imaging data. Presentations and workshop discussions covered: (1) principles of micro-CT fetal imaging; (2) concordance of findings with conventional skeletal evaluations; and (3) regulatory requirements for validating the system. Establishing these requirements for micro-CT examination can provide a path forward for laboratories considering implementing this technology and provide regulatory agencies with a basis to consider the acceptability of data generated via this technology.

The medical home bends cost curve.

While the Affordable Care Act is trying to manage health insurance, as well as mandating coverage, a number of projects around the country are trying to manage the underlying cost of health care. By bringing back the concept of a true primary care physician, who provides 90% of your care and coordinates with your specialists, these programs are bending the curve of health care cost trends. Most are seeing a reduction in emergency room visits and hospital days in the double digits. Others that are taking fee-for-service insurance out of the picture altogether are experiencing even higher reduction rates. The goal is to increase patient health, which includes the patient having an active role in understanding his or her condition, treatment options and self-care strategies. It is estimated that if all Americans had access to a medical home, our nation could save $37 billion annually.

Periadolescent rats (P41-50) exhibit increased susceptibility to D-methamphetamine-induced long-term spatial and sequential learning deficits compared to juvenile (P21-30 or P31-40) or adult rats (P51-60).

We have previously shown that P11-20 treatment with d-methamphetamine (MA) induces impaired spatial navigation in the Morris water maze (MWM), whereas P1-10 treatment does not. Little is known about the long-term behavioral consequences of MA during juvenile, adolescent, and early adult brain development. In dose-response experiments, we tested successive 10-day intervals of exposure to MA in rats (P21-30, P31-40, P41-50, and P51-60; four doses per day). MA dosing prior to P21 produces little or no toxicity; however, we observed an increased toxicity with advancing age. Across-age comparisons revealed no MWM acquisition or Cincinnati water maze (CWM) effects after MA treatment on P21-30 (2.5-10 mg/kg/dose), P31-40 (1.25-7.5 mg/kg/dose), or P51-60 (1.25-5.0 mg/kg/dose); however, significantly impaired MWM acquisition was observed after P41-50 MA treatment at the highest dose (6.25 mg/kg/dose). Learning in the CWM was also impaired in this group. No effects were seen at 1.25, 2.5, or 5 mg/kg/dose following P41-50 MA treatment. MWM reversal learning trials after P41-50 treatment showed a trend towards longer latency in all MA dose groups, but no effect on double-reversal trials. Reversal and double-reversal also showed no effects at the other exposure ages. No differences in straight channel swimming or cued learning in the MWM were seen after MA treatment at any exposure age. P41-50 is the periadolescent stage of brain development in rodents. The effects observed at this age may suggest a previously unrecognized period of susceptibility for MA-induced cognitive deficits.

Developmental D-methamphetamine treatment selectively induces spatial navigation impairments in reference memory in the Morris water maze while sparing working memory.

In previous studies, we have shown that P11-20 treatment with D-methamphetamine (MA) (10 mg/kg x 4/day at 2-h intervals) induces impairments in spatial learning and memory in the Morris water maze after the offspring reach adulthood. Using a split-litter, multiple dose, design (0, 5, 10, and 15 mg/kg MA administered s.c. 4/day at 2-h intervals), the spatial learning effect was further explored with a multiple shifted platform (reversal), reference memory-based procedure and a working memory procedure. Prior to spatial learning, animals were first tested for swimming ability (in a straight swimming channel), sequential learning (in the Cincinnati multiple-T water maze), and proximal cue learning (in the Morris water maze). Rats were then assessed in the hidden platform, reference memory-based spatial version of the Morris maze for acquisition and on five subsequent phases in which the platform was moved to new locations. After the reference memory-based, fixed platform position learning phases, animals were tested in the trial-dependent, matching-to-sample, working memory version of the Morris maze. No group differences were found in straight channel, sequential maze, or cued Morris maze performance. By contrast, all MA groups were impaired in spatial learning during acquisition, multiple shift, and shifted with a reduced platform phases of reference memory-based learning. In addition, MA animals were impaired on memory (probe) trials during the acquisition and shifted with a reduced platform phases of learning. No effects on trial-dependent, matching-to-sample, working memory were found. The findings demonstrate that neonatal treatment with MA induces a selective impairment of reference memory-based spatial learning while sparing sequential, cued, and working memory-based learning.

Developmental 3,4-methylenedioxymethamphetamine (MDMA) impairs sequential and spatial but not cued learning independent of growth, litter effects or injection stress.

Previously, we have shown that rats administered MDMA from postnatal (P) days 11-20 had reductions in body weight during the period of treatment and as adults they had deficits in sequential and spatial learning and memory. In the present study, to control for weight reductions, we used litters with double the number of offspring to induce growth restriction comparable to that of standard size litters treated with MDMA. Litters were treated twice daily from P11 to 20 with vehicle or MDMA (20 mg/kg) or only weighed. Males, but not females, exposed to MDMA had longer latencies and more errors in the Cincinnati water maze compared to males of the other treatments. In the Morris water maze (210 cm pool, 10x10 cm platform), the MDMA animals were impaired relative to all other treatments during acquisition. Only the MDMA females showed deficits when the platform was shifted to a new location, however, both MDMA males and females were impaired when the location of the platform was again shifted and a reduced platform (5x5 cm) used. No differences were observed in the ability to swim a straight channel, locate a platform with a cue, or the endocrine response to forced swim among the treatment groups. No differences were seen between animals injected with saline and those only weighed. The data suggest that factors, such as growth retardation, multiple injections, or the composition of the litter, do not affect the development of learning and memory impairments resulting from P11 to 20 MDMA exposure. The large litter approach offers a novel method to control for undernutrition during the preweaning period in rodents.

Administration of D,L-fenfluramine to rats produces learning deficits in the Cincinnati water maze but not the Morris water maze: relationship to adrenal cortical output.

Fenfluramine (FEN) is an amphetamine derivative with anorectic properties similar to amphetamine, but without the stimulatory or abuse potential. Administration of FEN produces an immediate release of serotonin as well as inhibits reuptake; ultimately FEN produces a decrease in serotonin stores in the central nervous system. We have previously shown that the administration of FEN to rats results in increased adrenal cortical hormones under resting conditions, without simultaneous elevations in adrenocorticotropin hormone (ACTH). We hypothesized that the adrenal output would be altered following stress and that the altered adrenal output would affect learning and memory, since the adrenal hormones influence learning and memory capability. In this series of experiments, we administered D,L-FEN (15 mg/kg) four times every 2 h on a single day to rats and investigated the effect on hormonal output following forced swim and the effect on sequential learning in the Cincinnati water maze and spatial learning in the Morris maze beginning 3 days after FEN administration. Animals that received FEN had increased corticosterone and aldosterone titers following forced swim relative to control animals, although no differences in ACTH or testosterone were noted. Animals exposed to FEN had lasting deficits in the Cincinnati water maze but not in the Morris water maze, regardless of testing order. These deficits in the Cincinnati water maze appear to be mediated by the elevation in adrenal output since adrenalectomy abolished the effect of FEN. Corticosterone levels were shown to be elevated during the behavioral testing period in animals exposed to FEN.