Strength of Activation and Temporal Dynamics of BioLuminescent-Optogenetics in Response to Systemic Injections of the Luciferin.

BioLuminescent OptoGenetics ("BL-OG") is a chemogenetic method that can evoke optogenetic reactions in the brain non-invasively. In BL-OG, an enzyme that catalyzes a light producing reaction (i.e., a luciferase) is tethered to an optogenetic element that is activated in response to bioluminescent light. Bioluminescence is generated by injecting a chemical substrate (luciferin, e.g., h-Coelenterazine; h-CTZ) that is catalyzed by the luciferase. By directly injecting the luciferin into the brain, we show that bioluminescent light is proportional to spiking activity, and this relationship scales as a function of luciferin dosage. Here, we build on these previous observations by characterizing the temporal dynamics and dose response curves of bioluminescence generated by luminopsins (LMOs), a proxy of BL-OG effects, to intravenous (IV) injections of the luciferin. We imaged bioluminescence through a thinned skull of mice running on a wheel, while delivering h-CTZ via the tail vein with different dosage concentrations and injection rates. The data reveal a systematic relationship between strength of bioluminescence and h-CTZ dosage, with higher concentration generating stronger bioluminescence. We also found that bioluminescent activity occurs rapidly (< 60 seconds after IV injection) regardless of concentration dosage. However, as expected, the onset time of bioluminescence is delayed as the injection rate decreases. Notably, the strength and time decay of bioluminescence is invariant to the injection rate of h-CTZ. Taken together, these data show that BL-OG effects are highly consistent across injection parameters of h-CTZ, highlighting the reliability of BL-OG as a minimally invasive neuromodulation method.

The TNFΔARE Mouse as a Model of Intestinal Fibrosis.

Crohn disease (CD) is a highly morbid chronic inflammatory disease. Although many patients with CD also develop fibrostenosing complications, there are no medical therapies for intestinal fibrosis. This is due, in part, to a lack of high-fidelity biomimetic models to enhance understanding and drug development, which highlights the need for developing in vivo models of inflammatory bowel disease-related intestinal fibrosis. This study investigates whether the TNFΔARE mouse, a model of ileal inflammation, also develops intestinal fibrosis. Several clinically relevant outcomes were studied, including features of structural fibrosis, histologic fibrosis, and gene expression. These include the use of a new luminal casting technique, traditional histologic outcomes, use of second harmonic imaging, and quantitative PCR. These features were studied in aged TNFΔARE mice as well as in cohorts of numerous ages. At >24 weeks of age, TNFΔARE mice developed structural, histologic, and transcriptional changes of ileal fibrosis. Protein and RNA expression profiles showed changes as early as 6 weeks, coinciding with histologic changes as early as 14 to 15 weeks. Overt structural fibrosis was delayed until at least 16 weeks and was most developed after 24 weeks. This study found that the TNFΔARE mouse is a viable and highly tractable model of ileal fibrosis. This model and the techniques used herein can be leveraged for both mechanistic studies and therapeutic development for the treatment of intestinal fibrosis.

Ulcerated diaper dermatitis: Child abuse mimicker.

Irritant diaper dermatitis is a common dermatologic problem among infants and young children. Severe erosive presentations, although uncommon, are diagnostically challenging and can mimic non-accidental trauma (NAT). Diagnosing inflicted injury and NAT where it does not exist can cause parental distress, yet failing to diagnose inflicted injury and NAT can result in re-injury. We describe three cases of severe erosive diaper dermatitis in pediatric patients aged 2-6 years that were initially concerning for inflicted scald burn or neglect.

Life in a fishbowl: Space and environmental enrichment affect behaviour of Betta splendens.

The public has expressed growing concern for the well-being of fishes, including popular pet species such as the Siamese fighting fish (Betta splendens). In captivity, male Bettas behave aggressively, often causing injuries and death if housed together. As a result, they are typically isolated in small fishbowls, which has been widely criticised as cruel. To investigate the impact of keeping Bettas in these conditions, we recorded the behaviour of individual males in containers of different sizes that were either bare or enriched with gravel, large rocks, and live plants. When male Bettas were housed individually in small bowls (0.5 L) they spent less time swimming than they did when they were kept in larger aquaria (10, 38, and 208 L). Fish that were kept in enriched containers exhibited more instances of swimming. To determine if two male Bettas housed together might coexist peacefully if given enough space and cover from plants and large rocks, we quantified the behaviour of pairs of male Bettas in bare or enriched aquaria of different sizes (10, 38, 208, 378 L). Fish performed fewer approaches and aggressive displays, but not attacks, and more bouts of foraging, when in larger aquaria. This study shows that the small fishbowls typically used in pet stores suppress swimming behaviour in male Bettas and at least a 10-L aquarium is required to ensure full expression of swimming behaviour. Furthermore, even the use of very large aquaria cannot guarantee peaceful cohabitation between two males.

Outcomes of Out-of-Hospital Cardiac Arrest Patients Who Received Naloxone in an Emergency Medical Services System With a High Prevalence Of Opioid Overdose.

BACKGROUND: Opioid-associated out-of-hospital cardiac arrest (OA-OHCA) is a subset of cardiac arrests that could benefit from measures outside of standard Advanced Cardiac Life Support (ACLS), such as naloxone. STUDY OBJECTIVES: In this study, we sought to examine whether OHCA patients chosen for naloxone therapy by emergency medical services (EMS) clinicians in a system with high rates of opioid overdose would have increased rates of return of spontaneous circulation (ROSC) and survival to hospital discharge. METHODS: The study took place in an urban EMS system with a high prevalence of opioid overdose. Paramedics could administer naloxone in cardiac arrest in addition to ACLS. It was often administered based on clinical gestalt for suspected OA-OHCA. The outcomes of OHCA patients who received naloxone were compared against those who received usual care in both an adjusted and unadjusted fashion. Lastly, we created a logistic regression model to test for an independent association of naloxone administration on ROSC and survival to hospital discharge. RESULTS: A consecutive sample of 769 OHCA patients was obtained, of which 175 (23%) received naloxone. On average, patients who received naloxone had significantly fewer comorbidities and were younger. There was no difference in ROSC, survival to hospital discharge, or modified Rankin Scores. Using logistic regression modeling, there was no statistically significant effect of naloxone administration on these outcomes. CONCLUSION: OHCA patients who received naloxone, despite being younger and having fewer comorbidities, had similar outcomes compared to those who received usual care. The difference in baseline characteristics suggests that paramedic gestalt reasonably selected for OA-OHCA.

Race and Ethnicity and the Utilization of Security Responses in a Hospital Setting.

BACKGROUND: Security emergency responses (SERs) are utilized by hospitals to ensure the safety of patients and staff but can cause unintended morbidity. The presence of racial and ethnic inequities in SER utilization has not been clearly elucidated. OBJECTIVE: To determine whether Black and Hispanic patients experience higher rates of SER and physical restraints in a non-psychiatric inpatient setting. DESIGN: Retrospective cohort study. PARTICIPANTS: All patients discharged from September 2018 through December 2019. EXPOSURE: Race and ethnicity, as reported by patients at time of registration. MAIN OUTCOMES: The primary outcome was whether a SER was called on a patient. The secondary outcome was the incidence of physical restraints among patients who experienced a SER. KEY RESULTS: Among 24,212 patients, 18,755 (77.5%) patients identified as white, 2,346 (9.7%) as Black, and 2,425 (10.0%) identified with another race. Among all patients, 1,827 (7.6%) identified as Hispanic and 21,554 (89.0%) as non-Hispanic. Sixty-six (2.8%) Black patients had a SER activated during their first admission, compared to 295 (1.6%) white patients. In a Firth logit multivariable model, Black patients had higher adjusted odds of a SER than white patients (adjusted odds ratio (aOR) 1.37 [95% confidence interval: 1.02, 1.81], p = 0.037). Hispanic patients did not have higher odds of having a SER called than non-Hispanic patients. In a Poisson multivariable model among patients who had a SER called, race and ethnicity were not found to be significant predictors of restraint. CONCLUSION: Black patients had higher odds of a SER compared to white patients. No significant differences were found between Hispanic and non-Hispanic patients. Future efforts should focus on assessing the generalizability of these findings, the underlying mechanisms driving these inequities, and effective interventions to address them.

Impact of Administering Buprenorphine to Overdose Survivors Using Emergency Medical Services.

STUDY OBJECTIVE: To evaluate the efficacy and safety of utilizing emergency medical services units to administer high dose buprenorphine after an overdose to treat withdrawal symptoms, reduce repeat overdose, and provide a next-day substances use disorder clinic appointment to initiate long-term treatment. METHODS: This was a retrospective matched cohort study of patients who experienced an overdose and either received emergency medical services care from a buprenorphine-equipped ambulance or a nonbuprenorphine-equipped ambulance in Camden, New Jersey, an urban community with high overdose rates. There were 117 cases and 123 control patients in the final sample. RESULTS: Compared with a nonbuprenorphine-equipped ambulance, exposure to a buprenorphine-equipped ambulance was associated with greater odds of engaging in opioid use disorder treatment within 30 days of an emergency medical services encounter (unadjusted odds ratio: 5.62, 95% confidence interval, 2.36 to 13.39). Buprenorphine-equipped ambulance engagement did not decrease repeat overdose compared to the comparison group. Patients who received buprenorphine experienced a decrease in withdrawal symptoms. Their clinical opiate withdrawal scale score decreased from an average of 9.27 to 3.16. buprenorphine-equipped ambulances increased on-scene time by 6.12 minutes. CONCLUSION: Patients who encountered paramedics trained to administer buprenorphine and able to arrange prompt substance use disorder treatment after an acute opioid overdose demonstrated a decrease in opioid withdrawal symptoms, an increase in outpatient addiction follow-up care, and showed no difference in repeat overdose. Patients receiving buprenorphine in the out-of-hospital setting did not experience precipitated withdrawal. Expanded out-of-hospital treatment of opiate use disorder is a promising model for rapid access to buprenorphine after an overdose in a patient population that often has limited contact with the health care system.

Addressing the Gap Between Academic Research and Grassroots Public Health Practice: Supporting Policy, Systems, and Environmental Changes in Rural Communities.

Public health practice continues to expand beyond traditional partners to increase reach and impact in communities. This is particularly important in rural communities, who face inequities in the social determinants of health and increased chronic disease burden. However, the capacity for non-traditional community organizations to understand and implement public health work varies widely. Promoting policy, systems, and environmental change strategies (PSE's) is a promising method to support public health in rural communities, due to their variety, flexibility, and potential impact.Using a mixed methods approach to data analysis, we explore the barriers, challenges, and lessons learned from efforts in two rural Appalachian counties to stimulate use of PSE strategies through micro-funding. Several significant barriers were identified: challenges with evaluation and reporting, and lack of understanding and limited utilization of PSE strategies. Successful approaches to overcome these barriers included (1) changing reporting processes to reduce reliance on technology and shift reporting burden from community partners to researchers, (2) adapting data collection to capitalize on strengths of project partners, and (3) abandoning scientific language to embrace more common terminology used in communities. Policy changes were the least utilized strategy. This strategy may be less relevant in rural grassroots organizations with a small staff. Additional research into barriers to policy change is recommended. Enhanced training and support for grassroots, local-level PSE interventions could expand public health promotion in rural areas, reducing rural health disparities.

A Survey of Patient Attitudes Towards Topical Minoxidil in the Treatment of Hair Loss.

Hair loss, specifically androgenetic alopecia (AGA), is a common outpatient dermatology complaint. AGA occurs in men and women, results from the effect of dihydrotestosterone miniaturizing scalp follicles, and commonly presents with thinning of the bitemporal, frontal, and vertex scalp.

Creatine Transporter, Reduced in Colon Tissues From Patients With Inflammatory Bowel Diseases, Regulates Energy Balance in Intestinal Epithelial Cells, Epithelial Integrity, and Barrier Function.

BACKGROUND & AIMS: Patients with inflammatory bowel diseases (IBDs) have intestinal barrier dysfunction. Creatine regulates energy distribution within cells and reduces the severity of colitis in mice. We studied the functions of the creatine transporter solute carrier family 6 member 8 (SLC6A8, also called CRT) in intestinal epithelial cells (IECs) and mice, and we measured levels in mucosal biopsies from patients with IBD. METHODS: Colon biopsy specimens from patients with IBD (30 with Crohn's disease and 27 with ulcerative colitis) and 30 patients without IBD (control individuals) and colon tissues from mice (with and without disruption of Crt) were analyzed by immunofluorescence, immunoblots, and/or quantitative reverse-transcription polymerase chain reaction (qRT-PCR). CRT was knocked down or overexpressed in T84 cells, which were analyzed by immunofluorescence, immunoblots, high-performance liquid chromatography (to measure creatine levels), qRT-PCR, transepithelial electrical resistance, barrier function, actin localization, wound healing, mitochondrial oxygen consumption, and glycolysis extracellular acidification rate assays. Organoids from colon cells of CRT-knockout mice and control mice were analyzed by qRT-PCR, immunoblot, and transepithelial electrical resistance. RESULTS: CRT localized around tight junctions (TJs) of T84 IECs. In analyses of IECs with CRT knockdown or overexpression, we found that CRT regulates intracellular creatine, barrier formation, and wound healing. CRT-knockout organoids also had diminished barrier formation. In the absence of adequate creatine, IECs transition toward a stressed, glycolysis-predominant form of metabolism; this resulted in leaky TJs and mislocalization of actin and TJ proteins. Colon tissues from patients with IBD had reduced levels of CRT messenger RNA compared with those from control individuals. CONCLUSIONS: In an analysis of IEC cell lines and colonoids derived from CRT-knockout mice, we found that CRT regulates energy balance in IECs and thereby epithelial integrity and barrier function. Mucosal biopsy specimens from patients with ulcerative colitis and inactive Crohn's disease have lower levels of CRT, which might contribute to the reduced barrier function observed in patients with IBD.

Distinct and Overlapping Functions of Miscanthus sinensis MYB Transcription Factors SCM1 and MYB103 in Lignin Biosynthesis.

Cell wall recalcitrance is a major constraint for the exploitation of lignocellulosic biomass as a renewable resource for energy and bio-based products. Transcriptional regulators of the lignin biosynthetic pathway represent promising targets for tailoring lignin content and composition in plant secondary cell walls. However, knowledge about the transcriptional regulation of lignin biosynthesis in lignocellulosic feedstocks, such as Miscanthus, is limited. In Miscanthus leaves, MsSCM1 and MsMYB103 are expressed at growth stages associated with lignification. The ectopic expression of MsSCM1 and MsMYB103 in N. benthamiana leaves was sufficient to trigger secondary cell wall deposition with distinct sugar and lignin compositions. Moreover, RNA-seq analysis revealed that the transcriptional responses to MsSCM1 and MsMYB103 overexpression showed an extensive overlap with the response to the NAC master transcription factor MsSND1, but were distinct from each other, underscoring the inherent complexity of secondary cell wall formation. Furthermore, conserved and previously described promoter elements as well as novel and specific motifs could be identified from the target genes of the three transcription factors. Together, MsSCM1 and MsMYB103 represent interesting targets for manipulations of lignin content and composition in Miscanthus towards a tailored biomass.

A Survey of Dermatologists' Preparedness for Natural and Manmade Disasters

Natural and manmade disasters cause a range of dermatologic manifestations, including secondary infections after a flood,1 irritation from blistering agents used in chemical warfare,2 or acute and chronic effects of cutaneous radiation syndrome.3 Recognizing and managing these disaster sequelae require diagnostic acumen, knowledge on reporting, and short- and long-term management strategies. However, a 2003 survey revealed that 88% of dermatologists felt unprepared to respond to a biological attack.4

Is TNF-α Inhibitor-Induced Psoriasiform Dermatitis Always Psoriasiform?

Tumor necrosis factor-α inhibitors (TNFIs) have significantly improved the quality of life for patients with psoriasis and psoriatic arthritis. Despite their beneficial effects, TNFIs have been reported to cause paradoxical 'psoriasiform' eruptions.1 Although this nomenclature has become pervasive in the dermatology lexicon, there is a growing body of literature highlighting the protean clinical presentation of this eruption (Figure 1), which could ultimately lead to a delayed diagnosis.2-5 The diversity of the morphology highlights the importance of identifying key histopathologic characteristics, which to date have not been well-characterized.2

The Influence of Dermatologists' Use of Social Media on Attracting Patients.

BACKGROUND: Many dermatologists consider social media to be a useful tool for building their practices and personal brands. However, limited data exists on patients’ perceptions of the value of social media in dermatology. OBJECTIVE: To examine how social media influences patients when choosing a dermatologist and which aspects of dermatologists’ sites offer the most benefit to patients. METHODS: A cross-sectional study was completed by sampling a diverse online population using a 10-question survey. RESULTS: The survey was sent to 1,481 individuals; of the 57.5% who qualified, 98.5% completed the survey (N=715). Of the qualified respondents, 58% were female and 42% were male. Twenty five percent were 18-29 years, 24% were 30-44 years, 33% were 45-60 years, and 19% were over 60 years. Fifty-seven percent reported that social media is only slightly important or not at all important when selecting a dermatologist. According to respondents, patient reviews (68%), years of experience (61%), and medical information written by the dermatologist (59%) were the most important aspects of dermatologists’ social media sites. Cosmetic patients (P<0.0001), younger patients (P<0.0001), and participants with fewer years of education (P=0.0006) valued social media significantly more when selecting a dermatologist compared to their counterpart populations. LIMITATIONS: Selection bias is possible given the survey was distributed only to SurveyMonkey® users. CONCLUSION: Given the majority of patients reported that social media is not important or only slightly important, dermatologists should consider means other than social media to attract new patients to their practices. For dermatologists who use social media, they should highlight patient reviews, experience level, and original medical content. J Drugs Dermatol. 2020;19(5):   doi:10.36849/JDD.2020.4849.

Hydrogen Peroxide Topical Solution, 40% (w/w) for the Treatment of Seborrheic Keratoses: A Review

HP40 (Eskata™) is a stabilized, topical solution of 40% hydrogen peroxide (H2O2) packaged in an applicator pen that is US FDA-approved to treat seborrheic keratoses (SKs). By harnessing the oxidative capabilities of H2O2 , 1-2 treatments with HP40 produced a higher rate of clearance of four SKs per patient compared to vehicle in two phase 3 trials. The clearance rate was higher for the face than the trunk and extremities. Similarly, the risks of pigmentary changes and scarring from HP40 were lower for the face than other locations. Further, based on an ex vivo study, HP40 may be less cytotoxic to melanocytes than cryotherapy, but clinical trials comparing these therapies are needed. Limitations of HP40 are its low efficacy and requirement of multiple treatments, which can result in elevated costs. The application can also be time-consuming, though extenders or even staff members can apply it. Therefore, HP40 may be better reserved for the treatment of facial SKs.

Cushing's Syndrome in a Pregnant Patient Secondary to Adrenal Adenoma: Treatment With Unilateral Adrenalectomy.

BACKGROUND: A pregnant woman presented with Cushing's syndrome (CS) secondary to adrenal adenoma and was treated with laparoscopic-assisted right adrenalectomy during the second trimester of pregnancy. SUMMARY: Our patient is a 33-year-old woman who presented with hypertension and cushingoid appearance at 21 weeks gestational age. Laboratory evidence indicated CS was likely, and imaging found a 2.3 x 3.0 cm right adrenal nodule as a suggested cause. Laparoscopic-assisted right adrenalectomy was performed at 23 weeks 4 days gestation without complication. Pathology of the removed specimen revealed an adrenal gland containing a 3.0 x 3.0 x 2.0 cm well-circumscribed proliferation of adrenal cortical cells without significant atypia. This report describes the rare occurrence of CS during pregnancy and subsequent successful surgical management. We review the diagnosis of CS during pregnancy and surgical considerations. CONCLUSION: CS, while a rare entity in the general population, is even more unique in the setting of pregnancy due to the negative effects of hypercortisolism on fertility. CS during pregnancy presents a diagnostically complicated scenario, along with specific considerations necessary for successful surgical management.

Hydrogen peroxide and cutaneous biology: Translational applications, benefits, and risks.

Hydrogen peroxide (H2O2) is an endogenous reactive oxygen species that contributes to oxidative stress directly as a molecular oxidant and indirectly through free radical generation. Topically applied 1% to 45% H2O2 can be used for a range of clinical purposes, which will be reviewed here in addition to its safety. In concentrations from 1% to 6%, H2O2 has antimicrobial properties and can act as a debriding agent through its effervescence, making low-concentration H2O2 useful for wound care. H2O2 has also been shown to promote venous insufficiency ulcer healing, but studies in other wound types are needed. In 1% formulations, H2O2 is used outside the United States to treat acne and has shown efficacy similar to or greater than benzoyl peroxide, with reduced side effects. In a concentration of 40%, H2O2 is US Food and Drug Administration-approved to treat seborrheic keratoses and may cause fewer pigmentary changes than cryotherapy, although elimination often requires 2 to 4 treatments. However, H2O2 should be used with caution, as exposure can cause adverse effects through its oxidant capabilities. Low H2O2 concentrations cause only transient symptoms (blanching and blistering), but exposure to 9% to 45% H2O2 can cause more severe skin damage, including epidermal necrosis leading to erythema and bullae. Overall, H2O2 has numerous therapeutic uses, and novel indications, such as treating actinic keratoses and skin cancers, continue to be explored.

Use of In-Office Preparations by Dermatologists for the Diagnosis of Cutaneous Fungal Infections

Cutaneous fungal infections account for millions of office visits per year, yet their varied presentations often lead to misdiagnosis. If dermatology clinics are Clinical Laboratory Improvement Amendment (CLIA) certified, direct microscopy with potassium hydroxide or other stains can be used to inexpensively and rapidly diagnose fungal infections. In this survey, we examined dermatologists' perceptions of fungal preparations and CLIA certification to identify barriers that prevent the use of these bedside diagnostics. The response rate was 13% (n=308, based on the number of emails opened). When a cutaneous fungal infection is suspected, 20.94% rarely/never and 19.86% sometimes perform fungal preparations, often because they think clinical diagnosis is adequate or that preparations take too long. 21.32% reported not having CLIA certification, most frequently because the process requires too much work, or they do not know how to apply. Of providers with CLIA certification, over 25% thought it was difficult to obtain. Our results demonstrate that numerous barriers prevent the common use of fungal preparations, including the perception that clinical diagnosis is sufficient and the lack of required CLIA certification. These barriers emphasize the need for additional education about cutaneous fungal infections and use of bedside diagnostics. Additionally, policy-based interventions are necessary to ease the process of CLIA certification.

Clinical Experience With 40% Hydrogen Peroxide Topical Solution for the Treatment of Seborrheic Keratosis

Despite reassurances about the benign nature of seborrheic keratoses (SKs), patients often request treatment due to cosmetic concerns or for symptomatic relief when SKs become irritated or pruritic. Treatment options include cryotherapy, surgical techniques, and topical therapies. In this study, we present two patients with SKs located on their face and neck who received in-office treatment with 40% Hydrogen Peroxide Topical Solution (Eskata™, HP40), a new FDA-approved topical therapy that has demonstrated efficacy in phase 3 trials. Compared to non-topical, more invasive techniques, HP40 may lead to less pigmentary changes, and may be more efficacious for SKs on the face and neck. Both patients received two treatment courses of HP40, which resulted in positive therapeutic outcomes, including the absence of scarring and pigmentary changes. In addition to the case presentations, we will discuss considerations for appropriate administration of HP40 to maximize clinical outcomes. J Drugs Dermatol. 2019;18(7 Suppl):s173-177.