Youth is Prized in Medicine, Old Age is Valued in Law: Analysis of Media Narratives Over 200 Years.

BACKGROUND: This is the first study to explore how age has influenced depictions of doctors and lawyers in the media over the course of 210 years, from 1810 to 2019. The media represents a significant platform for examining age stereotypes and possesses tremendous power to shape public opinion. Insights could be used to improve depictions of older professionals in the media. OBJECTIVE: This study aims to understand how age shapes the portrayals of doctors and lawyers. Specifically, it compares the difference in sentiments toward younger and older doctors as well as younger and older lawyers in the media over 210 years. METHODS: Leveraging a 600-million-word corpus of American media publications spanning 210 years, we compiled top descriptors (N=478,452) of nouns related to youth × occupation (eg, younger doctor or physician) and old age × occupation (eg, older lawyer or attorney). These descriptors were selected using well-established criteria including co-occurrence frequency and context relevance, and were rated on a Likert scale from 1 (very negative) to 5 (very positive). Sentiment scores were generated for "doctor/physician," "young(er) doctor/physician," "old(er) doctor/physician," "lawyer/attorney," "young(er) lawyer/attorney," and "old(er) lawyer/attorney." The scores were calculated per decade for 21 decades from 1810 to 2019. Topic modeling was conducted on the descriptors of each occupation in both the 1800s and 1900s using latent Dirichlet allocation. RESULTS: As hypothesized, the media placed a premium on youth in the medical profession, with portrayals of younger doctors becoming 10% more positive over 210 years, and those of older doctors becoming 1.4% more negative. Meanwhile, a premium was placed on old age in law. Positive portrayals of older lawyers increased by 22.6% over time, while those of younger lawyers experienced a 4.3% decrease. In the 1800s, narratives on younger doctors revolved around their participation in rural health care. In the 1900s, the focus shifted to their mastery of new medical technologies. There was no marked change in narratives surrounding older doctors from the 1800s to the 1900s, though less attention was paid to their skills in the 1900s. Narratives on younger lawyers in the 1800s referenced their limited experience. In the 1900s, there was more focus on courtroom affairs. In both the 1800s and 1900s, narratives on older lawyers emphasized their prestige, especially in the 1900s. CONCLUSIONS: Depending on the occupation, one's age may either be seen as an asset or a liability. Efforts must be expended to ensure that older professionals are recognized for their wealth of knowledge and skills. Failing to capitalize on the merits of an older workforce could ultimately be a grave disservice not only to older adults but to society in general.

Ponatinib, Lestaurtinib, and mTOR/PI3K Inhibitors Are Promising Repurposing Candidates against Entamoeba histolytica.

Dysentery caused by Entamoeba histolytica affects millions of people annually. Current treatment regimens are based on metronidazole to treat invasive parasites combined with paromomycin for luminal parasites. Issues with treatment include significant side effects, inability to easily treat breastfeeding and pregnant women, the use of two sequential agents, and concern that all therapy is based on nitroimidazole agents, with no alternatives if clinical resistance emerges. Thus, the need for new drugs against amebiasis is urgent. To identify new therapeutic candidates, we screened 11,948 compounds assembled for the ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) library against E. histolytica trophozoites. We identified 159 hits in the primary screen at 10 µM, and 46 compounds were confirmed in secondary assays. Overall, 26 were selected as priority molecules for further investigation, including 6 FDA approved, 5 orphan designations, and 15 that are currently in clinical trials (3 phase III, 7 phase II, and 5 phase I). We found that all 26 compounds are active against metronidazole-resistant E. histolytica, and 24 are able to block parasite recrudescence after drug removal. Additionally, 14 are able to inhibit encystation and 2 (lestaurtinib and LY-2874455) are active against mature cysts. Two classes of compounds are most interesting for further investigations: (i) the Bcr-Abl tyrosine kinase (TK) inhibitors, with ponatinib (50% effective concentration [EC50], 0.39) as the most potent; and (ii) mTOR or phosphatidylinositol 3-kinase (PI3K) inhibitors, with 8 compounds in clinical development, of which 4 have nanomolar potency. Overall, these are promising candidates and represent a significant advance for development of drugs against E. histolytica.

Repurposing the Kinase Inhibitor Mavelertinib for Giardiasis Therapy.

A phenotypic screen of the ReFRAME compound library was performed to identify cell-active inhibitors that could be developed as therapeutics for giardiasis. A primary screen against Giardia lamblia GS clone H7 identified 85 cell-active compounds at a hit rate of 0.72%. A cytotoxicity counterscreen against HEK293T cells was carried out to assess hit compound selectivity for further prioritization. Mavelertinib (PF-06747775), a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), was identified as a potential new therapeutic based on indication, activity, and availability after reconfirmation. Mavelertinib has in vitro efficacy against metronidazole-resistant 713-M3 strains. Other EGFR-TKIs screened in follow-up assays exhibited insignificant inhibition of G. lamblia at 5 µM, suggesting that the primary molecular target of mavelertinib may have a different mechanistic binding mode from human EGFR-tyrosine kinase. Mavelertinib, dosed as low as 5 mg/kg of body weight or as high as 50 mg/kg, was efficacious in the acute murine Giardia infection model. These results suggest that mavelertinib merits consideration for repurposing and advancement to giardiasis clinical trials while its analogues are further developed.

Can professionals "keep the tiller straight" in organizations? Resistance to reframing and decoy alternatives in workplace decision-making.

So far, little is known about the ability to contrast contextual bias as a protective factor in an ever-changing organizational environment. This study assessed whether professionals with different seniority can resist the reframing and the decoy effect under decision-making conditions and whether decision-making styles can predict the resistance to such covert influence tactics. To reach this aim, two groups of professionals divided into senior and junior professionals performed two novel tasks, a Resistance to Reframe Task (RRT) and a Resistance to Alternatives Task (RAT), which, by including ecological scenarios that represent typical decision situations that could arise in the company, can measure the resistance to such covert influence tactics. Decision-making styles were measured through the General Decision-Making Style (GDMS) and the Maximization Scale (MS). Results showed that all professionals were able to resist more to the reframing (at the RRT) than the decoy alternatives (RAT), without any difference between groups. In addition, higher GDMS-dependent subscale scores predict lower RRT scores, especially in the group of senior professionals. However, in the group of junior professionals, the GDMS-dependent subscale and MS high standards subscale predicted lower RAT scores. To conclude, this study showed that professionals know how to "keep the tiller straight" in organizations, especially when facing reframing conditions, rather than decoy alternatives; however, the predominance of dependent decision-making styles (for both senior and junior professionals) and the tendency to hold high standards in decisions (mainly for juniors) could undermine their resistance capacity and make them vulnerable to these covert influence tactics.

Comparison of IMU-Based Knee Kinematics with and without Harness Fixation against an Optical Marker-Based System.

The use of inertial measurement units (IMUs) as an alternative to optical marker-based systems has the potential to make gait analysis part of the clinical standard of care. Previously, an IMU-based system leveraging Rauch-Tung-Striebel smoothing to estimate knee angles was assessed using a six-degrees-of-freedom joint simulator. In a clinical setting, however, accurately measuring abduction/adduction and external/internal rotation of the knee joint is particularly challenging, especially in the presence of soft tissue artefacts. In this study, the in vivo IMU-based joint angles of 40 asymptomatic knees were assessed during level walking, under two distinct sensor placement configurations: (1) IMUs fixed to a rigid harness, and (2) IMUs mounted on the skin using elastic hook-and-loop bands (from here on referred to as "skin-mounted IMUs"). Estimates were compared against values obtained from a harness-mounted optical marker-based system. The comparison of these three sets of kinematic signals (IMUs on harness, IMUs on skin, and optical markers on harness) was performed before and after implementation of a REference FRame Alignment MEthod (REFRAME) to account for the effects of differences in coordinate system orientations. Prior to the implementation of REFRAME, in comparison to optical estimates, skin-mounted IMU-based angles displayed mean root-mean-square errors (RMSEs) up to 6.5°, while mean RMSEs for angles based on harness-mounted IMUs peaked at 5.1°. After REFRAME implementation, peak mean RMSEs were reduced to 4.1°, and 1.5°, respectively. The negligible differences between harness-mounted IMUs and the optical system after REFRAME revealed that the IMU-based system was capable of capturing the same underlying motion pattern as the optical reference. In contrast, obvious differences between the skin-mounted IMUs and the optical reference indicated that the use of a harness led to fundamentally different joint motion being measured, even after accounting for reference frame misalignments. Fluctuations in the kinematic signals associated with harness use suggested the rigid device oscillated upon heel strike, likely due to inertial effects from its additional mass. Our study proposes that optical systems can be successfully replaced by more cost-effective IMUs with similar accuracy, but further investigation (especially in vivo and upon heel strike) against moving videofluoroscopy is recommended.

Social media discourse on ageism, sexism, and racism: Analysis of 150 million tweets over 15 years.

BACKGROUND: Ageism is a major but oft-overlooked social determinant of health. In fact, it is widely accepted among scholars that ageism is one of the least acknowledged forms of inequality, although few empirical attempts have been made to substantiate this claim. This is the first study that quantifies the amount of discourse dedicated to ageism, sexism, and racism on Twitter. Specifically, we rely on the usage of hashtags as a proxy for the frequency of discussions surrounding each form of inequality over a 15-year period from 2007 to 2022. We also identify key events that triggered spikes in Twitter activity for each form of inequality. METHODS: Hashtags related to racism and sexism were extracted from past scholarship. We also employed a snowball sampling method whereby we queried the hashtags using Twitter's search function to identify other hashtags. As limited research has been conducted on ageism-related hashtags, we queried hashtags utilized by advocacy groups and adopted a snowball sampling method to compile other relevant hashtags. Tweets collected (N = 154,353,047) spanned 15 years, from August 23, 2007 to December 31, 2022. RESULTS: From 2007 to 2022, racism-related hashtags were used the most, followed by sexism-related hashtags and ageism-related hashtags. Racism-related hashtags (N = 99,250,348) were mentioned about 60 times more than ageism-related hashtags (N = 1,648,926). Sexism-related hashtags (N = 38,933,113) were mentioned 24 times more than ageism-related hashtags. The increasing linear trend of tweets associated with ageism (p < 0.001), sexism (p < 0.05), and racism (p < 0.05) reached significance. Incidents of racism and sexism often generated widespread public outrage. Conversely, instances of ageism rarely caused spikes in social media activity. Rather, these spikes were mainly observed during events such as the release of a report on ageism, a conference related to aging, or observances such as International Day of Older Persons. CONCLUSION: There is a need to hasten moves to raise awareness of ageism. To ensure that discussions on ageism are not confined to academic and policy circles, advocacy campaigns could be held to educate the public on the issue and its negative concomitants.

Protein target similarity is positive predictor of in vitro antipathogenic activity: a drug repurposing strategy for Plasmodium falciparum.

Drug discovery is an intricate and costly process. Repurposing existing drugs and active compounds offers a viable pathway to develop new therapies for various diseases. By leveraging publicly available biomedical information, it is possible to predict compounds' activity and identify their potential targets across diverse organisms. In this study, we aimed to assess the antiplasmodial activity of compounds from the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library using in vitro and bioinformatics approaches. We assessed the in vitro antiplasmodial activity of the compounds using blood-stage and liver-stage drug susceptibility assays. We used protein sequences of known targets of the ReFRAME compounds with high antiplasmodial activity (EC50 < 10 uM) to conduct a protein-pairwise search to identify similar Plasmodium falciparum 3D7 proteins (from PlasmoDB) using NCBI protein BLAST. We further assessed the association between the compounds' in vitro antiplasmodial activity and level of similarity between their known and predicted P. falciparum target proteins using simple linear regression analyses. BLAST analyses revealed 735 P. falciparum proteins that were similar to the 226 known protein targets associated with the ReFRAME compounds. Antiplasmodial activity of the compounds was positively associated with the degree of similarity between the compounds' known targets and predicted P. falciparum protein targets (percentage identity, E value, and bit score), the number of the predicted P. falciparum targets, and their respective mutagenesis index and fitness scores (R2 between 0.066 and 0.92, P < 0.05). Compounds predicted to target essential P. falciparum proteins or those with a druggability index of 1 showed the highest antiplasmodial activity.

Motivating patients towards better recovery after burn: The development of a booklet to reframe perspectives.

INTRODUCTION: Posttraumatic growth after burn results from integrated changes in worldview. It incorporates acceptance, belief in the self, compassion, determination and planning, emotional management and family/friend support. METHOD: The booklet was developed in two phases. In the first phase burn survivors were invited to tell their stories pertaining to their burn recovery experiences. These stories were categorised into the above framework, and presented alongside supporting information from the burn clinical psychologist in an initial draft of the booklet. In the second phase of the study, a combination of one-to-one interviews and a focus group of burn survivors discussed, suggested improvements to the final booklet and evaluated for usefulness and acceptability. RESULTS: A booklet was developed with a blend of patient stories and professional advice to positively reframe, integrate changed perspectives and motivate patients towards better psychological recovery after burn. It was evaluated to be useful and acceptable to new burn patients. CONCLUSION: This booklet, designed to positively reframe perspectives for better psychosocial burn recovery, was developed with patients and evaluated by patients. It was found to be useful and acceptable to new burn patients.

Portrayals of older adults in over 3000 films around the world.

BACKGROUND: Presently, most film analyses related to older adults are peculiar to American cinema. However, film industries outside the United States are influential in their own right. As ageism is a pan-cultural phenomenon, it is important to explore filmic representations of older persons globally. This study is the first to offer a portrait of how filmic portrayals of older persons differ across regions. METHODS: We leveraged a 200-million-word movie corpus comprising over 25,000 scripts from 88 countries in 11 regions. The movies span a period of nearly 90 years, from 1930 to 2018. We identified synonyms of "older adult(s)" and compiled the top descriptors that co-occurred most frequently with them. Seventeen thousand five hundred and eight descriptors were generated from 3384 movies. Using these descriptors, we calculated the valence of filmic portrayals of older adults on a scale of 1 (most negative) to 5 (most positive) in each region. RESULTS: Positive representations of older adults in movies were lacking in all 11 regions. Four regions fell into the neutral zone and the remaining seven in the negative zone. Representations of older persons were the least negative in East Asia and South Asia, and most negative in Southeast Asia as well as the Middle East and North Africa (MENA). Our topic modeling revealed that older adults were portrayed as venerable in both South and East Asia. Meanwhile, older people were associated with death in MENA. The idea that society is ill-equipped to handle an aging population was hinted at in Southeast Asia. CONCLUSIONS: As societies worldwide navigate a major demographic turning point, it is vital that filmmakers rethink portrayals of old age. In articulating the filmic narratives surrounding old age in different regions, our study lays the foundation to combat ageism on the big screen.

A playbook for effective age advocacy on Twitter.

BACKGROUND: Central to raising awareness of ageism are advocacy organizations dedicated to serving the needs and interests of older adults. Although many of these organizations have cultivated an online presence, inquiry into the effectiveness of age advocacy work on social media remains an untapped area. Our foray into this topic explores how different tweet features predict the level of engagement of posts uploaded by age advocacy organizations on Twitter. METHODS: Tweets (N = 403,426) were collected from 53 accounts and spanned 12 years from July 2009 to October 2021. After applying our exclusion criteria, 204,905 tweets were retained for analysis. We analyzed the tweet features (predictors) and engagement level (outcome variable) using a linear mixed-effects model. RESULTS: Tweets with higher engagement are those with a URL, with at least three hashtags, with visuals (GIF, photo, or video), which are quote tweets, and which are posted in the evening or at night Central Standard Time (CST), adjusting for account-level variables (e.g., follower count). Conversely, tweets with more than one mention, which are replies and which are uploaded in the morning are associated with lower engagement. CONCLUSION: The rise of digital media means that advocates have the opportunity to communicate their messages to reach a critical mass. This is the first known study to offer an evidence-informed playbook for age advocacy organizations to optimize outreach efforts by maximizing online engagement. These results represent a crucial step in ongoing efforts to tackle ageism, an issue that has long been under-discussed.

Holding Their Own and Being Resilient: Narratives of Parents over the First 12 Months of Their Child Having Tracheostomy.

Caring for a child with a tracheostomy can be challenging for parents and learning to safely manage their child's airway can be frightening due to their child's breathing issues, complex diagnosis and the difficult decisions they have to make. The aim of this longitudinal narrative study was to tell the stories of parents whose child had a new tracheostomy. Twenty three narrative interviews were conducted with twelve parents from nine families at three time points over a 12 month period. Data were analyzed using a socio-narratological approach. The stories told how parents were able to 'hold their own' despite experiencing shock, emotional upheaval and uncertainty during the period of their child's surgery. 'Holding their own' was possible for parents because resilience played an important part of their journey. Parents continued to be resilient as they adapted to being at home and dealt with ongoing challenging and stressful circumstances. All of the parents told stories reflecting on and recognizing that there were times when they exhibited higher levels of resilience and times when their resilience was lower. Looking back on their experiences parents appreciated that they reframed their initial often negative views about their child's need for a tracheostomy into more positive understandings and a future orientated perspective.

Screening the CALIBR ReFRAME Library in Search for Inhibitors of Candida auris Biofilm Formation.

Candida auris is an emerging yeast which, since its first isolation about a decade ago, has spread rapidly and triggered major infectious outbreaks in health care facilities around the world. C. auris strains often display resistance to clinically-used antifungal agents, contributing to high mortality rates. Thus, there is an urgent need for new antifungals to contain the spread of this emerging multi-drug resistant pathogen and to improve patient outcomes. However, the timeline for the development of a new antifungal agent typically exceeds 10­15 years. Thus, repurposing of current drugs could significantly accelerate the development and eventual deployment of novel therapies for the treatment of C. auris infections. Toward this end, in this study we have profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules in search for known molecules with antifungal activity against C. auris; more specifically, those capable of inhibiting C. auris biofilm formation. From this library, 100 compounds displaying antifungal activity were identified in the initial screen, including 26 compounds for which a dose-response relationship with biofilm-inhibitory activity against C. auris could be confirmed. Of these, five were identified as the most interesting potential repositionable candidates. Due to their known pharmacological and human safety profiles, identification of such compounds should allow for their accelerated preclinical and clinical development for the treatment of C. auris infections.

Identification of Inhibitors of ZIKV Replication.

Zika virus (ZIKV) was identified in 1947 in the Zika forest of Uganda and it has emerged recently as a global health threat, with recurring outbreaks and its associations with congenital microcephaly through maternal fetal transmission and Guillain-Barré syndrome. Currently, there are no United States (US) Food and Drug Administration (FDA)-approved vaccines or antivirals to treat ZIKV infections, which underscores an urgent medical need for the development of disease intervention strategies to treat ZIKV infection and associated disease. Drug repurposing offers various advantages over developing an entirely new drug by significantly reducing the timeline and resources required to advance a candidate antiviral into the clinic. Screening the ReFRAME library, we identified ten compounds with antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV). Moreover, we showed the ability of these ten compounds to inhibit influenza A and B virus infections, supporting their broad-spectrum antiviral activity. In this study, we further evaluated the broad-spectrum antiviral activity of the ten identified compounds by testing their activity against ZIKV. Among the ten compounds, Azaribine (SI-MTT = 146.29), AVN-944 (SI-MTT = 278.16), and Brequinar (SI-MTT = 157.42) showed potent anti-ZIKV activity in post-treatment therapeutic conditions. We also observed potent anti-ZIKV activity for Mycophenolate mofetil (SI-MTT = 20.51), Mycophenolic acid (SI-MTT = 36.33), and AVN-944 (SI-MTT = 24.51) in pre-treatment prophylactic conditions and potent co-treatment inhibitory activity for Obatoclax (SI-MTT = 60.58), Azaribine (SI-MTT = 91.51), and Mycophenolate mofetil (SI-MTT = 73.26) in co-treatment conditions. Importantly, the inhibitory effect of these compounds was strain independent, as they similarly inhibited ZIKV strains from both African and Asian/American lineages. Our results support the broad-spectrum antiviral activity of these ten compounds and suggest their use for the development of antiviral treatment options of ZIKV infection.

The ReFRAME library as a comprehensive drug repurposing library to identify mammarenavirus inhibitors.

Several mammarenaviruses, chiefly Lassa virus (LASV) in Western Africa and Junín virus (JUNV) in the Argentine Pampas, cause severe disease in humans and pose important public health problems in their endemic regions. Moreover, mounting evidence indicates that the worldwide-distributed mammarenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen of clinical significance. The lack of licensed mammarenavirus vaccines and partial efficacy of current anti-mammarenavirus therapy limited to an off-label use of the nucleoside analog ribavirin underscore an unmet need for novel therapeutics to combat human pathogenic mammarenavirus infections. This task can be facilitated by the implementation of "drug repurposing" strategies to reduce the time and resources required to advance identified antiviral drug candidates into the clinic. We screened a drug repurposing library of 11,968 compounds (Repurposing, Focused Rescue and Accelerated Medchem [ReFRAME]) and identified several potent inhibitors of LCMV multiplication that had also strong anti-viral activity against LASV and JUNV. Our findings indicate that enzymes of the rate-limiting steps of pyrimidine and purine biosynthesis, the pro-viral MCL1 apoptosis regulator, BCL2 family member protein and the mitochondrial electron transport complex III, play critical roles in the completion of the mammarenavirus life cycle, suggesting they represent potential druggable targets to counter human pathogenic mammarenavirus infections.

Identification of plicamycin, TG02, panobinostat, lestaurtinib, and GDC-0084 as promising compounds for the treatment of central nervous system infections caused by the free-living amebae Naegleria, Acanthamoeba and Balamuthia.

The free-living amebae Naegleria, Acanthamoeba, and Balamuthia cause rare but life-threatening infections. All three parasites can cause meningoencephalitis. Acanthamoeba can also cause chronic keratitis and both Balamuthia and Acanthamoeba can cause skin and systemic infections. There are minimal drug development pipelines for these pathogens despite a lack of available treatment regimens and high fatality rates. To identify anti-amebic drugs, we screened 159 compounds from a high-value repurposed library against trophozoites of the three amebae. Our efforts identified 38 compounds with activity against at least one ameba. Multiple drugs that bind the ATP-binding pocket of mTOR and PI3K are active, highlighting these compounds as important inhibitors of these parasites. Importantly, 24 active compounds have progressed at least to phase II clinical studies and overall 15 compounds were active against all three amebae. Based on central nervous system (CNS) penetration or exceptional potency against one amebic species, we identified sixteen priority compounds for the treatment of meningoencephalitis caused by these pathogens. The top five compounds are (i) plicamycin, active against all three free-living amebae and previously U.S. Food and Drug Administration (FDA) approved, (ii) TG02, active against all three amebae, (iii and iv) FDA-approved panobinostat and FDA orphan drug lestaurtinib, both highly potent against Naegleria, and (v) GDC-0084, a CNS penetrant mTOR inhibitor, active against at least two of the three amebae. These results set the stage for further investigation of these clinically advanced compounds for treatment of infections caused by the free-living amebae, including treatment of the highly fatal meningoencephalitis.