Notes

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In their new article in the Journal of Investigative Dermatology, Tseng et al. (2021) confirm that the sensitivity of melanoma cells to anti‒PD-L1 checkpoint inhibitor therapy is correlated with high PD-L1 surface expression. By blocking PD-L1 membrane clearing, controlled by LRP1 and PAI-1, the expression of high-cell-surface levels of PD-L1 was maintained.Although several anticytokine antibodies and inhibitors are available for the treatment of psoriasis, more effective or better-tolerated alternatives would be of interest. In their article in the Journal of Investigative Dermatology, Michiels et al. (2021) propose a new strategy that targets an alternative activation pathway of the IL-22 receptor to attenuate murine psoriasis-like skin inflammation without affecting IL-22‒dependent barrier defense in the gut.Getting from a GWAS hit to an actionable gene remains a challenge in complex disease genetics. In a new article of the Journal of Investigative Dermatology, Sobczyk et al. (2021) use a wide variety of genomic data to generate a prioritization algorithm to tackle this problem in atopic dermatitis, calling on the wisdom of the genome to generate promising results.The calcium-sensing receptor (CaSR) is important in the skin, contributing to several epidermal functions, including differentiation, water permeability barrier repair, and wound healing. Celli et al. (2021) show that CaSR levels are reduced in keratinocytes/skin from aged individuals, with resulting impairment of key functions. CaSR agonists can correct these defects, suggesting a possible therapy to combat aging-related delayed skin wound healing.Skin-targeted drug delivery is broadly employed for both local and systemic therapeutics and is an important tool for discovery efforts in cutaneous biology. Recently, emerging technologies support efforts toward skin-targeted biocargo delivery for local and systemic therapeutic benefit. Effective targeting of bioactive molecules, including large (molecular weight > 500 Da) or complex (hydrophilic and charged) molecules, to defined cutaneous microenvironments is intrinsically challenging owing to the protective barrier function of the skin. Dissolvable microneedle arrays (MNAs) have proven to be a promising technology to address the unmet need for controlled, minimally invasive, and reliable delivery of a wide range of biocargos to the skin. In this paper, we describe the unique properties of the skin that make it an attractive target for vaccine delivery, for immune-modulating therapies, and for systemic drug delivery and the structural characteristics of the skin that present obstacles to efficient intracutaneous and transdermal delivery of bioactive molecules. We provide an overview of MNA fabrication and the characteristics and mechanisms of dissolvable MNA cargo delivery to the cutaneous microenvironment. We present a representative example of a clinical application of MNAs and discuss future directions for MNA development and applications.A previously published review focused on generic and disease-specific patient-reported outcome measures (PROMs) relevant to vascular surgery but limited to arterial conditions. The objective of this project was to identify all available PROMs relevant to diseases treated by vascular surgeons and to evaluate vascular surgeon perceptions, barriers to widespread implementation, and concerns regarding PROMs. check details We provide an overview of what a PROM is and how they are developed, and summarize currently available PROMs specific to vascular surgeons. We also report results from a survey of 78 Society for Vascular Surgery members serving on committees within the Policy and Advocacy Council addressing the barriers and facilitators to using PROMs in clinical practice. Finally, we report the qualitative results of two focus groups conducted to assess granular perceptions of PROMS and preparedness of vascular surgeons for widespread implementation of PROMs. These focus groups identified a lack of awareness of existing PROMs, knowledge of how PROMs are developed and validated, and clarity around how PROMs should be used by the clinician as main subthemes for barriers to PROM implementation in clinical practice.Dickkopf-related protein 3 is a stress-induced, epithelial cell-derived glycoprotein that is promoted as a prognostic as well as a predictive urinary biomarker in acute and chronic kidney disease. Schunk et al. provided evidence that Dickkopf-related protein 3 identifies patients with chronic obstructive pulmonary disease and preserved kidney function at increased risk for a loss of estimated glomerular filtration rate and deterioration of pulmonary function. Experimental data highlighted Dickkopf-related protein 3-related pathophysiological similarities and interactions between chronic kidney disease and chronic obstructive pulmonary disease.Telomere length is considered as a clock mirroring aging and is influenced by oxidative stress and inflammation. Both conditions are highly prevalent in patients with chronic kidney disease and other degenerative disorders, such as cardiovascular disease. However, it is discussed controversially whether short telomeres are causally associated with chronic kidney disease or whether chronic kidney disease is contributing to an attrition of telomere length. Park et al., in this issue of Kidney International, use an extended 2-sample Mendelian randomization analysis with large data sets to shed new light on this research question.Podocyte loss is a key element underlying glomerulosclerosis. Various mechanisms have been proposed for cell loss. These include local hemodynamic effects and local stresses on cell and hemodynamic changes, which together may contribute to detachment of podocytes, leading to sclerosis. Elegant studies based on classic observations add state-of-the-art imaging, modeling, intravital microscopy, and ultrastructural geometry analyses and provide new insights into potential mechanisms for injury and loss of this key cell.Ketone bodies have a strong negative image in medicine because of ketoacidosis, a life-threatening complication in diabetes. However, Fang et al. report that ketone bodies exert antisenescent effects in podocytes under diabetic conditions, via activation of the nuclear factor E2-related factor 2-related antioxidative stress pathway. With recent progression of research on longevity, the beneficial effects of ketone bodies are being clarified, and a positive image of ketone bodies is gradually beginning to develop in many research fields including nephrology.The Johnson and Johnson Ad26.COV2.S single-dose vaccine represents an attractive option for coronavirus disease 2019 (COVID-19) vaccination in countries with limited resources. We examined the effect of prior infection with different SARS-CoV-2 variants on Ad26.COV2.S immunogenicity. We compared participants who were SARS-CoV-2 naive with those either infected with the ancestral D614G virus or infected in the second wave when Beta predominated. Prior infection significantly boosts spike-binding antibodies, antibody-dependent cellular cytotoxicity, and neutralizing antibodies against D614G, Beta, and Delta; however, neutralization cross-reactivity varied by wave. Robust CD4 and CD8 T cell responses are induced after vaccination, regardless of prior infection. T cell recognition of variants is largely preserved, apart from some reduction in CD8 recognition of Delta. Thus, Ad26.COV2.S vaccination after infection could result in enhanced protection against COVID-19. The impact of the infecting variant on neutralization breadth after vaccination has implications for the design of second-generation vaccines based on variants of concern.
PD-1 blockade is highly effective in patients with mismatch repair-deficient or microsatellite instability-high metastatic colorectal cancer. The role of single-agent PD-1 blockade in the neoadjuvant setting for resectable mismatch repair-deficient or microsatellite instability-high colorectal cancer remains unclear. We investigated the efficacy and safety of PD-1 blockade with toripalimab, with or without the COX-2 inhibitor celecoxib, as neoadjuvant treatment for mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancers.

The PD-1 Inhibitor in Microsatellite Instability Colorectal Cancer (PICC) trial was a single-centre, open-label, parallel-group, non-comparative, randomised, phase 2 study undertaken at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). Eligible patients were aged 18-75 years, had histologically confirmed mismatch repair-deficient or microsatellite instability-high colorectal cancer, had clinical stage T3-T4 or any T withtion of China, and the Chinese Society of Clinical Oncology-Junshi Biosciences Oncology Immunity Research.

For the Chinese translation of the abstract see Supplementary Materials section.
For the Chinese translation of the abstract see Supplementary Materials section.
Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic exposure. We aimed to assess the comparative efficacy and safety of biologics in patients with Crohn's disease.

We did a systematic review and network meta-analysis of phase 2 and phase 3 randomised controlled trials done in adults (≥18 years) with moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220-450) treated with tumour necrosis factor (TNF) antagonists, anti-integrin, anti-interleukin (IL)-12 and IL-23p40, or anti-IL23p19 agents, either alone or in combination with immunosuppressants, as their first-line biologic or after previous biologic exposure, compared with placebo or an active comparator. The minimum duration of therapy was 14 days for trials reporting induction of remission in active disease and 22 weeks in trials reporting maintenance of remission. We searched Medline, EMBASE, the Cochrane CENTRAL Register limumab might be preferred as a first-line therapy, and adalimumab (after infliximab loss of response) or risankizumab might be preferred as a second-line therapy, for induction of clinical remission.

None.
None.Borderline personality disorder (BPD) is a mental disorder with a high burden on patients, family members, and health-care systems. The condition was previously regarded as untreatable, but progress in understanding and management has resulted in earlier diagnosis and better treatment outcomes. A coherent syndrome of BPD typically onsets during adolescence (after age 12 years). BPD is often preceded by or co-develops with symptoms of internalising disorders (depression and anxiety), externalising disorders (conduct problems, hyperactivity, and substance use), or both. BPD is associated with various poor outcomes, including low occupational and educational attainment, lack of long-term relationships, increased partner conflict, sexual risk-taking, low levels of social support, low life satisfaction, and increased service use. Psychotherapy is the main treatment for BPD; drug treatment is only indicated for comorbid conditions that require medication, or during a crisis if psychosocial interventions are insufficient.
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