Clinical and Functional Studies of MTOR Variants in Smith-Kingsmore Syndrome Reveal Deficits of Circadian Rhythm and Sleep-Wake Behavior.

Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent 9 MTOR pathogenic variants. We conducted a detailed natural history study and found pathophysiological deficits among individuals with SKS, in addition to the common neurodevelopmental symptoms. These symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, indicative of homeostatic imbalance. To characterize these variants, we developed cell models and characterized their functional consequences. We showed that these SKS variants display a range of mTOR activities and respond to the mTOR inhibitor, rapamycin, differently. For example, the R1480_C1483del variant we identified here and the previously known C1483F are more active than wild-type controls and less responsive to rapamycin. Further, we showed that SKS mutations dampened circadian rhythms and low-dose rapamycin improved the rhythm amplitude, suggesting that optimal mTOR activity is required for normal circadian function. As SKS is caused by gain of function mutations in MTOR, rapamycin was used to treat several patients. While higher doses of rapamycin caused delayed sleep-wake phase disorder in a subset of patients, optimized lower doses improved sleep. Our study expands the clinical and molecular spectrum of SKS and support further studies for mechanism-guided treatment options to improve sleep-wake behavior and overall health.

Risk of Hemorrhagic Transformation after Mechanical Thrombectomy without versus with IV Thrombolysis for Acute Ischemic Stroke: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

BACKGROUND: When treating acute ischemic stroke due to large-vessel occlusion, both mechanical thrombectomy and intravenous (IV) thrombolysis carry the risk of intracerebral hemorrhage. PURPOSE: This study aimed to delve deeper into the risk of intracerebral hemorrhage and its subtypes associated with mechanical thrombectomy with or without IV thrombolysis to contribute to better decision-making in the treatment of acute ischemic stroke due to large-vessel occlusion. DATA SOURCES: PubMed, EMBASE, and Scopus databases were searched for relevant studies from inception to September 6, 2023. STUDY SELECTION: The eligibility criteria included randomized clinical trials or post hoc analysis of randomized controlled trials that focused on patients with acute ischemic stroke in the anterior circulation. After screening 4870 retrieved records, we included 9 studies (6 randomized controlled trials and 3 post hoc analyses of randomized controlled trials) with 3241 patients. DATA ANALYSIS: The interventions compared were mechanical thrombectomy + IV thrombolysis versus mechanical thrombectomy alone, with the outcome of interest being any form of intracerebral hemorrhage and symptomatic intracerebral hemorrhage after intervention. A common definition for symptomatic intracerebral hemorrhage was pooled from various classification systems, and subgroup analyses were performed on the basis of different definitions and anatomic descriptions of hemorrhage. The quality of the studies was assessed using the revised version of Cochrane Risk of Bias 2 assessment tool. Meta-analysis was performed using the random effects model. DATA SYNTHESIS: Eight studies had some concerns, and 1 study was considered high risk. Overall, the risk of symptomatic intracerebral hemorrhage was comparable between mechanical thrombectomy + IV thrombolysis and mechanial thrombectomy alone (risk ratio, 1.24 [95% CI, 0.89-1.72]; P = .20), with no heterogeneity across studies. Subgroup analysis of symptomatic intracerebral hemorrhage showed a non-significant difference between 2 groups based on the National Institute of Neurological Disorders and Stroke (P = .3), the Heidelberg Bleeding Classification (P = .5), the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (P = .4), and the European Cooperative Acute Stroke Study III (P = .7) criteria. Subgroup analysis of different anatomic descriptions of intracerebral hemorrhage showed no difference between the 2 groups. Also, we found no difference in the risk of any intracerebral hemorrhage between two groups (risk ratio, 1.10 [95% CI, 1.00-1.21]; P = .052) with no heterogeneity across studies. LIMITATIONS: There was a potential for performance bias in most studies. CONCLUSIONS: In this systematic review and meta-analysis, the risk of any intracerebral hemorrhage and symptomatic intracerebral hemorrhage, including its various classifications and anatomic descriptions, was comparable between mechanical thrombectomy + IV thrombolysis and mechanical thrombectomy alone.

Chirped Laser Pulse Control of Vibronic Wavepackets and Energy Transfer in Phycocyanin 645.

Photosynthetic organisms use light-harvesting complexes to increase the spectrum of light that they absorb from solar photons. Recent ultrafast spectroscopic studies have revealed that efficient (sub-ps) energy transfer is mediated by vibronic coherence in the phycobiliprotein phycocyanin 645 (PC645). Here, we report studies that employ broadband pump-probe spectroscopy with linearly chirped excitation pulses to further investigate the relationship between vibronic state preparation and energy transfer dynamics in PC645. Negatively chirped pulse excitation is found to enhance wavepackets of a high-frequency mode (1580 cm-1) and increase the rate of downhill energy transfer, while on the other hand, positively chirped pulses suppress these oscillatory features and decrease this rate. Model calculations incorporating the influence of the chirped pump pulse are used to understand its effect on initial state preparation. These results provide mechanistic insight into how the overall nonequilibrium rate of energy transfer is influenced by initial state preparation.

Can the Necrophagous Blow Fly Calliphora vicina (Diptera: Calliphoridae) Be Reared on Plant-Based Meal?

The use of the blow fly Calliphora vicina as a potential pollination species to augment the current reliance on honeybees (Apis mellifera) in Australian horticulture requires knowledge of how best to mass-rear this fly species. Calliphora vicina lays eggs onto carrion soon after death, and the resultant larvae that hatch are necrophagous and feed on the decomposing tissues of the dead animal. Newly hatched larvae of this fly were provided with plant-based meals (soya bean and canola) and compared with larvae provided with livestock-derived meatmeal to determine if plant-based meal could be used to mass-rear this blow fly species. Both soya bean and canola meal media did not support larval survival through to adult emergence. The addition of only 10% whole egg powder to the plant-based meals enabled survival to eclosion of 39% and 13% on soya bean and canola-based media, respectively, compared with 76% on livestock-based meatmeal with 10% whole egg powder. Larvae fed a diet of livestock-based meatmeal with 10% whole dried egg powder had the fastest development to the pupal stage, the highest pupation rate, the heaviest pupae, and the highest subsequent adult eclosion. This study concluded that the use of plant-based meals as a diet for the mass-rearing of the blow fly C. vicina was not a viable option.

Australian Marine and Terrestrial Streptomyces-Derived Surugamides, and Synthetic Analogs, and Their Ability to Inhibit Dirofilaria immitis (Heartworm) Motility.

A bioassay-guided chemical investigation of a bacterium, Streptomyces sp. CMB-MRB032, isolated from sheep feces collected near Bathurst, Victoria, Australia, yielded the known polyketide antimycins A4a (1) and A2a (2) as potent inhibitors of Dirofilaria immitis (heartworm) microfilaria (mf) motility (EC50 0.0013-0.0021 µg/mL), along with the octapeptide surugamide A (3) and the new N-methylated analog surugamide K (4). With biological data suggesting surugamides may also exhibit activity against D. immitis, a GNPS molecular network analysis of a library of microbes sourced from geographically diverse Australian ecosystems identified a further five taxonomically and chemically distinct surugamide producers. Scaled-up cultivation of one such producer, Streptomyces sp. CMB-M0112 isolated from a marine sediment collected at Shorncliff, Qld, Australia, yielded 3 along with the new acyl-surugamides A1-A4 (5-8). Solid-phase peptide synthesis provided additional synthetic analogs, surugamides S1-S3 (9-11), while derivatization of 3 returned the semi-synthetic surugamide S4 (12) and acyl-surugamides AS1-AS3 (13-15). The natural acyl-surugamide A3 (7) and semi-synthetic acyl-surugamide AS3 (15) were shown to selectively inhibit D. immitis mf motility (EC50 3.3-3.4 µg/mL), however, unlike antimycins 1 and 2, were inactive against the gastrointestinal nematode Haemonchus contortus L1-L3 larvae (EC50 > 25 µg/mL) and were not cytotoxic to mammalian cells (human colorectal carcinoma SW620, IC50 > 30 µg/mL). A structure-activity relationship (SAR) study on the surugamides 3-15 revealed that selective acylation of the Lys3-ε-NH2 correlates with anthelmintic activity.

Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance.

Receptor tyrosine kinases (RTKs) control stem cell maintenance vs. differentiation decisions. Casitas B-lineage lymphoma (CBL) family ubiquitin ligases are negative regulators of RTKs, but their stem cell regulatory roles remain unclear. Here, we show that Lgr5+ intestinal stem cell (ISC)-specific inducible Cbl-knockout (KO) on a Cblb null mouse background (iDKO) induced rapid loss of the Lgr5 Hi ISCs with transient expansion of the Lgr5 Lo transit-amplifying population. LacZ-based lineage tracing revealed increased ISC commitment toward enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro, Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single-cell RNA sequencing in organoids identified Akt-mTOR (mammalian target of rapamycin) pathway hyperactivation upon iDKO, and pharmacological Akt-mTOR axis inhibition rescued the iDKO defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine-tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation.

New records of helminth infections in Bothrops atrox Linnaeus, 1758 from Marajó Island-Brazil and a literature review with a check list of helminths infecting Bothrops species (Squamata, Viperidae) in the neotropical region.

Snakes of the genus Bothrops inhabit tropical forests in Central and South America and are important for the biomedical and pharmaceutical industries because of the chemical properties of their venom. They serve as either definitive or intermediate hosts for many parasitic helminths. The Marajó Island (Brazil) is the natural habitat of venomous snakes, Bothrops atrox and Bothrops marajoensis, which are often found around rural and peri-urban areas and are known to bite humans. Samples of helminths parasitizing the oral cavity, subcutaneous tissues, coelomic cavity, and intestine of four B. atrox from Marajó Island (Pará-Brazil) were collected. The specimens studied were taxonomically classified as trematodes of the species Stycholecitha serpentis, nematodes of the genera Eustrongylides and Camallanus and cystacanths of an acanthocephalan of the genus Centrorhynchus. The aims of the present study were: to record helminths found in B. atrox from the Marajó Island; to discuss their role as definitive, intermediate, or paratenic hosts; and to compile a list of helminths that have been recorded in snakes of the genus Bothrops of the Neotropical region.

Pipeline versus non-pipeline flow diverter treatment for M1 aneurysms: A systematic review and meta-analysis.

BACKGROUND: The flow diversion treatment of aneurysms located distal to the Circle of Willis has recently increased in frequency. We conducted a systematic review and meta-analysis of the clinical and radiological outcomes of flow diverter (FD) embolization in treating M1 aneurysms. METHODS: PubMed, Web of Science, Ovid Medline, Ovid Embase, and Scopus were searched up to May 2024 using the Nested Knowledge platform. We included studies assessing the long-term clinical and radiological outcomes for M1 aneurysms. Results of FDs classified as Pipeline Embolization Devices (PED) versus other types of FDs. Angiographic occlusion rates, ischemic and hemorrhagic complications, and favorable clinic outcomes were included. All data were analyzed using R software version 4.2.2. RESULTS: Thirteen studies with 112 total patients (58 patients for PED and 54 patients for other FD devices) were included in our meta-analysis. The overall adequate (complete + near-complete) occlusion rates were 85.1%. The complete occlusion rate was higher with PED than with other FD devices (72.9% PED and 41.6% for non-PED FDs, respectively, p-value <.01). The ischemic complications were 9.9% and 9.0% for the PED and non-PED groups, respectively (p-value = .89). The overall modified Rankin Scale 0-2 was 100% for the non-PED and 97.1% for the PED group (p-value = .51). In-stent stenosis rate was 7.5% for PED devices compared to 2.6% in the non-PED group (p-value = .35). CONCLUSIONS: This relatively small meta-analysis showed high rates of adequate and complete occlusion in FD treatment of M1 segment aneurysms, with favorable safety profiles. PEDs were associated with higher rates of complete aneurysm occlusion compared to other types of FDs.

Geometric deep learning-guided Suzuki reaction conditions assessment for applications in medicinal chemistry.

Suzuki cross-coupling reactions are considered a valuable tool for constructing carbon-carbon bonds in small molecule drug discovery. However, the synthesis of chemical matter often represents a time-consuming and labour-intensive bottleneck. We demonstrate how machine learning methods trained on high-throughput experimentation (HTE) data can be leveraged to enable fast reaction condition selection for novel coupling partners. We show that the trained models support chemists in determining suitable catalyst-solvent-base combinations for individual transformations including an evaluation of the need for HTE screening. We introduce an algorithm for designing 96-well plates optimized towards reaction yields and discuss the model performance of zero- and few-shot machine learning. The best-performing machine learning model achieved a three-category classification accuracy of 76.3% (±0.2%) and an F 1-score for a binary classification of 79.1% (±0.9%). Validation on eight reactions revealed a receiver operating characteristic (ROC) curve (AUC) value of 0.82 (±0.07) for few-shot machine learning. On the other hand, zero-shot machine learning models achieved a mean ROC-AUC value of 0.63 (±0.16). This study positively advocates the application of few-shot machine learning-guided reaction condition selection for HTE campaigns in medicinal chemistry and highlights practical applications as well as challenges associated with zero-shot machine learning.

Views and opinions of patients with glaucoma and age-related macular degeneration on vision home-monitoring: a UK-based focus group study.

OBJECTIVE: To investigate the views, hopes and concerns of patients living with glaucoma and age-related macular degeneration (AMD) regarding vision home-monitoring. DESIGN: Qualitative study using focus groups and questionnaires. Participants were given three disease-relevant home-monitoring tests to try. The tests consisted of three visual field tests for the glaucoma groups (Melbourne Rapid Fields, Eyecatcher, Visual Fields Fast) and three acuity and/or contrast-sensitivity tests for AMD groups (Alleye, PopCSF, SpotChecks). Focus group data were thematically analysed. SETTING: University meeting rooms in London, UK. PARTICIPANTS: Eight people with glaucoma (five women, median age 74) and seven people with AMD (four women, median age 77) volunteered through two UK-based charities. Participants were excluded if they did not self-report a diagnosis of glaucoma or AMD or if they lived further than a 1-hour travel distance from the university (to ensure minimal travel burden on participants). RESULTS: Six themes emerged from focus groups, the two most frequently referenced being: 'concerns about home-monitoring' and 'patient and practitioner access to results'. Overall, participants believed home-monitoring could provide patients with a greater sense of control, but also expressed concerns, including: the possibility of home-monitoring replacing face-to-face appointments; the burden placed on clinicians by the need to process additional data; struggles to keep up with requisite technologies; and potential anxiety from seeing worrying results. Most devices were scored highly for usability, though several practical improvements were suggested. CONCLUSION: Patients with mild-to-moderate glaucoma/AMD expect vision home-monitoring to be beneficial, but have significant concerns about its potential implementation.

Electrophile Determines Cellular Phenotypes among XPO1-Targeting Small Molecules.

Covalent drug discovery has experienced a renaissance, with numerous electrophilic small molecules recently gaining FDA approval. Many structurally diverse electrophilic small molecules target exportin-1 (XPO1/CRM1) at cysteine 528, including the selective inhibitor of nuclear export (SINE) selinexor, which was FDA-approved as an anticancer agent in 2019. Emerging evidence supports additional pharmacological classes of XPO1 modulators targeting Cys528, including the selective inhibitors of transcriptional activation (SITAs) and probes that induce rapid degradation of XPO1. Here, we analyzed structure-activity relationships across multiple structural series of XPO1 Cys528-targeting probes. We observe that the electrophilic moiety of Cys528-targeting small molecules plays a decisive role in the cellular behavior observed, with subtle changes in electrophile structure being sufficient to convert XPO1-targeting probes to different pharmacological classes. This investigation represents a unique case study in which the electrophile functionality used to target a specific cysteine determines the pharmacological effect among diverse XPO1-targeting small molecules.

Directed evolution of hyperactive integrases for site specific insertion of transgenes.

The ability to deliver large transgenes to a single genomic sequence with high efficiency would accelerate biomedical interventions. Current methods suffer from low insertion efficiency and most rely on undesired double-strand DNA breaks. Serine integrases catalyze the insertion of large DNA cargos at attachment (att) sites. By targeting att sites to the genome using technologies such as prime editing, integrases can target safe loci while avoiding double-strand breaks. We developed a method of phage-assisted continuous evolution we call IntePACE, that we used to rapidly perform hundreds of rounds of mutagenesis to systematically improve activity of PhiC31 and Bxb1 serine integrases. Novel hyperactive mutants were generated by combining synergistic mutations resulting in integration of a multi-gene cargo at rates as high as 80% of target chromosomes. Hyperactive integrases inserted a 15.7 kb therapeutic DNA cargo containing von Willebrand Factor. This technology could accelerate gene delivery therapeutics and our directed evolution strategy can easily be adapted to improve novel integrases from nature.

Systemic lupus erythematosus in Aboriginal and Torres Strait Islander peoples in Australia: addressing disparities and barriers to optimising patient care.

The first inhabitants of Australia and the traditional owners of Australian lands are the Aboriginal and Torres Strait Islander peoples. Aboriginal and Torres Strait Islander peoples are two to four times more likely to have systemic lupus erythematosus (SLE) than the general Australian population. Phenotypically, SLE appears distinctive in Aboriginal and Torres Strait Islander peoples and its severity is substantially increased, with mortality rates up to six times higher than in the general Australian population with SLE. In particular, Aboriginal and Torres Strait Islander peoples with SLE have increased prevalence of lupus nephritis and increased rates of progression to end-stage kidney disease. The reasons for the increased prevalence and severity of SLE in this population are unclear, but socioeconomic, environmental, and biological factors are all likely to be implicated, although there are no published studies investigating these factors in Aboriginal and Torres Strait Islander peoples with SLE specifically, indicating an important knowledge gap. In this Review, we summarise the data on the incidence, prevalence, and clinical and biological findings relating to SLE in Aboriginal and Torres Strait Islander peoples and explore potential factors contributing to its increased prevalence and severity in this population. Importantly, we identify health disparities and deficiencies in health-care provision that limit optimal care and outcomes for many Aboriginal and Torres Strait Islander peoples with SLE and highlight potentially addressable goals to improve outcomes.

Conserved and repetitive motifs in an intrinsically disordered protein drive ⍺-carboxysome assembly.

All cyanobacteria and some chemoautotrophic bacteria fix CO2 into sugars using specialized proteinaceous compartments called carboxysomes. Carboxysomes enclose the enzymes Rubisco and carbonic anhydrase inside a layer of shell proteins to increase the CO2 concentration for efficient carbon fixation by Rubisco. In the ⍺-carboxysome lineage, a disordered and highly repetitive protein named CsoS2 is essential for carboxysome formation and function. Without it, the bacteria require high CO2 to grow. How does a protein predicted to be lacking structure serve as the architectural scaffold for such a vital cellular compartment? In this study, we identify key residues present in the repeats of CsoS2, VTG and Y, which are necessary for building functional ⍺-carboxysomes in vivo. These highly conserved and repetitive residues contribute to the multivalent binding interaction and phase separation behavior between CsoS2 and shell proteins. We also demonstrate 3-component reconstitution of CsoS2, Rubisco, and shell proteins into spherical condensates, and show the utility of reconstitution as a biochemical tool to study carboxysome biogenesis. The precise self-assembly of thousands of proteins is crucial for carboxysome formation, and understanding this process could enable their use in alternative biological hosts or industrial processes as effective tools to fix carbon.

A nonoscillatory, millisecond-scale embedding of brain state provides insight into behavior.

The most robust and reliable signatures of brain states are enriched in rhythms between 0.1 and 20 Hz. Here we address the possibility that the fundamental unit of brain state could be at the scale of milliseconds and micrometers. By analyzing high-resolution neural activity recorded in ten mouse brain regions over 24 h, we reveal that brain states are reliably identifiable (embedded) in fast, nonoscillatory activity. Sleep and wake states could be classified from 100 to 101 ms of neuronal activity sampled from 100 µm of brain tissue. In contrast to canonical rhythms, this embedding persists above 1,000 Hz. This high-frequency embedding is robust to substates, sharp-wave ripples and cortical on/off states. Individual regions intermittently switched states independently of the rest of the brain, and such brief state discontinuities coincided with brief behavioral discontinuities. Our results suggest that the fundamental unit of state in the brain is consistent with the spatial and temporal scale of neuronal computation.

Workload and spirometry associated with untethered swimming in horses.

BACKGROUND: Swimming has been used empirically for rehabilitation and conditioning of horses. However, due to challenges imposed by recording physiological parameters in water, the intensity of free swimming effort is unknown. OBJECTIVES: Measure the physiological workload associated with untethered swimming in horses. Five fit Arabian endurance horses were assessed while swimming in a 100 m-long indoor pool. Horses were equipped with a modified ergospirometry facemask to measure oxygen consumption (V̇O2) and ventilatory parameters (inspired/expired volumes, VI, VE; peak inspiratory/expiratory flows, PkVI, PkVE; respiratory frequency, Rf; minute ventilation, VE; inspiratory/expiratory durations and ratios, tI, tE, tI/ttot, tE/ttot); and an underwater electrocardiogram that recorded heart rate (HR). Postexercise venous blood lactate and ammonia concentrations were measured. Data are reported as median (interquartile ranges). RESULTS: Horses showed bradypnea (12 breaths/min (10-16)) for the first 30 s of swimming. V̇O2 during swimming was 43.2 ml/(kg.min) (36.0-56.6). Ventilatory parameters were: VI = 16.7 L (15.3-21.8), VE = 14.7 L (12.4-18.9), PkVI = 47.8 L/s (45.8-56.5), PkVE = 55.8 L/s (38.3-72.5), Rf = 31.4 breaths/min (20.0-33.8), VE = 522.9 L/min (414.7-580.0), tI = 0.5 s (0.5-0.6), tE = 1.2 s (1.1-1.6), tI/ttot = 0.3 (0.2-0.4), tE/ttot = 0.7 (0.6-0.8). Expiratory flow tracings showed marked oscillations that coincided with a vibrating expiratory sound. HR was 178.0 bpm (148.5-182.0), lactate = 1.5 mmol/L (1.0-1.9) and ammonia = 41.0 µmol/L (36.5-43.5). CONCLUSIONS: Free (untethered) swimming represents a submaximal, primarily aerobic exercise in horses. The breathing pattern during swimming is unique, with a relatively longer apneic period at the beginning of the exercise and an inspiratory time less than half that of expiration.

Assessment of YouTube Videos in Patient Education for Coronary Artery Disease: A DISCERN-Based Cross-Sectional Analysis.

Introduction Cardiovascular disease has one of the highest mortality rates and continues to grow. Therefore, it is important for the medical community to get involved in widespread patient education efforts. As technology has steadily advanced, YouTube (Google LLC, Mountain View, California, United States) has become a popular source for patients to gather medical information. In this study, we aim to assess the quality of YouTube videos pertaining to coronary artery disease.  Methods We searched the following key terms on June 20, 2023, using the view count filter: coronary artery disease, coronary artery disease treatment, cardiac catheterization, and coronary artery bypass grafting (CABG). The top twenty videos for each keyword were recorded. After videos that were over 20 minutes, non-English, procedural videos without words, and duplicates were excluded, forty-five videos remained. Each video was assessed by three viewers using the DISCERN criteria (http://www.discern.org.uk). Numerical data was averaged into composite scores. Two-sided t-tests and one-way analysis of variance (ANOVA) tests were used to compare mean ratings between groups. A Spearman correlation was done to compare each of the following terms to one another: overall quality of videos, total likes a video received, and total views.  Results The mean ratings for coronary artery disease, coronary artery disease treatment, cardiac catheterization, and CABG were 2.30, 2.60, 2.05, and 2.92, respectively, with an overall mean of 2.42. The means between coronary artery disease and coronary artery disease treatment were significantly different (p adj = 0.01). The overall rating for videos with board-certified physicians was significantly higher than those without a board-certified physician (p < 0.001). There was a low correlation between likes and overall ratings (0.03) and views and overall ratings (-0.068). Conclusion The videos on coronary artery disease, coronary artery disease treatment, cardiac catheterization, and CABG had poor overall quality based on DISCERN criteria. The overall ratings from videos with board physicians are higher than those from non-physicians, suggesting that physicians should be encouraged to create content about important medical conditions. There was also a low correlation between the overall quality of a video and the likes and views, respectively, indicating a disconnect between what the public values and the actual value of a video.

Psoriasis Vulgaris Masked by Tinea Pedis in Two Unhoused Patients.

Psoriasis is a chronic inflammatory disease characterized by clearly marginated silvery plaques that affect men and women equally. Symptoms can vary among individuals; typically, it presents on the scalp, elbows, and knees. We present two cases of patients initially diagnosed with tinea pedis who showed no improvement with medical treatment. The first patient is an African American male in his 50s who arrived at a free clinic for unhoused persons with lesions to both feet initially diagnosed as tinea pedis. Although the patient was compliant with applying topical formulations of tolnaftate and clotrimazole, there was no discernible improvement in his symptoms and the skin lesions. After a thorough examination of the skin throughout the entire body, the diagnosis of psoriasis was considered. The patient started treatment with steroidal cream with improvement of the symptoms and lesions. The second patient is a Caucasian male in his 20s who also presented initially with complaints of a dry, intensely pruritic, and scaly rash on the dorsum of both his feet, as well as in between the digits of his feet for which an initial diagnosis of tinea pedis was also made. The patient remained non-compliant with treatment and, after reevaluation of his lesions along with an extensive survey of his body, was deemed to have psoriasis and prescribed topical hydrocortisone. The patient continued to remain non-compliant with his therapeutic regimen and subsequently developed cellulitis which is yet to resolve with treatment.

PGE2 Regulates the Plasminogen Activator Pathway in Human Endometrial Endothelial Cells: A New In Vitro Model to Investigate Heavy Menstrual Bleeding.

OBJECTIVE: To study the role of PGE2 in regulating plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in human primary endometrial endothelial cells (HEECs) from women with normal menstrual bleeding (NMB) and heavy menstrual bleeding (HMB). DESIGN: In vitro study using endometrial endothelial cells. SETTING: Research laboratory setting. PATIENTS: Women with normal menstrual bleeding (NMB) and heavy menstrual bleeding (HMB) provided endometrial biopsy samples. INTERVENTIONS: PGE2 and PGE2 receptor-selective agonists were administered to cultured HEECs. MAIN OUTCOME MEASURES: Levels of PAI-1 and tPA in NMB-HEECs and HMB-HEECs after treatment with PGE2 and receptor-selective agonists. RESULTS: PGE2 increased total PAI-1 levels in NMB-HEECs, but not in HMB-HEECs, which had higher baseline PAI-1 levels. PTGER1 and PTGER2 agonists increased PAI-1 in NMB-HEECs, while PTGER3 and PTGER4 did not. PGE2 had no effect on tPA levels in either NMB-HEECs or HMB-HEECs. CONCLUSIONS: PGE2, through PTGER1 and PTGER2, regulates the plasminogen activator system in NMB-HEECs, suggesting a role in reducing fibrinolytic activity during normal menstrual cycles. The lack of PGE2 effect and elevated baseline PAI-1 in HMB-HEECs support using this in vitro model to further understand prostaglandin pathways in normal and heavy menstrual bleeding.