Virtual Reality for Patient Education about Hypertension: A Randomized Pilot Study.

BACKGROUND: Hypertension challenges arise in part from poor adherence due to inadequate patient education. VR offers immersive learning to improve hypertension knowledge. OBJECTIVE: To compare VR education with traditional verbal education to improve hypertension knowledge. METHODS: In this randomised trial, 182 patients with hypertension were assigned to receive either traditional physician-led education (n = 88) or VR education (n = 94) with equivalent content. The VR group experienced a 3D video using Oculus Quest 2 headsets. Knowledge was assessed post-intervention using a 29-item questionnaire. The primary outcome was the objective score. Subjective satisfaction and responder characteristics were secondary outcomes. RESULTS: Median objective scores were significantly higher for VR (14, IQR 3) versus traditional education (10, IQR 5), p < 0.001, indicating superior hypertension knowledge acquisition with VR. Subjective satisfaction was high in both groups. Participants were categorized into low (first quartile) and medium-high (second to fourth quartiles) responders based on their scores. Low responders had a significantly higher prevalence of older women than medium-high responders (57% vs. 40% female, p = 0.024; 68 vs. 65 years), p = 0.036). CONCLUSIONS: VR outperforms traditional education. Tailoring to groups such as older women can optimise learning.

Getting it right the first time: an Irish paediatric dermatology perspective from a national care centre.

The Dermatology: 'Getting It Right the First Time' (GIRFT) Programme National Specialty Report recommended improving access to, and the quality of, paediatric dermatology services. Understanding referral patterns makes it easier to identify areas that can be improved. This study analysed 292 new referrals to a national care centre that provides secondary care to 50% of all Irish children. Results showed that 51% of new referrals could have been managed in primary care and 41% of new referrals were inappropriate, including 5.5% having no abnormal skin findings. These results indicate that up to 876 referrals could have been avoided over a 13-month period, freeing up resources and reducing wait times for cases more appropriate for a secondary and tertiary care centre. This would improve access for children, allowing them to be diagnosed at the right place and time, in alignment with GIRFT values.

The VASCERN-VASCA Working Group Diagnostic and Management Pathways for Venous Malformations.

To elaborate expert consensus patient pathways to guide patients and physicians toward efficient diagnostics and management of patients with venous malformations. Methods: VASCERN-VASCA (https://vascern.eu/) is a European network of multidisciplinary centers for Vascular Anomalies. The Nominal Group Technique was used to establish the pathways. Two facilitators were identified: one to propose initial discussion points and draw the pathways, and another to chair the discussion. A dermatologist (AD) was chosen as first facilitator due to her specific clinical and research experience. The draft was subsequently discussed within VASCERN-VASCA monthly virtual meetings and annual face-to-face meetings. Results: The Pathway starts from the clinical suspicion of a venous type malformation (VM) and lists the clinical characteristics to look for to support this suspicion. Strategies for subsequent imaging and histopathology are suggested. These aim to inform on the diagnosis and to separate the patients into 4 subtypes: (1) sporadic single VMs or (2) multifocal, (3) familial, multifocal, and (4) combined and/or syndromic VMs. The management of each type is detailed in subsequent pages of the pathway, which are color coded to identify sections on (1) clinical evaluations, (2) investigations, (3) treatments, and (4) associated genes. Actions relevant to all types are marked in separate boxes, including when imaging is recommended. When definite diagnoses have been reached, the pathway also points toward disease-specific additional investigations and recommendations for follow up. Options for management are discussed for each subtype, including conservative and invasive treatments, as well as novel molecular therapies. Conclusion: The collaborative efforts of VASCERN-VASCA, a network of the 9 Expert Centers, has led to a consensus Diagnostic and Management Pathways for VMs to assist clinicians and patients. It also emphasizes the role of multidisciplinary expert centers in the management of VM patients. This pathway will become available on the VASCERN website (http://vascern.eu/).

Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants.

BACKGROUND: Postzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA-related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007 PIK3CA-mutated patients, analysing our new data with previous literature to give a comprehensive picture. METHODS: We performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes and GNAQ, GNA11, RASA1 and TEK. Additionally, 914 patients previously reported were systematically reviewed. RESULTS: 93 of our 150 patients had PIK3CA pathogenetic variants. The merged PROS cohort showed that PIK3CA variants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-type PIK3CA allele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants in GNAQ, GNA11, RASA1 or TEK. CONCLUSION: We confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping 'vascular' phenotypes; (2) strongly activating PIK3CA variants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other than PIK3CA.

The VASCERN-VASCA working group diagnostic and management pathways for lymphatic malformations.

Lymphatic malformations (LMs) are developmental defects of lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size, and unexpected swelling, they may cause serious complications that threaten vital functions such as compression of the airways. A large swelling of the face or neck may also be disfiguring and thus constitute a psychological strain for patients and their families. LMs are also highly immunologically reactive, and are prone to recurrent infections and inflammation causing pain as well as chronic oozing wounds. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) is dedicated to gathering the best expertise in Europe. There are only few available guidelines on management and follow up of LMs, which commonly focus on very specific situations, such as head and neck LM (Zhou et al., 2011). It is still unclear, what constitutes an indication for treatment of LMs and how to follow up the patients. The Vascular Anomalies Working Group (VASCA-WG) of VASCERN decided to develop a diagnostic and management pathway for the management of LMs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following 2 face-to-face meetings and multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with lymphatic malformations in a practical manner; we present an algorithmic view of the results of our work.

The VASCERN-VASCA working group diagnostic and management pathways for severe and/or rare infantile hemangiomas.

The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN), is dedicated to gathering the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. Infantile Hemangiomas (IH) are benign vascular tumors of infancy that rapidly growth in the first weeks of life, followed by stabilization and spontaneous regression. In rare cases the extent, the localization or the number of lesions may cause severe complications that need specific and careful management. Severe IH may be life-threatening due to airway obstruction, liver or cardiac failure or may harbor a risk of functional impairment, severe pain, and/or significant and permanent disfigurement. Rare IHs include syndromic variants associated with extracutaneous abnormalities (PHACE and LUMBAR syndromes), and large segmental hemangiomas. There are publications that focus on evidence-based medicine on propranolol treatment for IH and consensus statements on the management of rare infantile hemangiomas mostly focused on PHACES syndrome. The Vascular Anomalies Working Group (VASCA-WG) decided to develop a diagnostic and management pathway for severe and rare IHs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following two face-to-face meetings and in multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with severe and rare IH in a practical manner; we present an algorithmic view of the results of our work.

Efficacy of Sirolimus in Patients Requiring Tracheostomy for Life-Threatening Lymphatic Malformation of the Head and Neck: A Report From the European Reference Network.

Extensive lymphatic malformations (LMs) of the head and neck region may require tracheostomy to secure the airway. Treatment of these life-threatening LMs is usually multimodal and includes sclerotherapy and surgery, among others. Recently, systemic therapy with sirolimus has been introduced as an effective treatment for venous and lymphatic malformations; its efficacy and safety profile in patients with extensive LM requiring tracheostomy are, however, as yet not fully known. We performed a retrospective, multicenter review and identified 13 patients with an extensive LM of the head and neck region, who previously underwent placement of tracheostomy and subsequently received sirolimus treatment with the aim to improve the local respiratory situation and remove the tracheostomy. Under sirolimus therapy, tracheostomy could be reversed in 8/13 (62%) patients, a further 2/13 (15%) patients improved markedly, and removal of the tracheostomy was planned at the time of writing, while 3/13 (23%) patients showed insufficient or absent response to sirolimus, rendering tracheostomy reversal not feasible. The median duration of sirolimus treatment until removal of tracheostomy was 18 months (range, 8 months to 5.6 years). Adverse events of sirolimus therapy were common [10/13 (77%) patients], yet the majority of these were mild [9/10 (90%) patients] and only one severe adverse event was recorded, with ulceration and necrosis at a catheter insertion site. In conclusion, sirolimus can be considered an effective and safe salvage treatment in patients with extensive LM even after placement of a tracheostomy, as closure of the latter was possible in the majority of patients (62%) of our retrospective cohort. A better understanding of when to start sirolimus therapy, of the duration of treatment, and of factors allowing the prediction of treatment response will require further investigation.

Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome.

BACKGROUND: PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods. RESULTS: Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22-28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported. CONCLUSION: We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).

RASA1 mosaic mutations in patients with capillary malformation-arteriovenous malformation.

BACKGROUND: Capillary malformation-arteriovenous malformation is an autosomal dominant disorder, characterised by capillary malformations and increased risk of fast-flow vascular malformations, caused by loss-of-function mutations in the RASA1 or EPHB4 genes. Around 25% of the patients do not seem to carry a germline mutation in either one of these two genes. Even if other genes could be involved, some individuals may have mutations in the known genes that escaped detection by less sensitive techniques. We tested the hypothesis that mosaic mutations could explain some of previously negative cases. METHODS: DNA was extracted from peripheral blood lymphocytes, saliva or vascular malformation tissues from four patients. RASA1 and EPHB4 coding regions and exon/intron boundaries were analysed by targeted custom gene panel sequencing. A second panel and/or Sanger sequencing were used to confirm the identified mutations. RESULTS: Four distinct mosaic RASA1 mutations, with an allele frequency ranging from 3% to 25%, were identified in four index patients with classical capillary malformation-arteriovenous malformation phenotype. Three mutations were known, one was novel. In one patient, a somatic second hit was also identified. One index case had three affected children, illustrating that the mosaicism was also present in the germline. CONCLUSION: This study shows that RASA1 mosaic mutations can cause capillary malformation-arteriovenous malformation. Thus, highly sensitive sequencing techniques should be considered as diagnostic tools, especially for patients with no family history. Even low-level mosaicism can cause the classical phenotype and increased risk for offspring. In addition, our study further supports the second-hit pathophysiological mechanism to explain the multifocality of vascular lesions in this disorder.

Generalized lymphatic anomaly successfully treated with long-term, low-dose sirolimus.

Generalized lymphatic anomaly is a rare, complex, lymphatic anomaly generally involving soft tissues, spleen, and bones. It can lead to focal skeletal fragility and pathologic effusions. A recent prospective trial of sirolimus for complicated vascular anomalies showed partial response in seven patients with generalized lymphatic anomaly treated with sirolimus with a target trough level of 10-15 ng/mL for 1 year (Adams et al). We describe successful treatment of generalized lymphatic anomaly with a lower-dose, long-term course of sirolimus.

Electrochemical quantum dots-based magneto-immunoassay for detection of HE4 protein on metal film-modified screen-printed carbon electrodes.

A novel enzyme-free electrochemical immunosensor was developed for highly sensitive detection and quantification of human epididymis protein 4 (HE4) in human serum. For the first time, core/shell CdSe/ZnS quantum dots were conjugated with anti-HE4 IgG antibodies for subsequent sandwich-type immunosensing with superparamagnetic microparticles functionalized with anti-HE4 IgG antibodies, which allow rapid and efficient HE4 capture from the sample. Electrochemical detection of anti-HE4 IgG - HE4 - anti-HE4 IgGCdSe/ZnS immunocomplex was performed by recording the current response of Cd(II) ions, released from dissolved quantum dots at screen-printed carbon electrode (SPCE), modified with mercury or bismuth film. The linear range of the detection was from 20 pM to 40 nM with limit of detection of 12 pM using three times the standard deviation of blank criterion at mercury-film SPCE and from 100 pM to 2 nM with limit of detection of 89 pM at bismuth-film SPCE. Proposed electrochemical immunosensor meets the requirements for fast and sensitive quantification of HE4 biomarker in early stage of ovarian cancer and due to the proper sensitivity and specificity presents a promising alternative to enzyme-based probes used routinely in clinical diagnostics.

Methotrexate for Severe Childhood Atopic Dermatitis: Clinical Experience in a Tertiary Center.

BACKGROUND/OBJECTIVES: Atopic dermatitis (AD) affects up to 20% of children. Although the majority of patients are adequately controlled using emollients, topical corticosteroids, topical calcineurin inhibitors, or phototherapy, children with moderate to severe AD may require systemic treatment for control. The objective of the current study was to evaluate the efficacy and safety of methotrexate in children with severe AD attending a tertiary referral center. METHODS: A retrospective chart review was undertaken of all children who received methotrexate for severe AD at our tertiary referral center from November 2010 to August 2015. RESULTS: Forty-seven children were started on methotrexate for AD during this period. The mean Investigator Global Assessment (IGA) at the 3- to 5-month follow-up improved from 4.25 to 2.8, with further improvement to 1.9 in the patients that continued therapy beyond 10 months. Changes in the Children's Dermatology Life Quality Index (CDLQI) mirrored changes in the IGA, with improvement in the mean CDLQI from 14.4 at the start of the treatment to 7.5 at the 3- to 5-month follow-up. Further improvement in the CDLQI to 6.6 in patients who continued methotrexate beyond 10 months confirmed continued improvement in disease control beyond medium-term therapy. The treatment was well tolerated. CONCLUSIONS: Methotrexate appears to be an effective, safe treatment for severe pediatric AD. Its therapeutic effects continue beyond the medium-term treatment period, as reflected by further improvement in IGA and CDLQI scores in patients who continued methotrexate therapy beyond 10 months.

Levels of heavy metals and their binding protein metallothionein in type 2 diabetics with kidney disease.

Hyperglycemia, a major metabolic disturbance present in diabetes, promotes oxidative stress. Activation of antioxidant defense is an important mechanism to prevent cell damage. Levels of heavy metals and their binding proteins can contribute to oxidative stress. Antiradical capacity and levels of metallothionein (MT), metals (zinc and copper), and selected antioxidants (bilirubin, cysteine, and glutathione) were determined in 70 type 2 diabetes mellitus (T2DM) subjects and 80 healthy subjects of Caucasian origin. Single nucleotide polymorphism (rs28366003) in MT gene was detected. Antiradical capacity, conjugated bilirubin, and copper were significantly increased in diabetics, whereas MT and glutathione were decreased. Genotype AA of rs28366003 was associated with higher zinc levels in the diabetic group. The studied parameters were not influenced by renal function. This is the first study comprehensively investigating differences in MT and metals relevant to oxidative stress in T2DM. Ascertained differences indicate increased oxidative stress in T2DM accompanied by abnormalities in non-enzymatic antioxidant defense systems.

Quality and Antioxidant Activity of Buckwheat-Based Cookies Designed for a Raw Food Vegan Diet as Affected by Moderate Drying Temperature.

Buckwheat cookies with various ingredients for raw food vegan diet are usually prepared by soaking them in water at ambient temperature followed by drying at moderate temperature. The aim of this study was to examine the temperature effect on the microbiological quality, antioxidant properties and oxidative stability of lipids of final dried samples. The mixture of ingredients was soaked for 20 h in distilled water, and then cookies were formed and dried in air-forced oven at constant temperature in the range from 40 to 60 °C. Total viable counts, fungi, yeasts, coliform and aerobic spore-forming bacteria counts were evaluated in dried samples and were found to decrease during drying at 50 and 60 °C. Antioxidant activity was determined by DPPH and ABTS assays, and the former showed the highest value at 40 °C. Superoxide dismutase activity was also higher at 40 °C in comparison with that at 60 °C. The percentage of lipid peroxidation inhibition increased with the increase in drying temperature until 4th day of incubation. While peroxide value was significantly higher in samples dried at 40 °C, TBARS values did not show significant changes during the drying process. The results of this study suggest that drying buckwheat-based cookies at 40 °C retained their good antioxidant properties but represent a potentially serious microbial hazard.

Dysfunctional protection against advanced glycation due to thiamine metabolism abnormalities in gestational diabetes.

While the pathogenic role of dicarbonyl stress and accelerated formation of advanced glycation end products (AGEs) to glucose intolerance and to the development of diabetic complications is well established, little is known about these processes in gestational diabetes mellitus (GDM), a condition pathogenically quite similar to type 2 diabetes. The aims of the present study were (i) to determine plasma thiamine and erythrocyte thiamine diphosphate (TDP) and transketolase (TKT) activity in pregnant women with and without GDM, (ii) to assess relationships between thiamine metabolism parameters and selected clinical, biochemical and anthropometric characteristics and, finally, (iii) to analyse relationship between variability in the genes involved in the regulation of transmembrane thiamine transport (i.e. SLC19A2 and SLC19A3) and relevant parameters of thiamine metabolism. We found significantly lower plasma BMI adjusted thiamine in women with GDM (P = 0.002, Mann-Whitney) while levels of erythrocyte TDP (an active TKT cofactor) in mid-trimester were significantly higher in GDM compared to controls (P = 0.04, Mann-Whitney). However, mid-gestational TKT activity - reflecting pentose phosphate pathway activity - did not differ between the two groups (P > 0.05, Mann-Whitney). Furthermore, we ascertained significant associations of postpartum TKT activity with SNPs SLC19A2 rs6656822 and SLC19A3 rs7567984 (P = 0.03 and P = 0.007, resp., Kruskal-Wallis). Our findings of increased thiamine delivery to the cells without concomitant increase of TKT activity in women with GDM therefore indicate possible pathogenic role of thiamine mishandling in GDM. Further studies are needed to determine its contribution to maternal and/or neonatal morbidity.

Hyperuricemia contributes to the faster progression of diabetic kidney disease in type 2 diabetes mellitus.

AIMS: The aims of the study were (i) to ascertain prognostic value of serum uric acid (SUA) for diabetic kidney disease (DKD) progression and major adverse cardiovascular event (MACE) in a cohort of T2DM patients, (ii) to ascertain eventual protective effect of allopurinol treatment, (iii) to determine the effect of genetic variability in UA transporters on DKD progression, and (iv) to define optimal cut-off values for SUA in patients with DKD. METHODS: Study comprised 422 subjects with diabetes duration at least 15years followed-up for a median of 43 [IQR 22-77] months. Participants were categorized into stable or progressors according to their change in albuminuria or chronic kidney disease (CKD) stage. At baseline, 68% patients had hyperuricemia (SUA≥420µmol/l for men and ≥360µmol/l for women and/or allopurinol treatment). Five SNPs in the SLC2A9 and ABCG2 genes were determined by PCR. RESULTS: Time-to-event analysis with subgroups defined by the presence/absence of initial hyperuricemia revealed significant differences in all three end-points (P<0.0001 for DKD progression, P=0.0022 for MACE and P=0.0002 for death, log-rank test). Subjects with normal SUA not requiring allopurinol had median time to DKD progression 49months compared with remaining subjects (32months, P=0.0002, log-rank test). Multivariate Cox regression model revealed hyperuricemia (i.e. high SUA and/or allopurinol treatment) significant predictor of DKD progression independent of baseline CKD stage. Optimal cut-off values identified by ROC analysis for T2DM subjects were ≤377.5µmol/l for men and ≤309.0µmol/l for women. We found no differences in allele or genotype frequencies in selected SNPs between patients with and without hyperuricemia (all P>0.05). CONCLUSIONS: Our study demonstrated that initial hyperuricemia or need for allopurinol is an independent risk factor for DKD progression and that SUA levels in diabetic subjects conferring protection against DKD progression might be lower than current cut-offs for general population.

Impact of maternal diabetes type 1 on proliferative potential, differentiation and apoptotic activity in villous capillaries of term placenta.

INTRODUCTION: Maternal diabetes mellitus changes morphology and impairs function of placental capillaries. Here, quantitative parameters characterizing cell proliferation using detection of Ki67, differentiation reflected by nestin expression and apoptosis in placental capillary bed with active caspase 3 as a marker were compared in normal term placentas and placentas from pregnancies complicated by Type 1 maternal diabetes mellitus. METHODS: Specimens of sixteen diabetic placentas and eight control placentas were collected by systematic uniform random sampling. Immunohistochemical detections of Ki67, nestin, and active caspase 3 were performed in histological sections of five haphazardly chosen blocks per placenta. Twenty fields of view per section, i.e. one hundred fields of view per placenta, were used for analysis of proliferation as well as of apoptosis, and in approximately 70 capillary cross-sections per placenta the nestin-positive segments of their circumference were measured. RESULTS: The percentage of Ki67-positive cells counted in the capillary wall was significantly lower in diabetic group. The counts of Ki67-labelled nuclei per villous area unit were significantly lower in cytotrophoblast and capillary wall of terminal villi in diabetic placenta. The proportion of nestin-labeled segments of capillary circumference was significantly higher in placentas of diabetic group. No differences in the numbers of apoptotic cells were found between studied groups. DISCUSSION: The results show that the term placenta in Type 1 diabetes has lower potential to enlarge the surface area of structures involved in maternofetal transport, and that the villous capillary bed displays delayed differentiation. Those factors may participate in decreased ability of diabetic placenta to comply with fetal requirements in the final stage of pregnancy.