Minimal Exposure Research Articles

WCF processing in the L2 curriculum: A look at type of WCF, type of linguistic item, and L2 performance

Whether type of written corrective feedback (WCF) impacts L2 learning has been investigated for decades. While many product-oriented studies report conflicting findings, the paucity of studies adopting both a process-oriented and curricular approach (e.g., Caras, 2019) underscores the call for further research on: a) the processing dimension of L2 writers’ engagement with WCF in this instructed setting (Manchón & Leow, 2020), b) from an ISLA applied perspective (Leow, 2019a; Leow & Manchón, 2022), and c) any potential relationship with subsequent performances. Also, whether type of linguistic item (e.g., morphological vs. syntactic) plays a role in the processing dimension also warrants further probing. This preliminary quasi-experimental study explored the cognitive processes of 10 adult L2 writers with minimal previous exposure to Spanish interacting with WCF (both direct and metalinguistic) on morphological and syntactic errors. Think aloud data gathered from three compositions written within the natural writing conditions of a foreign language curriculum were transcribed, coded for depth of processing (DoP) (Leow, 2015), and correlated with subsequent performances on the target items. The results revealed: 1) a higher DoP for metalinguistic WCF, 2) differences in processing of linguistic items, 3) similar DoP over time, and 4) a beneficial relationship between DoP and subsequent performances. Recommendations for future research underscore the importance of acknowledging variables within the instructed setting that may impact a pure effect of WCF on L2 development.

Synthetic Strategies for Improving Solubility: Optimization of Novel Pyrazolo[1,5-a]pyrimidine CFTR Activator That Ameliorates Dry Eye Disease.

Dry eye disease (DED) is one of the most prevalent ocular diseases but has limited treatment options. Cystic fibrosis transmembrane conductance regulator (CFTR), a major chloride channel that stimulates fluid secretion in the ocular surface, may pave the way for new therapeutic strategies for DED. Herein, we report the optimization of Cact-3, a potent CFTR activator with poor solubility, to 16d, a potent CFTR activator with suitable solubility for eye drop formulation. Notably, 16d was well distributed in target tissues including cornea and conjunctiva with minimal systemic exposure in rabbit. Topical ocular instillation of 16d significantly enhanced tear secretion and improved corneal erosion in a mouse model of DED. In addition, 16d significantly reduced mRNA expression of pro-inflammatory cytokines including IL-1β, IL-17, and TNF-α and MMP2 in cornea and conjunctiva of DED mice.

The Slit Lamp Examination: An Introduction

Alongside establishing a thorough history, the slit lamp examination forms the foundation of an ophthalmology consultation. Prior to ophthalmology placements, medical students and junior doctors have minimal exposure to the slit lamp microscope despite its value in visualising the eye and identifying ocular pathology. Understanding the structure and function of the slit lamp microscope is fundamental to carrying out an effective examination.

The impact of minimal exposure to affective information on mood and its moderation by prime visibility: a meta-analysis

ABSTRACT This article presents a meta-analysis of the impact of minimal exposure to affective stimuli on the emergence of enduring conscious affective feelings. Theories often assume that such affective feelings are linked to automatic appraisals of events (i.e. in the absence of an evaluative processing goal). However, few studies have tested this hypothesis. Moreover, they have provided divergent results. We propose a meta-analysis of these studies to get a clearer picture on this issue. The meta-analysis includes 22 studies (37 effect sizes; combined N = 2159) in which participants were repeatedly exposed to affective stimuli in the absence of an evaluative processing goal before their mood was measured. In this analysis, we focused on the type of stimulus presentation (i.e. visible vs. masked) as well as on the type of stimulus (i.e. faces, pictures, words). The results indicate that the effect of a stimulus is moderated by the visibility of the stimuli. Repeated exposure to visible stimuli leads to congruency effects (i.e. positive stimuli lead to positive feelings), whereas exposure to masked stimuli leads to contrast effects (i.e. positive stimuli lead to negative feelings). Moreover, these effects seem to be restricted to some types of stimuli, with no detectable effects of emotional faces.

<p>Electronic Currency and Its Impact On Market Fluctuations For The Purpose Of Reducing Product Costs: Analytical Study</p>

To prevent counterfeiting, control supply, and ensure the legitimacy of asset transfers, e-currency makes use of cryptography. The primary focus is on the profitability and volatility of Bitcoin trading. The volatility of an investment can be estimated by calculating its standard deviation in terms of logarithmic returns. The researchers in this study employed the specific test to check for data normality. The results of a plot, a statistical process control chart, and other analyses all pointed to significant fluctuations. More and more people place a premium on uncertainty. Investors are wary of Bitcoin at the moment due to its extreme price swings. This research was conducted to provide a framework for achieving optimal returns with minimal exposure to loss on the part of investors.

Panton-Valentine leucocidin-producing Staphylococcus aureus: a clinical review.

Panton-Valentine leucocidin (PVL) is a virulence factor produced by certain strains of Staphylococcus aureus (SA). Through its cytolytic action on the cell membranes of human polymorphonuclear neutrophils, PVL causes a range of pathologies collectively known as PVL-SA disease. The hallmark clinical signs of PVL-SA are recurrent boils and necrotizing skin and soft tissue infections (SSTIs) in otherwise healthy patients; however, it can lead to more severe and invasive presentations, including necrotizing haemorrhagic pneumonia, necrotizing fasciitis and purpura fulminans. Young adults with minimal previous exposure to healthcare settings tend to be at highest risk for acquiring PVL-SA disease, with close physical contact playing a central role in disease transmission. The prevalence of PVL-SA varies globally; however, this is often underestimated owing to a lack of routine PVL testing. In the UK, PVL-positive SA isolates have been rising over the past decade alongside an increasing prevalence of multidrug resistance in larger cities. This review article aims to raise awareness of the PVL toxin, to aid clinicians with diagnostic pointers and to provide guidance with treatment, with an emphasis on the need for further population-based studies.

Teaching artificial intelligence as a fundamental toolset of medicine

Artificial intelligence (AI) is transforming the practice of medicine. Systems assessing chest radiographs, pathology slides, and early warning systems embedded in electronic health records (EHRs) are becoming ubiquitous in medical practice. Despite this, medical students have minimal exposure to the concepts necessary to utilize and evaluate AI systems, leaving them under prepared for future clinical practice. We must work quickly to bolster undergraduate medical education around AI to remedy this. In this commentary, we propose that medical educators treat AI as a critical component of medical practice that is introduced early and integrated with the other core components of medical school curricula. Equipping graduating medical students with this knowledge will ensure they have the skills to solve challenges arising at the confluence of AI and medicine.

Delayed management of paediatric burn sepsis resulting in limb loss

Primary health care centres, community health centres and district hospitals often have medical staff that have minimal exposure to paediatric patients. This may contribute to the challenge of recognising a critically ill paediatric patient. It is already a difficult task as many clinicians are not comfortable or well equipped to manage burn patients, even in regional or tertiary facilities. Identification of the systemic inflammatory response syndrome (SIRS) versus sepsis is difficult in burns owing to the clinical presentation. Identifying the clinical signs determines the need for immediate treatment (i.e., fluid resuscitation) no matter the cause. Investigations will follow to determine the cause, further management and response to treatment. These two cases illustrate the deficit in skill and knowledge in the identification of the sick burninjured child. Although telemedicine has made large advances in allowing access to expert advice in remote locations, its usefulness is dependent on the clinical signs being identified and adequately portrayed to the expert. The way forward is better undergraduate and postgraduate training in this area with an emphasis on clinical acumen.

Patterns of Adverse Childhood Experiences Predict Event-Related Distress in Young Adults Following the 2016 Presidential Election

Adverse childhood experiences (ACEs) and sociopolitical stressors have negative consequences for young adults’ mental health. The current study examined how patterns of ACEs were associated with event-related clinical distress following the 2016 United States presidential election and tested whether difficulties in emotion regulation exacerbated ACE effects in 751 young adults. A latent class analysis (LCA) identified four classes of ACE exposure: Minimal Exposure (55.2%), Moderate Household Dysfunction (21.3%), High Verbal and Physical Abuse (17.8%), and Systemic Exposure (5.6%). Young adults in the Systemic Exposure class reported more event-related intrusion symptoms compared to all other classes. Lower levels of difficulty in emotion regulation were protective for classes with lower ACE exposure but were not relevant for classes with higher ACE exposure. Thus, ACEs may occur in unique constellations that have implications for sociopolitical stressors and mental health outcomes in young adulthood.

Use of high-fidelity simulation to ensure inclusivity and equality of international medical graduates

The UK medical profession is becoming increasingly diverse as the number of international medical graduates (IMGs) joining the UK medical workforce increases every year. However, IMGs face a number of significant sociocultural and educational challenges. Recent studies show that IMGs lack insight into the system and lack clarity in relation to the role of a supervisor, career pathways, and medico-legal and ethical issues [1,2]. They exhibit differences in clinical practices and team dynamics. Recent studies suggest the introduction of dedicated induction programs in the form of formal teaching sessions, or tailored online induction for IMGs prior to their first job [1–3]. Most IMGs have minimal exposure to simulation and human factors training with international medical schools favouring more didactic methods of education. We have designed a high-fidelity simulation course with frequently encountered clinical scenarios to improve inclusion and a harmonious transition for the IMGs. This provides an opportunity to familiarise themselves with the healthcare system and team dynamics within the NHS and instils confidence to perform to the best of their ability in their respective roles. The course has been designed specifically tailored to the needs of IMGs who may find it daunting at first to make their place in a completely new system. We employ high-fidelity simulation encompassing multiple frequently encountered clinical scenarios. The scenarios are followed by a debriefing, with a special focus on human factors, interpersonal and communication skills, and understanding of authority gradients. The attendees are also encouraged to reflect on their performance and to participate in the discussion, share their professional opinions, experiences, and cultural influences. The attendees are asked to fill a pre-course and post-course questionnaire. Two pilot courses were conducted with a total of 22 attendees. Pre- and post-course feedback with reflective questions about various aspects of the course was obtained. The scenarios assessed 5 categories, which the IMGs graded on a Likert scale. Pairwise comparison was performed between pre- and post-course feedback, showing a statistically significant increase in confidence levels related to all assessed categories; basic management skills (p <0.001), clinical skills (p=0.006), communication skills (p<0.001), teamwork (p<0.001), and leadership (p<0.001). Based on the positive feedback from attendees we believe that this induction simulation course can greatly help IMGs have a smooth transition into the NHS, and ensure inclusivity by equipping them with confidence, a knowledge of the system, and human factors. 1. Rasquinha M. Difficulties and educational challenges faced by international medical graduates in trust grade roles in the UK. British Journal of Hospital Medicine. 2022;83(4):1–7. 2. Hashim A. Educational challenges faced by international medical graduates in the UK. Advances in Medical Education and Practice. 2017;8:441–445. 3. Emery L, Jackson B, Oliver P, Mitchell C. International graduates’ experiences of reflection in postgraduate training: a cross-sectional survey. BJGP open. 2022.

SP-3164, a Novel Cereblon-Binding Protein Degrader, Shows Activity in Preclinical Lymphoma Models

Background: Targeted protein degradation (TPD) is attracting significant interest given the success of early protein degraders, e.g., lenalidomide and pomalidomide, and TPD's potential advantages over other therapeutic approaches. SP-3164, an oral, next-generation molecular glue, is currently in IND-enabling studies and is expected to enter the clinic in 2023. SP-3164 interacts with the cereblon (CRBN) component of a CRL4 E3 ligase, inducing recruitment of select proteins, i.e., Ikaros (IKZF1) and Aiolos (IKZF3), leading to their ubiquitination and proteasomal degradation. To date, most CRBN-binding compounds, including SP-3164, contain a chiral aminoglutarimide moiety and exist as (S)- and (R)-enantiomers. Studies have shown that in many of these CRBN-binding compounds, it is the (S)-enantiomer that binds to CRBN with increased affinity and thus may be the primary species resulting in the desired protein degradation and anti-cancer activity. However, the (S)- and (R)-enantiomers can chemically interconvert, preventing development of a single enantiomer. SP-3164 was designed using deuterium to stabilize the (S)-enantiomer with the potential for an improved therapeutic profile compared to the clinically studied racemate, avadomide. We previously demonstrated that compared to avadomide, SP-3164 shows increased binding affinity to CRBN, while the deuterium-stabilized (R)-enantiomer (SP-3165) does not bind CRBN at clinically relevant concentrations. Here, we further characterize SP-3164 pharmacological properties compared to avadomide, SP-3165, and lenalidomide, and demonstrate its activity in preclinical lymphoma models. Results: In addition to CRBN binding, efficiency of TPD is another critical parameter. In in vitro studies of diffuse large B cell lymphoma (DLBCL) cell lines of different subtypes (WSU-DLCL2, SU-DHL-5, SU-DHL-10 and U-2932), SP-3164 (500 nM) resulted in greater IKZF1 degradation at 6 hours (Figure 1A), when compared to avadomide (AVA, 1 µM) or lenalidomide (LEN, 10 µM). By contrast, SP-3165 (500 nM) did not result in meaningful IKZF1 depletion, further corroborating the (R)-enantiomer as the inactive species. Pharmacokinetics (PK) of SP-3164, SP-3165, and avadomide were studied in mice. Oral administration of either SP-3164 or SP-3165 resulted in increased exposure to the dosed enantiomer when compared to an equivalent dose of avadomide, and minimal exposure to the other enantiomer, while the elimination half-life of SP-3164 and SP-3165 was approximately half that of the enantiomers of avadomide. Therefore, SP-3164 has the potential to be administered at lower doses in clinic and provide a more flexible dosing regimen compared to avadomide, while still maintaining sufficient exposure for anticancer activity. The in vivo efficacy of SP-3164 for lymphoma was studied in a WSU-DLCL2 mouse xenograft model (Figure 1B). Compared to lenalidomide, SP-3164 exhibited significantly increased tumor growth inhibition (TGI). SP-3164 and avadomide showed similar activity at comparable doses and dosing regimens (SP-3164, 15 mg/kg QD, and avadomide, 30 mg/kg QD). SP-3165 lacked significant anti-cancer effects indicating that the (R)-enantiomer does not contribute to the direct anti-cancer activity of avadomide, as anticipated based on its lack of binding to CRBN. Due to the shorter elimination half-life of SP-3164 compared to avadomide, SP-3164 was also dosed BID. The SP-3164 BID treated group had the largest TGI, suggesting that the in vivo anti-cancer activity may be due to sustained exposure of SP-3164 at the tumor resulting in prolonged reduction of target protein levels. Conclusion: SP-3164 is a novel, CRBN-binding molecular glue with potential attractive therapeutic properties compared to the racemate, avadomide, and to lenalidomide. SP-3164 showed increased IKZF1 degradation efficiency compared to other molecular glues and significant anti-cancer activity as a monotherapy in an in vivo lymphoma mouse xenograft model. Future studies will evaluate SP-3164 efficacy and direct potential combinations to support clinical development of SP-3164 in DLBCL and other non-Hodgkin's lymphomas. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

C-Arm a Useful Tool for Surgeons in Reduction of Zygomatic Complex Fracture: A Comparative Study: Article Type-Original Research.

Reduction of zygomaticomaxillary (ZMC) fracture is often difficult to evaluate intraoperatively because of it peculiar anatomy and limited accessibility. The purpose of this study is to evaluate the efficacy of use of C-arm as a tool for intraoperative monitoring of ZMC fracture reduction. Group I (C-Arm) and Group II (control group) comprised of patients with isolated unilateral displaced Zygomatic complex (ZMC) fractures and having orbital volume change. The efficacy of use of C-arm intra-operatively was evaluated to analyse the reduction of fracture. It was observed that mean change in ocular volume was around 1.07cm2 for Group I and 1.51cm2 in Group II. Thus post-operative eye volume was near to normal in Group I than Group II. The change in ocular volume post-operatively was observed to be statistically significant (p-value < 0.05) in both the groups. Post HOC Tukey statistical analysis determined the intergroup relation in change in eye volume between normal, pre- and post-operative and was found to be statistically significant (p-value < 0.05). The intergroup comparison between Group I and Group II was done using ANOVA statistical analysis and was found to be statistically significant (p-value < 0.05). Our study revealed that C-arm is definitively an effective tool in the oral and maxillofacial surgery armamentarium, giving better results with minimal surgical exposure and by eliminating operator related error. The online version contains supplementary material available at 10.1007/s12070-022-03221-y.

Heschl's gyrus duplication pattern and clinical characteristics in borderline personality disorder: A preliminary study.

Inter-individual variations in the sulco-gyral pattern of Heschl's gyrus (HG) might contribute to emotional processing. However, it remains largely unknown whether borderline personality disorder (BPD) patients exhibit an altered HG gyrification pattern, compared with healthy individuals, and whether such a brain morphological feature, if present, might contribute to their clinical characteristics. The present study used magnetic resonance imaging to investigate the distribution of HG gyrification patterns (single or duplicated) and their relationship to clinical characteristics in teenage BPD patients with minimal treatment exposure. No significant difference was noted for the prevalence of HG patterns between 20 BPD and 20 healthy participants. However, the BPD participants with left duplicated HG were characterized by higher prevalence of comorbid disruptive behavior disorders, with higher externalizing score compared with those with left single HG. Our preliminary results suggest that neurodevelopmental pathology associated with gyral formation might be implicated in the neurobiology of early BPD, especially for emotional and behavioral control.

SUCCESSFUL TREATMENT OF SOLAR URTICARIA WITH OMALIZUMAB

<h3>Introduction</h3> Solar urticaria is a rare condition characterized by the development of hives upon exposure to sunlight. Treatment is challenging, usually involving antihistamines and sun avoidance. Recent case series suggest a role for omalizumab, an anti-IgE monoclonal antibody, in treating this disease. <h3>Case Description</h3> A 43-year-old woman with no significant medical history presented with a 10-year history of urticaria within minutes of sunlight exposure. She avoided being outdoors, but developed urticaria even with minimal exposure, such as sitting near a window. She denied any other triggers or associated angioedema. She trialed first- and second-generation antihistamines and montelukast, with minimal effect. Antihistamine use was limited by sedation, which was unacceptable given her work as a radiologist. She initiated omalizumab 300 mg by subcutaneous injection every 28 days. By the third dose, she experienced near complete remission. She could spend upwards of 1 hour in sunlight, with few or no hives. She reported a marked improvement in quality of life, being able to exercise outdoors and engage in social activities. <h3>Discussion</h3> The decision to use omalizumab was informed by the intolerable side effects of antihistamines and the inability to fully avoid sunlight. Her near complete response to omalizumab is notable, as most patients reported in the current literature only experienced a partial response with omalizumab, even at high doses. Omalizumab may be considered for patients with solar urticaria unable to use antihistamines, or with a low threshold for developing lesions. Importantly, omalizumab therapy may help in improving quality of life given the substantial burden of this disease.

Cultural Pride: Exploring Indigenous athlete culture and wellbeing

Indigenous people are over-represented as professional players in many sporting codes, and recently a trend has developed whereby Indigenous athletes are choosing to play internationally for their heritage nations as opposed to the top-tier countries they reside in. With regard to rugby league and rugby union, many of these athletes are Pasifika who have had minimal exposure to their heritage nations, being born and raised in, for example, Aotearoa New Zealand, Australia or the United States. Nevertheless, this cohort is increasingly choosing to play for their heritage nations, despite the substantial cut in pay and available resources this decision entails. Throughout this commentary, these athletes are not viewed as mere individuals. Instead, we acknowledge their relationality—that is, the fact that they are intertwined in collective networks of family and nationhood. As researchers from the Pasifika community, we explore the factors which contribute to Pasifika athletes choosing to play for their heritage nations. By analysing the rise of Mate Ma‘a Tonga, Tonga’s national rugby league team, we aim to gain a deeper understanding of the cultural pride—the connection to family and heritage nation—that drives these athletes to play for this team, and the subsequent implications for wellbeing and performance.

Evaluation of antibacterial oxygen/ozone mixture in vitro activity on bacteria isolated from cervico-vaginal mucus of cows with acute metritis

Ozone is an oxidating gas showing a strong microbicidal activity on bacteria, fungi, viruses and protozoa. The aim of this study was to test the in vitro bacteriocidal action of an Ozone/Oxygen gas mixture on bacteria isolated from the cervico-vaginal mucus of cows affected by acute metritis. A pilot study was initially carried out on reference strains (Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and Mycoplasma bovigenitalium ATCC 19852) that were tested with three different treatments: a control positive baseline group (B-group) was incubated without gas treatment, a control positive oxygen group (O2-group) was treated with pure oxygen 100%, and the treated group (T-group) was exposed to a gaseous constant flow of an Ozone/Oxygen mixture, at 50, 35, 20 μg Ozone/ml and for 5, 3 and 1 min for every different Ozone concentration. In both positive control groups, the number of colony forming units (CFU) per ml was higher than 300 CFU/ml (E. coli and S. aureus) and higher than 30 CFU/ml for M. bovigenitalium, after incubation. The T-groups showed a minimal bacterial growth equal to or lower than 1 CFU/ml per plate.Based on the results of the pilot study, a second phase was performed on bacteria isolated from the cervico-vaginal mucus (Klebsiella pneumoniae, Enterobacter agglomerans, E. coli, Proteus mirabilis and M. bovigenitalium) using the lower concentration of 20 μg/ml of Ozone for the minimum exposure time of 1 min. The E. coli and S. aureus reference strains and the clinical isolates (K. pneumoniae, E. agglomerans, E. coli, P. mirabilis) were incubated at 37 °C for 48 h and the colonies were manually counted at 24 h and 48 h following inoculation. The cultures of M. bovigenitalium (both ATCC and clinical isolate) were incubated in a jar with modified atmosphere conditions with 5% CO2 at 37 °C for 4–7 days and colony counting was performed. The second phase showed a low number of CFUs (equal to or less than 7 CFU/ml) for the clinical isolates K. pneumoniae, E. agglomerans, E. coli and P. mirabilis, and, of note, for M. bovigenitalium, both ATCC and clinical isolate, the growth was completely inhibited. Ozone was demonstrated to have a bacteriocidal activity. This study encourages further research of in vivo application of low doses of gaseous Ozone for the treatment of metritis in cows by using minimal exposure times.

Donor-derived cell-free DNA as a diagnostic tool in transplantation.

There is a need to improve personalized immunosuppression in organ transplantation to reduce premature graft loss. Biomarkers are needed to better detect rejection, asymptomatic graft injury, and under-immunosuppression. Assessment of minimal necessary exposure to guide tapering and prevent immune activation is also important. There is robust clinical evidence from a large number of published studies supporting the role of dd-cfDNA for monitoring graft integrity and detection or exclusion of rejection. Dd-cfDNA indicates graft cell death without being rejection specific. It can be determined in plasma through droplet digital PCR using preselected SNPs or next generation sequencing. Changes in recipient cfDNA (e.g., by infection) can affect the results of dd-cfDNA fractional determination. This limitation can be overcome using absolute dd-cfDNA quantification. The combination of fractional and absolute determination including total cfDNA is recommended for meaningful interpretation of the results. The value proposition for the patient includes earlier transplant injury detection and intervention, less full blown rejection risk, an alternative to invasive biopsies, and personalized immunosuppression with potential for improved long-term outcome. Transplant physicians benefit from better immunosuppressive guidance and having an alternative when biopsies are refused or contraindicated. Further advantages are improved biopsy interpretation, less trial and error changes in immunosuppression, and less time dealing with complications. The laboratory medicine specialist can provide more effective services. Hospital management and insurance companies could benefit from more cost-effective surveillance of transplant recipients. Potential cost savings would result from fewer biopsies as a result of the tests' high negative predictive value, fewer re-transplantations, and less organ failure with return to dialysis. A pathway to implementation and metrics is suggested to measure the effectiveness of dd-cfDNA testing.

Ocular Distribution and Pharmacokinetics of 8-Oxo-2'-Deoxyguanosine: A Novel Therapeutic Candidate of Ocular Surface Diseases.

Purpose: This study evaluated the ocular distribution and plasma pharmacokinetics (PKs) of 8-oxo-2'-deoxyguanosine (8-oxo-dG) in rabbits and rats, respectively. Methods: A test formulation containing radiolabeled [14 C]8-oxo-dG and unlabeled 8-oxo-dG was ocularly administered to rabbits as a single dose of 1 mg per body and intravenously injected to rats as a single dose of 5 mg/kg. The ocular distribution of [14 C]8-oxo-dG was evaluated using autoradiography until 48 h postdose. Plasma radioactivity in rabbits and rats was determined until 72 and 168 h, respectively. Results: After ocular instillation, [14 C]8-oxo-dG distributed into ocular tissues, and high radioactivity concentrations were observed in the ciliary body, conjunctiva, and cornea. The maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-t) were highest in the ciliary body and conjunctiva, respectively. In the conjunctiva, cornea, and aqueous humor, time to reach Cmax (Tmax) was 0.5 h, and the half-lives were 11.2, 30.2, and 15.1 h, respectively. The radioactivity of [14 C]8-oxo-dG in plasma of rabbits displayed a double-peak phenomenon with the second peak considered as Cmax (37.9 ± 3.1 ng eq./mL) occurring 24 h postdose. After systemic exposure of [14 C]8-oxo-dG in rats, a rapid decline in the initial phase and a terminal half-life of 56.1 ± 31.3 h were observed. Conclusions: Rapid ocular distribution and high concentrations in anterior ocular tissues with minimal systemic exposure were observed after the ocular instillation of 8-oxo-dG in rabbits. These PK profiles are favorable for the treatment of ocular surface diseases.

Polymersome-stabilized doxorubicin-lipiodol emulsions for high-efficacy chemoembolization therapy.

Transarterial chemoembolization (TACE) with free doxorubicin-lipiodol emulsions (free DOX/L) is a favored clinical treatment for advanced hepatocellular carcinoma (HCC) patients ineligible for radical therapies; however, its inferior colloidal stability not only greatly reduces its tumor retention but also hastens drug release into blood circulation, leading to suboptimal clinical outcomes. Here, we find that disulfide-crosslinked polymersomes carrying doxorubicin (Ps-DOX) form super-stable and homogenous water-in-oil microemulsions with lipiodol (Ps-DOX/L). Ps-DOX/L microemulsions had tunable sizes ranging from 14 to 44μm depending on the amount of Ps-DOX, were stable over 2months storage as well as centrifugation, and exhibited nearly zero-order DOX release within 15days. Of note, Ps-DOX induced 2.3-13.4 fold better inhibitory activity in all tested rat, murine and human liver tumor cells than free DOX likely due to its efficient redox-triggered intracellular drug release. Interestingly, transarterial administration of Ps-DOX/L microemulsions in orthotopic rat N1S1 syngeneic HCC model showed minimal systemic DOX exposure, high and long hepatic DOX retention, complete tumor elimination, effective inhibition of angiogenesis, and depleted adverse effects, significantly outperforming clinically used free DOX/L emulsions. This smart polymersome stabilization of doxorubicin-lipiodol microemulsions provides a novel TACE strategy for advanced tumors.

Evaluating Statin Tolerability in Historically Intolerant Patients After Correcting for Subclinical Hypothyroidism and Vitamin D Insufficiency.

Atherosclerotic cardiovascular disease (ASCVD) is the major cause of morbidity and mortality worldwide. Statins provide primary and secondary ASCVD prevention. Intolerance due to statin-associated myalgias reduces long-term adherence, thus muting potential benefits. Our analysis sought to determine whether transition from a lipophilic statin to a water-soluble statin, or correction of subclinical hypothyroidism and/or vitamin D insufficiency/deficiency (metabolic abnormalities), improved statin tolerance. We performed a retrospective analysis of the data from patients referred to our lipid clinic because of statin intolerance. Patients intolerant to a lipophilic statin were switched to a water-soluble statin. Patients having vitamin D insufficiency/deficiency or subclinical hypothyroidism were re-challenged with a water-soluble statin (or lipophilic statin with minimal systemic exposure) after correction of the metabolic abnormality. 169 patients were statin intolerant. 86% (n = 145) were white and 48% (n = 81) were male. 82 of these patients had one or both metabolic abnormalities. The remaining patients (n = 87) had no metabolic abnormality, however, were unable to tolerate a lipophilic statin. 72% (n = 73) of eligible patients (n = 101), defined as those with a corrected metabolic abnormality or without a metabolic abnormality on a lipophilic statin, were able to tolerate a water-soluble statin or lipophilic statin with minimal systemic exposure. In addition, 75% (n = 127) of this total cohort met their LDL-C goal. Our findings suggest that either correction of subclinical hypothyroidism and/or vitamin D insufficiency/deficiency or transition from a lipophilic statin to water-soluble statin (or lipophilic statin with minimal systemic exposure) improves statin tolerance.