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Mary Patricia Smith, Karen Ly, Quinn Thibodeaux, Tina Bhutani, Wilson Liao, Kristen M BeckDepartment of Dermatology, University of California, San Francisco, CA, USAAbstract: Acrodermatitis continua of Hallopeau (ACH) is a rare, sterile pustular eruption of one or more digits. The condition presents with tender pustules and underlying erythema on the tip of a digit, more frequently arising on a finger than a toe. As far as classification, ACH is considered a localized form of pustular psoriasis. The eruption typically occurs after local trauma or infection, but such a history is not always present and various other etiologies have been described including infectious, neural, inflammatory, and genetic causes. The natural progression of ACH is chronic and progressive, often resulting in irreversible complications such as onychodystrophy that can result in anonychia, as well as osteitis that can result in osteolysis of the distal phalanges. Because of the rarity of ACH, there have been no randomized controlled studies to evaluate therapies, resulting in an absence of standardized treatment guidelines. In clinical practice, a wide variety of treatments have been attempted, with outcomes ranging from recalcitrance to complete resolution. In recent years, the introduction of biologics has provided a new class of therapy that has revolutionized the treatment of ACH. Specifically, rapid and sustained responses have been reported with the use of anti-tumor necrosis factor agents like infliximab, adalimumab, and etanercept; IL-17 inhibitors like secukinumab; IL-12/23 inhibitors like ustekinumab; and IL-1 inhibitors like anakinra. Nevertheless, there remains a considerable need for more research into treatment for the benefit of individual patients with ACH as well as for the clinical knowledge gained by such efforts. The purpose of this review is to provide a comprehensive overview of the key features of ACH as well as a discussion of clinical management strategies for this unique and debilitating condition.Keywords: acrodermatitis continua of Hallopeau, psoriasis, pustular psoriasis, generalized pustular psoriasis, palmoplantar pustulosis

Karen Ly,1 Kristen M Beck,1 Mary P Smith,1 Ana-Maria Orbai,2 Wilson Liao11Department of Dermatology, University of California San Francisco, San Francisco, CA, USA; 2Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USACorrespondence: Kristen M BeckDepartment of Dermatology, University of California San Francisco, 515 Spruce Street, San Francisco, CA 94118, USATel +1 415 476 4701Fax +1 415 502 4126Email kristenbeckmd@gmail.comAbstract: Tofacitinib is an oral Janus kinase inhibitor approved for the treatment of psoriatic arthritis (PsA). It provides an alternative option for patients who have had an inadequate response and tolerance to other disease modifying antirheumatic drugs (DMARDs). It has demonstrated comparable efficacy to biologics, is effective in the management of treatment resistant disease, and is reported to improve enthesitis, dactylitis, and radiographic progression. Tofacitinib is also associated with an increased risk of serious infections, malignancy, and laboratory abnormalities. There is currently a large armamentarium of therapies for psoriatic arthritis, and choosing among treatments can be challenging. Due to this wide selection, a thorough assessment of psoriatic disease phenotype, patient preference, disease presentation, and comorbidities is critical. This review addresses key considerations in patient selection for the treatment of PsA with tofacitinib.Keywords: tofacitinib, psoriatic arthritis, janus kinase, kinase inhibitors

Karen Ly,* Kristen M Beck*, Mary P Smith, Quinn Thibodeaux, Tina BhutaniDepartment of Dermatology, University of California, San Francisco, CA, USA*These authors contributed equally to this work Abstract: Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening variant of psoriasis that is characterized by recurrent, acute onset, widely distributed pustular eruptions on inflamed, erythematous skin. It is important to recognize acute GPP as a subtype of psoriasis associated with high morbidity and mortality so therapy can be initiated without delay. Since GPP was first described in 1910 by Leopold von Zumbusch, it has been inconsistently defined, stratified, and diagnosed in the literature. Multiple definitions and diagnostic criteria have been proposed over the years. Recently, formal consensus guidelines on GPP have been published by international groups. This article reviews the current evidence and understanding in the diagnosis and screening of GPP.Keywords: generalized pustular psoriasis, acute generalized pustular psoriasis of von Zumbusch, pustular psoriasis, diagnostic criteria

Mary Patricia Smith,1 Karen Ly,1 Quinn Thibodeaux,1 Tina Bhutani,1 Mio Nakamura21Department of Dermatology, University of California San Francisco, San Francisco, CA, USA; 2Department of Dermatology, University of Michigan, Ann Arbor, MI, USAAbstract: Vitiligo is a chronic autoimmune condition involving selective dysfunction and destruction of melanocytes in the skin, hair, or both. The typical presentation is well-demarcated depigmented skin patches. Given vitiligo is the most common cause of depigmentation worldwide and early disease responds best to treatment, prompt diagnosis and proactive management of vitiligo are critical. While a wide variety of treatments has demonstrated variable effectiveness in treating vitiligo, phototherapy remains standard of care because of its proven efficacy and favorable side effect profile. However, many patients with vitiligo are unable to access affordable, consistent, or convenient phototherapy. To address these issues, home-based phototherapy has emerged as a patient-centered alternative. The purpose of this review is to discuss management of vitiligo with a specific focus on access to home-based phototherapy (HBPT) for patients with this condition. Key challenges to HBPT include misperceptions around safety and efficacy, inadequate physician education and training, insurance and financial barriers, and appropriate patient selection. Solutions to these challenges are presented, such as approaches to improve physician education and increasing the evidence surrounding the effectiveness and safety of this treatment for vitiligo. In addition, various practical considerations are discussed to guide dermatologists on how to approach HBPT as a treatment option for patients with vitiligo.Keywords: vitiligo, pigmentation disorders, phototherapy, photomedicine

Eric J Yang,1,2 Mary Patricia Smith,1,3 Karen Ly,1,4 Tina Bhutani1 1Department of Dermatology, University of California San Francisco, San Francisco, CA, USA; 2Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA; 3Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4School of Medicine, Wayne State University, Detroit, MI, USA Abstract: The approval of guselkumab marks the entry of the IL-23 inhibitor class into the therapeutic armamentarium for patients with moderate-to-severe plaque psoriasis. This class specifically targets the upstream portion of the type 17 helper T (Th17) axis, which has been implicated as a key driver of the abnormal inflammatory state observed in psoriasis. Guselkumab is highly efficacious, with over 85% of the patients achieving ≥75% reduction in Psoriasis Area and Severity Index from baseline (PASI 75) and over 70% of the patients achieving PASI 90 response in its Phase III clinical trials. Additionally, this medication is well-tolerated, with non-serious infections such as nasopharyngitis and upper respiratory infections (URIs) being the most common adverse events (AEs) reported in its clinical trials. Guselkumab offers yet another effective treatment option in the rapidly growing list of available biological therapies for moderate-to-severe plaque psoriasis. Keywords: biologics, guselkumab, IL-23 inhibitor, plaque psoriasis, biologic selection

Trypanosoma brucei is the causative agent of African sleeping sickness in humans and one of the causes of nagana in cattle. This protozoan parasite evades the host immune system by antigenic variation, a periodic switching of its variant surface glycoprotein (VSG) coat. VSG switching is spontaneous and occurs at a rate of about [10.sup.-2[-10.sup.-3] per population doubling in recent isolates from nature, but at a markedly reduced rate ([10.sup.-5][-10.sup.-6]) in laboratory-adapted strains (1-3). VSG switching is thought to occur predominantly through gene conversion, a form of homologous recombination initiated by a DNA lesion that is used by other pathogens (for example, Candida albicans, Borrelia sp. and Neisseria gonorrhoeae) to generate surface protein diversity, and by B lymphocytes of the vertebrate immune system to generate antibody diversity. Very little is known about the molecular mechanism of VSG switching in T. brucei. Here we demonstrate that the introduction of a DNA double-stranded break (DSB) adjacent to the ~70-base-pair (bp) repeats upstream of the transcribed VSG gene increases switching in vitro ~250-fold, producing switched clones with a frequency and features similar to those generated early in an infection. We were also able to detect spontaneous DSBs within the 70-bp repeats upstream of the actively transcribed VSG gene, indicating that a DSB is a natural intermediate of VSG gene conversion and that VSG switching is the result of the resolution of this DSB by break-induced replication., The T. brucei genome contains >1,000 VSG genes and pseudogenes, yet the single transcribed VSG gene is invariably found in 1 of ~15 large (40-60 kb) telomeric expression sites (4-6). [...]

Abstract Background To assess patterns of injecting drug use and HIV prevalence among injecting drug users (IDUs) in an international border area along a major heroin trans-shipment route. Methods Cross-sectional surveys of IDUs in 5 sites in Lang Son Province, Vietnam (n = 348) and 3 sites in Ning Ming County, Guangxi Province, China (n = 308). Respondents were recruited through peer referral ("snowball") methods in both countries, and also from officially recorded lists of IDUs in Vietnam. A risk behavior questionnaire was administered and HIV counseling and testing conducted. Results Participants in both countries were largely male, in their 20s, and unmarried. A majority of subjects in both countries were members of ethnic minority groups. There were strong geographic gradients for length of drug injecting and for HIV seroprevalence. Both mean years injecting and HIV seroprevalence declined from the Vietnamese site farthest from the border to the Chinese site farthest from the border. 10.6% of participants in China and 24.5% of participants in Vietnam reported crossing the international border in the 6 months prior to interview. Crossing the border by IDUs was associated with (1) distance from the border, (2) being a member of an ethnic minority group, and (3) being HIV seropositive among Chinese participants. Conclusion Reducing the international spread of HIV among IDUs will require programs at the global, regional, national, and "local cross border" levels. At the local cross border level, the programs should be coordinated on both sides of the border and on a sufficient scale that IDUs will be able to readily obtain clean injection equipment on the other side of the border as well as in their country of residence.

Background: Multiple hypertension guidelines recommend out-of-office measurements for the diagnosis of hypertension in non-pregnant adults, whereas pregnancy guidelines recommend in-office blood pressure measurements. The objective of our study was to determine how Canadian Obstetric Medicine and Maternal Fetal Medicine specialists measure blood pressure in pregnancy. Methods: An email survey was sent to 69 Canadian Obstetric Medicine and Maternal Fetal Medicine specialists in academic centers across Canada to explore the practice patterns of blood pressure measurement in pregnant women. Results: The response rate was 48%. The majority of respondents (63.6%) preferred office blood pressure measurement for diagnosing hypertension, but relied on home blood pressure readings for ongoing monitoring and management of hypertension during pregnancy (59.4%). The preferred method of out-of-office blood pressure measurement was home monitoring; 24-hour ambulatory blood pressure monitoring was not used due to limited availability and cost. Conclusions: There is wide practice variation in methods of measuring blood pressure among Canadian specialists managing hypertension in pregnancy. [ABSTRACT FROM AUTHOR]

Background: The 2016 World Health Organization Classification of Central Nervous System Tumors categorizes gliomatosis cerebri growth pattern (GC) as a subgroup of diffuse infiltrating gliomas, defined by extent of brain involvement on magnetic resonance imaging (MRI). Clinical and radiographic features in GC patients are highly heterogeneous; however, prognosis has historically been considered poor. Subjects, Materials, and Methods: We performed a retrospective search for patients at our institution meeting radiographic criteria of primary, type I GC (defined as diffuse tumor infiltration without associated tumor mass and contrast enhancement on MRI) and analyzed their clinical, imaging, and histopathologic features. Results: A total of 34 patients met radiographic criteria of primary, type I GC, and 33 had a confirmed histologic diagnosis of an infiltrating glial neoplasm. Age >47 years at diagnosis was associated with worse overall survival (OS) compared with age ≤47 years (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.01–1.07, p =.003). Patients with grade 2 tumors demonstrated a trend for improved OS compared with those with grade 3 tumors (HR 2.65, 95% CI 0.99–7.08, p =.051). Except for brainstem involvement, extent or location of radiographic involvement did not detectably affect clinical outcome. IDH mutation status identified a subgroup of GC patients with particularly long survival up to 25 years and was associated with longer time to progression (HR 4.81, 95% CI 0.99–23.47, p =.052). Conclusion: Patients with primary, type I GC do not uniformly carry a poor prognosis, even in the presence of widespread radiographic involvement. Consistent with other reports, IDH mutation status may identify patients with improved clinical outcome. Molecular characterization, rather than MRI features, may be most valuable for prognostication and management of GC patients. Implications for Practice: Patients with gliomatosis cerebri growth pattern (GC) constitute a challenge to clinicians, given their wide range of clinical, histologic, and radiographic presentation, heterogeneous outcome patterns, and the lack of consensus on a standardized treatment approach. This study highlights that radiographic extent of disease—albeit category‐defining—does not detectably influence survival and that IDH mutations may impact clinical outcome. Practicing oncologists should be aware that select GC patients may demonstrate exceptionally favorable survival times and prognosticate patients based on molecular markers, rather than imaging features alone. Gliomatosis cerebri growth pattern (GC) is a rare presentation of a primary widely infiltrating glial tumor of the central nervous system. In this retrospective case series, the clinical, radiographic, and histopathologic findings of 34 patients with histologically proven primary, type I GC are evaluated. [ABSTRACT FROM AUTHOR]

Inhibitors of the mutant isocitrate dehydrogenase 1 (IDH1) entered recently in clinical trials for glioma treatment. Mutant IDH1 produces high levels of 2-hydroxyglurate (2HG), thought to initiate oncogenesis through epigenetic modifications of gene expression. In this study, we show the initial evidence of the pharmacodynamics of a new mutant IDH1 inhibitor in glioma patients, using non-invasive 3D MR spectroscopic imaging of 2HG. Our results from a Phase 1 clinical trial indicate a rapid decrease of 2HG levels by 70% (CI 13%, P = 0.019) after 1 week of treatment. Importantly, inhibition of mutant IDH1 may lead to the reprogramming of tumor metabolism, suggested by simultaneous changes in glutathione, glutamine, glutamate, and lactate. An inverse correlation between metabolic changes and diffusion MRI indicates an effect on the tumor-cell density. We demonstrate a feasible radiopharmacodynamics approach to support the rapid clinical translation of rationally designed drugs targeting IDH1/2 mutations for personalized and precision medicine of glioma patients [ABSTRACT FROM AUTHOR]

The central component AcrB of the Escherichia coli drug efflux complex AcrA–AcrB–TolC has been extensively investigated by X‐ray crystallography of detergent–protein 3‐D crystals. In these crystals, AcrB packs as trimers – the functional unit. We visualized the AcrB–AcrB interaction in its native environment by examining E. coli lipid reconstituted 2‐D crystals, which were overwhelmingly formed by asymmetric trimers stabilized by strongly‐interacting monomers from adjacent trimers. Most interestingly, we observed lattices formed by an arrangement of AcrB monomers distinct from that in traditional trimers. This hitherto unobserved packing, might play a role in the biogenesis of trimeric AcrB.E. coli lipid reconstituted AcrB 2D crystals show predominantly asymmetric trimers. Inter monomer–monomer interactions stabilize adjacent AcrB trimers in 2D crystal. Crystals of AcrB containing non‐trimeric arrangement of monomers were also observed. [ABSTRACT FROM AUTHOR]

Background: To assess patterns of injecting drug use and HIV prevalence among injecting drug users (IDUs) in an international border area along a major heroin trans-shipment route. Methods: Cross-sectional surveys of IDUs in 5 sites in Lang Son Province, Vietnam (n = 348) and 3 sites in Ning Ming County, Guangxi Province, China (n = 308). Respondents were recruited through peer referral ("snowball") methods in both countries, and also from officially recorded lists of IDUs in Vietnam. A risk behavior questionnaire was administered and HIV counseling and testing conducted. Results: Participants in both countries were largely male, in their 20s, and unmarried. A majority of subjects in both countries were members of ethnic minority groups. There were strong geographic gradients for length of drug injecting and for HIV seroprevalence. Both mean years injecting and HIV seroprevalence declined from the Vietnamese site farthest from the border to the Chinese site farthest from the border. 10.6% of participants in China and 24.5% of participants in Vietnam reported crossing the international border in the 6 months prior to interview. Crossing the border by IDUs was associated with (1) distance from the border, (2) being a member of an ethnic minority group, and (3) being HIV seropositive among Chinese participants. Conclusion: Reducing the international spread of HIV among IDUs will require programs at the global, regional, national, and "local cross border" levels. At the local cross border level, the programs should be coordinated on both sides of the border and on a sufficient scale that IDUs will be able to readily obtain clean injection equipment on the other side of the border as well as in their country of residence. [ABSTRACT FROM AUTHOR]