MyD88 in osteoclast- and osteoblast-lineages differentially controls bone remodeling in homeostasis and malaria.

Chronic bone loss is an under-recognized complication of malaria, the underlying mechanism of which remains incompletely understood. We have previously shown that persistent accumulation of Plasmodium products in the bone marrow leads to chronic inflammation in osteoblast (OB) and osteoclast (OC) precursors causing bone loss through MyD88, an adaptor molecule for diverse inflammatory signals. However, the specific contribution of MyD88 signaling in OB or OC precursors in malaria-induced bone loss remains elusive. To assess the direct cell-intrinsic role of MyD88 signaling in adult bone metabolism under physiological and infection conditions, we used the Lox-Cre system to specifically deplete MyD88 in the OB or OC lineages. Mice lacking MyD88 primarily in the maturing OBs showed a comparable decrease in trabecular bone density by microcomputed tomography (µCT) to that of controls after PyNL infection. In contrast, mice lacking MyD88 in OC precursors showed significantly less trabecular bone loss than controls, suggesting that malaria-mediated inflammatory mediators are primarily controlled by MyD88 in the OC lineage. Surprisingly, however, depletion of MyD88 in OB, but not in OC precursors, resulted in reduced bone mass with decreased bone formation rates in the trabecular areas of femurs under physiological conditions. Notably, IGF-1, a key molecule for OB differentiation, was significantly lower locally and systemically when MyD88 was depleted in OBs. Thus, our data demonstrate an indispensable intrinsic role for MyD88 signaling in OB differentiation and bone formation, while MyD88 signaling in OC lineages plays a partial role in controlling malaria-induced inflammatory mediators and following bone pathology. These findings may lead to the identification of novel targets for specific intervention of bone pathologies, particularly in malaria-endemic regions.

Anti-tumor immunity by transcriptional synergy between TLR9 and STING activation.

Agonists for TLR9 and stimulator of IFN genes (STING) offer therapeutic applications as both anti-tumor agents and vaccine adjuvants, though their clinical applications are limited; the clinically available TLR9 agonist is a weak IFN inducer and STING agonists induce undesired type 2 immunity. Yet, combining TLR9 and STING agonists overcame these limitations by synergistically inducing innate and adaptive IFNγ to become an advantageous type 1 adjuvant, suppressing type 2 immunity, in addition to exerting robust anti-tumor activities when used as a monotherapeutic agent for cancer immunotherapy. Here, we sought to decipher the immunological mechanisms behind the synergism mediated by TLR9 and STING agonists and found that their potent anti-tumor immunity in a Pan02 peritoneal dissemination model of pancreatic cancer was achieved only when agonists for TLR9 and STING were administered locally, and was via mechanisms involving CD4 and CD8 T cells as well as the co-operative action of IL-12 and type I IFNs. Rechallenge studies of long-term cancer survivors suggested that the elicitation of Pan02-specific memory responses provides protection against the secondary tumor challenge. Mechanistically, we found that TLR9 and STING agonists synergistically induce IL-12 and type I IFN production in murine APCs. The synergistic effect of the TLR9 and STING agonists on IL-12p40 was at protein, mRNA and promoter activation levels, and transcriptional regulation was mediated by a 200 bp region situated 983 bp upstream of the IL-12p40 transcription initiation site. Such intracellular transcriptional synergy may hold a key in successful cancer immunotherapy and provide further insights into dual agonism of innate immune sensors during host homeostasis and diseases.

Successful Treatment of Keloids and Hypertrophic Scars With Systemic and Intralesional Dupilumab.

Keloids and hypertrophic scars negatively impact the quality of life for millions of people in the world. Unfortunately, though many thera-peutic approaches are used to treat scars, they are often limited in efficacy with high rates of recurrence. Lately, a better understanding of the immune dysregulation of several dermatologic conditions has led to the emergence of multiple cytokine-targeted therapies for numerous conditions. Several studies have implicated T helper 2 (Th2) immune dysregulation in the development of scars and keloids, with interleukins (IL)-4 and -13 identified as pro-fibrotic mediators. Dupilumab is an IL-4 receptor alpha antagonist that inhibits the ex-pression of both IL-4 and -13. Herein, we describe a 44-year-old woman who developed numerous disfiguring hypertrophic scars and keloids after suffering from a severe herpes zoster infection. Given the number of scars, intralesional corticosteroid injections were not feasible. Therefore, treatment with systemic dupilumab was initiated. Many scars flattened, several even developing a cigarette-paper-like texture due to rapid involution. The largest and most recalcitrant keloid was further treated with intralesional dupliumab injec-tions every 2 weeks with an even more dramatic improvement noted in 2 months. To our knowledge, this is the first report of treating multiple keloids and hypertrophic scars with both systemic and intralesional dupilumab. Dermatologists may want to consider treating keloids that cover a large area with systemic dupilumab, a therapy with an established, reassuring safety profile. The most recalcitrant areas may further benefit from concentrating dupilumab by intralesional delivery. J Drugs Dermatol. 2023;22(12):1220-1222.  doi:10.36849/JDD.6385.

A Target Population Derived Method for Developing a Competency Standard in Radiograph Interpretation.

CONSTRUCT: For assessing the skill of visual diagnosis such as radiograph interpretation, competency standards are often developed in an ad hoc method, with a poorly delineated connection to the target clinical population. BACKGROUND: Commonly used methods to assess for competency in radiograph interpretation are subjective and potentially biased due to a small sample size of cases, subjective evaluations, or include an expert-generated case-mix versus a representative sample from the clinical field. Further, while digital platforms are available to assess radiograph interpretation skill against an objective standard, they have not adopted a data-driven competency standard which informs educators and the public that a physician has achieved adequate mastery to enter practice where they will be making high-stakes clinical decisions. APPROACH: Operating on a purposeful sample of radiographs drawn from the clinical domain, we adapted the Ebel Method, an established standard setting method, to ascertain a defensible, clinically relevant mastery learning competency standard for the skill of radiograph interpretation as a model for deriving competency thresholds in visual diagnosis. Using a previously established digital platform, emergency physicians interpreted pediatric musculoskeletal extremity radiographs. Using one-parameter item response theory, these data were used to categorize radiographs by interpretation difficulty terciles (i.e. easy, intermediate, hard). A panel of emergency physicians, orthopedic surgeons, and plastic surgeons rated each radiograph with respect to clinical significance (low, medium, high). These data were then used to create a three-by-three matrix where radiographic diagnoses were categorized by interpretation difficulty and significance. Subsequently, a multidisciplinary panel that included medical and parent stakeholders determined acceptable accuracy for each of the nine cells. An overall competency standard was derived from the weighted sum. Finally, to examine consequences of implementing this standard, we reported on the types of diagnostic errors that may occur by adhering to the derived competency standard. FINDINGS: To determine radiograph interpretation difficulty scores, 244 emergency physicians interpreted 1,835 pediatric musculoskeletal extremity radiographs. Analyses of these data demonstrated that the median interpretation difficulty rating of the radiographs was -1.8 logits (IQR -4.1, 3.2), with a significant difference of difficulty across body regions (p < 0.0001). Physician review classified the radiographs as 1,055 (57.8%) as low, 424 (23.1%) medium or 356 (19.1%) high clinical significance. The multidisciplinary panel suggested a range of acceptable scores between cells in the three-by-three table of 76% to 95% and the sum of equal-weighted scores resulted in an overall performance-based competency score of 85.5% accuracy. Of the 14.5% diagnostic interpretation errors that may occur at the bedside if this competency standard were implemented, 9.8% would be in radiographs of low-clinical significance, while 2.5% and 2.3% would be in radiographs of medium or high clinical significance, respectively. CONCLUSION(S): This study's novel integration of radiograph selection and a standard setting method could be used to empirically drive evidence-based competency standard for radiograph interpretation and can serve as a model for deriving competency thresholds for clinical tasks emphasizing visual diagnosis.

Heparin induces neutrophil elastase-dependent vital and lytic NET formation.

Heparin is used extensively as an anticoagulant in a broad range of diseases and procedures; however, its biological effects are not limited to coagulation and remain incompletely understood. Heparin usage can lead to the life-threatening complication known as heparin-induced thrombocytopenia (HIT), caused by the development of antibodies against heparin/PF4 complexes. Here, we demonstrate the ability of heparin to induce neutrophil extracellular traps (NETs). NETs occurred with cell lysis and death, but live neutrophils releasing extracellular DNA strands, known as vital NETs, also occurred abundantly. Formation of NETs was time and dose dependent, and required reactive oxygen species and neutrophil elastase. Other compounds related to heparin such as low molecular weight heparin, fondaparinux and heparan sulfate either failed to induce NETs, or did so to a much lesser extent. Our findings suggest the ability of heparin to directly induce NET formation should be considered in the context of heparin treatment and HIT pathogenesis.

The CROWN act and dermatology: Taking a stand against race-based hair discrimination.

Race-based hair discrimination continues to disadvantage people of color who have been sent home from school or dismissed from their jobs on the premise that certain hairstyles, such as dreadlocks and knots, do not meet standards of professionalism. The Create a Respectful and Open World for Natural Hair (CROWN) Act, which was recently passed by several states and the House of Representatives, prohibits such discrimination based on a person's hair texture or hairstyle associated with race. Dermatologists serve a vital role in advocating for the skin and hair needs of all patients, spanning from the personal or clinical encounters level to population-level policy legislation. The act represents a critical opportunity for dermatologists to coalesce and support this important piece of legislation that defends skin of color and the fundamental human right to nondiscrimination.

Expanding the palette of pediatric playthings: A call to action for pediatric dermatologists.

Children recognize race and skin color from a young age. Given the important role of play in the development of children's understanding of social norms and cultural values, it is essential to incorporate toys and other educational materials with diverse skin tones to teach children about race and skin color. Analyses of children's books and toys have shown a lack of diversity in representation of races and skin types. Pediatric dermatologists are uniquely positioned to foster conversations about skin tone and advocating for more diverse materials in classrooms and clinics. In this manuscript, we discuss best practices and resources for facilitating discussions on skin tone with children in the dermatology clinic.

Differences in Utilization of Nonvideo Telemedicine Visits for Dermatologic Concerns in Underserved Populations During the COVID-19 Pandemic.

Background: Usage of telemedicine for virtual dermatology care during the COVID-19 pandemic on a national scale is poorly characterized, particularly for nonvideo encounters. Objective: We sought to compare utilization of telephone and asynchronous virtual care for dermatologic concerns 3 months before (December 2019-February 2020) and during the pandemic (March-May 2020) across patient populations. Methods: A retrospective study was performed using a national claims database with >280 million patients within the COVID-19 Research Database to identify monthly telephone and asynchronous virtual visits by diagnosis, age, income, and patient race/ethnicity. Results: Although overall visits for dermatologic concerns decreased by 27.2% during the pandemic, telephone and asynchronous visits increased significantly. Patients most likely to use telephone visits during the pandemic were of older age (relative risk ratio [RRR] = 1.043, p < 0.001), African American race (RRR = 2.03, p < 0.001), and household income <$29,000 (RRR = 1.51, p < 0.001). Limitations: Racial and ethnic data were available for 39.04% of patients and income data for 38.1% of patients. Conclusions: Underserved populations including African Americans, elderly, and low-income patients were more likely to utilize telephone formats during the pandemic. Further studies are needed to determine the reasons for these observed differences and whether there is differential quality between nonvideo and video telemedicine encounters to ensure that all patients are given equal access to the highest quality of virtual care.

Using Point-of-Care Ultrasound to Characterize Acute Inguinal Swelling of Young Children in the Pediatric Emergency Department.

Acute inguinal swelling in young children is frequently assumed to be an inguinal hernia, often prompting a bedside reduction attempt. We report 3 cases of inguinal swelling where the use of point-of-care ultrasound changed the patients' management by identifying an alternate diagnosis, thus avoiding unnecessary and painful procedures as well as their associated sedation risks.

Rapid Quantification of NETs In Vitro and in Whole Blood Samples by Imaging Flow Cytometry.

Neutrophil extracellular trap (NET) formation involves the release of DNA outside the cell to neutralize pathogens. Techniques such as live microscopy, flow cytometry, and intravital imaging allow the characterization of NETs, but these either cannot be applied in vivo, lack specificity or require invasive procedures. We developed an automated analysis method to rapidly acquire and characterize cells as NETs or NET precursors, as opposed to cells undergoing other forms of cell death, using imaging flow cytometry. NETs were maintained in solution using a novel three-dimensional cell culture system in which cells are suspended at the interface of two liquids of different density. Critically, we identify NETs using an image analysis algorithm based on morphological data showing the extrusion of DNA beyond the cell boundaries. In vitro, we used this technique to demonstrate different requirements for NET formation in human and mouse neutrophils. We also measured NETs in whole blood during infection of mice with the malaria parasite Plasmodium yoelii. We expect this technique will provide a valuable approach to better understand the process of NET formation and its importance in disease. © 2019 International Society for Advancement of Cytometry.

Research: Validity of Measurements when Reusing Icare Probes.

BACKGROUND: It has been reported that reusing Icare tonometer probes may not pose a considerable risk of transmission of infection, thereby supporting this practice under extraordinary circumstances, such as mass glaucoma screenings in developing countries. The present study sought to determine whether reusing the probes reduced the validity of pressure readings. METHODS: Thousands of measurements were made with the same Icare probe on a purpose-built calibration device. A second set of measurements was made during which the Icare probe head was wiped with an alcohol pad between each reading. RESULTS: Statistically different readings were observed between the no-wipe and wipe groups for most of the settings evaluated. In addition, statistically significant readings were noted for a few of the settings as the number of readings increased for either group. However, these differences would not be considered clinically significant. CONCLUSION: This study suggests that reusing Icare tonometer probes, even for hundreds of measurements, would not reduce the clinical utility of the pressure readings. For mass screenings in developing countries where cost savings is crucial, considering the reuse of Icare tonometer probes seems reasonable.

Home Medication Regimens Increase in Complexity After Admission for Fall in the Older Trauma Patient.

BACKGROUND: Hospitalization for the older trauma patient is an opportunity to assess polypharmacy. We hypothesized that medication regimen complexity (RxCS) and pain medication prescriptions (PRxs) would increase in older home-going patients admitted for a fall. METHODS: We retrospectively chart reviewed patients ≥45 years old admitted for a fall at a level 1 trauma center who were discharged home with full medication documentation. RxCS was compared pre-admission and post-discharge with Wilcoxon signed-rank tests; opioid and non-opioid PRxs were compared with Fisher's exact test, α = .05. RESULTS: 103 patients met inclusion criteria; 58% were ≥65 years old. RxCS (9 [.5-13] to 11 [4.5-15], P < .01) increased on discharge. Opioid PRx rates increased significantly in all age groups. Non-opioid PRx rates increased significantly for patients <65 but not for patients ≥65. CONCLUSIONS: Admission for a fall was associated with increases in RxCS, while PRx changes were age-dependent. Providers should recognize that admissions for older patients who fall after trauma are underutilized opportunities to address polypharmacy in high-risk patients.

Global herpes zoster incidence, burden of disease, and vaccine availability: a narrative review.

Herpes zoster (HZ) is a neurocutaneous disease that causes significant morbidity worldwide. The disease is caused by the reactivation of the varicella-zoster virus (VZV), which leads to the development of a painful, vesicular rash and can cause complications such as post-herpetic neuralgia and vision loss. Globally, the incidence of HZ is increasing, and it incurs billions in cost annually to the healthcare system and to society through loss of productivity. With the advent of effective vaccines such as the live attenuated vaccine, Zostavax®, in 2006, and more recently the adjuvant recombinant subunit vaccine, Shingrix®, in 2017, HZ has become a preventable disease. However, access to the vaccines remains mostly limited to countries with developed economies, such as the United States and Canada. Even among countries with developed economies that license the vaccine, few have implemented HZ vaccination into their national immunization schedules due to cost-effectiveness considerations. In this review, we discuss the currently available HZ vaccines, landscape of HZ vaccine guidelines, and economic burden of disease in countries with developed and developing economies, as well as barriers and considerations in HZ vaccine access on a global scale.