Enhancing carbapenem antimicrobial dosing optimization: synergy of antimicrobial stewardship teams and ward-based clinical pharmacists.

Antimicrobial-product package inserts and insufficient staffing impede routine carbapenem monitoring in the inpatient setting in Japan. The collaboration between antimicrobial stewardship teams and clinical pharmacists was associated with a sustained improvement in carbapenem dosing optimization. Our findings could be of use to countries with inadequate monitoring of carbapenem antimicrobial use.

Alopecia areata: What's new in the diagnosis and treatment with JAK inhibitors?

Alopecia areata (AA) affects individuals of all ages and is intractable in severe relapsing cases. Dermatologists and other healthcare providers should consider AA in the medical context and prioritize treatment. Several randomized controlled clinical studies on Janus kinase (JAK) inhibitors with different specificities for the treatment of AA are ongoing. These studies have encouraged us to appreciate the importance of a definitive diagnosis and accurate evaluation of AA before and during treatment. Following our previous review article in 2017, here we provide the second part of this two-review series on the recent progress in the multidisciplinary approaches to AA from more than 1800 articles published between July 2016 and December 2022. This review focuses on the evaluation, diagnosis, and treatment of AA. We also provide the latest information on the safety and efficacy of JAK inhibitors for the treatment of AA and describe their mechanisms of action.

TRPV1-positive sensory nerves and neuropeptides are involved in epidermal barrier repair after tape stripping in mice.

BACKGROUND: The integumentary system of the skin serves as an exceptional protective barrier, with the stratum corneum situated at the forefront. This outermost layer is composed of keratinocytes that biosynthesize filaggrin (encoded by the gene Flg), a pivotal constituent in maintaining skin health. Nevertheless, the precise role of sensory nerves in restoration of the skin barrier after tape stripping-induced epidermal disruption, in contrast to the wound-healing process, remains a tantalizing enigma. OBJECTIVE: This study aimed to elucidate the cryptic role of sensory nerves in repair of the epidermal barrier following tape stripping-induced disruption. METHODS: Through the implementation of resiniferatoxin (RTX)-treated denervation mouse model, we investigated the kinetics of barrier repair after tape stripping and performed immunophenotyping and gene expression analysis in the skin or dorsal root ganglia (DRG) to identify potential neuropeptides. Furthermore, we assessed the functional impact of candidates on the recovery of murine keratinocytes and RTX-treated mice. RESULTS: Ablation of TRPV1-positive sensory nerve attenuated skin barrier recovery and sustained subcutaneous inflammation, coupled with elevated IL-6 level in ear homogenates after tape stripping. Expression of the keratinocyte differentiation marker Flg in the ear skin of RTX-treated mice was decreased compared with that in control mice. Through neuropeptide screening, we found that the downregulation of Flg by IL-6 was counteracted by somatostatin or octreotide (a chemically stable somatostatin analog). Furthermore, RTX-treated mice given octreotide exhibited a partial improvement in barrier recovery after tape stripping. CONCLUSION: Sensory neurons expressing TRPV1 play an indispensable role in restoring barrier function following epidermal injury. Our findings suggest the potential involvement of somatostatin in restoring epidermal repair after skin injury.

Inflammatory loops in the epithelial-immune microenvironment of the skin and skin appendages in chronic inflammatory diseases.

The epithelial-immune microenvironment (EIME) of epithelial tissues has five common elements: (1) microbial flora, (2) barrier, (3) epithelial cells, (4) immune cells, and (5) peripheral nerve endings. EIME provides both constant defense and situation-specific protective responses through three-layered mechanisms comprising barriers, innate immunity, and acquired immunity. The skin is one of the largest organs in the host defense system. The interactions between the five EIME elements of the skin protect against external dangers from the environment. This dysregulation can result in the generation of inflammatory loops in chronic inflammatory skin diseases. Here, we propose an understanding of EIME in chronic skin diseases, such as atopic dermatitis, psoriasis, systemic lupus erythematosus, alopecia areata, and acne vulgaris. We discuss the current treatment strategies targeting their inflammatory loops and propose possible therapeutic targets in the future.

Alopecia areata: What's new in the epidemiology, comorbidities, and pathogenesis?

BACKGROUND: Alopecia areata (AA) is a common, acquired, and nonscarring type of hair loss that affects people of every generation and is intractable in severe and relapsing cases. Patients with AA, especially those with greater scalp involvement, have poor health-related quality-of-life scores. PURPOSE: Following our previous review article in the April 2017 issue of the Journal of Dermatological Science, we aim to provide a pair of review articles on recent progress in multidisciplinary approaches to AA. MAIN FINDINGS: We found more than 1800 publications on AA from July 2016 to December 2022. CONCLUSIONS: In this review, we focused on the latest information on the epidemiology, comorbidities, and pathogenesis of AA.

Incidental finding of extramammary Paget's disease during active surveillance for early-stage prostate cancer in a prostate biopsy.

Introduction: Skin tissue contamination within transcutaneous visceral organ biopsies is seldom found. We encountered a rare case of extramammary Paget's disease incidentally diagnosed by prostate biopsy during active surveillance for prostate cancer. Case presentation: A 71-year-old Japanese patient was diagnosed with prostate cancer, and active surveillance was selected. After 1 year, prostate biopsy was performed by a transperitoneal approach, and 16 biopsy cores were taken. One biopsy core contained skin tissue showing extramammary Paget's disease. Careful skin examination confirmed the presence of an extramammary Paget's disease lesion in the left perineum, and curative surgical resection was performed. Recurrence and metastasis did not occur after 6 months of follow-up. Conclusion: Although the perianal region is a common site of extramammary Paget's disease, early-stage extramammary Paget's disease is often asymptomatic. Thus, during a transcutaneous biopsy, it is important to consider the appearance of the skin and the pathological features of migrating skin tissue.

Acute generalized exanthematous pustulosis during apalutamide treatment in a patient with prostate cancer.

Introduction: Acute generalized exanthematous pustulosis is a type of severe cutaneous drug adverse reaction. While apalutamide is known for its high incidence of cutaneous adverse events, it remains unknown whether acute generalized exanthematous pustulosis can develop during apalutamide treatment. Case presentation: A 72-year-old man with metastatic castration-sensitive prostate cancer developed small erythema on the face and trunk after 41 days of apalutamide treatment. Three days later, apalutamide was discontinued. However, 9 days after the discontinuation of apalutamide, the patient had a high fever with hemodynamic instability and showed diffuse erythema throughout the body with numerous small pustules. Skin biopsy revealed subcorneal and intraepidermal pustules admixed with many eosinophils, which led to the diagnosis of acute generalized exanthematous pustulosis. The skin rash improved in 14 days with systemic corticosteroid administration. Conclusion: We present the first case of a skin rash with clinical features of acute generalized exanthematous pustulosis during apalutamide treatment.

A Phenotypic Analysis of Involucrin-Membrane-Bound Ovalbumin Mice after Adoptive Transfer of Ovalbumin-Specific CD8+ T Cells.

To investigate the mechanism of autoimmunity and peripheral tolerance in the skin, several transgenic mouse strains expressing membrane-bound ovalbumin (mOVA) as an epidermal self-antigen under the control of keratinocyte-specific promotors, such as keratin 5 and keratin 14, were employed in combination with adoptive transfer of CD8+ T cells from OT-I mice (OT-I T cells) that recognize an ovalbumin-derived peptide. However, these strains showed bodyweight loss and required additional inflammatory stimuli, such as γ-irradiation and tape-stripping, to induce skin inflammation. In this study, we generated a mouse strain expressing mOVA under the control of human involucrin promoter (involucrin-mOVA mice). In contrast to previous strains, involucrin-mOVA mice spontaneously developed skin inflammation after the transfer of OT-I T cells in the absence of external stimuli without significant bodyweight loss. We focused on the skin infiltration process of OT-I T cells and found that transferred OT-I T cells accumulated around the hair follicles in the early phase of skin inflammation, and in the later phase, the skin inflammation spontaneously resolved despite the remaining OT-I T cells in the skin. Our involucrin-mOVA mice will provide a promising tool to investigate the pathogenesis and the tolerance mechanisms of cytotoxic skin autoimmunity.

Real-world analysis of apalutamide-associated skin adverse events in Japanese patients with advanced prostate cancer: a multi-institutional study in the Chu-shikoku Japan Urological Consortium.

BACKGROUND: Apalutamide-associated skin adverse events are more common in the Japanese than in the global population. However, limited clinical data have hampered further understanding. This real-world study investigated the clinical characteristics of skin adverse events in patients with advanced prostate cancer. METHODS: We retrospectively reviewed 119 patient records from 16 institutions in Japan. Skin adverse events were graded according to the Common Terminology Criteria for Adverse Events (v5.0). The incidence and characteristics of skin adverse events (along with the clinical risk factors for their incidence, worsening, and recurrence) were evaluated. RESULTS: Fifty-five patients (46.2%) experienced skin adverse events. The median times to the incidence and remission of skin adverse events were 62 and 30 days, respectively. Grade 3 skin adverse events were observed in 15 patients (12.6%). The median time from the first incidence to apalutamide interruption was significantly longer in patients with progression to grade 3 skin adverse events than in those without such a progression (8 vs. 0 days, p = 0.005). Skin adverse events were observed in 45.2% of patients who resumed apalutamide treatment (median treatment interruption time: 31.5 days). Sixteen patients (13.4%) permanently discontinued apalutamide due to skin adverse events. No significant clinical risk factors for the incidence, worsening and recurrence of apalutamide-associated skin adverse events were observed. CONCLUSIONS: Nearly half of the Japanese patients in this study experienced skin adverse events following apalutamide administration. The time to apalutamide discontinuation after the incidence of skin adverse events was positively correlated with the worsening of these events.

C10orf99/GPR15L Regulates Proinflammatory Response of Keratinocytes and Barrier Formation of the Skin.

The epidermis, outermost layer of the skin, forms a barrier and is involved in innate and adaptive immunity in an organism. Keratinocytes participate in all these three protective processes. However, a regulator of keratinocyte protective responses against external dangers and stresses remains elusive. We found that upregulation of the orphan gene 2610528A11Rik was a common factor in the skin of mice with several types of inflammation. In the human epidermis, peptide expression of G protein-coupled receptor 15 ligand (GPR15L), encoded by the human ortholog C10orf99, was highly induced in the lesional skin of patients with atopic dermatitis or psoriasis. C10orf99 gene transfection into normal human epidermal keratinocytes (NHEKs) induced the expression of inflammatory mediators and reduced the expression of barrier-related genes. Gene ontology analyses showed its association with translation, mitogen-activated protein kinase (MAPK), mitochondria, and lipid metabolism. Treatment with GPR15L reduced the expression levels of filaggrin and loricrin in human keratinocyte 3D cultures. Instead, their expression levels in mouse primary cultured keratinocytes did not show significant differences between the wild-type and 2610528A11Rik deficient keratinocytes. Lipopolysaccharide-induced expression of Il1b and Il6 was less in 2610528A11Rik deficient mouse keratinocytes than in wild-type, and imiquimod-induced psoriatic dermatitis was blunted in 2610528A11Rik deficient mice. Furthermore, repetitive subcutaneous injection of GPR15L in mouse ears induced skin inflammation in a dose-dependent manner. These results suggest that C10orf99/GPR15L is a primary inducible regulator that reduces the barrier formation and induces the inflammatory response of keratinocytes.

IFN-γ‒Induced APOBEC3B Contributes to Merkel Cell Polyomavirus Genome Mutagenesis in Merkel Cell Carcinoma.

Merkel cell polyomavirus (MCPyV) is the causative agent of an aggressive skin tumor, Merkel cell carcinoma. The viral genome is integrated into the tumor genome and harbors nonsense mutations in the helicase domain of large T antigen. However, the molecular mechanisms by which the viral genome gains the tumor-specific mutations remain to be elucidated. Focusing on host cytosine deaminases APOBEC3s, we find that A3A, A3B, or A3G introduces A3-specific mutations into episomal MCPyV genomes in MCPyV-replicating 293-derivative cells. Sequence analysis of MCPyV genomes retrieved from the NCBI database revealed a decrease of TpC dinucleotide, a preferred target for A3A and A3B, in the 3'-region of the large T antigen‒coding sequence. The viral DNA isolated from tumors contained mutated cytosines, with a remarkable bias toward TpC dinucleotide. Analysis of publicly available microarray data showed that expression of IFN-γ and cytotoxic T lymphocyte markers was positively correlated with the A3A, A3B, and A3G levels in MCPyV-positive but not in MCPyV-negative tumors. Finally, IFN-γ treatment induced A3B and A3G expression in the MCPyV-positive Merkel cell carcinoma cell line MS-1. These results suggest that the IFN-γ-A3B axis plays pivotal roles in evolutionally shaping MCPyV genomic sequences and in generating tumor-specific large T antigen mutations during development of Merkel cell carcinoma.

Apalutamide-associated skin rash in patients with prostate cancer: Histological evaluation by skin biopsy.

INTRODUCTION: Apalutamide-associated skin rash is a more common adverse event in the Japanese population than in the global population. However, its mechanism remains elusive, and limited histopathological information hampers further understanding. CASE PRESENTATION: Case 1: a 71-year-old man with metastatic castration-sensitive prostate cancer developed a skin rash after 70 days of apalutamide treatment. Case 2: a 71-year-old man with non-metastatic castration-resistant prostate cancer developed a skin rash after 71 days of apalutamide treatment. In both cases, the skin rash presented as a slightly exudative erythema. The histology showed spongiosis of the epidermis and perivascular and interstitial infiltration of lymphocytes and eosinophils in the upper dermis without necrotic keratinocytes. CONCLUSION: Apalutamide-induced skin rashes can involve an eczematous reaction clinically and histologically.