Topically Applied Therapies for the Treatment of Skin Disease: Past, Present, and Future.

The purpose of this review is to summarize essential biological, pharmaceutical, and clinical aspects in the field of topically applied medicines that may help scientists when trying to develop new topical medicines. After a brief history of topical drug delivery, a review of the structure and function of the skin and routes of drug absorption and their limitations is provided. The most prevalent diseases and current topical treatment approaches are then detailed, the organization of which reflects the key disease categories of autoimmune and inflammatory diseases, microbial infections, skin cancers, and genetic skin diseases. The complexity of topical product development through to large-scale manufacturing along with recommended risk mitigation approaches are then highlighted. As such topical treatments are applied externally, patient preferences along with the challenges they invoke are then described, and finally the future of this field of drug delivery is discussed, with an emphasis on areas that are more likely to yield significant improvements over the topical medicines in current use or would expand the range of medicines and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of the skin and its associated diseases and current treatments along with the intricacies of topical formulation development should be helpful in making judicious decisions about the development of new or improved topical medicines. These aspects include the choices of the active ingredients, formulations, the target patient population's preferences, limitations, and the future with regard to new skin diseases and topical medicine approaches.

Development of a core outcome set for basal cell carcinoma.

BACKGROUND: There is variation in the outcomes reported in clinical studies of basal cell carcinoma. This can prevent effective meta-analyses from answering important clinical questions. OBJECTIVE: To identify a recommended minimum set of core outcomes for basal cell carcinoma clinical trials. METHODS: Patient and professional Delphi process to cull a long list, culminating in a consensus meeting. To be provisionally accepted, outcomes needed to be deemed important (score, 7-9, with 9 being the maximum) by 70% of each stakeholder group. RESULTS: Two hundred thirty-five candidate outcomes identified via a systematic literature review and survey of key stakeholders were reduced to 74 that were rated by 100 health care professionals and patients in 2 Delphi rounds. Twenty-seven outcomes were provisionally accepted. The final core set of 5 agreed-upon outcomes after the consensus meeting included complete response; persistent or serious adverse events; recurrence-free survival; quality of life; and patient satisfaction, including cosmetic outcome. LIMITATIONS: English-speaking patients and professionals rated outcomes extracted from English language studies. CONCLUSION: A core outcome set for basal cell carcinoma has been developed. The use of relevant measures may improve the utility of clinical research and the quality of therapeutic guidance available to clinicians.

Practice Patterns for Mohs Surgeons of Varying Clinical Experience: A Cross-Sectional Analysis of a Medicare Claims Database.

BACKGROUND: Use of Mohs micrographic surgery (MMS) is highly prevalent, but little data are available on how surgeon experience affects surgical practice patterns. OBJECTIVE: To determine differences in use of MMS among surgeons of varying experience. MATERIALS AND METHODS: This cross-sectional study sampled from clinicians billing ≥200 mean annual Mohs surgery claims from the 2012 to 2018 Medicare Public Use File. The primary outcome was mean annual Mohs surgery claims for clinicians of varying experience. Secondary outcomes included use of flaps/grafts and prescribing of oral antibiotics, benzodiazepines, and opioids. RESULTS: Among 1,759 unique surgeons, those with 16 to 20 years of experience performed the most mean annual (95% confidence interval) Mohs surgical cases (578.7 [556.7-600.6]). Surgeons with 21 to 25 years of experience prescribed the most antibiotics (240.2 [216.5-263.8] mean annual claims), whereas those with >35 years of experience prescribed the longest courses (15.3 [14.2-16.4] days). CONCLUSION: Midcareer surgeons performed the most mean annual Mohs surgery cases, whereas later career surgeons prescribed more frequent and longer courses of antibiotics suggesting changing practice patterns with additional years of experience.

Athletic Injuries of the Thoracic Cage.

A variety of sports require exposure to high-impact trauma or characteristic repetitive movements that predispose to injuries around the thorax. Appropriate prognostication and timely management are vital, as untreated or undertreated injuries can lead to pain, disability, loss of playing time, or early termination of sports participation. The authors review common athletic injuries of the thoracic cage, encompassing muscular, osseous, and vascular conditions, with an emphasis on mechanism, imaging features, and management. The authors also review pertinent soft-tissue and bony anatomy, along with relevant sports biomechanics. Generalized muscle trauma and more specific injuries involving the pectoralis major, latissimus dorsi, teres major, pectoralis minor, lateral abdominal wall and intercostals, serratus anterior, and rectus abdominis muscles are discussed. Osseous injuries such as stress fractures, sternoclavicular dislocation, costochondral fractures, and scapular fractures are included. Finally, thoracic conditions such as snapping scapula, thoracic outlet syndrome, and Paget-Schroetter syndrome are also described. Specific MRI protocols are highlighted to address imaging challenges such as the variable anatomic orientation of thoracic structures and artifact from breathing motion. Athletes are susceptible to a wide range of musculoskeletal thoracic trauma. An accurate imaging diagnosis of thoracic cage injury and assessment of injury severity allow development of an adequate treatment plan. This can be facilitated by an understanding of functional anatomy, sports biomechanics, and the unique injuries for which athletes are at risk. ©RSNA, 2021.

Indications and Outcomes of Mohs Micrographic Surgery Using a Multidisciplinary Approach: A Decade of Experience.

BACKGROUND: Traditional approaches of staged outpatient Mohs Micrographic Surgery (MMS) in nonmelanoma skin cancer (NMSC) followed by reconstruction is not possible in a subset of patients. OBJECTIVE: Assess the indications and outcomes of a multidisciplinary approach MMS. METHODS AND MATERIALS: Retrospective, single-surgeon, single Mohs specialist, university-based tertiary care referral practice, including all MMS performed in the operating room setting with concurrent reconstruction in patients from 2008 to 2018 with minimum follow-up of 6 months. Patients with NMSCs who completed multidisciplinary MMS approach were included. Number of Mohs stages, duration of procedure, reconstruction techniques, and complications including flap loss, bleeding, hematoma, wound infections, dehiscence, and local recurrence rates were reviewed. RESULTS: Three hundred twenty patients were included, 160 male and 160 female with mean ages of 71.6 and 72.1 years, respectively. Indications for a multidisciplinary approach MMS were as follows: neuro/psych 22.5%, extensive anticipated defect size 55%, patient request/convenience 4.4%, medical intolerance 5%, multiple reasons 8.1%, and unknown in 5%. Average stage required to clear margins was 1.57 ± 0.64. Mean operative times by increasing Mohs stages up to 3 including reconstruction were 125.1, 159.3, and 195.5 minutes, respectively (p < .00001). CONCLUSION: Indications for a multidisciplinary approach MMS were extensive defects and neuro/psych issues. Advantages include patient tolerance and single-stage procedure.

An in vitro bioassay for evaluating the effect of inhaled bronchodilators on airway smooth muscle.

PURPOSE: The development of inhaled drug products is expensive and involves time-consuming pharmacokinetic (PK) and pharmacodynamic (PD) studies. There are few in vitro cell-based assays to evaluate the disposition and action of orally inhaled drugs to guide early product development and minimise risk. The aim of the present study was to develop a co-culture bioassay, combining an airway epithelial cell line (Calu-3) with cultured human primary airway smooth muscle cells (ASM), integrated with apparatus to deliver pharmaceutical aerosols. METHODS: An assay for measuring cyclic adenosine monophosphate (cAMP) in ASM derived from healthy donors was adapted to provide a biochemical surrogate for ASM relaxation. Concentration-response curves for cAMP were established for three drugs that elicit ASM relaxation: isoprenaline (ISO), forskolin (FOR) and salbutamol sulphate. The ASM bioassay was incorporated into a co-culture model in which air-interfaced Calu-3 cell layers, representing the permeability barrier of the airway epithelium, were grown on transwell inserts above ASM cells cultured in the well of the base-plate. The sensitivity of this bioassay to salbutamol delivered using different formulations and aerosol products was evaluated. RESULTS: ASM responded with concentration dependent increases in cAMP when exposed to 10-9 to 10-5 M ISO, FOR or salbutamol sulphate solutions for 15 or 30 min. Salbutamol formulated with different counter ions elicited differential cAMP responses in ASM (xinafoate > base = sulphate) suggesting that this bioassay could discriminate between formulations with different potency. A similar rank order of potency was observed for the different salbutamol salts when applied as aerosols to the co-culture model. DISCUSSION: We have developed a novel bioassay using human ASM in co-culture with human respiratory epithelial cells to better mimic various elements that contribute to the rate and extent of local drug availability in the lungs following topical administration. The bioassay offers an opportunity to investigate the factors determining the activity of inhaled bronchodilator drugs in a more biologically relevant system than that has previously been described and with further development and validation, this novel bioassay could provide a method to guide the more efficient development of inhaled bronchodilators, reducing the current reliance on in vivo studies.

Nodal staging of high-risk cutaneous squamous cell carcinoma.

BACKGROUND: While progress has been made in defining the clinical and histopathologic features of high-risk cutaneous squamous cell carcinoma (HRcSCC), optimal staging guidelines remain elusive. OBJECTIVE: We seek to guide clinical practice regarding nodal staging options for patients with HRcSCC via review of evolving definitions of HRcSCC, nodal staging options, and how nodal staging may impact treatment and affect outcomes. METHODS: This was a retrospective review of the published peer-reviewed literature regarding risk stratification, nodal staging, and treatment and outcomes for patients with HRcSCC via PubMed. RESULTS: For patients without clinical lymphadenopathy, based on literature from head and neck SCC, preoperative nodal staging with ultrasonography may be more useful than computed tomography or magnetic resonance imaging. Early nodal disease is usually curable, and therefore obtaining a sentinel lymph node biopsy specimen may be considered in those with negative imaging while we await studies of nodal staging outcomes. LIMITATIONS: More data are needed to validate the relationships between primary tumor stage and sentinel lymph node biopsy status and to determine if early detection of nodal disease impacts survival for patients with HRcSCC. CONCLUSION: It is reasonable to consider nodal staging for patients with HRcSCC (Brigham and Women's Hospital stage T2b and T3) in the absence of clinically palpable lymphadenopathy via radiographic imaging and, if negative, sentinel lymph node biopsy.

Validation of an analytical method to quantify the permeation and penetration of flurbiprofen into human pharynx tissue.

The aim of this investigation was to develop receiver and extraction fluids, and subsequently validate an analytical method to quantify the permeation and penetration of flurbiprofen into human pharynx tissue using a Franz diffusion cell. The solubility and stability of flurbiprofen in a suitable receiver fluid, and a suitable extraction method and fluid to recover and quantitate flurbiprofen from human pharynx tissue, were investigated using high-performance liquid chromatography (HPLC). The potential interference of human pharynx tissue in the receiver fluid was also investigated. The HPLC analytical method was successfully validated according to current guidelines. The final receiver fluid demonstrated sufficient solubility and stability, and the extraction method and fluid resulted in >95% recovery of flurbiprofen following exposure to human pharynx tissue. The lower limit of quantitation of flurbiprofen was 0.045 µg/mL in both the receiver and extraction fluids. There was no interference of the human pharynx tissue with the HPLC method. This investigation validated an analytical method for quantitating flurbiprofen, and determined a suitable receiver fluid and extraction method and fluid, which can be used to investigate the permeation and penetration of flurbiprofen through human pharynx tissue using the Franz diffusion cell method.

Sebomic identification of sex- and ethnicity-specific variations in residual skin surface components (RSSC) for bio-monitoring or forensic applications.

BACKGROUND: "Residual skin surface components" (RSSC) is the collective term used for the superficial layer of sebum, residue of sweat, small quantities of intercellular lipids and components of natural moisturising factor present on the skin surface. Potential applications of RSSC include use as a sampling matrix for identifying biomarkers of disease, environmental exposure monitoring, and forensics (retrospective identification of exposure to toxic chemicals). However, it is essential to first define the composition of "normal" RSSC. Therefore, the aim of the current study was to characterise RSSC to determine commonalities and differences in RSSC composition in relation to sex and ethnicity. METHODS: Samples of RSSC were acquired from volunteers using a previously validated method and analysed by high-pressure liquid chromatography-atmospheric pressure chemical ionisation-mass spectrometry (HPLC-APCI-MS). The resulting data underwent sebomic analysis. RESULTS: The composition and abundance of RSSC components varied according to sex and ethnicity. The normalised abundance of free fatty acids, wax esters, diglycerides and triglycerides was significantly higher in males than females. Ethnicity-specific differences were observed in free fatty acids and a diglyceride. CONCLUSIONS: The HPLC-APCI-MS method developed in this study was successfully used to analyse the normal composition of RSSC. Compositional differences in the RSSC can be attributed to sex and ethnicity and may reflect underlying factors such as diet, hormonal levels and enzyme expression.

Evaluation of the Ability of a Novel Miconazole Formulation To Penetrate Nail by Using Three In Vitro Nail Models.

In an effort to increase the efficacy of topical medications for treating onychomycosis, several new nail penetration enhancers were recently developed. In this study, the ability of 10% (wt/wt) miconazole nitrate combined with a penetration enhancer formulation to permeate the nail is demonstrated by the use of a selection of in vitro nail penetration assays. These assays included the bovine hoof, TurChub zone of inhibition, and infected-nail models.

Pigmented epithelioid melanocytoma (animal-type melanoma): An institutional experience.

BACKGROUND: Pigmented epithelioid melanocytoma (PEM) is an uncommon, recently described entity with unknown biologic behavior. There is a high rate of regional metastases, but limited evidence of distant metastases or disease-related death. OBJECTIVE: We sought to report our series of patients given a diagnosis of PEM at our institution and provide mutational analysis of genes commonly implicated in melanoma in 2 cases. METHODS: The pathology database was queried for cases of PEM diagnosed at the University of Rochester. Charts were reviewed for follow-up information. Mutational analysis of melanoma-associated genes was performed on 2 cases. RESULTS: Nine cases of PEM were retrieved in a 10-year retrospective review. Five patients underwent sentinel lymph node biopsy with 3 of 5 having a positive sentinel lymph node. All 9 patients are alive and disease-free with average follow-up of 38.75 months. Two tumors were tested for common melanoma-associated mutations, and were negative, except for a telomerase reverse transcriptase promoter deletion detected in 1 sample. The deletion has not been associated with melanoma, and therefore its biologic significance is unclear. LIMITATIONS: Small sample size, retrospective nature, and single institution experience are limitations. CONCLUSIONS: PEM appears to have an indolent behavior. However, currently the evidence is too limited to provide insight into its true biologic potential.

DHA-rich Fish Oil Increases the Omega-3 Index and Lowers the Oxygen Cost of Physiologically Stressful Cycling in Trained Individuals.

Dietary fish oil, providing docosahexaenoic acid (DHA) modulates oxygen consumption and fatigue in animal models. However, in humans predominately supplemented with high eicosapentaenoic acid (EPA), there is no evidence of endurance performance enhancement. Therefore, this study examined if DHA-rich fish oil could improve repeated bouts of physiologically stressful cycling and a subsequent time trial in a state of fatigue. Twenty-six trained males took part in a double-blind study and were supplemented with either 2 × 1g/day soy oil, Control) or DHA-rich tuna fish oil (Nu-Mega) (FO) (560mg DHA / 140mg eicosapentaenoic acid (EPA), for 8 weeks. Maximal cycling power (3 × 6s), isometric quadriceps strength (MVC), Wingate cycling protocol (6 × 30s) and a 5min cycling time-trial were assessed at baseline and eight weeks. The Omega-3 Index was not different at baseline (Control: 4.2 ± 0.2; FO: 4.7 ± 0.2%) and increased in the FO group after eight weeks (Control: 3.9 ± 0.2; FO: 6.3 ± 0.3%, p < .01). There was no effect of DHA-rich fish oil on power output of maximal 6s cycle sprinting (Control: Pre 1100 ± 49 Post 1067 ± 51; FO: Pre 1070 ± 46 Post 1042 ± 46W), during 5min time trail (Control: Pre 267 ± 19 Post 278 ± 20; FO: Pre 253 ± 16 Post 265 ± 16 W) or maximal voluntary contraction force (Control: Pre 273 ± 19 Post 251 ± 19; FO: Pre 287 ± 17 Post 283 ± 16 Nm). Nevertheless, relative oxygen consumption was reduced the FO group during the cycling time trial (Control: -23 ± 26; FO: -154 ± 59ml O2/min/100W p < .05) suggesting improved economy of cycling. We conclude that DHA-rich fish oil, successful at elevating the Omega-3 Index, and reflective of skeletal muscle membrane incorporation, can modulate oxygen consumption during intense exercise.

Is Moderate Intensity Cycling Sufficient to Induce Cardiorespiratory and Biomechanical Modifications of Subsequent Running?

Walsh, JA, Dawber, JP, Lepers, R, Brown, M, and Stapley, PJ. Is moderate intensity cycling sufficient to induce cardiorespiratory and biomechanical modifications of subsequent running? J Strength Cond Res 31(4): 1078-1086, 2017-This study sought to determine whether prior moderate intensity cycling is sufficient to influence the cardiorespiratory and biomechanical responses during subsequent running. Cardiorespiratory and biomechanical variables measured after moderate intensity cycling were compared with control running at the same intensity. Eight highly trained, competitive triathletes completed 2 separate exercise tests; (a) a 10-minute control run (no prior cycling) and, (b) a 30-minute transition run (TR) (preceded by 20-minute of variable cadence cycling, i.e., run versus cycle-run). Respiratory, breathing frequency (fb), heart rate (HR), cost of running (Cr), rate constant, stride length, and stride frequency variables were recorded, normalized, and quantified at the mean response time (MRT), third minute, 10th minute (steady state), and overall for the control run (CR) and TR. Cost of running increased (p ≤ 0.05) at all respective times during the TR. The V[Combining Dot Above]E/V[Combining Dot Above]CO2 and respiratory exchange ratio (RER) were significantly (p < 0.01) elevated at the MRT and 10th minute of the TR. Furthermore, overall mean increases were recorded for Cr, V[Combining Dot Above]E, V[Combining Dot Above]E/V[Combining Dot Above]CO2, RER, fb (p < 0.01), and HR (p ≤ 0.05) during the TR. Rate constant values for oxygen uptake were significantly different between CR and TR (0.48 ± 0.04 vs. 0.89 ± 0.15; p < 0.01). Stride length decreased across all recorded points during the TR (p ≤ 0.05) and stride frequency increased at the MRT and 3 minutes (p < 0.01). The findings suggest that at moderate intensity, prior cycling influences the cardiorespiratory response during subsequent running. Furthermore, prior cycling seems to have a sustained effect on the Cr during subsequent running.

Short Cationic Antimicrobial Peptides Display Superior Antifungal Activities toward Candidiasis and Onychomycosis in Comparison with Terbinafine and Amorolfine.

Novel antifungals are in high demand due to the challenges associated with resistant, persistent, and systemic fungal infections. Synthetic mimics of antimicrobial peptides are emerging as a promising class of compounds for antifungal treatment. In the current study, five synthetic cationic antimicrobial tripeptides were evaluated as antifungal therapeutics against 24 pathogenic strains of fungi. Three of the peptides displayed strong general antifungal properties at low micromolar inhibitory concentrations. The most promising peptide, compound 5, was selected and evaluated as an antifungal remedy for Candida albicans candidiasis in a human skin model and for the treatment of Trichophyton rubrum induced onychomycosis in an infected human nail model. Compound 5 was shown to display antifungal properties and a rapid mode of action superior to those of both the commercial comparators Loceryl and Lamisil. Compound 5 was also active against a clinical isolate of Candida albicans with acquired fluconazole resistance.

Using Salt Counterions to Modify ß2-Agonist Behavior in Vivo.

There is a paucity of data describing the impact of salt counterions on the biological performance of inhaled medicines in vivo. The aim of this study was to determine if the coadministration of salt counterions influenced the tissue permeability and airway smooth muscle relaxation potential of salbutamol, formoterol, and salmeterol. The results demonstrated that only salbutamol, when formulated with an excess of the 1-hydroxy-2-naphthoate (1H2NA) counterion, exhibited a superior bronchodilator effect (p < 0.05) compared to salbutamol base. The counterions aspartate, maleate, fumarate, and 1H2NA had no effect on the ability of formoterol or salmeterol to reduce airway resistance in vivo. Studies using guinea pig tracheal sections showed that the salbutamol:1H2NA combination resulted in a significantly faster (p < 0.05) rate of tissue transport compared to salbutamol base. Furthermore, when the relaxant activity of salbutamol was assessed in vitro using electrically stimulated, superfused preparations of guinea pig trachea, the inhibition of contraction by salbutamol in the presence of 1H2NA was greater than with salbutamol base (a total inhibition of 94.13%, p < 0.05). The reason for the modification of salbutamol's behavior upon administration with 1H2NA was assigned to ion-pair formation, which was identified using infrared spectroscopy. Ion-pair formation is known to modify a drug's physicochemical properties, and the data from this study suggested that the choice of counterion in inhaled pharmaceutical salts should be considered carefully as it has the potential to alter drug action in vivo.

Inter- and intra-observer agreement of femoroacetabular impingement (FAI) parameters comparing plain radiographs and advanced, 3D computed tomographic (CT)-generated hip models in a surgical patient cohort.

PURPOSE: The purpose of our study was to investigate whether advanced, 3D computed tomographic (CT)-generated hip models improves inter-and intra-observer agreement when compared to plain radiographs in identifying femoroacetabular impingement (FAI) morphology. METHODS: Eight consecutive patients who underwent surgery for FAI pathology were selected for this study. Preoperative CT scan image data were used to create high resolution, 3D hip reconstruction models. Four observers (two attending hip surgeons and radiologists) performed a blinded review of preselected radiographs and 3D CT hip models. Alpha and lateral center-edge angle measurements, location of cam lesion and the presence of a "crossover sign" were assessed. Inter- and intra-observer agreement was determined by calculating the intra-class correlation coefficients (ICC) or kappa coefficients to evaluate agreement for categorical variables. RESULTS: The parameter that demonstrated the highest and poorest inter-observer agreement was the presence of a "crossover sign" using 3D CT-generated high resolution hip models (ICC = 0.76, p = 0.00) and anteroposterior pelvis radiography, respectively (ICC = 0.20, p = 0.02). Alpha angle values were significantly higher using plain radiographs when compared to 3D hip reconstruction models (61.1° ± 10.4° versus 55.4° ± 14.4°, p = 0.003). Furthermore, when compared to radiographs, 3D hip reconstruction models demonstrated significantly higher intra-observer agreement (ICC = 0.856 versus 0.405, p = 0.005) when determining the presence of a "crossover sign". CONCLUSIONS: Our findings were suggestive that for most commonly used FAI morphology parameters, CT-generated hip models demonstrated little benefit over plain radiographs in improving inter-observer agreement among providers. LEVEL OF EVIDENCE: III.