The 2020 report of The Lancet Countdown on health and climate change: responding to converging crises.

TRANSLATIONS: For the Chinese, French, German, and Spanish translations of the abstract see Supplementary Materials section.

Vitiligo: a comprehensive overview Part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up.

Vitiligo is an acquired pigmentary disorder of unknown etiology that is clinically characterized by the development of white macules related to the selective loss of melanocytes. The prevalence of the disease is around 1% in the United States and in Europe, but ranges from less than 0.1% to greater than 8% worldwide. A recorded predominance of women may reflect their greater willingness to express concern about cosmetically relevant issues. Half of all patients develop the disease before 20 years of age. Onset at an advanced age occurs but is unusual, and should raise concerns about associated diseases, such as thyroid dysfunction, rheumatoid arthritis, diabetes mellitus, and alopecia areata. Generalized vitiligo is the most common clinical presentation and often involves the face and acral regions. The course of the disease is unpredictable and the response to treatment varies. Depigmentation may be the source of severe psychological distress, diminished quality of life, and increased risk of psychiatric morbidity. Part I of this two-part series describes the clinical presentation, histopathologic findings, and various hypotheses for the pathogenesis of vitiligo based on past and current research.

XPC silencing in normal human keratinocytes triggers metabolic alterations that drive the formation of squamous cell carcinomas.

DNA damage is a well-known initiator of tumorigenesis. Studies have shown that most cancer cells rely on aerobic glycolysis for their bioenergetics. We sought to identify a molecular link between genomic mutations and metabolic alterations in neoplastic transformation. We took advantage of the intrinsic genomic instability arising in xeroderma pigmentosum C (XPC). The XPC protein plays a key role in recognizing DNA damage in nucleotide excision repair, and patients with XPC deficiency have increased incidence of skin cancer and other malignancies. In cultured human keratinocytes, we showed that lentivirus-mediated knockdown of XPC reduced mitochondrial oxidative phosphorylation and increased glycolysis, recapitulating cancer cell metabolism. Accumulation of unrepaired DNA following XPC silencing increased DNA-dependent protein kinase activity, which subsequently activated AKT1 and NADPH oxidase-1 (NOX1), resulting in ROS production and accumulation of specific deletions in mitochondrial DNA (mtDNA) over time. Subcutaneous injection of XPC-deficient keratinocytes into immunodeficient mice led to squamous cell carcinoma formation, demonstrating the tumorigenic potential of transduced cells. Conversely, simultaneous knockdown of either NOX1 or AKT1 blocked the neoplastic transformation induced by XPC silencing. Our results demonstrate that genomic instability resulting from XPC silencing results in activation of AKT1 and subsequently NOX1 to induce ROS generation, mtDNA deletions, and neoplastic transformation in human keratinocytes.

Combination systemic therapies in psoriatic arthritis.

Psoriatic arthritis (PsA) is a chronic, progressive, and debilitating disorder. When monotherapy fails, combination therapy is necessary for the long-term management of these patients. There is currently no review on this subject, and the purpose of this study was to investigate and describe the current literature on combination therapy in PsA. A PubMed MeSH search was performed for psoriatic arthritis and combination therapy, which yielded at total of 83 articles. After excluding reviews and commentaries, and pursuing relevant citations, a total of 21 articles on the subject were found: one study of NSAIDs and methotrexate, three studies of cyclosporine and methotrexate, three studies of non-TNF biologic inhibitors (alefacept, ustekinumab) and methotrexate, and 14 studies of anti-TNF-inhibitors (etanercept, adalimumab, infliximab, golimumab) and methotrexate. The combination of cyclosporine and methotrexate reduces the dosages and also the side effects of each agent, allowing better disease control with less toxicity. Methotrexate in combination with biologic agents, either non-TNF inhibitors or anti-TNF inhibitors, may have a role in decreasing side effects, but it does not appear to improve clinical symptoms beyond those attained by biologic monotherapy.

Cost-effectiveness of a hydroquinone/tretinoin/fluocinolone acetonide cream combination in treating melasma in the United States.

BACKGROUND: Melasma, a disorder of facial hyperpigmentation, presents a treatment obstacle to many physicians. Combination therapy with hydroquinone, tretinoin, and fluocinolone acetonide has proven effective, but it is generally more expensive than other treatments. OBJECTIVE: To assess the cost-effectiveness of daily triple combination therapy (TCT) compared with daily use of each possible pair of agents (dyads) and twice daily use of hydroquinone (HQ) alone from a payer's perspective. METHODS: Efficacy data were obtained from two clinical trials with the primary endpoint being complete clearance at 8 weeks. For all treatments, total cost per successful treatment was calculated. The incremental cost-effectiveness ratio (ICER) was calculated for each dyad and for HQ monotherapy in comparison with TCT. Sensitivity analyses for efficacy and number of office visits were similarly performed. RESULTS AND CONCLUSION: TCT consistently had the lowest cost per primary success in all the analyses performed. Furthermore, ICERs were low, indicating that TCT's superior efficacy is attained at marginal cost increases. Our results indicate that TCT is the most cost-effective treatment when compared with any of its dyads or with hydroquinone alone.