Adherence to Hidradenitis Suppurativa Treatment.

Hidradenitis suppurativa (HS) is a chronic, debilitating skin condition that requires multimodal treatment. Adherence remains a significant challenge for many patients due to complex nature of treatment, thus presenting a barrier to management success. This review summarizes the current literature on the factors associated with adherence to medications, and lifestyle behaviors in patients with HS and proposes strategies to improve adherence. In February 2023, a systematic literature search was conducted by two independent authors on PubMed and EMBASE for articles from 2000 to 2023 on hidradenitis suppurativa adherence. A total of 21 articles met inclusion/exclusion criteria for this review. Of the studies, 11 addressed systemic medication adherence, 3 addressed topical medication adherence, 2 addressed both systemic and topical medication adherence, and 5 addressed lifestyle/behavioral modification adherence. The generalizability of results was limited by differences in study design, outcome measures, and sample size. English-only articles with full texts were used. The most reported reasons for non-adherence included presence of side effects, cost of medications, low efficacy, and unclear instructions. Proposed strategies to improve adherence in HS patients include management of side effects, use of reminder systems, improved patient education, patient support groups, aid of family and caregivers, personalization of the medication regimen, and regular follow-ups with patients. PROSPERO Registration Number: CRD42023488549.

Treatments for Dissecting Cellulitis of the Scalp: A Systematic Review and Treatment Algorithm.

BACKGROUND: Dissecting cellulitis of the scalp (DCS) is a chronic inflammatory skin condition characterized by abscesses, nodules, fistulas, and scarring alopecia. Management of this oftentimes debilitating dermatosis can be challenging due to its recalcitrant nature. There is limited data regarding the efficacy of treatment options for DCS. OBJECTIVE: The aim of this study was to conduct a systematic review of the literature to explore the efficacy and safety of reported DCS treatments. METHODS: In October 2022, MEDLINE and EMBASE databases were searched for articles on treatments for DCS. Studies that contained outcome efficacy data for DCS treatments were included. Reviews, conference abstracts, meta-analyses, commentaries, non-relevant articles, and articles with no full-text available were excluded. Data extraction was performed by two independent reviewers. RESULTS: A total of 110 relevant articles with 417 patients were identified. A majority of studies (86.4%) were case reports or series. Treatment options included systemic antibiotics, oral retinoids, biologics, procedural treatments, combination agents, and topical treatments. Oral retinoids and photodynamic therapy were the most extensively studied medical and procedural interventions, respectively. CONCLUSION: Overall, randomized controlled trials are needed to evaluate various treatment regimens for DCS and provide patients with a robust, evidence-based approach to therapy.

Efficacy of medical treatments for pediatric hidradenitis suppurativa: A systematic review.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin condition that has been insufficiently studied in the pediatric population. Timely and effective medical treatments may improve quality of life, mitigate disease burden, and prevent the need for invasive procedural interventions such as surgical excisions. However, there is a paucity of research on the efficacy of medical management strategies for HS in children and adolescents. The aim of this study was to perform a systematic review of the literature on the efficacy and safety of medical treatments for HS in patients <18 years of age. In April 2022, MEDLINE and EMBASE databases were searched for articles on the efficacy of medical treatments for HS in the pediatric population. Between 1984 and 2022, 35 articles (101 patients) met the inclusion criteria. Most patients had Hurley Stage II disease (46.7%, 35/75) followed by Stage I (36%, 27/75), and Stage III (17.3%, 13/75). 100% (23/23) of patients responded to antibiotics, 100% (8/8) to finasteride, 93.9% (31/33) to biologics, 80% (4/5) to oral retinoids, and 50% (6/12) to metformin. Overall, this study demonstrates that medical treatment regimens can improve HS symptoms in pediatric patients, but the extent of improvement is unclear, and the results were largely based on case reports or case series. Prospective studies are warranted to better understand the efficacy and safety of medical treatments for pediatric HS. Clinical trials of HS therapies need to be inclusive of pediatric patients to help define the optimal timing of treatment initiation and guide patient selection.

Serum-Free Production of Human Stem Cell-Derived Liver Spheres for Cancer Metastasis Research.

Renewable and scalable human liver tissue platforms are a powerful tool to study organ physiology and model diseases, such as cancer. Stem cell-derived models provide an alternative to cell lines, which can display limited relevance to primary cells and tissue. Historically, two-dimensional (2D) cultures have been used to model liver biology as they are easy to scale and deploy. However, 2D liver models lack functional diversity and phenotypic stability in long-term culture. To address those issues, protocols for generating the three-dimensional (3D) tissue aggregates have been developed. Here, we describe a methodology to generate 3D liver spheres from pluripotent stem cells. Liver spheres are composed of three key liver cell types (hepatic progenitor cells, endothelial cells, and hepatic stellate cells) and have been used to study human cancer cell metastasis.

Efficacy of procedural treatments for pediatric hidradenitis suppurativa: A systematic review.

Hidradenitis suppurativa (HS) is a painful, inflammatory skin disease that has historically been understudied in the pediatric population. Procedural interventions, such as surgical excisions, skin grafts, and lasers, are important for comprehensive HS disease management. However, there is a lack of data on procedural treatments for HS in pediatric patients. The purpose of this study was to conduct a systematic review of the literature on the efficacy and safety of procedural treatments for HS in pediatric patients. In April 2022, MEDLINE and EMBASE databases were searched for articles on the efficacy of procedural treatments for HS in patients <18 years of age. Two independent reviewers extracted data from relevant studies. From 1974 to 2021, 23 articles with 81 patients were identified. Patients' Hurley stages included stage I (9.1%, 1/11), II (36.4%, 4/11), and III (54.5%, 6/11). The most extensively studied procedural interventions include negative pressure wound therapy (n = 30), surgical excision with skin graft/flap (n = 19), and endoscopic electrode or laser treatment (n = 11). In all, promising response rates for procedural management strategies were observed in the literature but the findings were largely based on case reports/series. Randomized controlled trials (RCTs), especially those geared toward minimally invasive procedural treatments, are needed to help guide clinicians on the most efficacious treatment modalities for pediatric patients with HS.

Interleukin-15 augments NK cell-mediated ADCC of alemtuzumab in patients with CD52+ T-cell malignancies.

Interleukin-15 (IL-15) monotherapy substantially increases the number and activity of natural killer (NK) cells and CD8+ T cells but has not produced clinical responses. In a xenograft mouse model, IL-15 enhanced the NK cell-mediated antibody-dependent cell cytotoxicity (ADCC) of the anti-CD52 antibody alemtuzumab and led to significantly more durable responses than alemtuzumab alone. To evaluate whether IL-15 potentiates ADCC in humans, we conducted a phase 1 single-center study of recombinant human IL-15 and alemtuzumab in patients with CD52-positive mature T-cell malignances. We gave IL-15 subcutaneously 5 days per week for 2 weeks in a 3 + 3 dose escalation scheme (at 0.5, 1, and 2 µg/kg), followed by standard 3 times weekly alemtuzumab IV for 4 weeks. There were no dose-limiting toxicities or severe adverse events attributable to IL-15 in the 11 patients treated. The most common adverse events were lymphopenia (100%), alemtuzumab-related infusion reactions (90%), anemia (90%), and neutropenia (72%). There were 3 partial and 2 complete responses, with an overall response rate of 45% and median duration of response 6 months. Immediately after 10 days of IL-15, there was a median 7.2-fold increase in NK cells and 2.5-fold increase in circulating CD8+ T cells, whereas the number of circulating leukemic cells decreased by a median 38% across all dose levels. Treatment with IL-15 was associated with increased expression of NKp46 and NKG2D, markers of NK-cell activation, and increased ex vivo ADCC activity of NK cells, whereas inhibitory receptors PD1 and Tim3 were decreased. This trial was registered at www.clinicaltrials.gov as #NCT02689453.

Attenuating persistent sodium current-induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress.

Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown. We crossbred mice expressing human F1759A-NaV1.5 channels with mice expressing human mitochondrial catalase (mCAT). Increased expression of mCAT attenuated mitochondrial and cellular reactive oxygen species (ROS) and the structural remodeling that was induced by persistent F1759A-Na+ current. Despite the heterogeneously prolonged atrial action potential, which was unaffected by the reduction in ROS, the incidences of spontaneous AF, pacing-induced after-depolarizations, and AF were substantially reduced. Expression of mCAT markedly reduced persistent Na+ current-induced ryanodine receptor oxidation and dysfunction. In summary, increased persistent Na+ current in atrial cardiomyocytes, which is observed in patients with AF, induced atrial enlargement, fibrosis, mitochondrial dysmorphology, early after-depolarizations, and AF, all of which can be attenuated by resolving mitochondrial oxidative stress.

Increased Incidence of Chronic Kidney Injury in African Americans Following Cardiac Transplantation.

OBJECTIVES: This study examined whether African American race was associated with an elevated risk of chronic kidney disease (CKD) post-cardiac transplantation. BACKGROUND: CKD often occurs after cardiac transplantation and may require renal replacement therapy (RRT) or renal transplant. African American patients have a higher risk for kidney disease as well as worse post-cardiac transplant morbidity and mortality. It is unclear, however, if there is a propensity for African Americans to develop CKD after cardiac transplant. METHODS: The Institutional Review Board of Columbia University Medical Center approved the retrospective study of 151 adults (57 African American and 94 non-African American) who underwent single-organ heart transplant from 2013 to 2016. The primary outcome was a decrease in estimated glomerular filtration rate (eGFR), development of CKD, and end-stage renal disease (ESRD) requiring RRT after 2 years. RESULTS: African American patients had a significant decline in eGFR post-cardiac transplant compared to non-African American patients (- 34 ± 6 vs. - 20 ± 4 mL/min/1.73 m2, p < 0.0006). African American patients were more likely to develop CKD stage 2 or worse (eGFR < 90 mL/min/1.73 m2) than non-African American patients (81% vs. 59%, p < 0.0005). CONCLUSIONS: This is the first study to report that African American patients are at a significantly higher risk for eGFR decline and CKD at 2 years post-cardiac transplant. Future investigation into risk reduction is necessary for this patient population.

Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs.

Adult hematopoietic stem cells (HSCs) with serially transplantable activity comprise two subtypes. One shows a balanced output of mature lymphoid and myeloid cells; the other appears selectively lymphoid deficient. We now show that both of these HSC subtypes are present in the fetal liver (at a 1:10 ratio) with the rarer, lymphoid-deficient HSCs immediately gaining an increased representation in the fetal bone marrow, suggesting that the marrow niche plays a key role in regulating their ensuing preferential amplification. Clonal analysis of HSC expansion posttransplant showed that both subtypes display an extensive but variable self-renewal activity with occasional interconversion. Clonal analysis of their differentiation programs demonstrated functional and molecular as well as quantitative HSC subtype-specific differences in the lymphoid progenitors they generate but an indistinguishable production of multipotent and myeloid-restricted progenitors. These findings establish a level of heterogeneity in HSC differentiation and expansion control that may have relevance to stem cell populations in other hierarchically organized tissues.

Prospective isolation and molecular characterization of hematopoietic stem cells with durable self-renewal potential.

Hematopoietic stem cells (HSCs) are generally defined by their dual properties of pluripotency and extensive self-renewal capacity. However, a lack of experimental clarity as to what constitutes extensive self-renewal capacity coupled with an absence of methods to prospectively isolate long-term repopulating cells with defined self-renewal activities has made it difficult to identify the essential components of the self-renewal machinery and investigate their regulation. We now show that cells capable of repopulating irradiated congenic hosts for 4 months and producing clones of cells that can be serially transplanted are selectively and highly enriched in the CD150(+) subset of the EPCR(+)CD48(-)CD45(+) fraction of mouse fetal liver and adult bone marrow cells. In contrast, cells that repopulate primary hosts for the same period but show more limited self-renewal activity are enriched in the CD150(-) subset. Comparative transcriptome analyses of these 2 subsets with each other and with HSCs whose self-renewal activity has been rapidly extinguished in vitro revealed 3 new genes (VWF, Rhob, Pld3) whose elevated expression is a consistent and selective feature of the long-term repopulating cells with durable self-renewal capacity. These findings establish the identity of a phenotypically and molecularly distinct class of pluripotent hematopoietic cells with lifelong self-renewal capacity.

Steel factor coordinately regulates the molecular signature and biologic function of hematopoietic stem cells.

Hematopoietic stem cells (HSCs) regenerated in vivo display sustained differences in their self-renewal and differentiation activities. Variations in Steel factor (SF) signaling are known to affect these functions in vitro, but the cellular and molecular mechanisms involved are not understood. To address these issues, we evaluated highly purified HSCs maintained in single-cell serum-free cultures containing 20 ng/mL IL-11 plus 1, 10, or 300 ng/mL SF. Under all conditions, more than 99% of the cells traversed a first cell cycle with similar kinetics. After 8 hours in the 10 or 300 ng/mL SF conditions, the frequency of HSCs remained unchanged. However, in the next 8 hours (ie, 6 hours before any cell divided), HSC integrity was sustained only in the 300 ng/mL SF cultures. The cells in these cultures also contained significantly higher levels of Bmi1, Lnk, and Ezh2 transcripts but not of several other regulators. Assessment of 21 first division progeny pairs further showed that only those generated in 300 ng/mL SF cultures contained HSCs and pairs of progeny with similar differentiation programs were not observed. Thus, SF signaling intensity can directly and coordinately alter the transcription factor profile and long-term repopulating ability of quiescent HSCs before their first division.