TEMPI syndrome: difficult to diagnose, "easy" to treat?

TEMPI syndrome is a rare, acquired disorder with multisystemic manifestations. It is classified as a plasma cell disorder and is characterized by telangiectasias, erythrocytosis, monoclonal gammopathy, perinephric fluid collections and intrapulmonary shunt. Even though TEMPI's pathophysiology remains elusive, it responds to anti-myeloma therapy indicating that the monoclonal protein or clone plays a key role. We present a challenging case of a 73-year-old man with erythrocytosis and deteriorating renal function with nephrotic-range proteinuria in whom after extensive work up, the diagnosis of TEMPI syndrome was made. He was received treatment with daratumumab-bortezomib-cyclophosphamide and dexamethasone (Dara-VCD) and achieved a hematological and clinical response. We also report preliminary data on a multiplex assay for cytokines and growth factors for two patients with TEMPI syndrome and note lower levels for non-specific innate immunity related cytokines. A direct link between renal impairment and TEMPI syndrome is not currently established; cytokine deregulation could potentially be involved in the ischemic changes observed in the renal biopsy of our patient.

Telangiectasias, recurrent epistaxis and a strong family history-a case of Osler- Weber-Rendu Syndrome in Pakistan.

Osler-Weber-Rendu syndrome or Hereditary Haemorrhagic Telangiectasia (HHT) is a rare condition, with very few reported cases, especially in Pakistan. As healthcare workers, we encounter multiple cases of recurrent epistaxis in the emergency as well as outpatient departments. However, patients are usually treated symptomatically without a thorough workup. HHT should be considered among the differentials for recurrent epistaxis, as a clinical diagnosis can be made with detailed family history and physical examination. Here is the case of a 58-year-old male who presented to the Gastroenterology OPD, Combined Military Hospital, Lahore, in November 2021, with complaints of generalised weakness and blood in stools. He had a history of recurrent epistaxis and telangiectasias, and further inquiry revealed a strong family history of similar symptoms. He was diagnosed as a case of Osler-Weber- Rendu Syndrome. Informed consent was taken from the patient prior to the writing of the manuscript.

Efficacy, tolerance and acceptability of pulsed dye laser on facial and neckline telangiectasias in systemic scleroderma: a prospective open-label monocentric study in 21 patients.

Facial and neckline telangiectasias have an underestimated yet important impact on quality of life of patients with systemic scleroderma (SSc). This monocentric, prospective, open-label, intra-patient comparative study was conducted in 21 consecutive patients with SSc. Patients underwent 4 sessions of PDL 8 weeks apart. A final quadruple assessment was performed by several raters 2 months after the last session, based on the following criteria: change in telangiectasia number; subjective improvement score (LINKERT scale); impact on the quality of life (QoL; SKINDEX score); visual analog pain scale; adverse effects (AEs), including treatment discontinuation for PDL-induced purpura and patient satisfaction. The mean telangiectasia number decreased by 5 (32%) at the end of the protocol. Eighteen patients (85.7%) reported an improvement or a strong improvement, versus 73.81% for the expert committee. Immediate session pain (mean = 3.4/10) was slightly less than overall pain (mean = 4.6/10). Ten patients (47%) experienced at least one AE (oozing/crusts, edema, epidermal blistering), including PDL-induced purpura in 3 patients (14%). AEs were mostly transient (<1 week) and mild (CTCAE grade 1). All QoL parameters improved after treatment, and 85% of patients were satisfied.

MINI-INVASIVE TREATMENT METHODS OF SPIDER VEINS: SCLEROTHERAPY AND RADIOFREQUENCY THERMOCOAGULATION.

OBJECTIVE: The aim: This study was conducted to compare the results of spider vein: sclerotherapy or radiofrequency thermocoagulation. PATIENTS AND METHODS: Materials and methods: The study included 52 patients with spider veins, who were randomized into two treatment groups: sclerotherapy or radiofrequency thermocoagulation. Treatment outcomes were assessed using: a self-assessed questionnaire, CIVIQ 20 questionnaire, computer evaluation of images, registration relapses complications, negative manifestations, and intensity of the pain syndrome. RESULTS: Results: Both methods showed a statistically significant difference in the quality of life indicators before and one month after treatment (p<0.001 for both groups). Radiofrequency thermocoagulation showed a greater impact on the patient's quality of life (p = 0.003). The average length of spider veins in the treatment area decreased the most with radiofrequency thermocoagulation (by 92.1%), slightly less after sclerotherapy (by 73.4%) (p < 0,01). CONCLUSION: Conclusions: Both treatments have shown good results for spider veins and were reasonably safe with few negative manifestations. Radiofrequency coagulation better eliminates small veins, less than 0.3 mm.

Lasers' Q-switched treatment in skin and subcutaneous lesions - review.

The numerous medical fields like dermatology, ophthalmology and surgery widely use laser therapy including Q-switched lasers. This review aims to provide information on the application and effectiveness of Q-switched lasers in dermal and vascular lesions. Q-switched lasers play a crucial part in the athlete's foot treatment and onychomycosis both in mono- and polytherapy. Laser therapy remains the gold standard for tattoo removal. Additionally, laser therapy shows high effectiveness in melasma, telangiectasias and photoaging therapy. The ability to adjust precise laser parameters like length or beam energy provides tight control of the treated area, significantly reducing the risk of adverse effects.

Cutaneous collagenous vasculopathy: A report of three cases.

Cutaneous collagenous vasculopathy is a rare pauci-inflammatory, superficial, cutaneous vasculopathy characterized by progressive fine-branching telangiectasias clinically, while light microscopically one observes dilated venules and capillaries within the superficial dermis exhibiting excessive Type IV collagen within the vessel wall. We present three cases of collagenous vasculopathy. Two cases were associated with certain autoimmune stigmata, including a positive serologic anti-endothelial cell antibody assay and positive lupus anticoagulant in one, while the third case had positive anti-ribonucleoprotein (RNP) antibodies. The latter case was associated with chronic hydroxyurea therapy for an underlying myeloproliferative disorder. We explore the role of immune- and non-immune-based endothelial cell injury in the pathogenesis of collagenous vasculopathy.

Combination of Specific Vascular Lasers and Vascular Intense Pulsed Light Improves Facial Telangiectasias and Redness.

Background and objectives: Facial telangiectasias are dilated blood vessels that can represent a cosmetic issue for patients. They may be associated with other conditions, such as rosacea. Laser and light treatments are nowadays becoming a cornerstone in the management of these lesions. Materials and Methods: In total, 68 patients seeking medical treatment for facial telangiectasias were enrolled from 1 March 2019 to 1 March 2020 at the Dermatological Unit of Magna Graecia University (Catanzaro, Italy). A protocol consisting of a 1064 Nd:YAG laser for darker blue telangiectasias and 532 nm Nd:YAG for red lesions followed by intense pulsed light with an optimized spectrum for vascular lesion 3 weeks after the first procedure was proposed. A three-month follow-up visit assessed patient's satisfaction using a visual analog scale (VAS). Two dermatologists measured clinical results using a 4-point scale, comparing pictures before treatment and at follow-up. Results: A total of 68 patients (32 males and 36 females) completed the study, performing all requested treatments. No severe side effects were reported. Patient satisfaction was very high (8.15 ± 1.05 out of a 10-point VAS scale), as well as dermatologists' clinical evaluations (2.19 ± 0.74 out of 3). Conclusions: The combination of vascular lasers and Vascular Intense Pulsed Light acting specifically on small blood vessels may help to improve the aesthetic outcome, reducing side effects. A prospective study with a larger number of participants will be necessary to confirm this study's findings.

A Rare Case of Upper Gastrointestinal Bleeding: Osler-Weber-Rendu Syndrome.

Osler-Weber-Rendu disease, also known as hereditary hemorrhagic telangiectasia (HHT), is a rare, autosomal dominant condition that affects approximately 1 in 5000 patients causing abnormal blood vessel formation. HHT patients have mucocutaneous telangiectasias and arteriovenous malformations in various organs. The most prominent symptom of HHT is epistaxis, which, together with gastrointestinal bleeding, may cause iron deficiency anemia. This study is a case report of a 62-year-old patient who was admitted to the Department of Gastroenterology due to acute upper gastrointestinal bleeding and a history of recurrent epistaxis and melena for 4 days, which was confirmed in digital rectal examination. Urgent upper gastrointestinal endoscopy revealed active bleeding from multiple angioectatic spots with bright-looking salmon-colored patches in the antrum and the body suggestive of HHT. The bleeding from two angioectatic spots was stopped by argon plasma coagulation, and four clips were placed to provide good hemostasis. The patient was treated with a proton pomp inhibitor infusion and iron infusion. She was discharged with no signs of GI bleeding, normalized iron levels and a diagnosis of HHT. She was referred to further genetic testing, including evaluation of first-degree relatives. She also had performed unenhanced thin-cut computed tomography (CT) with angiography to exclude the presence of pulmonary arteriovenous malformations (PAVMs). Due to the fact that the patient did not manifest any other HHT-related symptoms and that the instrumental screening discloses no silent AVMs in other organs, the "watch-and-wait strategy" was applied. Although, Osler-Weber-Rendu syndrome is widely described in the medical literature, effective treatment of gastrointestinal telangiectasias is not always available and still lacks standardization to date, which makes the management of gastroenterological involvement still a challenging issue.

Polidocanol Plus Glucose Versus Glucose Alone for the Treatment of Telangiectasias: Triple Blind, Randomised Controlled Trial (PG3T).

OBJECTIVE: The aim of this study was to compare the effectiveness and safety of two sclerosing agents used to treat telangiectasias in the lower limbs: 0.2% polidocanol + 70% hypertonic glucose (HG) vs. 75% HG alone. METHODS: A prospective, randomised, triple blind, controlled, parallel group trial with patients randomly assigned in a 1:1 ratio between January and December 2015, with a two month follow up, from a single academic medical centre in Brazil, was carried out. Participants were women aged 18-65 years with telangiectasias on the lateral aspect of one thigh, classified as C1EpAsPn who underwent sclerotherapy in a single session with 0.2% polidocanol + 70% HG or 75% HG alone to treat the telangiectasias on an area limited by a rectangular template. The primary effectiveness endpoint was elimination of 75% of the telangiectasias within 60 days vs. the pre-treatment pattern. The length of vessels was measured on images obtained before and after treatment using ImageJ software. Safety outcomes were analysed immediately, 7 days, and 60 days after the treatment, and included pigmentation. RESULTS: A total of 115 patients were included, 98 of whom completed the study. Sclerotherapy with 0.2% polidocanol + 70% HG was significantly more effective than with 75% HG alone to treat telangiectasias in the target area (82.2% vs. 63.9%; p < .001); considering a minimum improvement of 75%, there was a 0.49 risk reduction (95% confidence interval 0.24-0.98; p = .047). No severe adverse events occurred in either group. Pigmentation was the most common minor adverse event and was significantly shorter in length in the group treated with 0.2% polidocanol + 70% HG (median 0 cm vs. 0.5 cm, respectively; p = .033). CONCLUSION: Polidocanol 0.2% plus 70% HG had better results than 75% HG alone in sclerosing telangiectasias. No severe adverse events occurred. Pigmentation occurred in both groups and was shorter in length in the group treated with 0.2% polidocanol + 70% HG.

Sclerotherapy of telangiectasias: A prospective, randomized, comparative clinical trial of hypertonic glucose versus sodium tetradecyl sulfate.

To compare the disappearance of the telangiectasias after sclerotherapy with 75% glucose (HG) versus 0.2% sodium tetradecyl sulfate (STS). This prospective, randomized clinical trial compared the results of sclerotherapy of the telangiectasias with HG and STS. The primary efficacy end point was telangiectasia disappearance within 14, 28, 42, and 56 days following treatment. The clearing of the vessels was assessed using a six-point scale (from 0 to 5). A total of 159 women were treated (81 in the STS group; 78 in the HG group). The median score of the vessels clearing (IQR) was significantly lower in the STS group than in the HG group: 3 (2-4) versus 4 (3-5) after 56 days, p < 0.001. Pigmentation was frequently observed in the STS group (38.3% vs 2.6%; p < 0.001). In conclusion, throughout the entire follow-up period, sclerotherapy of telangiectasias with glucose was significantly superior to that with STS. Moreover, pigmentation and intravascular clots frequently occurred with STS treatment. Russian Registry of Treatment of Chronic Venous Diseases (RRT CVD) ID: VRCVD 1.005.

Restorative oncodermatology: Diagnosis and management of dermatologic sequelae from cancer therapies.

The long-term survival of patients with cancer has risen dramatically during the last few decades. Despite this remarkable success, the same treatments that have enabled cure or remission often secondarily affect the skin, hair, and nails. Conditions including scarring, striae distensae, persistent alopecia, pigmentary changes, nail alterations, chronic radiation dermatitis, and radiation fibrosis have been associated with anxiety, depression, decreased quality of life, and impaired function. These dermatologic changes are cosmetically disfiguring, may limit activities, and are a visual reminder of past illness. Interventions toward improving these untoward sequelae and restoring the appearance and function of skin and appendages are critical for normalization and may contribute to improved quality of life in cancer survivors. Here, we outline dermatologic sequelae of cancer therapies with a review of medical and procedural treatment strategies to restore dermatologic health in the survivorship population.

Inter-observer evaluation of erythema-directed photography for the assessment of erythema and telangiectasias in rosacea.

BACKGROUND: Persistent centrofacial erythema associated with telangiectasias is one of the most common phenotypes of rosacea in clinical practice, and the assessment of each component is crucial as each of them may require a different approach. The aim of this study was to evaluate the inter-observer reliability of standard photography vs erythema-directed photography for the assessment of erythema and telangiectasias in rosacea. MATERIALS AND METHODS: One hundred full-face images of 50 rosacea patients (50 standard photographs and 50 erythema-directed digital photographs) were evaluated by 8 independent experienced dermatologists using a 5-item score for erythema and telangiectasias, respectively. Inter-rater reliability, by comparing erythema and telangiectasias scores and calculating the percentage of agreement between evaluators, was assessed and the strength of agreement using the Cohen's Kappa values (95% CI) was calculated. RESULTS: Poor and fair strength of agreement for erythema and telangiectasias using standard photography vs moderate and good strength of agreement using erythema-directed digital photography was found. CONCLUSION: Erythema-directed digital photography may provide a better strength of agreement and higher reliability among independent observers compared to standard photography in the assessment of erythema and telangiectasias in rosacea, thus suggesting new horizons for digital appraisal of skin diseases.

Oxymetazoline and Energy-Based Therapy in Patients with Rosacea: Evaluation of the Safety and Tolerability in an Open-Label, Interventional Study.

BACKGROUND AND OBJECTIVES: The objectives of this study were to evaluate the safety, tolerability, and efficacy of oxymetazoline hydrochloride cream, 1% (oxymetazoline) when used as an adjunctive treatment with energy-based therapy for patients with moderate to severe facial erythema associated with rosacea. STUDY DESIGN/MATERIALS AND METHODS: In this Phase 4, multicenter, interventional, open-label study, eligible patients received one of four energy-based therapies (potassium titanyl phosphate laser, intense pulsed light therapy, pulsed-dye laser Vbeam Perfecta, or pulsed-dye laser Cynergy) on day 1 and day 29 and once-daily application of oxymetazoline on days 3 through 27 and days 31 through 56. Improvement from baseline in Clinician Erythema Assessment (CEA) score, patient satisfaction measures, incidence of treatment-emergent adverse events (TEAEs), and worsening from baseline on dermal tolerability assessments and the Clinician Telangiectasia Assessment (CTA) were assessed. Data were summarized using descriptive statistics. RESULTS: A total of 46 patients (mean age, 51.1 years; 78.3% female) enrolled in this study. Similar numbers of patients received each of the energy-based therapies in addition to oxymetazoline. All patients demonstrated an improvement from baseline in CEA during the study with 39 of 43 evaluable patients (90.7%) demonstrating an improvement 6 hours posttreatment on day 56. Most patients were satisfied or very satisfied with treatment at the end of the study. All TEAEs were mild or moderate in severity. Some patients experienced worsening in dermal tolerability assessment symptoms (range: 4-21 patients; 8.7-45.7%). Worsening in CEA and CTA were each reported by three patients (6.5%) at any time during the study. CONCLUSIONS: Treatment with oxymetazoline as adjunctive therapy with energy-based therapy was safe, well tolerated, and reduced facial erythema in patients with moderate to severe persistent facial erythema associated with rosacea. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.

Periorbital hypopigmentation and telangiectasias: Clues to diagnosing neonatal lupus in skin of color.

Neonatal lupus erythematosus (NLE) is an autoimmune disease characterized by a periorbital erythematous rash. Although post-inflammatory hypopigmentation and telangiectasias are known possible sequelae, these features may be particularly noticeable in skin of color. Herein, we describe two infants with skin of color in whom periorbital hypopigmentation and telangiectasias were clues to the diagnosis of NLE.

[Purpura annularis telangiectodes : Case report and review of the literature]. / Purpura anularis teleangiectodes : Fallbericht und Literaturübersicht.

Pupura annularis telangiectodes (PAT) is a rare entity belonging to the spectrum of the pigmented purpuric dermatoses. PAT presents clinically as symmetric, annular erythema with teleangiectasia on the lower extremities and preferably affects young women. Histology usually reveals extravasated erythrocytes accompanied by a lymphocyte-dominated inflammatory infiltrate in the superficial dermis. Medication can often be identified as causative. In patients with idiopathic disease, topical corticoidsteroids are the treatment of choice. Compression therapy may be supportive.

Analysis of breast cosmetic effects 3 years after breast-conserving surgery and intraoperative radiotherapy with and without adjuvant whole breast irradiation.

INTRODUCTION: Intraoperative radiotherapy (IORT) based on low-kV photons may be an option for early breast cancer patients. Following Targit trial results some of those patients should undergo whole breast irradiation (WBRT) additionally. MATERIAL AND METHODS: Since April 2010, IORT has been applied to early breast cancer patients. One hundred and fifty patients were prospectively followed up and examined to evaluate the side effects (pain, fibrosis, breast edema, telangiectasias). We present the results 3 years post-treatment. WBRT was given to 82 (54.7%) patients. RESULTS: Tumor cavity fibrosis grade II and more was observed in 18 (12%) patients, as grade III only in 2 (1.33%) patients. Breast tissue fibrosis outside tumor cavity grade II was observed only in 2 (1.33%) patients. Breast edema was present in 10 (6.66%) patients. WBRT administration led to increased frequency of higher grade tumor cavity fibrosis (P < .0001), breast fibrosis (P < .0001), breast edema (P = .003), and occurrence of telangiectasias (P = .03), with no influence on pain reported by patients. In case of WBRT, tumor location (P = .026) and size of the irradiated breast (P = .015) were independent risk factors for higher degree of breast fibrosis, as seroma evacuation 6 months post-WBRT (P = .036) was the only independent risk factor for higher level of tumor cavity fibrosis in multiple regression. CONCLUSIONS: The cosmetic result after IORT is good and comparable to other accelerated partial breast irradiation techniques. Administration of WBRT post-IORT in breast cancer patients increases the level of fibrotic changes, breast edema and telangiectasias 3 years post-treatment, but with no influence on pain.

The anti-aging protein alpha-Klotho in systemic sclerosis patients: does a relationship to telangiectasia exist?

OBJECTIVE: The anti-aging protein alpha-Klotho has been reported to have an emerging role in the pathogenesis of systemic sclerosis (SSc). More studies are needed to approach this issue. This study aimed to assess the serum levels of α­Klotho in SSc patients compared to healthy controls, and to correlate them with the disease parameters. METHODS: Forty-two SSc patients were included in this study. History taking, clinical examination, and related investigations were performed. The modified Rodnan skin score (mRss) was used to assess skin tightness in SSc patients. Twenty-seven age- and sex-matched healthy participants served as controls. Serum α­Klotho was assessed in the two groups. RESULTS: SSc patients comprised 39 females and 3 males; mean age was 42.2 ± 12.1 years and mean disease duration 8.5 ± 6.3 years. Serum α­Klotho levels were decreased in scleroderma patients in comparison to healthy controls (p < 0.001). Scleroderma patients who had higher frequencies of telangiectasias and digital ischemic lesions had higher serum α­Klotho levels (p = 0.01 and p = 0.04, respectively). By simple regression, only telangiectasias were significantly associated with higher α­Klotho levels (p = 0.01). No other significant relationships were found between serum α­Klotho and SSc disease parameters. CONCLUSION: Scleroderma patients had significantly lower serum α­Klotho levels than healthy controls. Higher α­Klotho levels were significantly associated with telangiectasias. An imbalance in serum α­Klotho levels may be involved in systemic sclerosis. Further longitudinal studies in a larger population of systemic sclerosis patients may provide a clearer clue for its role.

Hereditary sensory and autonomic neuropathy type IC accompanied by upper motor neuron abnormalities and type II juxtafoveal retinal telangiectasias.

Hereditary sensory and autonomic neuropathy type I (HSAN-1) is an autosomal dominant sensory neuropathy occurring secondary to mutations in the SPTLC1 and SPTLC2 genes. We present two generations of a single family with Ser384Phe mutation in the SPTLC2 gene located on chromosome 14q24 characterized by a typical HSAN-1c presentation, with additional findings upper motor neuron signs, early demyelinating features on nerve conduction studies, and type II juxtafoveal retinal telangiectasias also known as macular telangiectasias (MacTel II). Although HSAN1 is characterized as an axonal neuropathy, demyelinating features were identified in two subjects on serial nerve conduction studies comprising motor conduction block, temporal dispersion, and prolongation of F-waves. MacTell II is a rare syndrome characterized by bilateral macular depigmentation and Müller cell loss. It has a presumed genetic basis, and these cases suggest that the accumulation of toxic sphingoplipids may lead to Müller cell degeneration, subsequent neuronal loss, depigmentation, and progressive central macular thinning.

One-year follow-up of a TRASER clinical trial for the treatment of nasal telangiectasias.

OBJECTIVES: To evaluate the long-term efficacy of treating nasal telangiectasias with the TRASER device. METHODS: Subjects from the TRASER efficacy analysis clinical trial were invited for a 1-year follow-up. Standardized photographs were taken to compare to baseline. The same clinical trial evaluator graded the subjects' current vessel clearance using the 5-point telangiectasia scale. The data was compiled and analyzed. RESULTS: Of the subjects with available follow-up data, 44% maintained "complete vessel clearance," 44% dropped down one grade to "almost complete vessel clearance," and 11% dropped down to "moderately clear vessel clearance." All showed clinically significant improvement in nasal telangiectasias from baseline. CONCLUSIONS: The TRASER effectively treats nasal telangiectasias with minimal to mild recurrence at 1-year follow-up. Lasers Surg. Med. 50:61-63, 2018. © 2017 Wiley Periodicals, Inc.

Effect of laser therapy on quality of life in patients with radiation-induced breast telangiectasias.

OBJECTIVE: To evaluate the effects of laser monotherapy on quality of life in breast cancer patients with chronic radiation dermatitis. STUDY DESIGN: A prospective, IRB-approved study was conducted at Memorial Sloan Kettering Cancer Center. Breast cancer patients with chronic radiation dermatitis completed health-related quality of life (HR-QOL) questionnaires before and after laser monotherapy for radiation-induced breast telangiectasias (RIBT). METHODS: After informed consent, all patients were issued the Skindex-16 and Breast-Q Adverse Effects of Radiation HR-QOL questionnaires prior to receiving laser treatment. Patients were treated with a 595 nm pulsed dye laser at 4- to 6-week intervals, with percent telangiectasia clearance and adverse events recorded at each visit. Post-treatment HR-QOL questionnaires were collected after clinician-assessed telangiectasia clearance of >50%. Median HR-QOL scores before and after therapy were reported for individual HR-QOL domains (Skindex-16) and HR-QOL totals (Skindex-16 and Breast-Q Adverse Effects of Radiation). Before- and after-differences were calculated using the Wilcoxon Signed-Rank Test. RESULTS: Twenty-two female patients (average age 56 years) enrolled in this study. A majority (13/22, 59%) exhibited telangiectasias across the décolletage and axilla in addition to the breast. Sixteen patients reached the 50% RIBT clearance threshold during the study period, and 11 of these patients (69%) completed follow-up HR-QOL questionnaires. Patients showed statistically significant improvements in emotional and functional Skindex-16 HR-QOL domains and in overall Skindex-16 HR-QOL score. Breast-Q scores also improved significantly, illustrating a decrease in specific physical and cosmetic concerns common to radiated breast skin. Common adverse events were transient post-treatment pain and redness. CONCLUSION: Breast cancer patients with RIBT presented with substantial deficits in several HR-QOL arenas. Laser monotherapy effectively treated the appearance of radiation dermatitis in these patients and also significantly improved HR-QOL. Lasers Surg. Med. 50:284-290, 2018. © 2017 Wiley Periodicals, Inc.