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The purpose of this study was to examine the clinical outcomes associated with the Columbus primary total knee replacement (B. Braun Aesculap, Tuttlingen, Germany), correlate these outcomes with variables measured intra-operatively with the OrthoPilot navigation system (B. Braun Aesculap), and explore the full potential of automating the process of intraoperative data collection. Clinical and functional outcomes at 2.5 years were similar to results reported in previous studies. Correlations were seen between initial mechanical axis deformity and postoperative range of motion as well as between final mechanical axis alignment and the presence of flexion contractures at later follow-up. It is now possible to potentially stratify particular segments of patients and develop specific intraoperative alignment targets that are most likely to yield positive clinical and functional outcomes. [ABSTRACT FROM AUTHOR]

1 The disposition in urine of debrisoquine and its hydroxylated metabolites has been studied in subjects of the 'extensive metabolizer' (EM; n = 5) and 'poor metabolizer' (PM; n = 5) phenotypes. The 4- hydroxylation of debrisoquine by PM subjects following a 10 mg oral dose was capacity-limited and displayed significant dose-dependency over a range of 1-20 mg. In contrast, the EM subjects' ability to perform this metabolic oxidation did not deviate from first-order kinetics over a dose range of 10-40 mg. 2 The disposition of debrisoquine in plasma following a 10 mg oral dose has been studied in EM (n = 4) and PM (n = 3) subjects. Whilst PM subjects displayed significantly higher plasma levels of debrisoquine at all time points following 1 h post-dosing, and higher values for areas under the plasma concentration-time curve (EM: 105.6 +/- 7.0 ng ml-1 h; PM: 371.4 +/- 22.4 ng ml-1 h, 2P less than 0.0001), neither debrisoquine plasma half- life (EM: 3.0 +/- 0.5 h; PM: 3.3 +/- 0.4 h) nor renal clearance of the drug (EM: 152.8 +/- 30.3 ml min-1; PM: 137 +/- 4.5 ml min-1) displayed significant inter-phenotype differences. 3 The results of these investigations show that the phenotyping of individuals for debrisoquine oxidation status by means of a 'metabolic ratio' derived from a single 0-8 h urine sample has a sound kinetic basis. The kinetic differences between the two phenotypes would strongly suggest that the metabolic defect manifested in PM subjects is one of pre-systemic elimination capacity. [ABSTRACT FROM AUTHOR]

64-year-old woman with a history of esophageal strictures presented in 2015 for evaluation of progressive depigmented patches that developed over the preceding year. She was prescribed topical steroids with no improvement. Narrow-band ultraviolet B (NB-UVB) and topical tacrolimus were eventually added to the topical steroids accompanying an oral steroid taper. The patient discontinued topical tacrolimus because of irritation. The patient was lost to follow-up for the next 3 years, during which she did not take any treatment and her vitiligo had worsened (Figure 1). At her visit 3 years later, she repeated an oral prednisone taper and restarted mid-potency topical steroid. In January 2020, the patient was approved for and started oral tofacitinib 5 mg twice daily. Consistent improvement was observed on the subsequent visits in March 2020 and November 2020. The only adverse reaction reported by the patient was an increase in furuncles on her pelvis and thighs.

Per- and poly-fluoroalkyl substances (PFAS) are emerging contaminants of concern because of their wide use, persistence, and potential to be hazardous to both humans and the environment. Several PFAS have been designated as substances of concern; however, most PFAS in commerce lack toxicology and exposure data to evaluate their potential hazards and risks. Cardiotoxicity has been identified as a likely human health concern, and cell-based assays are the most sensible approach for screening and prioritization of PFAS. Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes are a widely used method to test for cardiotoxicity, and recent studies showed that many PFAS affect these cells. Because iPSC-derived cardiomyocytes are available from different donors, they also can be used to quantify human variability in responses to PFAS. The primary objective of this study was to characterize potential human cardiotoxic hazard, risk, and inter-individual variability in responses to PFAS. A total of 56 PFAS from different subclasses were tested in concentration-response using human iPSC-derived cardiomyocytes from 16 donors without known heart disease. Kinetic calcium flux and high-content imaging were used to evaluate biologically-relevant phenotypes such as beat frequency, repolarization, and cytotoxicity. Of the tested PFAS, 46 showed concentration-response effects in at least one phenotype and donor; however, a wide range of sensitivities were observed across donors. Inter-individual variability in the effects could be quantified for 19 PFAS, and risk characterization could be performed for 20 PFAS based on available exposure information. For most tested PFAS, toxicodynamic variability was within a factor of 10 and the margins of exposure were above 100. This study identified PFAS that may pose cardiotoxicity risk and have high inter-individual variability. It also demonstrated the feasibility of using a population-based human in vitro method to quantify population variability and identify cardiotoxicity risks of emerging contaminants., (© 2024. The Author(s).)

Extramammary Paget disease is a rare cutaneous malignancy that most commonly affects the genitals, perianal area, and axilla of elderly patients. Delays in care often lead to high levels of disease burden for patients. Thus, evidence-based recommendations are paramount in mitigating morbidity and mortality for this unique patient population. This 2-part continuing medical education series provides a complete picture of extramammary Paget disease. Part 2 of this continuing medical education series focuses on the complex management of extramammary Paget disease including surgical and noninvasive therapies, as well as novel approaches for advanced disease., Competing Interests: Conflicts of interest Dr Rossi has no relevant conflicts of interest related to this article but has received grant funding from The Skin Cancer Foundation and the A. Ward Ford Memorial Grant, served on advisory board, as a consultant, given educational presentations for Almirall, Allergan Inc, Galderma Inc, Evolus Inc, Elekta, Biofrontera (Quantia), Merz Inc, Dynamed, Skinuvia, Perf-Action, Cutera, and LAM therapeutics, and holds equity in DAR companies. Dr Funt has received research support from AstraZenecaAstraZeneca, GenentechGenentech/RocheRoche, and Decibel Therapeutics, is a consultant/advisory board member for MerckMerck and BioNTech, and owns stock in Urogen, Allogene Therapeutics, Neogene Therapeutics, Kronos Bio, ByHeart, 76Bio, Vida Ventures, Ginkgo Bioworks, Doximity, and Inconovir. The other authors have no conflicts of interest to declare., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Extramammary Paget disease (EMPD) is a rare skin cancer of apocrine-rich skin that mimics common inflammatory and infectious dermatoses, leading to delays in diagnosis and increased patient morbidity. Better clinical recognition of this entity, multidisciplinary patient assessment, and deeper understanding of the underlying pathophysiology are essential to improve patient care and disease outcomes. It is important to distinguish primary intraepithelial/micro-invasive EMPD from invasive EMPD or cases with adenocarcinoma arising within EMPD. This 2-part continuing medical education series provides a complete picture of EMPD. Part 1 of this continuing medical education series reviews the epidemiology, oncogenesis, clinical and histopathologic presentation, workup, and prognosis of this rare cancer., Competing Interests: Conflict of interest Anthony Rossi: Dr Rossi has no relevant conflicts of interest related to this manuscript. He also served on advisory board, as a consultant, or given educational presentations for: Almirall; Allergan, Inc; Galderma Inc; Evolus Inc; Elekta; Biofrontera, Quantia; Merz Inc; Dynamed; Skinuvia; Perf-Action; Cutera; and LAM therapeutics. Equity in DAR companies., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

The scalp microbiome represents an array of microorganisms important in maintaining scalp homeostasis and mediating inflammation. Scalp microbial dysregulation has been implicated in dermatologic conditions including alopecia areata (AA), dandruff/seborrheic dermatitis (D/SD), scalp psoriasis (SP) and folliculitis decalvans (FD). Understanding the impact of scalp microbial dysbiosis gives insight on disease pathophysiology and guides therapeutic decision making. Herein we review the scalp microbiome and its functional role in scalp conditions by analysis of metagenomic medical literature in alopecia, D/SD, SP, and other dermatologic disease.Increased abundance of Malassezia, Staphylococcus, and Brevibacterium was associated with SD compared to healthy controls. A higher proportion of Corynebacterium, actinobacteria, and firmicutes are present in AA patients, and lower proportions of Staphylococcus caprae are associated with worse clinical outcomes. Decreased prevalence of actinobacteria and Propionibacterium and increased firmicutes, staphylococcus, and streptococcus are associated with scalp psoriasis. Studies of central centrifugal cicatricial alopecia (CCCA) suggest scalp microbial composition contributes to CCCA's pro-inflammatory status. The most common organisms associated with FD include methicillin-resistant S. aureus and S. lugdunensis. Antifungals have been a mainstay treatment for these diseases, while other alternatives including coconut oils and shampoos with heat-killed probiotics have shown considerable potential efficacy by replenishing the scalp microbiome., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To use pharyngeal pressure recordings to distinguish different upper airway collapse patterns in obstructive sleep apnea (OSA) patients, and to assess whether these pressure recordings correlate with candidacy assessment for hypoglossal nerve stimulator (HGNS) implantation., Study Design: Prospective case series., Setting: Single tertiary-quaternary care academic center., Methods: Subjects with OSA prospectively underwent simultaneous drug-induced sleep endoscopy (DISE) and transnasal pharyngeal pressure recording with a pressure-transducing catheter. Pressure was recorded in the nasopharynx and oropharynx, and endoscopic collapse patterns were classified based on site, extent, and direction of collapse. Pressure recordings were classified categorically by waveform shape as well as numerically by inspiratory and expiratory amplitudes and slopes. Waveform shape, amplitude, and slope were then compared with the endoscopic findings., Results: Twenty-five subjects with OSA were included. Nasopharyngeal waveform shape was associated with the extent of collapse at the level of the palate ( P  = .001). Oropharyngeal waveform shape was associated with anatomical site of collapse ( P  < .001) and direction of collapse ( P  = .019) below the level of the palate. Pressure amplitudes and slopes were also associated with the extent of collapse at various sites. Waveform shape was also associated with favorable collapse pattern on endoscopy for HGNS implantation ( P  = .043), as well as surgical candidacy for HGNS ( P  = .004)., Conclusion: Characteristic pharyngeal pressure waveforms are associated with different airway collapse patterns. Pharyngeal pressure is a promising adjunct to DISE in the sleep surgery candidacy evaluation., Competing Interests: The authors declare that there is no conflict of interest., (© 2024 The Author(s). OTO Open published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail N -acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 ( 70 ) that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized.

Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and organ injuries. Per- and polyfluoro alkyl substances (PFAS) and polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that bioaccumulate and have been associated with steatosis in the liver. Although PFAS and PAH are classified as chemicals of concern, their molecular mechanisms of toxicity remain to be explored in detail. In this study, we aimed to identify potential mechanisms by which an acute exposure to PFAS and PAH chemicals can induce lipid accumulation and whether the responses depend on chemical class, dose, and sex. To this end, we analyzed mechanisms beginning with the binding of the chemical to a molecular initiating event (MIE) and the consequent transcriptomic alterations. We collated potential MIEs using predictions from our previously developed ToxProfiler tool and from published steatosis adverse outcome pathways. Most of the MIEs are transcription factors, and we collected their target genes by mining the TRRUST database. To analyze the effects of PFAS and PAH on the steatosis mechanisms, we performed a computational MIE-target gene analysis on high-throughput transcriptomic measurements of liver tissue from male and female rats exposed to either a PFAS or PAH. The results showed peroxisome proliferator-activated receptor (PPAR)-α targets to be the most dysregulated, with most of the genes being upregulated. Furthermore, PFAS exposure disrupted several lipid metabolism genes, including upregulation of fatty acid oxidation genes ( Acadm , Acox1 , Cpt2 , Cyp4a1 - 3 ) and downregulation of lipid transport genes ( Apoa1 , Apoa5 , Pltp ). We also identified multiple genes with sex-specific behavior. Notably, the rate-limiting genes of gluconeogenesis ( Pck1 ) and bile acid synthesis ( Cyp7a1 ) were specifically downregulated in male rats compared to female rats, while the rate-limiting gene of lipid synthesis ( Scd ) showed a PFAS-specific upregulation. The results suggest that the PPAR signaling pathway plays a major role in PFAS-induced lipid accumulation in rats. Together, these results show that PFAS exposure induces a sex-specific multi-factorial mechanism involving rate-limiting genes of gluconeogenesis and bile acid synthesis that could lead to activation of an adverse outcome pathway for steatosis., Competing Interests: Authors AH, MA, and VP were employed by The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Authors MB-M, DM, DP, ES, and RS were employed by Sciome LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hari, AbdulHameed, Balik-Meisner, Mav, Phadke, Scholl, Shah, Casey, Auerbach, Wallqvist and Pannala.)

The COVID-19 pandemic has changed many facets of medical care and has resulted in a rise in delayed treatments across all specialties, including cosmetic dermatology. Delayed care for squamous cell carcinomas (SCC) and basal cell carcinoma (BCC) is not only a burden for medical providers, but also confers a risk to patients, as delayed surgeries are associated with increased metastatic risk and tumor size. Mohs micrographic surgery (MMS) delayed by more than one year leads to increased risk of complications, including bleeding and impaired wound healing, especially in the elderly population. To decrease bleeding risks, we have developed a modified MMS technique known as the "rim and deep margin" technique. Here, we present additional cases using this technique to minimize bleeding and operative time for patients with an increased risk of morbidity. This technique has been used successfully in the past for large tumors and can now be used for patients who have faced delay of care, as evidenced by its success during the COVID-19 pandemic., Competing Interests: DISCLOSURES: The authors have no conflicts of interest relevant to the content of this article., (Copyright © 2024. Matrix Medical Communications. All rights reserved.)

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have emerged as a therapeutic modality to induce targeted protein degradation (TPD) by harnessing cellular proteolytic degradation machinery. PROTACs which ligand the E3 ligase in a covalent manner have attracted intense interest; however, covalent PROTACs with a broad protein of interest (POI) scope have proven challenging to discover by design. Here, we report the structure-guided design and optimization of Von Hippel-Lindau (VHL) protein-targeted sulfonyl fluorides which covalently bind Ser110 in the HIF1α binding site. We demonstrate that their incorporation in bifunctional degraders induces targeted protein degradation of BRD4 or the androgen receptor without further linker optimization. Our study discloses the first covalent VHL ligands which can be implemented directly in bifunctional degrader design, expanding the substrate scope of covalent E3 ligase PROTACs.

Per- and poly-fluoroalkyl substances (PFAS) are extensively used in commerce leading to their prevalence in the environment. Due to their chemical stability, PFAS are considered to be persistent and bioaccumulative; they are frequently detected in both the environment and humans. Because of this, PFAS as a class (composed of hundreds to thousands of chemicals) are contaminants of very high concern. Little information is available for the vast majority of PFAS, and regulatory agencies lack safety data to determine whether exposure limits or restrictions are needed. Cell-based assays are a pragmatic approach to inform decision-makers on potential health hazards; therefore, we hypothesized that a targeted battery of human in vitro assays can be used to determine whether there are structure-bioactivity relationships for PFAS, and to characterize potential risks by comparing bioactivity (points of departure) to exposure estimates. We tested 56 PFAS from 8 structure-based subclasses in concentration response (0.1-100 μM) using six human cell types selected from target organs with suggested adverse effects of PFAS - human induced pluripotent stem cell (iPSC)-derived hepatocytes, neurons, and cardiomyocytes, primary human hepatocytes, endothelial and HepG2 cells. While many compounds were without effect; certain PFAS demonstrated cell-specific activity highlighting the necessity of using a compendium of in vitro models to identify potential hazards. No class-specific groupings were evident except for some chain length- and structure-related trends. In addition, margins of exposure (MOE) were derived using empirical and predicted exposure data. Conservative MOE calculations showed that most tested PFAS had a MOE in the 1-100 range; ∼20% of PFAS had MOE<1, providing tiered priorities for further studies. Overall, we show that a compendium of human cell-based models can be used to derive bioactivity estimates for a range of PFAS, enabling comparisons with human biomonitoring data. Furthermore, we emphasize that establishing structure-bioactivity relationships may be challenging for the tested PFAS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: Lucie C. Ford reports financial support was provided by Texas A&M University. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dietary assessments are important clinical tools used by Registered Dietitians (RDs). Current methods pose barriers to accurately assess the nutritional intake of older adults due to age-related increases in risk for cognitive decline and more complex health histories. Our qualitative study explored whether implementing Voice assistant systems (VAS) could improve current dietary recall from the perspective of 20 RDs. RDs believed the implementing VAS in dietary assessments of older adults could potentially improve patient accuracy in reporting food intake, recalling portion sizes, and increasing patient-provider efficiency during clinic visits. RDs reported that low technology literacy in older adults could be a barrier to implementation. Our study provides a better understanding of how VAS can better meet the needs of both older adults and RDs in managing and assessing dietary intake.

Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300-1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

Recently, treatment outcomes in patients with toenail onychomycosis have improved considerably due to more effective oral antifungal medications such as terbinafine and itraconazole. These medications can either be used continuously for several weeks at a lower dose or intermittently (pulsed) at a higher dose. Previous literature comparing pulse and continuous therapy has generated mixed results.&nbsp; Our study aims to compare the efficacy, in terms of clinical cure rate, of continuous vs pulse dose terbinafine regimens for toenail onychomycosis. Sixty patients with onychomycosis of Fitzpatrick skin types IV to VI, between 15 and 65 years of age, were divided into a continuous treatment group receiving 250 mg terbinafine once daily for 12 weeks and a pulse treatment group receiving 250 mg twice daily terbinafine for 1 week repeated every 4 weeks for 12 weeks. Each patient was followed up at weeks 4, 8, and 12.&nbsp; Efficacy of the continuous treatment group was significantly greater at 76.67% compared with 26.67% in the pulse treatment group. Thus, we conclude that the clinical cure rate of a continuous dose regimen of terbinafine is a superior treatment option for toenail onychomycosis. However, we also suggest further studies including combinations of multiple agents and hybrid regimen models for the optimal onychomycosis treatment.&nbsp;&nbsp; J Drugs Dermatol. 2023;22(10):&nbsp; &nbsp; &nbsp;doi:10.36849/JDD.7323R1.

Melasma is a common dermatologic condition affecting all skin types. Increasing rates of melasma warrant identification of a reliable topical treatment. In recent years, off-label tranexamic acid (TA) has emerged as a potential treatment of melasma. Although the mechanism of action remains unclear, it is thought that TA inhibits melanin synthesis by blocking the interaction between melanocytes and keratinocytes while reversing the abnormal dermal changes associated with melasma. Our study assessed the efficacy of TA solution 5% for the treatment of melasma in patients with darker skin types.