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.

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.

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.

Fingertip Injuries in Mask Factory Workers during the COVID-19 Pandemic.

Background: The COVID-19 pandemic has caused a dramatic increase in the demand of face masks. The aim of this study is to look into the demographics, clinical details, clinical outcome and the risk factors for fingertip injuries in mask manufacturing factory workers. Methods: This is a retrospective review of all patients admitted to a regional hospital following a fingertip injury sustained at a mask making factory over a 6-month period from March 2020 to August 2020. Data with regard to gender, age, hand dominance, job position, injured finger, type of injury, mechanism of injury, treatment, clinical outcome (time to return to work), as well as risk factors for injuries (training before work, duration of work before injury, previous experience on working on similar machines, protective measures and working hours) were collected and analysed. Results: There were seven patients in total (M:F = 6:1) with a mean age of 38.4 years. Four patients had injuries on their dominant hands. The most commonly injured finger was the middle finger (n = 3). The most common injury pattern was fingertip amputation (n = 5). Five patients required operative management. Only four patients received training before work and six patients were injured within the first month of work. No patient had previous experience in operating similar machines. Long working hours is also a related risk factor. Conclusions: Better occupational safety and training should be employed to prevent these injuries. Level of Evidence: Level IV (Therapeutic).

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.

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.

Towards gender equity in artificial intelligence and machine learning applications in dermatology.

There has been increased excitement around the use of machine learning (ML) and artificial intelligence (AI) in dermatology for the diagnosis of skin cancers and assessment of other dermatologic conditions. As these technologies continue to expand, it is essential to ensure they do not create or widen sex- and gender-based disparities in care. While desirable bias may result from the explicit inclusion of sex or gender in diagnostic criteria of diseases with gender-based differences, undesirable biases can result from usage of datasets with an underrepresentation of certain groups. We believe that sex and gender differences should be taken into consideration in ML/AI algorithms in dermatology because there are important differences in the epidemiology and clinical presentation of dermatologic conditions including skin cancers, sex-specific cancers, and autoimmune conditions. We present recommendations for ensuring sex and gender equity in the development of ML/AI tools in dermatology to increase desirable bias and avoid undesirable bias.

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.

Providing social support for inpatients: Insights from a virtual medical student initiative.

BACKGROUND: Although the COVID-19 pandemic increased social isolation among hospitalised patients given isolation precautions, visitor restrictions and curtailed interactions with healthcare teams, medical students had limited opportunities for involvement in the care of inpatients. APPROACH: We designed a humanistic and narrative medicine intervention to engage medical students in combating social isolation in hospitalised patients during the COVID-19 pandemic at a tertiary care teaching hospital. In our programme, medical students provided virtual social support to hospitalised patients via phone by providing assistance connecting with family members, having informal conversations and check-ins and writing up patient life narratives. EVALUATION: From April 2020 to March 2021, we received 126 referrals of potentially isolated patients from inpatient medical teams. Fifty patients accepted and received our intervention, including 26 who completed life narratives. Feedback was positive, demonstrating benefit to medical students in learning about humanism and connecting with patients through their life stories. In addition, patients and medical teams felt more supported. We share key operational lessons and resources to facilitate the implementation of this intervention elsewhere. IMPLICATIONS: Our intervention allows medical students to meaningfully contribute to the care of inpatients, support beleaguered inpatient teams and learn important lessons about humanism in medicine. This educational and patient care intervention holds promise in other settings, including beyond the COVID-19 pandemic.

B cell-intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice.

The germinal center (GC) is a site where somatic hypermutation and clonal selection are coupled for antibody affinity maturation against infections. However, how GCs are formed and regulated is incompletely understood. Here, we identified an unexpected role of Tank-binding kinase-1 (TBK1) as a crucial B cell-intrinsic factor for GC formation. Using immunization and malaria infection models, we show that TBK1-deficient B cells failed to form GC despite normal Tfh cell differentiation, although some malaria-infected B cell-specific TBK1-deficient mice could survive by GC-independent mechanisms. Mechanistically, TBK1 phosphorylation elevates in B cells during GC differentiation and regulates the balance of IRF4/BCL6 expression by limiting CD40 and BCR activation through noncanonical NF-κB and AKTT308 signaling. In the absence of TBK1, CD40 and BCR signaling synergistically enhanced IRF4 expression in Pre-GC, leading to BCL6 suppression, and therefore failed to form GCs. As a result, memory B cells generated from TBK1-deficient B cells fail to confer sterile immunity upon reinfection, suggesting that TBK1 determines B cell fate to promote long-lasting humoral immunity.

Physician Perspectives on the Effect of Topical Steroid Costs on Patients and Proposed Solutions.

IMPORTANCE: Rising costs of topical steroids have increased overall health care and patient out-of-pocket costs while increasing administrative burden on dermatologists and office staff. OBJECTIVE: To explore factors affecting the decision-making process for dermatologists around topical steroid prescriptions, determine the association of insurance coverage and cost, and assess willingness to implement solutions to decrease out-of-pocket topical steroid costs for patients. DESIGN, SETTING, AND PARTICIPANTS: This qualitative study was conducted from June to November 2020 and used semistructured interviews of 16 dermatologists who reflected a mix of physicians in academic, nonacademic, and private practice until thematic saturation was reached. Each interview was independently coded by 2 researchers. Code frequency and interrater reliability were determined using NVIVO software. Data analysis was conducted from November 2020 to March 2021. MAIN OUTCOMES AND MEASURES: Factors influencing dermatologist decision-making around topical steroid selection, outcomes of unaffordable medications on patients, solution recommendations, and perspectives on a system to automatically substitute topical steroid for cheaper alternatives of the same class and vehicle. RESULTS: Of the 16 dermatologists, 8 (50.0%) were women, 8 (50.0%) were men, 1 (6.3%) was Asian, 2 (12.5%) were Latinx, and 12 (75.0%) were White. The interrater reliability ranged from κ = 0.86 to κ = 0.98, indicating excellent agreement. Most physicians (13 [81%]) thought about costs regularly when making choices about topical steroids. All physicians identified a scenario in which patients could not obtain medication based on cost. In these cases, 15 (94%) reported that they try to find an alternative medication by calling the pharmacist or insurance company. Despite a desire to consider cost at the time of prescribing, physicians reported not knowing medication costs before prescribing because of the variability of insurance coverage (15 [94%]), lack of transparency (12 [75%]), and fluctuating drug prices (12 [75%]). In addition to affecting patients, 14 physicians (88%) reported that a patient's inability to afford medications increases administrative burden. Physicians suggested that they were open to solutions that focused on increased cost transparency (10 [63%]) and improved electronic health record technologies. Furthermore, 14 (88%) were willing to use a system to allow the substitution of one topical steroid for another of the same class and vehicle. CONCLUSIONS AND RELEVANCE: The results of this qualitative study suggest that opacity around drug costs reduces access for patients and is followed by administrative stress for physicians and staff. Dermatologists are receptive to systems that provide greater transparency for drug costs or automate substitution of equivalent cheaper drugs for patients.

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.

Transdermal approaches to vaccinations in the COVID-19 pandemic era.

The COVID-19 pandemic has necessitated rapid vaccine development for the control of the disease. Most vaccinations, including those currently approved for COVID-19 are administered intramuscularly and subcutaneously using hypodermic needles. However, there are several disadvantages including pain and fear of needlesticks, the need for two doses, the need for trained health care professionals for vaccine administration, and barriers to global distribution given the need for cold supply chain. Recently, transdermal techniques have been under investigation for vaccines including COVID-19. Microneedle array technology utilizes multiple microscopic projections from a plate which delivers a vaccine in the form of a patch placed on the skin, allowing for painless antigen delivery with improved immune response. In this review, we discuss challenges of existing vaccines and review the literature on the science behind transdermal vaccines including microneedles, current evidence of application in infectious diseases including COVID-19, and considerations for implementation and global access.