An Overview on the Management of Atrophic Acne Scars: The Role of Trifarotene as an Adjunct.

Acne vulgaris is a common, often chronic inflammatory disease that can affect all ages and skin tones. Beyond acute lesions, the sequelae of acne - specifically scarring and dyspigmentation - can be long-lasting, challenging to treat and have substantial psychosocial impact on affected individuals. For acne scarring, treatment modalities include topical, physical, and laser and light therapies, with combination approaches typically yielding optimal outcomes. Trifarotene is a novel fourth generation retinoid with targeted action towards retinoid acid receptor gamma (RAR-γ), the most common isotype found in the epidermis, that has previously been approved for the management of moderate-to-severe facial and truncal acne in individuals over the age of 12 years. Recently, data on trifarotene supports its application in acne scarring. Herein, we provide a succinct review on various treatments for acne scarring and explore how trifarotene and its mechanism of action present an additional topical approach to target atrophic acne scarring.

Energy-Based Devices for the Treatment of Cutaneous Verrucae: A Systematic Review.

BACKGROUND: Warts are one of the most common benign neoplasms caused by human papillomavirus infection and often pose a therapeutic challenge. OBJECTIVE: To summarize the current evidence on the safety and efficacy of laser and energy-based devices for the treatment of cutaneous verrucae. METHODS: A comprehensive systematic review of the literature on laser and energy-based devices for the treatment of cutaneous verrucae was performed. RESULTS: A total of 904 unique studies were identified, of which 109 were included in this review. The most commonly used lasers as a single treatment modality for verrucae included the long-pulsed Nd:Yag (n = 20) and pulsed dye (n = 18) lasers. Other modalities included the CO2 ablative laser (n = 10), photodynamic therapy (n = 11), local hyperthermia (n = 11), microwave therapy (n = 2), and nanopulse stimulation (n = 1). Other studies combined energy-based modalities with additional treatments, such as retinoids, imiquimod, and intralesional bleomycin. Overall, such devices were generally well-tolerated, with only a mild side effect profile. CONCLUSION: Overall, the use of laser and energy-based devices is a safe and well-tolerated option for cutaneous verrucae that is relatively less invasive than surgical interventions. Future studies using more consistent outcome assessment tools will be valuable to help clinicians develop device-specific protocols and treatment regimens to ensure replicable and effective outcomes.

Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss.

The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.

Family income and cardiovascular disease risk in American adults.

Socioeconomic status is an overlooked risk factor for cardiovascular disease (CVD). Low family income is a measure of socioeconomic status and may portend greater CVD risk. Therefore, we assessed the association of family income with cardiovascular risk factor and disease burden in American adults. This retrospective analysis included data from participants aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) cycles between 2005 and 2018. Family income to poverty ratio (PIR) was calculated by dividing family (or individual) income by poverty guidelines specific to the survey year and used as a measure of socioeconomic status. The association of PIR with the presence of cardiovascular risk factors and CVD as well as cardiac mortality and all-cause mortality was examined. We included 35,932 unweighted participants corresponding to 207,073,472 weighted, nationally representative participants. Participants with lower PIR were often female and more likely to belong to race/ethnic minorities (non-Hispanic Black, Mexican American, other Hispanic). In addition, they were less likely to be married/living with a partner, to attain college graduation or higher, or to have health insurance. In adjusted analyses, the prevalence odds of diabetes mellitus, hypertension, coronary artery disease (CAD), congestive heart failure (CHF), and stroke largely decreased in a step-wise manner from highest (≥ 5) to lowest PIR (< 1). In adjusted analysis, we also noted a mostly dose-dependent association of PIR with the risk of all-cause and cardiac mortality during a mean 5.7 and 5.8 years of follow up, respectively. Our study demonstrates a largely dose-dependent association of PIR with hypertension, diabetes mellitus, CHF, CAD and stroke prevalence as well as incident all-cause mortality and cardiac mortality in a nationally representative sample of American adults. Public policy efforts should be directed to alleviate these disparities to help improve cardiovascular outcomes in vulnerable groups with low family income.

How to Address Scar Pincushioning and Webbing of the Nasal Dorsum Using Surgical Defatting and Z-plasty.

Nonmelanoma skin cancer is the most common cancer, typically growing in sun-exposed areas, such as the nose. After complete excision of the tumor, the subsequent scar may exhibit multiple complications that are easily noticeable and cosmetically unsatisfactory. When performing a revision of such a scar, using a single surgical technique may be insufficient; rather, the surgeon may need to carefully plan and utilize several techniques to achieve the best cosmetic outcome. Here, we report a case that demonstrates successful use of surgical defatting and Z-plasty techniques to revise a scar of the nasal dorsum that exhibited pincushioning and webbing.

Takotsubo syndrome: A current review of presentation, diagnosis, and management.

Takotsubo syndrome is a syndrome of acute heart failure due to left ventricular systolic dysfunction that is associated with increased cardiovascular morbidity and mortality. It occurs in both sexes and at all ages, but predominates in post-menopausal women for reasons that are unclear. In a patient who presents with cardiac symptoms, electrocardiographic changes, and/or biomarker elevation indicating myocardial stress (i.e. troponin elevation), this condition should be considered in the differential diagnosis. Cardiac imaging is critical for a timely diagnosis of this condition and has management implications. This syndrome can occur with or without underlying coronary artery disease, and while there are various characteristic myocardial patterns described on imaging, the most common one is left ventricular dysfunction due to apical stunning with basal hyperkinesis. In the acute phase, Takotsubo syndrome can lead to life-threatening sequelae, including cardiogenic shock, pulmonary edema, thromboembolism, and arrhythmias. Multiple pathophysiologic mechanisms are implicated, including an acute increase in left ventricular afterload in the setting of sympathetic activation with a catecholamine storm, multi-vessel coronary vasospasm, coronary endothelial microvascular dysfunction, and inflammation. In this review, we discuss the current knowledge surrounding presentation, diagnosis, and treatment of this under-diagnosed condition.

Phosphorylation of BRCA1 by ATM upon double-strand breaks impacts ATM function in end-resection: A potential feedback loop.

BRCA1 maintains genome stability by promoting homologous recombination (HR)-mediated DNA double-strand break (DSB) repair. Mutation of mouse BRCA1-S1152, corresponding to an ATM phosphorylation site in its human counterpart, resulted in increased genomic instability and tumor incidence. In this study, we report that BRCA1-S1152 is part of a feedback loop that sustains ATM activity. BRCA1-S1152A mutation impairs recruitment of the E3 ubiquitin ligase SKP2. This in turn attenuates NBS1-K63 ubiquitination by SKP2 at DSB, impairs sustained ATM activation, and ultimately leads to deficient end resection, the commitment step in the HR repair pathway. Auto-phosphorylation of human ATM at S1981 is known to be important for its kinase activation; we mutated the corresponding amino acid residue in mouse ATM (S1987A) to characterize potential roles of mouse ATM-S1987 in the BRCA1-SKP2-NBS1-ATM feedback loop. Unexpectedly, MEFs carrying the ATM-S1987A knockin mutation maintain damage-induced ATM kinase activation, suggesting a species-specific function of human ATM auto-phosphorylation.

A rare case of lues maligna in an HIV-negative woman.

We describe an HIV-negative 43-year-old woman presenting with a diffuse ulceronodular eruption and positive serological tests for syphilis consistent with lues maligna. Lues maligna is a severe and rare variant of secondary syphilis characterized by prodromal constitutional symptoms followed by the formation of multiple well-circumscribed nodules with ulceration and crust. This case depicts a particularly rare presentation as lues maligna usually involves HIV-positive men. The clinical presentation of lues maligna can pose a diagnostic challenge, with infections, sarcoidosis, and cutaneous lymphoma as just a few entities in its broad differential diagnosis. However, with a high index of suspicion, clinicians can diagnose and treat this entity earlier and reduce morbidity.

A novel diagnostic approach for the classification of small B-cell lymphoid neoplasms based on the NanoString platform.

Small B-cell lymphoid neoplasms (SBCLNs) are a heterogeneous group of diseases characterized by malignant clonal proliferation of mature B-cells. However, the classification of SBCLNs remains a challenge, especially in cases where histopathological analysis is unavailable or those with atypical laboratory findings or equivocal pathologic data. In this study, gene expression profiling of 1039 samples from 27 gene expression omnibus (GEO) datasets was first investigated to select highly and differentially expressed genes among SBCLNs. Samples from 57 SBCLN cases and 102 nonmalignant control samples were used to train a classifier using the NanoString platform. The classifier was built by employing a cascade binary classification method based on the random forest algorithm with 35 refined gene signatures. Cases were successively classified as chronic lymphocytic leukemia/small lymphocytic lymphoma, conventional mantle cell lymphoma, follicular lymphoma, leukemic non-nodal mantle cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia, and other undetermined. The classifier algorithm was then validated using an independent cohort of 197 patients with SBCLNs. Under the distribution of our validation cohort, the overall sensitivity and specificity of proposed algorithm model were >95%, respectively, for all the cases with tumor cell content greater than 0.72. Combined with additional genetic aberrations including IGH-BCL2 translocation, MYD88 L265P mutation, and BRAF V600E mutation, the optimal sensitivity and specificity were respectively found at 0.88 and 0.98. In conclusion, the established algorithm demonstrated to be an effective and valuable ancillary diagnostic approach for the sub-classification and pathologic investigation of SBCLN in daily practice.

Alternative Cosmetic and Medical Applications of Injectable Deoxycholic Acid: A Systematic Review.

BACKGROUND: Beyond submental fat reduction, injectable deoxycholic acid (DCA) has gained popularity in recent years for various minimally invasive lipolysis applications. OBJECTIVE: To summarize and evaluate the evidence of off-label uses of injectable DCA. METHODS: MEDLINE, Embase, CINAHL, Web of Science, and CENTRAL were searched. The outcomes measured included applications of DCA, treatment regimen, and its efficacy. An overall success rate for each condition was calculated based on the improvement defined in the included studies. RESULTS: Eleven studies evaluated the cosmetic use of DCA for excess adipose tissue on various anatomical locations. The outcomes were evaluated at time points ranging from 1 to 21 months post-treatment, with overall success rates over 85%. Eight case reports and series reported the success of using DCA treating lipomas, xanthelasmas, paradoxical adipose hyperplasia, fibrofatty residue of infantile hemangioma, piezogenic pedal papules, and HIV-associated lipohypertrophy. Although the preliminary efficacies were high, the overall recommendations for off-label uses are weak because of the lack of high-level studies. CONCLUSION: The review emphasizes the diversity of injectable DCA as a minimally invasive technique for lipolysis. Further high-level studies demonstrating consistent treatment regimens and methods of evaluation are warranted to make more definitive recommendations regarding off-label DCA use.

The CoVID-TE risk assessment model for venous thromboembolism in hospitalized patients with cancer and COVID-19.

BACKGROUND: Hospitalized patients with COVID-19 have increased risks of venous (VTE) and arterial thromboembolism (ATE). Active cancer diagnosis and treatment are well-known risk factors; however, a risk assessment model (RAM) for VTE in patients with both cancer and COVID-19 is lacking. OBJECTIVES: To assess the incidence of and risk factors for thrombosis in hospitalized patients with cancer and COVID-19. METHODS: Among patients with cancer in the COVID-19 and Cancer Consortium registry (CCC19) cohort study, we assessed the incidence of VTE and ATE within 90 days of COVID-19-associated hospitalization. A multivariable logistic regression model specifically for VTE was built using a priori determined clinical risk factors. A simplified RAM was derived and internally validated using bootstrap. RESULTS: From March 17, 2020 to November 30, 2020, 2804 hospitalized patients were analyzed. The incidence of VTE and ATE was 7.6% and 3.9%, respectively. The incidence of VTE, but not ATE, was higher in patients receiving recent anti-cancer therapy. A simplified RAM for VTE was derived and named CoVID-TE (Cancer subtype high to very-high risk by original Khorana score +1, VTE history +2, ICU admission +2, D-dimer elevation +1, recent systemic anti-cancer Therapy +1, and non-Hispanic Ethnicity +1). The RAM stratified patients into two cohorts (low-risk, 0-2 points, n = 1423 vs. high-risk, 3+ points, n = 1034) where VTE occurred in 4.1% low-risk and 11.3% high-risk patients (c statistic 0.67, 95% confidence interval 0.63-0.71). The RAM performed similarly well in subgroups of patients not on anticoagulant prior to admission and moderately ill patients not requiring direct ICU admission. CONCLUSIONS: Hospitalized patients with cancer and COVID-19 have elevated thrombotic risks. The CoVID-TE RAM for VTE prediction may help real-time data-driven decisions in this vulnerable population.

The Use of Lasers and Light Devices in Acne Management: An Update.

Acne vulgaris is a disease of the pilosebaceous unit and the most common inflammatory dermatosis worldwide. It is also associated with significant economic burden. Limitations of conventional topical and systemic treatments include long treatment course, intolerable adverse effects, antibiotic resistance, and patient compliance. Therefore, laser and light-based interventions present as alternative options over the past decade and have been used in combination with conventional pharmacological therapies and other physical modalities. An updated overview on the use of lasers and light-based devices in acne management is presented to help clinicians understand the safety and efficacy of these treatment options. The effectiveness of neodymium:yttrium aluminum garnet (Nd:YAG) for treating acne is supported by more high-level studies compared with other laser devices. There is limited evidence to support the use of CO2 lasers, potassium titanyl phosphate lasers, and 1565-nm non-ablative fractional lasers for treating acne. Among light devices, photodynamic therapy is the most studied, showing higher efficacies than some of the conventional topical and oral acne therapies. Intense-pulsed light and blue light therapies also show favorable outcomes. A limitation is that most studies are non-randomized and lack a control group, and report on a variety of device settings, treatment regimens, and outcome measures, making it challenging to summarize and generalize findings. Although the use of laser and light devices to treat acne is promising, further work with randomized controlled study designs and larger sample sizes will provide improved guidance on the application of these modalities.

Does signal reduction imply predictive coding in models of spoken word recognition?

Pervasive behavioral and neural evidence for predictive processing has led to claims that language processing depends upon predictive coding. Formally, predictive coding is a computational mechanism where only deviations from top-down expectations are passed between levels of representation. In many cognitive neuroscience studies, a reduction of signal for expected inputs is taken as being diagnostic of predictive coding. In the present work, we show that despite not explicitly implementing prediction, the TRACE model of speech perception exhibits this putative hallmark of predictive coding, with reductions in total lexical activation, total lexical feedback, and total phoneme activation when the input conforms to expectations. These findings may indicate that interactive activation is functionally equivalent or approximant to predictive coding or that caution is warranted in interpreting neural signal reduction as diagnostic of predictive coding.

Structural Basis of Tirasemtiv Activation of Fast Skeletal Muscle.

Troponin regulates the calcium-mediated activation of skeletal muscle. Muscle weakness in diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy occurs from diminished neuromuscular output. The first direct fast skeletal troponin activator, tirasemtiv, amplifies the response of muscle to neuromuscular input. Tirasemtiv binds selectively and strongly to fast skeletal troponin, slowing the rate of calcium release and sensitizing muscle to calcium. We report the solution NMR structure of tirasemtiv bound to a fast skeletal troponin C-troponin I chimera. The structure reveals that tirasemtiv binds in a hydrophobic pocket between the regulatory domain of troponin C and the switch region of troponin I, which overlaps with that of Anapoe in the X-ray structure of skeletal troponin. Multiple interactions stabilize the troponin C-troponin I interface, increase the affinity of troponin C for the switch region of fast skeletal troponin I, and drive the equilibrium toward the active state.

89% Vichy mineralizing water with hyaluronic acid is a well-tolerated adjunct treatment that helps restore skin barrier function in dry skin-related inflammatory dermatoses and post-procedure skin care: A Canadian study.

INTRODUCTION: Minéral 89 (M89), comprised of 89% Vichy mineralizing water and hyaluronic acid, has been formulated to help strengthen and restore skin barrier. AIM: Assess tolerance and efficacy of M89 in post-esthetic procedures and dry skin-related facial dermatoses. METHOD: Adults post-esthetic procedure or presenting with inflammatory dermatoses (47 subjects; mean age 40.9 ± 13.2 years; any Fitzpatrick or skin phototype), applied M89 for 4 weeks, once or twice daily, as an adjuvant treatment. Information on clinical signs and subject-reported symptoms, skin characteristics, tolerance, and subject and investigator satisfaction were collected. RESULTS: Following 4 weeks of M89 use, significant decreases with complete resolution of erythema (27.6%), desquamation (29.8%), irritation (32%), and skin dehydration (35.8%), as compared to baseline signs and symptoms, were observed. Overall grading improvements for erythema (84.8%; p < 0.001), desquamation (91.7%; %; p < 0.003), irritation (91.7%; %; p < 0.015), and skin hydration (46.2%; p < 0.015) were noted. There was no significant improvement in papules and pustules. Evaluation of subjective signs demonstrated significant decreases in skin sensations such as burning (-73%; p < 0.0001), itching (-71%; p < 0.0001), stinging-tingling (-66.7%; p < 0.0001), as well as in skin dryness (-60%; p < 0.0001). M89 texture was rated very pleasant by 90% of patients. Investigators assessed M89 tolerance to be either good or very good (93%), and satisfactory or highly satisfactory impact on patient's skin (91.5%). CONCLUSION: M89 is a highly tolerable adjuvant treatment that significantly improved clinical signs and symptoms related to a compromised skin barrier in various facial dermatoses and post-aesthetic procedures.

Primary bone lymphoma of the ilium successfully treated without radiation.

The addition of radiation therapy to chemotherapy and impact on outcomes in primary bone lymphoma is not clear. Nonetheless, tumor location must be considered as radiation to marrow-rich bone areas can lead to myelosuppression and myelotoxicity.

Dermatologic Laser Side Effects and Complications: Prevention and Management.

The evolution of modern laser and light-based systems has mirrored the demand for clinically effective treatments and the need for safer technologies with reduced postoperative recovery, side effects, and complications. With each new generation of lasers, more selective tissue destruction can be achieved with reduced unwanted sequelae. Patient selection and preparation, operator technique, and expeditious recognition and management of post-treatment side effects are paramount in avoiding complications and patient dissatisfaction. An overview of important variables to consider for dermatologic laser treatments are presented in order to provide a framework to reduce the severity and duration of possible post-treatment side effects and complications.