Clinical outcomes of COVID-19 in patients taking tumor necrosis factor inhibitors or methotrexate: A multicenter research network study.

BACKGROUND: Data on the impact of biologics and immunomodulators on coronavirus disease 2019 (COVID-19)-related outcomes remain scarce. OBJECTIVE: We sought to determine whether patients taking tumor necrosis factor inhibitors (TNFis) or methotrexate are at increased risk of COVID-19-related outcomes. METHODS: In this large comparative cohort study, real-time searches and analyses were performed on adult patients who were diagnosed with COVID-19 and were treated with TNFis or methotrexate compared with those who were not treated. The likelihood of hospitalization and mortality were compared between groups with and without propensity score matching for confounding factors. RESULTS: More than 53 million (53,511,836) unique patient records were analyzed, of which 32,076 (0.06%) had a COVID-19-related diagnosis documented starting after January 20, 2020. Two hundred fourteen patients with COVID-19 were identified with recent TNFi or methotrexate exposure compared with 31,862 patients with COVID-19 without TNFi or methotrexate exposure. After propensity matching, the likelihood of hospitalization and mortality were not significantly different between the treatment and nontreatment groups (risk ratio = 0.91 [95% confidence interval, 0.68-1.22], P = .5260 and risk ratio = 0.87 [95% confidence interval, 0.42-1.78], P = .6958, respectively). LIMITATIONS: All TNFis may not behave similarly. CONCLUSION: Our study suggests that patients with recent TNFi or methotrexate exposure do not have increased hospitalization or mortality compared with patients with COVID-19 without recent TNFi or methotrexate exposure.

Benign Glandular Schwannoma With Ancient Change.

Benign glandular schwannomas are rare and should be distinguished from malignant peripheral nerve sheath tumors with similar divergent tissue differentiation. The authors present a benign glandular schwannoma with ancient change that developed in the subcutis of a 46-year-old man's posterior calf. He lacked stigmata of neurofibromatosis type 1 (NF1). The glandular elements stained positively for epithelial membrane antigen and pancytokeratin. The spindled cells stained positively for SOX10 and S100 protein, supporting schwannian (neural crest) differentiation. The tumor's location and histopathology suggest that the pathogenesis stems from entrapment of sweat glands. Finally, it must be recognized that ancient change may mimic malignancy in these neoplasms as the malignant counterparts have a greater association with NF1 and a poorer prognosis.

Type I Cutaneous Meningioma (Rudimentary Meningocele) With Intradural Attachment to the Phylum Terminale.

Cutaneous meningiomas (CM) are a small subset of meningiomas, further classified into three subtypes. The authors present a 15-year-old male with a symptomatic congenital type I CM and describe the histopathological and immunohistochemical findings. To the authors' knowledge, this is the first report of an extraspinal lumbar type I CM with intradural attachment to the phylum terminale.

Correlation of rosacea with hot beverage intake.

In this report, we correlated the incidence of rosacea with coffee (regular and decaffeinated) and tea consumption in a large cohort of middle-aged men and women living within the United Kingdom. Caffeinated coffee drinkers had lower odds for rosacea diagnosis compared to non-coffee drinkers. We hypothesize that the vasoconstrictive effects of caffeine in regular coffee overpower the vasodilatory effects associated with hot beverages and support it to be protective against rosacea.

Association Between Alopecia Areata and Natural Hair Color Among White Individuals.

IMPORTANCE: Alopecia areata (AA) is a complex immune-mediated disorder that causes nonscarring hair loss. Previous reports have documented preferential targeting of pigmented hair follicles with sparing of gray, nonpigmented hair follicles in alopecia lesions. Thus, immune targeting of melanogenesis-associated proteins in melanocytes and keratinocytes represents a potential mechanism for the inflammation that targets anagen hairs in alopecia areata. OBJECTIVE: To investigate the association of alopecia areata with hair color among White residents of the UK. DESIGN, SETTING, AND PARTICIPANTS: This matched, case-control study conducted in October 2020 used a large prospectively acquired cohort and included data that were collected from the UK Biobank, a large-scale prospective resource designed to study phenotypic and genotypic determinants in adults. A total of 502 510 UK Biobank participants were reviewed for inclusion. Among these individuals, 1673 cases of alopecia areata with reported hair color were captured and matched by age and sex to 6692 controls without alopecia areata using 1:4 matching. MAIN OUTCOMES AND MEASURES: Conditional logistic regression analysis was performed, in which the outcome variable was alopecia areata and the main predictor was natural hair color before graying. The variables considered included diabetes, hypothyroidism, hyperthyroidism, and vitiligo. RESULTS: Of 464 353 participants, 254 505 (54.8%) were women, and the mean (SD) age for those with alopecia areata was 46.9 (16.5) years. Alopecia areata was significantly more common in individuals with black (adjusted odds ratio [aOR], 2.97; 95% CI, 2.38-3.71) and dark brown hair (aOR, 1.26; 95% CI, 1.11-1.42) compared with light brown hair. In contrast, blond individuals exhibited significantly decreased alopecia areata compared with those with light brown hair (aOR, 0.69; 95% CI, 0.56-0.85). Red hair color was not significantly different from light brown hair. CONCLUSIONS AND RELEVANCE: The findings of this matched case-control study seem to indicate that alopecia areata is modulated by natural hair color, preferentially targeting darker hair. Our results support a previously proposed model of alopecia areata in which immunity is directed against melanogenesis-associated proteins in the anagen hair follicles. However, further study is needed to more precisely understand the immunopathogenic association between alopecia areata and hair color.

Validation of CP-GEP (Merlin Assay) for predicting sentinel lymph node metastasis in primary cutaneous melanoma patients: A U.S. cohort study.

BACKGROUND: Approximately 85% of melanoma patients who undergo a sentinel lymph node biopsy (SLNB) are node-negative. Melanoma incidence is highest in patients ≥65 years, but their SLNB positivity rate is lower than in younger patients. CP-GEP, a model combining clinicopathologic and gene expression variables, identifies primary cutaneous melanoma (CM) patients who may safely forgo SLNB due to their low risk for nodal metastasis. Here, we validate CP-GEP in a U.S. melanoma patient cohort. METHODS: A cohort of 208 adult patients with primary CM from the Mayo Clinic and West Virginia University was used. Patients were stratified according to their risk for nodal metastasis: CP-GEP High Risk and CP-GEP Low Risk. The main performance measures were SLNB reduction rate (RR) and negative predictive value (NPV). RESULTS: SLNB positivity rate for the entire cohort was 21%. Most patients had a T1b (34%) or T2a (31%) melanoma. In the T1-T2 group (153 patients), CP-GEP achieved an SLNB RR of 41.8% (95% CI: 33.9-50.1) at an NPV of 93.8% (95% CI: 84.8-98.3). Subgroup analysis showed similar performance in T1-T2 patients ≥65 years of age (51 patients; SLNB positivity rate, 9.8%): SLNB RR of 43.1% (95% CI: 29.3-57.8) at an NPV of 95.5% (95% CI: 77.2-99.9). CONCLUSION: We confirmed the potential of CP-GEP to reduce negative SLNB in all relevant age groups. Our findings are especially relevant to patients ≥65 years, where surgery is often elective. CP-GEP may guide SLNB decision-making in clinical practice.

Rho A and the Rho kinase pathway regulate fibroblast contraction: Enhanced contraction in constitutively active Rho A fibroblast cells.

Fibroblast cells play a central role in the proliferation phase of wound healing processes, contributing to force development. The intracellular signaling pathways regulating this non-muscle contraction are only partially understood. To study the relations between Rho A and contractile responses, constitutively active Rho A (CA-Rho A) fibroblast cells were reconstituted into fibers and the effects of calf serum (CS) on isometric force were studied. CS-induced force in CA-Rho A fibroblast fibers was twice as large as that in wild type (NIH 3T3) fibroblast fibers. During this response, the translocation of Rho A from the cytosol to the membrane was detected by Rho A activity assays and Western blot analysis. Pre-treatment with a Rho specific inhibitor (C3-exoenzyme) suppressed translocation as well as contraction. These results indicate that Rho A activation is essential for fibroblast contraction. The Rho kinase inhibitor (Y27632) inhibited both NIH 3T3 and CA-Rho A fibroblast fiber contractions. Activation of Rho A is thus directly coupled with Rho kinase activity. We conclude that the translocation of Rho A from the cytosol to the membrane and the Rho kinase pathway can regulate wound healing processes mediated by fibroblast contraction.

Tissue-selective effects of injected deoxycholate.

BACKGROUND: Recent studies suggest that the principal active ingredient in phosphatidylcholine-containing injectable fat-reduction formulations is actually deoxycholate (DC). This bile acid acts as a detergent to rapidly disrupt cell membranes. Thus, it is not obvious why DC would preferentially target fat. OBJECTIVE: To investigate possible mechanisms for the selectivity of DC for fat tissue using in vivo and in vitro models. METHODS AND MATERIALS: Histology, drug distribution studies, and cell viability assays were used to examine possible mechanisms contributing to DC selectivity. RESULTS: In vitro, DC caused the lysis of all cell types tested within the tested concentration range. DC injected into fat tissue caused adipocyte death, whereas other cell types appeared less affected. Physiological concentrations of albumin or protein-rich tissues decrease the ability of DC to lyse cells. Furthermore, DC relocated to the gastrointestinal tract in animals within hours of injection. This suggests that similar mechanisms may be present in humans. CONCLUSION: We report observations that provide a possible explanation for the in vivo preferential fat targeting by DC. Fat tissue, being deficient in cell-associated proteins and interstitial albumin, may be unable to sufficiently neutralize the detergent activity of DC, possibly making fat uniquely sensitive to DC.

Hereditary Trichilemmal Cysts are Caused by Two Hits to the Same Copy of the Phospholipase C Delta 1 Gene (PLCD1).

The autosomal dominant presentation of trichilemmal cysts is one of the most common single gene familial diseases in humans. However, the genetic basis for the inheritance and genesis of these lesions has remained unknown. We first studied patients with multiple trichilemmal cysts using exome and Sanger sequencing. Remarkably, 21 of 21 trichilemmal cysts from 16 subjects all harbored a somatic p.S745L (c.2234 G > A) mutation in phospholipase C delta 1 (PLCD1), a proposed tumor suppressor gene. In addition to this specific somatic mutation in their tumors, 16 of the 17 subjects with multiple trichilemmal cysts were also heterozygous for a p.S460L (c.1379 G > A) germline variant in PLCD1 which is normally present in only about 6% of this population. The one patient of 17 that did not show the p.S460L germline variant had a germline p.E455K (c.1363 C > T) mutation in the same exon of PLCD1. Among 15 additional subjects, with a history suggesting a single sporadic trichilemmal cyst, six were likely familial due to the presence of the p.S460L germline variant. Of the remaining truly sporadic trichilemmal cysts that could be sequenced, only half showed the p.S745L somatic mutation in contrast to 100% of the familial cysts. Surprisingly, in contrast to Knudsen's two hit hypothesis, the p.S745L somatic mutation was always on the same chromosome as the p.S460L germline variant. Our results indicate that familial trichilemmal cysts is an autosomal dominant tumor syndrome resulting from two hits to the same allele of PLCD1 tumor suppressor gene. The c.1379 G > A base change and neighboring bases are consistent with a mutation caused by ultraviolet radiation. Our findings also indicate that approximately one-third of apparently sporadic trichilemmal cysts are actually familial with incomplete penetrance. Sequencing data suggests that the remaining, apparently sporadic, trichilemmal cysts are genetically distinct from familial cysts due to a lack of the germline mutations that underlie familial cysts and a decreased prevalence of the p.S745L somatic mutation relative to familial trichilemmal cysts.

Wild-type blocking polymerase chain reaction for detection of single nucleotide minority mutations from clinical specimens.

Detection and sequencing of mutations from clinical specimens is often complicated by the presence of an excess of nonmutated cells. To facilitate the detection and sequencing of minority mutations from clinical specimens, we developed wild-type blocking polymerase chain reaction (WTB-PCR). This technique allows sensitive detection of minority mutations in a tissue sample containing excess wild-type DNA. In WTB-PCR, a nonextendable locked nucleic acid (LNA) oligonucleotide binds tightly to a region of wild-type DNA known to develop point mutations. This LNA sequence blocks amplification of wild-type DNA during PCR while permitting amplification of mutant exon 15. Our results show that the LNA blocking oligonucleotide inhibits amplification of wild-type DNA in a dose-dependent manner. WTB-PCR was able to detect mutant DNA in clinical samples of melanoma tissue containing an excess of nonmelanoma cells. This method was also able to detect small amounts of point mutated or tandem mutated DNA diluted with a much larger concentration of wild-type DNA. This rapid and simple assay overcomes the limitations of current methods to detect minority mutations. The potential applications of WTB-PCR include early diagnosis and prognosis of various cancers.