mRNA-based vaccines and therapeutics: an in-depth survey of current and upcoming clinical applications.

mRNA-based drugs have tremendous potential as clinical treatments, however, a major challenge in realizing this drug class will promise to develop methods for safely delivering the bioactive agents with high efficiency and without activating the immune system. With regard to mRNA vaccines, researchers have modified the mRNA structure to enhance its stability and promote systemic tolerance of antigenic presentation in non-inflammatory contexts. Still, delivery of naked modified mRNAs is inefficient and results in low levels of antigen protein production. As such, lipid nanoparticles have been utilized to improve delivery and protect the mRNA cargo from extracellular degradation. This advance was a major milestone in the development of mRNA vaccines and dispelled skepticism about the potential of this technology to yield clinically approved medicines. Following the resounding success of mRNA vaccines for COVID-19, many other mRNA-based drugs have been proposed for the treatment of a variety of diseases. This review begins with a discussion of mRNA modifications and delivery vehicles, as well as the factors that influence administration routes. Then, we summarize the potential applications of mRNA-based drugs and discuss further key points pertaining to preclinical and clinical development of mRNA drugs targeting a wide range of diseases. Finally, we discuss the latest market trends and future applications of mRNA-based drugs.

The Role of Antihistamines and Dupilumab in the Management of Alopecia Areata: A Systematic Review.

BACKGROUND: Approximately 30% to 40% of alopecia areata (AA) patients have atopic dermatitis. Studies suggest that antihistamines and dupilumab may be effective treatments; however, the potential benefit of these therapies as either adjunct or monotherapy has yet to be elucidated. OBJECTIVE: To evaluate the use of antihistamines and dupilumab in the treatment of AA. METHODS: A literature search was conducted in August 2021 according to PRISMA guidelines. Inclusion criteria were articles describing the use of antihistamines or dupilumab for AA or those discussing AA development as an adverse event of these therapies. RESULTS: Forty-two articles with 395 patients describe the use of antihistamines or dupilumab in AA. The most common antihistamine regimens were oxatomide 30 mg twice a day, fexofenadine 60 or 120 mg/day, and ebastine 10 mg/day; and the majority of cases reported significant hair regrowth, decreased pruritus, and erythema. Studies on the use of dupilumab for AA demonstrated remarkable hair growth in some patients (n=23), no change in others (n=3), and no new hair loss in a patient with resolved alopecia universalis (AU) (n=1). In contrast, dupilumab therapy for AD has been implicated as a cause of AA (n=21), drug-induced alopecia (n=2), and AA-like psoriasis (n=1). CONCLUSION: Current literature is promising for the use of antihistamines as adjunct treatments for AA, while monotherapy needs to be further explored. The role of dupilumab in AA treatment and/or development also requires further research.J Drugs Dermatol. 2022;21(10):1070-1083. doi:10.36849/JDD.6553.

Diminished Visual Attention to Emotional Faces Is Associated with Poor Emotional Valence Perception in Frontotemporal Dementia.

AIM: The current study examined whether visual attention to emotional facial expressions is lower in individuals with frontotemporal dementia (FTD) compared to healthy controls, and whether visual attention to emotional facial expressions is associated with the ability to perceive others' emotional valence accurately. METHODS: Participants with FTD (n = 17) and healthy controls (n = 23) passively viewed pairs of emotional and neutral faces while their visual attention was measured using eye-tracking. A subsample of participants (n = 28) also completed an emotional valence perception task. RESULTS: Individuals with FTD spent less time looking at emotional faces than healthy controls. However, there was no difference in the amount of time individuals with FTD spent looking at neutral faces as compared to healthy controls. In the subsample, less time spent looking at emotional faces (but not neutral faces) was associated with a less accurate perception of others' emotional valence. CONCLUSION: Individuals with FTD displayed diminished visual attention to emotional facial expressions compared to healthy controls. Reduced attention towards emotional faces was associated with poorer emotional valence perception. Findings point toward diminished visual attention as potentially relevant for understanding oft-observed impairments in socioemotional functioning in FTD.

A critical overview of current progress for COVID-19: development of vaccines, antiviral drugs, and therapeutic antibodies.

The novel coronavirus disease (COVID-19) pandemic remains a global public health crisis, presenting a broad range of challenges. To help address some of the main problems, the scientific community has designed vaccines, diagnostic tools and therapeutics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rapid pace of technology development, especially with regard to vaccines, represents a stunning and historic scientific achievement. Nevertheless, many challenges remain to be overcome, such as improving vaccine and drug treatment efficacies for emergent mutant strains of SARS-CoV-2. Outbreaks of more infectious variants continue to diminish the utility of available vaccines and drugs. Thus, the effectiveness of vaccines and drugs against the most current variants is a primary consideration in the continual analyses of clinical data that supports updated regulatory decisions. The first two vaccines granted Emergency Use Authorizations (EUAs), BNT162b2 and mRNA-1273, still show more than 60% protection efficacy against the most widespread current SARS-CoV-2 variant, Omicron. This variant carries more than 30 mutations in the spike protein, which has largely abrogated the neutralizing effects of therapeutic antibodies. Fortunately, some neutralizing antibodies and antiviral COVID-19 drugs treatments have shown continued clinical benefits. In this review, we provide a framework for understanding the ongoing development efforts for different types of vaccines and therapeutics, including small molecule and antibody drugs. The ripple effects of newly emergent variants, including updates to vaccines and drug repurposing efforts, are summarized. In addition, we summarize the clinical trials supporting the development and distribution of vaccines, small molecule drugs, and therapeutic antibodies with broad-spectrum activity against SARS-CoV-2 strains.

A booster dose of Delta × Omicron hybrid mRNA vaccine produced broadly neutralizing antibody against Omicron and other SARS-CoV-2 variants.

BACKGROUND: With the continuous emergence of new SARS-CoV-2 variants that feature increased transmission and immune escape, there is an urgent demand for a better vaccine design that will provide broader neutralizing efficacy. METHODS: We report an mRNA-based vaccine using an engineered "hybrid" receptor binding domain (RBD) that contains all 16 point-mutations shown in the currently prevailing Omicron and Delta variants. RESULTS: A booster dose of hybrid vaccine in mice previously immunized with wild-type RBD vaccine induced high titers of broadly neutralizing antibodies against all tested SARS-CoV-2 variants of concern (VOCs). In naïve mice, hybrid vaccine generated strong Omicron-specific neutralizing antibodies as well as low but significant titers against other VOCs. Hybrid vaccine also elicited CD8+/IFN-γ+ T cell responses against a conserved T cell epitope present in wild type and all VOCs. CONCLUSIONS: These results demonstrate that inclusion of different antigenic mutations from various SARS-CoV-2 variants is a feasible approach to develop cross-protective vaccines.

Safety and Efficacy of Deoxycholic Acid for Reduction of Upper Inner Thigh Fat.

BACKGROUND: Deoxycholic acid is an FDA-approved injectable for treatment of excess submental fat. OBJECTIVE: Study purpose was to evaluate the safety and efficacy of deoxycholic acid for reduction of upper inner thigh fat. METHODS AND MATERIALS: Fifteen subjects received 2–4 treatment sessions of deoxycholic acid 10 mg/mL injected into upper inner thigh fat. Subjects were followed to 12 weeks after last treatment. Adverse events were monitored. Efficacy measures were changes in thigh circumference, upper inner thigh skin fold thickness, and “thigh gap;” and percent accuracy by two independent blinded physicians in identifying post-treatment photographs. Patient satisfaction was assessed with questionnaires. RESULTS: There were no serious adverse events. All patients experienced expected side effects. At 12-week follow-up, decreases in thigh circumference (average change -2.2 cm) and upper inner thigh skin fold thickness (average change -8.8 mm) were observed. Average increase in “thigh gap” was 1.6 cm. Two blinded investigators correctly identified the post-treatment photograph for 83% of patients. On Subject Self-Rating Scale (6-point scale), there was average +3.0 improvement; 86% of patients were satisfied with treatment. CONCLUSION: Deoxycholic acid injection was safe and effective for reduction of upper inner thigh fat in this Phase I study. J Drugs Dermatol. 2022;21(1):66-70. doi:10.36849/JDD.5919.

Optimizing Parameters for Smoke Evacuation.

BACKGROUND: Current literature lacks recommendations regarding the ideal organization of the smoke evacuation system to minimize inhalation of surgical smoke. OBJECTIVE: This study determines optimal parameters of the smoke evacuation system with respect to the surgical field. MATERIALS AND METHODS: This study was conducted in an outpatient surgical facility at a tertiary care center. After 30 seconds of continuous electrocautery of tissue, particulate measurements were recorded using the TSI DustTrak Aerosol Monitor 8520 (>2.5 µm particles) and the TSI P-Trak Ultrafine Particle Counter 8525 (<1 µm particles) while changing the angle and distance of the smoke evacuation system. RESULTS: Particulate matter measurements were lower when suction angle was at 45° than at 90°. For both small-sized and large-sized particles, the lowest particulate matter was recorded when the evacuator was maintained at a 45° angle, 2 to 4 inches away from the cauterizing procedure. Particulate matters dramatically increased after increasing the distance of the smoke evacuator beyond 8 inches from the procedural site. CONCLUSION: In an effort to reduce smoke inhalation, the authors recommend that smoke evacuation should be placed at a 45° suction angle, no further than 8 inches away from the surgical site, while preserving the surgeon's field of vision.

Rapid generation of mouse model for emerging infectious disease with the case of severe COVID-19.

Since the pandemic of COVID-19 has intensely struck human society, small animal model for this infectious disease is in urgent need for basic and pharmaceutical research. Although several COVID-19 animal models have been identified, many of them show either minimal or inadequate pathophysiology after SARS-CoV-2 challenge. Here, we describe a new and versatile strategy to rapidly establish a mouse model for emerging infectious diseases in one month by multi-route, multi-serotype transduction with recombinant adeno-associated virus (AAV) vectors expressing viral receptor. In this study, the proposed approach enables profound and enduring systemic expression of SARS-CoV-2-receptor hACE2 in wild-type mice and renders them vulnerable to SARS-CoV-2 infection. Upon virus challenge, generated AAV/hACE2 mice showed pathophysiology closely mimicking the patients with severe COVID-19. The efficacy of a novel therapeutic antibody cocktail RBD-chAbs for COVID-19 was tested and confirmed by using this AAV/hACE2 mouse model, further demonstrating its successful application in drug development.

Urgent safety considerations for dermatologic surgeons in the COVID-19 pandemic.

Dermatologic surgeons are at increased risk of contracting SARS-COV-2. At time of writing, there is no published standard for the role of pre-operative testing or the use of smoke evacuators, and personal protective equipment (PPE) in dermatologic surgery. Risks and safety measures in otolaryngology, plastic surgery, and ophthalmology are discussed. In Mohs surgery, cases involving nasal or oral mucosa are highest risk for SARS-COV-2 transmission; pre-operative testing and N95 masks should be urgently prioritized for these cases. Other key safety recommendations include strict control of patient droplets and expanded pre-clinic screening. Dermatologic surgeons are encouraged to advocate for appropriate pre-operative tests, smoke evacuators, and PPE. Future directions would include national consensus guidelines with continued refinement of safety protocols.

Performance Measures in Dermatologic Surgery: A Review of the Literature and Future Directions.

BACKGROUND: In recent years, health care reform initiatives have aimed to assess quality of care through the use of performance measures. Multiple specialties, including dermatology, have implemented registries to track and report health care quality. OBJECTIVE: The authors review the history and rationale for assessing quality in dermatologic surgery. The authors also discuss the different types of performance measures and the current efforts to develop clinically relevant dermatologic surgery-specific measures. MATERIALS AND METHODS: An extensive literature review was conducted using OVID, MEDLINE, PubMed, and government and health care-related websites to identify articles related to surgical performance measures. RESULTS: Few performance measures are established to assess quality in dermatologic surgery. The authors propose specific candidate measures and discuss how clinical registries can capture measures that meet federal reporting requirements. CONCLUSION: Assessment of health care quality will become increasingly important in health care reform. Physicians need to take an active role in selecting appropriate, clinically relevant performance measures that will help improve patient care while containing health care costs and meeting government-mandated reporting requirements.

Mohs Micrographic Surgery in the Veterans Health Administration.

Veterans with skin cancer have seen improved access to Mohs micrographic surgery over the past 10 years, yet the challenges of travel distance and care coordination remain.

Validity of skin cancer malignancy reporting to the Organ Procurement Transplant Network: A cohort study.

BACKGROUND: The Organ Procurement Transplant Network (OPTN) registry collects data on posttransplant malignancies in solid organ transplant recipients. Complete and accurate registry data on skin cancer is critical for research on epidemiology and interventions. OBJECTIVE: The study goal was to determine the validity of Organ Procurement Transplant Network skin cancer data. METHODS: This cohort study compared reporting of posttransplant squamous cell carcinoma (SCC) and malignant melanoma (MM) in OPTN to medical-record review-derived data from the Transplant Skin Cancer Network (TSCN) database. In total, 4934 organ transplant recipients from the TSCN database were linked to patient-level OPTN malignancy data. We calculated sensitivity, specificity, correct classification (CC), positive predictive value (PPV), and negative predictive value (NPV) for SCC and MM reporting in the OPTN database. RESULTS: OPTN reporting for SCC (population prevalence 11%) had sensitivity 41%, specificity 99%, PPV 88%, NPV 93%, and CC 93%. OPTN reporting for MM (population prevalence 1%) had sensitivity 22%, specificity 100%, PPV 73%, NPV 99%, and CC 99%. LIMITATIONS: Only a subset of patients in the TSCN cohort had matched United Network for Organ Sharing cancer registry data for comparison. CONCLUSION: OPTN reporting had poor sensitivity but excellent specificity for SCC and MM. Dermatologists and transplant physicians are encouraged to improve the validity of OPTN skin cancer data through improved communication and reporting.

Complications of hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent painful nodules and abscesses involving intertriginous areas. Repeated episodes of profound inflammation in HS can lead to a number of complications, causing significant morbidity and decreasing quality of life. Complications of HS may affect the skin alone or may have systemic impact. Cutaneous complications of HS include sinus tracts, fistulae, scarring and contractures, squamous cell carcinoma, and lymphedema. Systemic complications of HS include chronic pain, systemic amyloidosis, and possibly anemia. Preventing disease complications by controlling primary disease is a key component of HS management. Clinicians should be prepared to recognize complications early, as prompt management is necessary to minimize negative impacts.

The h-index for associate and full professors of dermatology in the United States: an epidemiologic study of scholastic production.

Promotion in academic dermatology requires evidence of scholastic production. The h-index is a bibliometric measure that combines both volume and impact of scientific contributions. Its calculation better predicts future scientific success than do publication or citation counts. In this epidemiologic survey of associate and full professors of dermatology in residency training programs in the United States, we measured mean and median h-indices among associate and full professors as well as regional differences in h-index. These findings could be used to track individual achievement and as a parameter in considering an individual for professional advancement in dermatology.

Customized bilaminar resorbable mesh with BMP-2 promotes cranial bone defect healing.

BACKGROUND: For repair of cranial vault (skull) defects, alloplastic (methylmethacrylate or titanium mesh) techniques may result in nonhealing or infectious complications and autogenous (split rib or calvarial) techniques may result in excessive blood loss or donor-site morbidity. Osteogenic factors such as bone morphogenetic protein-2 (BMP-2) provide promising alternatives for repairing bone defects. As a new option for this reconstructive challenge, we investigated by using a bilaminar resorbable construct made from computer-aided design and computer-aided manufacturing computed tomographic scan technology with BMP-2 in hopes of providing initial structural support for the skull, followed by bone healing without permanent foreign body problems. METHODS: Outcomes of consecutive adult patients with long-standing critical-sized cranial vault defects who underwent cranial vault reconstruction between 1999 and 2010 were studied (n = 69). Reconstructive options were titanium mesh, cryopreserved bone, patient-specific implants, autogenous (split calvarial), and a new bilaminar resorbable mesh construct sandwiched with BMP-2. These reconstructive options were compared for operating room time, blood loss, complications, reoperations, and bone healing (3-dimensional computed tomographic scans). RESULTS: Defects in the group were similar, 92 cm (60-176 cm). The autogenous bone group had the longest operating room time (1.1 times longer than the BMP-2 construct group) and the greatest blood loss (1.5 times more than the BMP-2 construct group). Perioperative complications and reoperation rates were lower in autogenous bone (5%) and BMP-2 construct groups (14%) when compared with alloplastic groups (22%-36%). Bone healing was superior with BMP-2 construct and autogenous bone (85%; 90%) versus cryopreserved bone (18%) and minimal healing for alloplastic. CONCLUSIONS: In select cases, a customized bilaminar resorbable construct with BMP-2 resulted in improved bone healing with fewer complications than alloplastic options and without the morbidity and blood loss associated with autogenous bone grafting. This allowed critically sized calvarial defects in adults to be successfully corrected with no residual foreign body.

Successful treatment of lower eyelid melanoma in situ.

SUMMARY: We present a brief literature review of the topical immune-modulating medication Imiquimod. The treatment of periorbital melanoma in situ typically requires surgical resection. Here we discuss a case of lower eyelid melanoma in situ successfully treated non-operatively with Imiquimod.