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Background Vaginoplasty is a crucial part of genital gender-affirming surgery with the number of trans women undergoing this intervention steadily, however, up to date, there is still no standardized vaginoplasty technique. Aim This retrospective single-center study compares single-stage vs two-stage penile skin inversion vaginoplasty techniques and their long-term outcomes. Methods Medical records of 63 consecutive patients who underwent single-stage vaginoplasty, as described by Dr Preecha Tiewtranon, and 62 consecutive patients who underwent 2-stage vaginoplasty were reviewed. Results The mean postoperative hospital stay was 7 days for patients who underwent single-stage vaginoplasty vs 16 days for patients who underwent 2-stage vaginoplasty. Neovaginal depth proved constant in patients who underwent single-stage vaginoplasty, whereas a loss of more than 30% was observed in patients who underwent 2-stage vaginoplasty during the first postoperative year. Early complications were more common than late-onset complications in both groups. The most common complication in the single-stage group was wound dehiscence (4.8%). There were significantly more complications in 2-stage collective, among which wound dehiscence (33.9%), unsatisfactory cosmetic outcome (25.8%), and urethral stenosis (14.5%) were the most common. In the single-stage cohort, 4 (6.4%) patients needed one revision surgery, whereas 35 (56.5%) patients in the 2-stage cohort necessitated one or more reoperations with up to 10 quaternary revisions. All patients reported to have sensitivity to neoclitoris in the single-stage group, whereas 3 (4.8%) patients in the 2-stage group were deprived of it because of neoclitoral necrosis. Clinical Implications Optimizing a vaginoplasty surgical technique and its postoperative protocol. Strengths & Limitations The present retrospective study with a mean follow-up of more than 3.5 years offers the first ever comparison of 2 different PSI vaginoplasty surgical techniques performed in the same center. Conclusion Significantly lower complication and revision rates, shorter recovery time, and superior esthetic and functional outcomes were observed in the single-stage than in the two-stage penile skin inversion vaginoplasty surgical technique. Fakin RM, Giovanoli P. A Single-Center Study Comparison of Two Different Male-to-Female Penile Skin Inversion Vaginoplasty Techniques and Their 3.5-Year Outcomes. J Sex Med 2021;18:391–399.

Achromatopsia has been proposed to be a morphologically predominately stable retinopathy with rare reports of progression of structural changes in the macula. A five-grade system of optical coherence tomography (OCT) features has been used for the classification of structural macular changes. However, their association with age remains questionable. We characterized the Slovenian cohort of 12 patients with pathogenic variants in CNGA3 or CNGB3 who had been followed up with OCT for up to 9 years. Based on observed structural changes in association with age, the following four-stage classification of retinal morphological changes was proposed: (I) preserved inner segment ellipsoid band (Ise), (II) disrupted ISe, (III) ISe loss and (IV) ISe and RPE loss. Data from six previously published studies reporting OCT morphology in CNGA3 and CNGB3 patients were additionally collected, forming the largest CNGA3/CNGB3 cohort to date, comprising 126 patients aged 1–71 years. Multiple regression analysis showed a significant correlation of OCT stage with age (p < 0.001) and no correlation with gene (p > 0.05). The median ages of patients with stages I–IV were 12 years, 23 years, 27 years and 48 years, respectively, and no patient older than 50 years had continuous ISe. Our findings suggest that achromatopsia presents with slowly but steadily progressive structural changes of the macular outer retinal layers. However, whether morphological changes in time follow the proposed four-stage linear pattern needs to be confirmed in a long-term study.

Purpose To describe the optical coherence tomography features of vitamin A deficiency. Methods Case series includes three male patients aged 50-66 years with vitamin A deficiency and visual symptoms ranging from 2-8 months. Examination included optical coherence tomography (OCT), fundus autofluorescence imaging (FAF), full-field electroretinography (ERG) and laboratory work-up. Results Patient 1 had inoperable pancreatic neuroendocrine tumour and presented with worsening nyctalopia. The ERG showed absent rod function two months after the onset of symptoms, followed by a decrease of cone function eight months after the onset. OCT showed poorly distinguishable outer segments of the photoreceptors (OS) with the disappearance of the interdigitation zone (IZ). At that time vitamin A deficiency along with several other deficiencies was confirmed. After the initiation of parenteral nutrition, a substantial improvement of the patient's overall well-being was noted and the OCT showed normalization of the retinal structure. Two other patients were diagnosed with vitamin A deficiency based on similar OCT features. Conclusion Disruption of the outer segments of the photoreceptors and the disappearance of the interdigitation zone on OCT may be helpful in recognition of vitamin A deficiency. Early detection and malnutrition evaluation are especially important in patients with a history of gastrointestinal disorders who may have several other underlying deficiencies. Treatment with either enteral or parenteral nutrition not only leads to resolution of visual symptoms but vastly improves their general condition and quality of life.

To report the safety, anatomical and functional outcomes of autologous neurosensory retinal transplant in patients with a refractory large unclosed macular hole. This is a prospective case series of four patients with large chronic macular hole that underwent vitrectomy and free-flap neurosensory retinal transplantation surgery with silicone oil tamponade. The hole was closed with an autologous retinal transplant of an approximate diameter of 1.5–1.8 mm, harvested outside the vascular arcades. Anatomical and functional outcomes were assessed using best-corrected visual acuity (BCVA-Snellen), optical coherence tomography (OCT), OCT angiography, microperimetry (MP), and multifocal electroretinography (mfERG). There were 2 male and 2 female patients with median age of 73 (60–81) years. The median follow-up period was 17 (13–23) months. The median preoperative size of the macular hole was 1872.5 (868–2591) μm at the widest basal diameter and 828 (556–1099) μm at the minimum diameter. Surgery resulted in the anatomical closure of the macular hole in all cases. The OCT showed structural integration of the transplant and reappearance of the inner segment ellipsoid to different extents. The BCVA improved from preoperative 0.1 (6/60; + 1.0 logMAR), 0.1 (6/60; + 1.0 logMAR), 0.05 (6/120; + 1.3 logMAR), and 0.005 (6/1200; + 2.3 logMAR) to 0.2 (6/30; + 0.7 logMAR) postoperatively in cases 1, 2, and 4, and to 0.1 (6/60; + 1.0 logMAR) in case 3. MP showed retinal function in the region corresponding to the area of the transplant (circle of 1.8 mm in diameter) in all patients after the surgery (median sensitivity in that region was 4.0 dB, range 1.8–12.4 dB). Improvement was noted in the patient that had MP performed before the surgery (mean sensitivity improved from 0 to 1.8 dB). Detectable function was mostly located in the peripheral regions of the transplant. Multifocal ERG showed abnormal function of the central ring and normal function of the second ring in 3 of 4 cases. The OCT angiography showed normal perfusion, without signs of neovascularization. There were no intra- or postoperative complications. Autologous retinal transplantation surgery is a successful technique for closing of large refractory macular holes. The procedure is safe and provides good anatomical results. Visual acuity, microperimetry, and mfERG suggest some gradual functional integration of outer regions of the transplants, but no central functional restitution has been detected as yet.

Graphical abstract, Highlights • Three novel gelsolin amyloidogenic substitutions cluster at the G4:G5 interface. • Mutations impair stability through strand distortion, charge and steric repulsion. • Mutations do not increase sensitivity to furin, the first step of the canonical pathway. • In the unproteolysed form these variants tend to aggregate and are proteotoxic. • The variants aggregate via an alternative, likely proteolysis-independent, mechanism., Gelsolin comprises six homologous domains, named G1 to G6. Single point substitutions in this protein are responsible for AGel amyloidosis, a hereditary disease causing progressive corneal lattice dystrophy, cutis laxa, and polyneuropathy. Although several different amyloidogenic variants of gelsolin have been identified, only the most common mutants present in the G2 domain have been thoroughly characterized, leading to clarification of the functional mechanism. The molecular events underlying the pathological aggregation of 3 recently identified mutations, namely A551P, E553K and M517R, all localized at the interface between G4 and G5, are here explored for the first time. Structural studies point to destabilization of the interface between G4 and G5 due to three structural determinants: β-strand breaking, steric hindrance and/or charge repulsion, all implying impairment of interdomain contacts. Such rearrangements decrease the temperature and pressure stability of gelsolin but do not alter its susceptibility to furin cleavage, the first event in the canonical aggregation pathway. These variants also have a greater tendency to aggregate in the unproteolysed forms and exhibit higher proteotoxicity in a C. elegans-based assay. Our data suggest that aggregation of G4G5 variants follows an alternative, likely proteolysis-independent, pathway.

In contrast to USH2A, variants in ADGRV1 are a minor cause of Usher syndrome type 2, and the associated phenotype is less known. The purpose of the study was to characterize the retinal phenotype of 18 ADGRV1 patients (9 male, 9 female, median age 52 years) and compare it with that of 204 USH2A patients (111 male, 93 female, median age 43 years) in terms of nyctalopia onset, best corrected visual acuity (BCVA), fundus autofluorescence (FAF), and optical coherence tomography (OCT) features. There was no statistical difference in the median age at onset (30 and 18 years, Mann–Whitney U test, p = 0.13), the mean age when 50% of the patients reached legal blindness (≥1.0 log MAR) based on visual acuity (64 years for both groups, log-rank, p = 0.3), the risk of developing advanced retinal degeneration (patch or atrophy) with age (multiple logistic regression, p = 0.8), or the frequency of cystoid macular edema (31% vs. 26%, Fisher’s exact test, p = 0.4). ADGRV1 and USH2A retinopathy were indistinguishable in all major functional and structural characteristics, suggesting that the loss of function of the corresponding proteins produces similar effects in the retina. The results are important for counseling ADGRV1 patients, who represent the minor patient subgroup.

Mutations in RPGRORF15 are associated with rod-cone or cone/cone-rod dystrophy, the latter associated with mutations at the distal end. We describe the phenotype associated with a novel variant in the terminal codon of the RPGRORF15 c.3457T&gt, A (Ter1153Lysext*38), which results in a C-terminal extension. Three male patients from two families were recruited, aged 31, 35, and 38 years. Genetic testing was performed by whole exome sequencing. Filtered variants were analysed according to the population frequency, ClinVar database, the variant’s putative impact, and predicted pathogenicity, and were classified according to the ACMG guidelines. Examination included visual acuity (Snellen), colour vision (Ishihara), visual field, fundus autofluorescence (FAF), optical coherence tomography (OCT), and electrophysiology. All patients were myopic, and had central scotoma and reduced colour vision. Visual acuities on better eyes were counting fingers, 0.3 and 0.05. Electrophysiology showed severely reduced cone-specific responses and macular dysfunction, while the rod-specific response was normal. FAF showed hyperautofluorescent ring centred at the fovea encompassing an area of photoreceptor loss approximately two optic discs in diameter (3462–6342 μm). Follow up after 2–11 years showed enlargement of the diameter (avg. 100 μm/year). The novel c.3457T&gt, A (Ter1153Lysext*38) mutation in the terminal RPGRORF15 codon is associated with cone dystrophy, which corresponds to the previously described phenotypes associated with mutations in the distal end of the RPGRORF15. Minimal progression during follow-up years suggests a relatively stable disease after the initial loss of the central cones.

Mutations in rhodopsin gene (RHO) are a frequent cause of retinitis pigmentosa (RP) and less often, congenital stationary night blindness (CSNB). Mutation p.G90D has previously been associated with CSNB based on the examination of one family. This study screened 60 patients. Out of these 60 patients, 32 were affected and a full characterization was conducted in 15 patients. We described the clinical characteristics of these 15 patients (12 male, median age 42 years, range 8–71) from three families including visual field (Campus Goldmann), fundus autofluorescence (FAF), optical coherence tomography (OCT) and electrophysiology. Phenotypes were classified into four categories: CSNB (N = 3, 20%) sector RP (N = 3, 20%), pericentral RP (N = 1, 6.7%) and classic RP (N = 8, 53.3% (8/15)). The phenotypes were not associated with family, sex or age (Kruskal–Wallis, p &gt, 0.05), however, cystoid macular edema (CME) was observed only in one family. Among the subjects reporting nyctalopia, 69% (22/32) were male. The clinical characteristics of the largest p.G90D cohort so far showed a large frequency of progressive retinal degeneration with 53.3% developing RP, contrary to the previous report.

Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. Results: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Conclusion: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases. Fil: Khan, Mubeen. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Cornelis, Stéphanie S.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Del Pozo Valero, Marta. Hospital Universitario Fundación Jiménez Díaz; España. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Whelan, Laura. Trinity College; Estados Unidos Fil: Runhart, Esmee H.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Mishra, Ketan. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Bults, Femke. Radboud University Nijmegen Medical Centre; Países Bajos Fil: AlSwaiti, Yahya. St John of Jerusalem Eye Hospital Group; Palestina (ANP) Fil: AlTalbishi, Alaa. St John of Jerusalem Eye Hospital Group; Palestina (ANP) Fil: De Baere, Elfride. University of Ghent; Bélgica Fil: Banfi, Sandro. Seconda Universita Degli Studi Di Napoli; Italia Fil: Banin, Eyal. The Hebrew University of Jerusalem; Israel Fil: Bauwens, Miriam. University of Ghent; Bélgica Fil: Ben Yosef, Tamar. The Ruth And Bruce Rappaport Faculty Of Medicine; Israel Fil: Boon, Camiel J. F.. Leiden University. Leiden University Medical Center; Países Bajos Fil: van den Born, L. Ingeborgh. Rotterdam Ophthalmic Institute; Países Bajos Fil: Defoort, Sabine. Universite Lille; Francia Fil: Devos, Aurore. Universite Lille; Francia Fil: Dockery, Adrian. Trinity College; Estados Unidos Fil: Dudakova, Lubica. Charles University and General University Hospital; República Checa Fil: Fakin, Ana. Charles University and General University Hospital; República Checa Fil: Farrar, G. Jane. Trinity College; Estados Unidos Fil: Ferraz Sallum, Juliana Maria. Universidade Federal de Sao Paulo; Brasil Fil: Fujinami, Kaoru. UCL Institute of Ophthalmology; Reino Unido Fil: Gilissen, Christian. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Glavac, Damjan. University of Ljubljana; Eslovenia Fil: Gorin, Michael B.. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: Greenberg, Jacquie. University of Cape Town; Sudáfrica Fil: Hayashi, Takaaki. The Jikei University School of Medicine; Japón Fil: Hettinga, Ymkje M.. Bartiméus Diagnostic Center for Complex Visual Disorders; Países Bajos Fil: Hoischen, Alexander. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Hoyng, Carel B.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Hufendiek, Karsten. University Eye Hospital Hannover Medical School; Alemania Fil: Jägle, Herbert. University Regensburg; Alemania Fil: Kamakari, Smaragda. OMMA Ophthalmological Institute of Athens; Grecia Fil: Karali, Marianthi. Seconda Universita Degli Studi Di Napoli; Italia Fil: Kellner, Ulrich. No especifíca; Fil: Klaver, Caroline C. W.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Kousal, Bohdan. Charles University and General University Hospital; República Checa Fil: Lamey, Tina M.. University of Western Australia; Australia Fil: MacDonald, Ian M.. University of Alberta; Canadá Fil: Matynia, Anna. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: McLaren, Terri L.. University of Western Australia; Australia Fil: Mena, Marcela D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Meunier, Isabelle. Université Montpellier II; Francia Fil: Miller, Rianne. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Newman, Hadas. Universitat Tel Aviv; Israel Fil: Ntozini, Buhle. University of Cape Town; Sudáfrica Fil: Oldak, Monika. No especifíca; Fil: Pieterse, Marc. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Puech, Bernard. Universite Lille; Francia Fil: Ramesar, Raj. University of Cape Town; Sudáfrica Fil: Rüther, Klaus. No especifíca; Fil: Salameh, Manar. No especifíca; Fil: Salles, Mariana Vallim. Universidade de Sao Paulo; Brasil Fil: Sharon, Dror. The Hebrew University of Jerusalem; Israel Fil: Simonelli, Francesca. Seconda Universita Degli Studi Di Napoli; Italia Fil: Spital, Georg. No especifíca; Fil: Steehouwer, Marloes. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Szaflik, Jacek P.. No especifíca; Fil: Thompson, Jennifer A.. No especifíca; Fil: Thuillier, Caroline. Universite Lille; Francia Fil: Tracewska, Anna M.. No especifíca; Fil: van Zweeden, Martine. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Vincent, Andrea L.. University of Auckland; Nueva Zelanda Fil: Zanlonghi, Xavier. No especifíca; Fil: Liskova, Petra. Charles University and General University Hospital; República Checa Fil: Stöhr, Heidi. Universitat Regensburg; Alemania Fil: De Roach, John N.. University of Western Australia; Australia Fil: Ayuso, Carmen. Hospital Universitario Fundación Jiménez Díaz; España Fil: Roberts, Lisa. University of Cape Town; Sudáfrica Fil: Weber, Bernhard H. F.. Universitat Regensburg; Alemania Fil: Dhaenens, Claire Marie. Universite Lille; Francia Fil: Cremers, Frans P. M.. Radboud University Nijmegen Medical Centre; Países Bajos

PURPOSE: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. METHODS: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. RESULTS: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. CONCLUSION: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders. ispartof: GENETICS IN MEDICINE vol:21 issue:8 pages:1761-1771 ispartof: location:United States status: published

Purpose: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability.Methods: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects.Results: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects.Conclusion: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.

X-linked retinopathies represent a significant proportion of monogenic retinal disease. They include progressive and stationary conditions, with and without syndromic features. Many are X-linked recessive, but several exhibit a phenotype in female carriers, which can help establish diagnosis and yield insights into disease mechanisms. The presence of affected carriers can misleadingly suggest autosomal dominant inheritance. Some disorders (such as RPGR-associated retinopathy) show diverse phenotypes from variants in the same gene and also highlight limitations of current genetic sequencing methods. X-linked disease frequently arises from loss of function, implying potential for benefit from gene replacement strategies. We review X-inactivation and X-linked inheritance, and explore burden of disease attributable to X-linked genes in our clinically and genetically characterised retinal disease cohort, finding correlation between gene transcript length and numbers of families. We list relevant genes and discuss key clinical features, disease mechanisms, carrier phenotypes and novel experimental therapies. We consider in detail the following: RPGR (associated with retinitis pigmentosa, cone and cone-rod dystrophy), RP2 (retinitis pigmentosa), CHM (choroideremia), RS1 (X-linked retinoschisis), NYX (complete congenital stationary night blindness (CSNB)), CACNA1F (incomplete CSNB), OPN1LW/OPN1MW (blue cone monochromacy, Bornholm eye disease, cone dystrophy), GPR143 (ocular albinism), COL4A5 (Alport syndrome), and NDP (Norrie disease and X-linked familial exudative vitreoretinopathy (FEVR)). We use a recently published transcriptome analysis to explore expression by cell-type and discuss insights from electrophysiology. In the final section, we present an algorithm for genes to consider in diagnosing males with non-syndromic X-linked retinopathy, summarise current experimental therapeutic approaches, and consider questions for future research.

Giant cell arteritis (GCA) is the most common vasculitis in adults aged ≥ 50 years in Europe. Recently, colour Doppler ultrasonography (CDS) and positron emission tomography-computed tomography (PET/CT) have improved the diagnostic sensitivity. The aim of our study was to determine the incidence of GCA in a well-defined Slovenian region, supported by the temporal artery (TA) biopsy (TAB) or CDS or PET/CT. This prospective study was conducted at the University Medical Centre Ljubljana, the only secondary/tertiary centre in the region, serving a population of 323,297 residents aged ≥ 50 years. Patients with suspected GCA are referred either to the Department of Rheumatology, or in case of severe visual disturbances, to the Department of Ophthalmology. We included all GCA cases diagnosed between 1 January 2012 and 31 December 2017. We diagnosed cranial GCA (c-GCA) using the American College of Rheumatology (ACR) 1990 classification criteria and a positive TAB or TA-CDS. Large vessel GCA (lv-GCA) was diagnosed using CDS or PET/CT. During the 6-year observation, we identified 169 incipient GCA cases (66.3% female, median (IQR) age of 75.1 (68.6-80.0) years). Forty-two (24.8%) patients had lv-GCA, and the others had c-GCA. The estimated annual incidence rates of GCA were overall 8.7 (95% CI 7.5-10.1), c-GCA 6.5 (95% CI 5.5-7.8) and lv-GCA 2.2 (95%CI 1.6-2.9) per 100,000 aged ≥ 50 years. GCA is the most common vasculitis in adults aged ≥ 50 years, with an annual incidence rate of 8.7 per 100,000.

Purpose: Usher syndrome (USH) is a multisensory deficiency involving vision, hearing and the vestibular system. The purpose of this study is to report on the functional data (i.e. electroretinography, visual fields, visual acuity) of patients with retinitis pigmentosa (RP) due to Usher syndrome that were collected in a multicentre European study (TREATRUSH). Methods: A total of 268 genetically confirmed USH patients underwent electrophysiological examinations in the context of multimodal ophthalmological examination in the study (75 USH1, 189 USH2 and four USH3). Full-field electroretinography (ERG) was performed according to ISCEV standards, visual field determination was carried out with either the Octopus or Goldmann perimeters and visual acuity was examined with either ETDRS or Snellen charts. The data were compared between USH subtypes (USH1/USH2/USH3) and correlated with age. Results: Visual acuity decreases significantly with age for both USH1 and USH2 (p < 0.001), without a difference between the two cohorts. When corrected for age, the preserved kinetic visual field was significantly larger in USH2 than in USH1 (p = 0.04). Furthermore, the preserved kinetic visual field area showed a significant decrease with age (based on an exponential fit) in both USH1 and USH2 (p < 0.001). In USH1 patients, however, the visual field was already vastly reduced at an early age. The ERG results were abnormal in all patients. Detectable data for scotopic ERG were obtained from nine patients, and data of photopic ERG were obtained from 24 patients, without a difference between USH1 and USH2 subtypes. Conclusions: There are differences in the phenotypes of RP in USH subtypes, most visible in the progression of visual fields between USH1 and USH2. The perimetric reduction occurs earlier in USH1 than in USH2. In both subtypes, visual acuity decreases significantly with age and the ERG is not detectable already at early ages. Purpose: Usher syndrome (USH) is a multisensory deficiency involving vision, hearing and the vestibular system. The purpose of this study is to report on the functional data (i.e. electroretinography, visual fields, visual acuity) of patients with retinitis pigmentosa (RP) due to Usher syndrome that were collected in a multicentre European study (TREATRUSH). Methods: A total of 268 genetically confirmed USH patients underwent electrophysiological examinations in the context of multimodal ophthalmological examination in the study (75 USH1, 189 USH2 and four USH3). Full-field electroretinography (ERG) was performed according to ISCEV standards, visual field determination was carried out with either the Octopus or Goldmann perimeters and visual acuity was examined with either ETDRS or Snellen charts. The data were compared between USH subtypes (USH1/USH2/USH3) and correlated with age. Results: Visual acuity decreases significantly with age for both USH1 and USH2 (p < 0.001), without a difference between the two cohorts. When corrected for age, the preserved kinetic visual field was significantly larger in USH2 than in USH1 (p = 0.04). Furthermore, the preserved kinetic visual field area showed a significant decrease with age (based on an exponential fit) in both USH1 and USH2 (p < 0.001). In USH1 patients, however, the visual field was already vastly reduced at an early age. The ERG results were abnormal in all patients. Detectable data for scotopic ERG were obtained from nine patients, and data of photopic ERG were obtained from 24 patients, without a difference between USH1 and USH2 subtypes. Conclusions: There are differences in the phenotypes of RP in USH subtypes, most visible in the progression of visual fields between USH1 and USH2. The perimetric reduction occurs earlier in USH1 than in USH2. In both subtypes, visual acuity decreases significantly with age and the ERG is not detectable already at early ages.

Purpose: The aim of this study is to report on the results of color vision testing in a European cohort of patients with Usher syndrome (USH). We describe the results in relation to Usher type (USH1 and USH2), age and visual acuity. Methods and methods: The color vision of 220 genetically confirmed adult USH patients, aged 18–70 years, was analyzed with one of three methods: the Farnsworth D-15 Dichotomous test (D-15) along with the Lanthony desaturated 15 Hue tests (D-15d), the Roth 28-Hue test, or the Ishihara 14-plate test. Visual acuity was measured with either the ETDRS or the SNELLEN charts. The Confusion index, the Selectivity index and the Confusion angle were calculated for the panel tests and used for analysis. The numbers of plates that could not be read were analyzed for the Ishihara test. Results: For the panel tests, the degree of color loss (Confusion index) is similar in both subtypes of USH, but the polarization of error scores (Selectivity index) is significantly lower in USH1 than USH2, showing more diffuse errors than those found in USH2. There is no significant correlation between logMAR visual acuity and the Confusion or the Selectivity indices. Additionally, we find a significant correlation between patient age and the degree and the polarity of the loss only in USH2. There was no difference between USH1 and USH2 in the results of the Ishihara test. Conclusions: The examination of color vision in patients with USH shows a significant difference in the pattern of color vision loss in USH1 and USH2 patients, but not in the severity of the loss. In USH2, we find a correlation between patient age and the degree and the polarity of the loss. These results may be due to differences in the pathogenesis of retinal dystrophy in USH1 and USH2. Purpose: The aim of this study is to report on the results of color vision testing in a European cohort of patients with Usher syndrome (USH). We describe the results in relation to Usher type (USH1 and USH2), age and visual acuity.Methods and methods: The color vision of 220 genetically confirmed adult USH patients, aged 18-70years, was analyzed with one of three methods: the Farnsworth D-15 Dichotomous test (D-15) along with the Lanthony desaturated 15 Hue tests (D-15d), the Roth 28-Hue test, or the Ishihara 14-plate test. Visual acuity was measured with either the ETDRS or the SNELLEN charts. The Confusion index, the Selectivity index and the Confusion angle were calculated for the panel tests and used for analysis. The numbers of plates that could not be read were analyzed for the Ishihara test.Results: For the panel tests, the degree of color loss (Confusion index) is similar in both subtypes of USH, but the polarization of error scores (Selectivity index) is significantly lower in USH1 than USH2, showing more diffuse errors than those found in USH2. There is no significant correlation between logMAR visual acuity and the Confusion or the Selectivity indices. Additionally, we find a significant correlation between patient age and the degree and the polarity of the loss only in USH2. There was no difference between USH1 and USH2 in the results of the Ishihara test.Conclusions: The examination of color vision in patients with USH shows a significant difference in the pattern of color vision loss in USH1 and USH2 patients, but not in the severity of the loss. In USH2, we find a correlation between patient age and the degree and the polarity of the loss. These results may be due to differences in the pathogenesis of retinal dystrophy in USH1 and USH2.

Breast augmentation surgery is one of the crucial procedures in male-to-female gender reassignment surgery. It is performed by implantation of silicone prostheses and/or lipofilling and can, if requested, be well integrated within the vaginoplasty surgical session, hence avoiding further anesthesia. This procedure, however, remains challenging as there are fundamental anatomical landmarks and differences between trans woman and cis woman chest. This is particularly relevant in assessing the thoracic proportions, breast and nipple positioning, their forms and sizes, as well as the synchrony with the rest of the body. Furthermore, the treatment should be personalized, addressing the patient’s individual desires and significantly contributing to the healing process of gender dysphoria.

Stargardt disease is a progressive retinal disorder caused by bi-allelic mutations in the ABCA4 gene that encodes the ATP-binding cassette, subfamily A, member 4 transporter protein. Over the past few years, we and others have identified several pathogenic variants that reside within the introns of ABCA4, including a recurrent variant in intron 36 (c.5196+1137G>A) of which the pathogenicity so far remained controversial. Detailed clinical characterization of this variant confirmed its pathogenic nature, and classified it as an allele of intermediate severity. Moreover, we discovered several additional ABCA4 variants clustering in intron 36. Several of these variants resulted in aberrant splicing of ABCA4, i.e., the inclusion of pseudoexons, while the splicing defects caused by the recurrent c.5196+1137G>A variant strongly increased upon differentiation of patient-derived induced pluripotent stem cells into retina-like cells. Finally, all splicing defects could be rescued by the administration of antisense oligonucleotides that were designed to specifically block the pseudoexon insertion, including rescue in 3D retinal organoids harboring the c.5196+1137G>A variant. Our data illustrate the importance of intronic variants in ABCA4 and expand the therapeutic possibilities for overcoming splicing defects in Stargardt disease., Graphical Abstract, Khan et al. report on the clinical characterization of patients harboring a recurrent deep-intronic variant in ABCA4 underlying retinal disease and demonstrate that this, and other variants close by, lead to splicing defects that can be rescued by antisense oligonucleotides.

International audience; USH2A mutation is the most common cause of retinitis pigmentosa, with or without hearing impairment. Patients most commonly exhibit hyperautofluorescent ring on fundus autofluorescence imaging (FAF) and rod-cone dystrophy on electrophysiology. A detailed study of three USH2A patients with a rare pattern of double hyperautofluorescent rings was performed. Twenty-four patients with typical single hyperautofluorescent rings were used for comparison of the ages of onset, visual fields, optical coherence tomography, electrophysiology, and audiograms. Double rings delineated the area of pericentral retinal degeneration in all cases. Two patients exhibited rod-cone dystrophy, whereas the third had a cone-rod dystrophy type of dysfunction on electrophysiology. There was minimal progression on follow-up in all three. Patients with double rings had significantly better visual acuity, cone function, and auditory performance than the single ring group. Double rings were associated with combinations of null and missense mutations, none of the latter found in the single ring patients. According to these findings, the double hyperautofluorescent rings indicate a mild subtype of USH2A disease, characterized by pericentral retinal degeneration, mild to moderate hearing loss, and either a rod-cone or cone-rod pattern on electrophysiology, the latter expanding the known clinical spectrum of USH2A-retinopathy.

Missing heritability in human diseases represents a major challenge. Although whole-genome sequencing enables the analysis of coding and non-coding sequences, substantial costs and data storage requirements hamper its large-scale use to (re)sequence genes in genetically unsolved cases. The ABCA4 gene implicated in Stargardt disease (STGD1) has been studied extensively for 22 years, but thousands of cases remained unsolved. Therefore, single molecule molecular inversion probes were designed that enabled an automated and cost-effective sequence analysis of the complete 128-kb ABCA4 gene. Analysis of 1,054 unsolved STGD and STGD-like probands resulted in bi-allelic variations in 448 probands. Twenty-seven different causal deep-intronic variants were identified in 117 alleles. Based on in vitro splice assays, the 13 novel causal deep-intronic variants were found to result in pseudo-exon (PE) insertions (n=10) or exon elongations (n=3). Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions that were accompanied by flanking exon deletions. Structural variant analysis revealed 11 distinct deletions, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Integrated complete gene sequencing combined with transcript analysis, identified pathogenic deep-intronic and structural variants in 26% of bi-allelic cases not solved previously by sequencing of coding regions. This strategy serves as a model study that can be applied to other inherited diseases in which only one or a few genes are involved in the majority of cases.

The purpose of this study was to methodically illustrate and highlight the crucial steps of stromal vascular fraction (SVF)-enriched fat grafting as a novel treatment of symptomatic end-neuromata of peripheral sensory nerves, and in this study, specifically of the superficial branch of the radial nerve (SBRN). Despite a multitude of existing treatments, persistent postoperative pain and common pain relapse are still very common, independent of the procedure assessed. The neuroma is microsurgically excised accordingly to standardized protocol. Instead of the relocation of the regenerating nerve stump in neighboring anatomical structures, such as muscle or bone, a fat graft is applied perifocally and acts as a mechanical barrier. In order to reduce the fat resorption rate and boost the regenerative potential of the graft, the highly concentrated SVF is integrated in the grafting. The SVF is isolated from subcutaneous fat by enzymatic and mechanic separation of the lipoaspirate by a specific commercial isolation system. The SVF-enriched fat graft provides both a mechanical barrier and various biological effects at the cellular level, including improving angiogenesis, inflammation, and fibrosis. Both mechanical and biologic effects help to reduce the disorganized axonal outgrowth of the nerve stump during nerve regeneration and hence prevent the recurrence of painful end-neuromata.

Fifteen consecutive patients with severely comminuted Rolando fractures were treated by closed reduction and fixation with a modified Suzuki frame without rubber bands, followed by immediate mobilization. All the fractures healed within 5 weeks. At 3 months, no rotational deformity was observed. The Kapandji score was equal that of the contralateral thumb in eight cases. No residual pain was recorded. Grip strength was 78% and pinch strength was 78% of the contralateral hand. One patient needed the frame tension modified. One patient developed a sensory deficit in the area of the superficial branch of the radial nerve that resolved spontaneously in 3 months. One patient healed with a 2-mm articular step-off, but the clinical outcome was good. Our retrospective study suggests that the small modification we made to the Suzuki frame provides a relatively simple and minimally invasive technique for the treatment of comminuted Rolando fractures.

Fournier's gangrene is an acute and potentially lethal necrotizing fasciitis that can lead to extensive defects of the perineoscrotal area and lower abdominal wall as well. Such defect poses challenging tasks for both functional and cosmetic reconstruction. Local perforator pedicle flaps and muscle flaps can be employed and combined for such a reconstruction. In this report we present a case of reconstruction of a massive perineoscrotal and upper medial thigh defect because of Fournier's gangrene using a bilateral pedicle anterolateral thigh (ALT) flap and sartorius muscle flap. A 61 year-old male who suffered from Fournier's gangrene resulted in a perineal, scrotal, and medial thigh defect of 27 × 30 cm2 with exposure of the femoral vessels. A bilateral pedicle ALT flap measuring 30 × 9 cm2 based on two perforators and a bilateral sartorius muscle flap were harvested for soft tissue defect reconstruction and inguinal vessels coverage, respectively. The flaps survived completely, with no recipient or donor site morbidity. The length of follow-up was 6 months and was uneventful. A bilateral pedicle ALT flap combined with bilateral sartorius flap may be considered as a valid and safe option for an extensive inguinal and perineoscrotal reconstruction in selected cases. © 2016 Wiley Periodicals, Inc. Microsurgery 37:669-673, 2017.

Gelsolin amyloidosis typically presents with corneal lattice dystrophy and is most frequently associated with pathogenic GSN variant p.Asp214Asn. Here we report clinical and histopathological features of gelsolin amyloidosis associated with a novel GSN variant p.Glu580Lys. We studied DNA samples of seven members of a two-generation family. Exome sequencing was performed in the proband, and targeted Sanger sequencing in the others. The heterozygous GSN variant p.Glu580Lys was identified in six patients. The patients exhibited corneal dystrophy (5/6), loose skin (5/6) and/or heart arrhythmia (3/6) and one presented with bilateral optic neuropathy. The impact of the mutation on the protein structure was evaluated in silico. The substitution is located in the fifth domain of gelsolin protein, homologous to the second domain harboring the most common pathogenic variant p.Asp214Asn. Structural investigation revealed that the mutation might affect protein folding. Histopathological analysis showed amyloid deposits in the skin. The p.Glu580Lys is associated with corneal dystrophy, strengthening the association of the fifth domain of gelsolin protein with the typical amyloidosis phenotype. Furthermore, optic neuropathy may be related to the disease and is essential to identify before discussing corneal transplantation.

Purpose: to determine a detailed clinical and haplotypic variability of the Slovenian USH2A patients with homozygous c.11864G>A (p.Trp3955Ter) nonsense mutation and to develop sensitive, accurate and rapid screening test. Methods: Ten unrelated homozygous patients with detailed ophthalmological exam were included in our study. The High-Resolution Melting (HRM) method was developed for fast and reliable detection of the c.11864G>A mutation. Results: The c.11864G>A mutation represents the vast majority of pathogenic alleles in Slovenian USH2A-Usher syndrome population (84%). The median age of onset of nyctalopia was 16 years and all patients younger than 40 years had hyperautofluorescent rings on fundus autofluorescence imaging. The Kaplan Meier survival analysis showed a decline of central vision after the age of 40, with 50% patients reaching visual acuity (VA) ≤ 0.05 at the average age of 66 years visual field diameter less than 20° at the average age of 59 years. There was a relatively large phenotypic variability in the retinal and audiological phenotype. Analysis of the p.Trp3955Ter-homozygous patients revealed four different haplotypes, with the frequency of the most common haplotype ~65%. Disease severity did not correlate with the haplotype. Conclusions: According to the natural history of homozygous p.Trp3955Ter patients any therapy aimed to slow disease progression in these patients would be best started before the age of 40. Phenotypic variability suggests the presence of cis and/or trans factors outside the USH2A gene that are able to affect disease severity. High frequency of p.Trp3955Ter mutation in Slovenian USH2A gene pool appears to be initiated from different unrelated founders because of migrations from neighboring populations. The mutation on haplotype 2 seems to be the major founder allele.

Background Giant cell arteritis (GCA) represents the most common vasculitis in adults over age of 50 years in Europe. Recently the diagnostic options greatly improved with the implementation of imaging techniques such as colour Doppler ultrasonography (CDS) and positron emission tomography-computed tomography (PET/CT). Objectives The aim of our single centre prospective study was to determine the incidence of GCA in well-defined Slovenian region, based on the temporal artery (TA) biopsy (TAB) and/or the result of CDS and/or PET/CT. Methods The study was conducted at University medical centre Ljubljana (UMC Ljubljana), that represents the only secondary/tertiary centre in a region, serving a population of 3 23 297 residents aged 50 years or more (1 76 104 females and 1 47 193 males). Patients with suspected GCA are referred either to the Department of Rheumatology, or in case of severe visual disturbances, to the Department of Ophthalmology. In the analysis we included all GCA cases diagnosed between 1 January 2012 and 31 December 2017. The diagnosis of cranial GCA (c-GCA) was established with the help of American College of Rheumatology (ACR) 1990 classification criteria, positive TAB and/or TA CDS. Cases of extracranial large vessel vasculitis (lv-GCA) were diagnosed using CDS of branches of the aortic arch and/or PET-CT. Results During the six-year observation we identified 169 new GCA cases (66.3% females), with a median (IQR) age of 75.1 (68.6–80.0) years. Forty-two (24.8%) patients had lv-GCA, and the others had c-GCA. One-hundred and thirty-nine patients (24 lv-GCA and 115 c-GCA) fulfilled ACR 1990 classification criteria. The others patients had positive arterial CDS or PET-CT (18 CDS, 9 CDS and PET-CT, 3 PET-CT). TAB was performed in 119 patients and was positive in 88.2%. Clinical characteristics of our GCA cases are presented in table 1. The estimated annual incidence rate of GCA was 8.7 per 1 00 000 adults aged ≥50 years (95% CI 7.5–10.1), in c-GCA 6.5 per 100.000 adults aged ≥50 years (95% CI 5.5–7.8) and in lv-GCA 2.2 per 100.000 aged ≥50 years (95% CI 1.6–2.9). Conclusions GCA is the most common vasculitis in adults aged 50 years or above, with an annual incidence rate of 8.7 per 100.000. c-GCA is nearly 3 times more common than lv-GCA. Disclosure of Interest None declared

To investigate the prevalence of suggestive signs for ocular sarcoidosis proposed by the International Workshop on Ocular Sarcoidosis (IWOS) in patients with sarcoidosis-associated uveitis.A retrospective study included 53 patients (77% female), with uveitis, who were seen in the period of 2010-2013 at the University Eye Hospital Ljubljana, Slovenia. All patients had confirmed pulmonary sarcoidosis based on clinical presentation, imaging and lung biopsy according to the ATS/ERS criteria. The presence of the seven clinical signs, suggested by the IWOS was determined in 47 patients with sufficient clinical data.Patients commonly exhibited bilaterality (79%), keratic precipitates/iris nodules (49%), and multiple chorioretinal peripheral lesions (36%). Three or more signs were observed in 40% (19/47) of patients or 79% (11/14) of patients with primary ocular involvement.Results add to the validation of IWOS criteria and emphasize the high percentage of at least three suggestive for ocular sarcoidosis in patients with primary ocular involvement.

International audience; Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1-3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods.

PURPOSE: We describe the phenotypes associated with nullizigosity and nine splicing mutations in the ABCA4 gene. METHODS: The study included 19 patients with biallelic null mutations (Group A, nullizygous), 27 with splicing mutations in the homozygous state or in trans with a null mutation (Group B), and 20 with p.G1961E in trans with a null mutation (Group C, control). Ages at onset and visual acuities were determined from medical histories. Area of decreased autofluorescence within a 30° × 30° fundus autofluorescence (FAF) image was measured with the Region Finder (N = 58). Full-field electroretinography (ERG) was performed incorporating the International Society for Clinical Electrophysiology of Vision (ISCEV) standard (N = 40). RESULTS: For groups A to C, the median ages of onset were 6, 8, and 17, respectively. Kaplan Meier survival analysis estimated that 50% of patients reached visual acuity below 20/400 at the ages of 29, 48, and 66 years, respectively. The area of reduced FAF was estimated to increase by 1.5, 1.2, and 0.03 mm2 per year, respectively, and cone-rod dystrophy was present in 10/12, 13/15, and 0/13 of cases, respectively. Splicing mutation c.5714+5G>A was associated with a significantly milder phenotype in comparison with nullizygous patients for all parameters. CONCLUSIONS: Nullizygosity for ABCA4 is associated with early onset cone-rod dysfunction with rapid progression shown by enlargement of central atrophy on FAF, decline of ERG amplitudes with age, and a high risk of reaching legal blindness by the fourth decade. Most studied splicing mutations were associated with a similarly severe phenotype. Estimated rates of progression may facilitate further genotype-phenotype correlations and inform the design of treatment trials.

Background Infection is one of the most common causes of mortality and morbidity in burn patients. The incidence and frequency of microbiological micro-organisms are known to vary across different models of intensive care units. To date, no study has attempted to describe the different findings in burn patients treated in an open, general intensive care unit (GICU) versus a dedicated burns intensive care unit (BICU). Only limited data is available on the effect of these microbiological micro-organisms on patients’ length of stay. Aim To characterize and compare the microbiological flora and antibiotic resistance patterns encountered in two different models of burn intensive care and to determine the effect of specific microbiological types on length of intensive care unit (ICU) and overall stay. Methods A retrospective case-control study of 209 burn patients treated in two highly specialized, Western burn referral centres between September 2009 and March 2014. Results 9710 culture results were analysed, of which 2590 (26.7%) yielded positive results (1537 in the GICU and 1050 in the BICU). Gram-positive cultures were more frequently found in the GICU, whereas Gram-negative and yeast cultures were more prevalent in the BICU. The most frequently encountered micro-organisms in both units were similar and included Staphylococcus aureus, Pseudomonas aeruginosa, coagulase-negative staphylococci (CoNS) and Candida albicans. Significantly more resistant bacteria were detected in the BICU. Testing positive across all types of microbiological isolates, as well as for both Gram-positive and -negative bacteria significantly prolonged patient length of stay. This effect was even more pronounced if the micro-organisms were resistant to antimicrobial therapy. Conclusion There are notable differences in the microbiological isolate and antibiotic resistance patterns between burn patients treated in a GICU compared to a designated BICU. In both units, testing positive for resistant microbiological micro-organisms is significantly associated with longer hospital stay.

Purpose of this study was to characterize retinal disease in Usher syndrome using fundus autofluorescence and optical coherence tomography. Study included 54 patients (26 male, 28 female) aged 7–70years. There were 18 (33%) USH1 and 36 (67%) USH2 patients. 49/52 (94%) patients were found to carry at least one mutation in Usher genes. Ophthalmological examination included assessment of Snellen visual acuity, color vision with Ishihara tables, Goldmann visual fields (targets II/1–4 and V/4), microperimetry, fundus autofluorescence imaging and optical coherence tomography. Average age at disease onset (nyctalopia) was significantly lower in USH1 than USH2 patients (average 9 vs. 17years, respectively; p

To determine the degree of neurocognitive dysfunction after placement of internal cardioverter defibrillators (ICD) and its relationship to the extent of neuronal injury, we studied 42 patients undergoing ICD (n = 21) or pacemaker (PM) insertion (control patients, n = 21). The Mini Mental State Examination, the Trailmaking A test and the forward and backward Digit Span tests were used and P300 latencies were determined preoperatively and postoperatively. Serum neuron-specific enolase (NSE) was determined before and at the end of, as well as 2, 6, and 24 h after surgery. Preoperatively, PM patients scored worse in the Digit Span backward and the Trailmaking tests and showed prolonged P300 latencies. Postoperatively, the Digit Span backward scores declined and NSE levels increased only in the ICD group (P < or = 0.05). The difference between preoperative and postoperative Digit Span backward scores correlated with the increase in serum NSE levels (r2 = 0.3, P < or = 0.05). Moreover, P300 latencies increased in 13 of 17 ICD patients, but decreased in 7 of 10 PM patients (P < or = 0.05). PM patients even improved in the Trailmaking test (P < or = 0.05). Neuronal injury from even brief periods of global brain ischemia seems to be associated with deteriorating neurocognitive function.

Mechanical aortic valves are a possible source of microemboli potentially causing cerebral injury. Therefore, the long-term impact of mechanical aortic valve replacement on neurocognitive function is uncertain.In this prospective, contemporary study, we followed 32 consecutive patients (aged 51 +/- 8 years; range, 38 to 70; EuroSCORE [European System for Cardiac Operative Risk Evaluation] 4.4 +/- 1.7) undergoing isolated aortic valve replacement with a mechanical prosthesis. A cohort of age- and sex-matched patients (n = 28, aged 50 +/- 7 years) served as nonsurgical controls. After aortic valve replacement, neurocognitive function was serially reevaluated at 7-day (n = 32), 4-month (n = 31), and 3-year (n = 29) follow-up. Neurocognitive function was measured by means of P300 auditory evoked potentials.Before the operation, P300 peak latencies were comparable between surgical patients (361 +/- 32 ms) and nonsurgical controls (365 +/- 33 ms, p = 0.783). In patients undergoing aortic valve replacement, P300 peak latencies were prolonged 7 days after surgery (380 +/- 32 ms) as compared with before the operation (361 +/- 32 ms, p0.0001) and as compared with nonsurgical controls (364 +/- 34 ms, p = 0.002). At 4-month (369 +/- 30 ms, p = 0.752) and 3-year (370 +/- 31 ms, p = 0.825) follow-up, P300 peak latencies normalized as compared with before operation and as compared with nonsurgical controls (4-month follow-up 363 +/- 31 ms, p = 0.832; 3-year follow-up 366 +/- 32 ms, p = 0.432). We found no difference in patients with different valve types.Despite previous assumptions based on the potential occurrence of microemboli in patients with mechanical valves, mechanical aortic valve replacement has no adverse long-term impact on neurocognitive function. This finding is only valid for patients with a comparable age range undergoing isolated aortic valve replacement.

Author(s): Lambertus, Stanley; Bax, Nathalie M; Fakin, Ana; Groenewoud, Joannes MM; Klevering, B Jeroen; Moore, Anthony T; Michaelides, Michel; Webster, Andrew R; van der Wilt, Gert Jan; Hoyng, Carel B | Abstract: BackgroundEach inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options-including gene therapy-are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (g 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration.Methods and findingsWe used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30-0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33-0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients.ConclusionsThese results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders.

Purpose of this study was to molecularly characterize a family in which two brothers (46 and 36years) presented with a combination of retinitis pigmentosa (RP) and severe sensorineural hearing loss while father and sister (71 and 41years) presented with isolated RP. Retinal phenotype was compared with phenotype of 17 patients with Usher syndrome type 1. Ophthalmological examination included assessment of Snellen visual acuity, color vision with Ishihara tables, Goldmann perimetry (targets II/1–4) and microperimetry. Fundus autofluorescence imaging and optical coherence tomography were performed. Direct sequencing of all coding exons and flanking intronic sequences of GJB2 (gap junction protein, beta 2) and PRPH2 (peripherin 2) genes was performed in younger brother. Other family members were analyzed with sequencing (GJB2), high resolution melt analysis (GJB2) or restriction enzymes (PRPH2). Brothers with hearing loss were found to carry a homozygous c.35delG mutation in GJB2, the most common mutation associated with recessive hearing loss. All patients were found to carry a novel heterozygous mutation c.389T>C (p.Leu130Pro) on PRPH2. Age of onset was higher in PRPH2 than USH1 patients, however with some overlap. Differentiation from retinal phenotype of USH1 could only be made in the oldest patient, who retained good central visual function after more than three decades of disease.

Purpose To further investigate functional aspects of hyperautofluorescent ring, seen in retinal dystrophies. Methods Full ophthalmologic examination was performed, autofluorescence imaging was done by Heidelberg Engineering Spectralis/OCT, microperimetry with MP1 and electrophysiology. Results Hzperautofluorescent ring exhibited different characteristics in RP-related diseases and very heterogenous characteristics in cone dystrophies, cone/rod dystrophies and macular dystrophies such as Stargardt disease, Best's disease and other dystrophies affecting central retina. Conclusion Hyperautofluorescent ring is a specific feature that represents boundary between functioning and disfunctional retina and its origin is at present unknown. Different forms of ring are seen in different diseases and its functional correlations are important to understand the underlying mechanisms.

The purpose of this study was to investigate visual field defects in different clinical presentations of giant cell arteritis. Retrospective study of 36 patients from 1996–2010 with giant cell arteritis (67% female, average age 79, range 62–92 years), with typical clinical picture and/or positive biopsy (78%, 18/23 performed). Visual fields charted by Goldmann perimeter were categorized into specific categories. Respect for horizontal meridian was noted. Loss of vision was unilateral (65%) or bilateral (35%). The most common ischaemic lesions were anterior ischaemic optic neuropathy (AION; 16 unilateral, 4 bilateral) and posterior ischaemic optic neuropathy (PION; 5 unilateral, 5 bilateral). Other lesions included central retinal artery occlusion (CRAO) and internuclear ophthalmoplegia (INO). More than half of the affected eyes (53%) had visual acuity of counting fingers to no light perception. We observed 11 types of visual field defects. AION presented most commonly with peripheral island (35%) and sector defect (35%). Inferior altitudinal defect occurred in 18%. There was a tendency to affect nasal and inferior halves of visual fields. PION occurred in 31% of patients and most often presented with scotoma with or without peripheral defect. AION most commonly presented with peripheral island (35%) or sector defect (35%). Visual field defects in AION almost universally showed respect for horizontal meridian, except where only small residual island remained. Inferior altitudinal defect occurred less commonly than expected (18%). PION was more prevalent in our study (31%) compared to others and most often presented with scotoma with or without peripheral defect.

To test the hypothesis that the lectin-like domain of tumor necrosis factor, mimicked by the TIP peptide, can improve lung function after unilateral orthotopic lung isotransplantation. Because of a lack of a specific treatment for ischemia reperfusion-mediated lung injury, accompanied by a disrupted barrier integrity and a dysfunctional alveolar liquid clearance, alternative therapies restoring these parameters after lung transplantation are required.Prospective, randomized laboratory investigation.University-affiliated laboratory.Adult female rats.Tuberoinfundibular peptide, mimicking the lectin-like domain of tumor necrosis factor, mutant TIP peptide, N,N'-diacetylchitobiose/TIP peptide, and amiloride/TIP peptide were instilled intratracheally in the left lung immediately before the isotransplantation was performed. An additional group received an intravenous TIP peptide treatment, 1.5 mins before transplantation. Studies using isolated rat type II alveolar epithelial cell monolayers and ovine pulmonary endothelial cells were also performed.Intratracheal pretreatment of the transplantable left lung with the TIP peptide, but not with an inactive mutant TIP peptide, resulted in significantly improved oxygenation 24 hrs after transplantation. This treatment led to a significantly reduced neutrophil content in the lavage fluid. Both the effects on oxygenation and neutrophil infiltration were inhibited by the epithelial sodium channel blocker amiloride. The TIP peptide blunted reactive oxygen species production in pulmonary artery endothelial cells under hypoxia and reoxygenation and reduced reactive oxygen species content in the transplanted rat lungs in vivo. Ussing chamber experiments using monolayers of primary type II rat pneumocytes indicated that the primary site of action of the peptide was on the apical side of these cells.These data demonstrate that the TIP peptide significantly improves lung function after lung transplantation in the rat, in part, by reducing neutrophil content and reactive oxygen species generation. These studies suggest that the TIP peptide is a potential therapeutic agent against the ischemia reperfusion injury associated with lung transplantation.

The effect of successful ventricular assist device (VAD) implantation on neurocognitive function in terminal heart failure is uncertain. Additionally, the different impact of continuous versus pulsatile blood flow devices is unknown. A total of 29 patients (mean age 53 years), surviving implantation of a ventricular assist device as bridge to transplantation were prospectively followed (continuous flow: Micromed DeBakey, n = 11; pulsatile flow: Thoratec and Novacor, n = 18). Normative data were obtained in 40 age- and sex-matched healthy subjects (mean age 54 years). Neurocognitive function was objectively measured by means of cognitive P300 auditory evoked potentials before operation (baseline), at intensive care unit (ICU) discharge, and at the 8-week and 12-week follow-up. Before implantation of the VAD, cognitive P300 evoked potentials were impaired (prolonged) compared with age- and sex-matched healthy subjects (p < 0.001). After successful VAD implantation, P300 evoked potentials markedly improved compared with before operation (ICU discharge, p = 0.007; 8-week follow-up, p = 0.022; 12-week follow-up, p < 0.0001). Importantly, there was no difference between continuous and pulsatile VADs (before operation, p = 0.676; ICU discharge, p = 0.736; 8-week follow-up, p = 0.911 and 12-week follow-up, p = 0.397; respectively). Nevertheless, P300 peak latencies did not fully normalize at 12-week follow-up compared with healthy subjects (p = 0.012). Successful VAD implantation improves neurocognitive impairment in patients with terminal heart failure. Importantly, this effect is independent of the type of VAD (pulsatile vs. continuous blood flow).

Essa investigação identificou e analisou o sistema de medicação de 04 hospitais universitários, localizados nas cidades de Recife, Ribeirão Preto, Goiânia e São Paulo, após a aprovação nos Comitês de Ética em Pesquisa e da autorização da direção dos hospitais. Os dados foram coletados através de entrevista estruturada com um dos profissionais responsáveis pelo sistema de medicação e observação não participante e direta, por uma semana, nos vários sub-sistemas. Os resultados indicaram pontos que necessitam de aperfeiçoamentos como utilização de abreviações, falta de padronização de horários de administração de medicamentos, falta de informações atualizadas e completas do paciente, farmácia não funcionando 24 horas em um hospital, falta de centro de informações de medicamentos e outros. Evidenciou-se no hospital A 66 etapas, no B 58 etapas, no C 70 etapas e no D 80 etapas do sistema de medicação. Simplificar os processos, diminuindo o número de etapas, é a chave para a redução de erros de medicação. This study identified and analyzed the medication systems in 04 university hospitals located in Recife, Ribeirão Preto, Goiânia and São Paulo, Brazil, after approval by the Research Ethics Committee and authorization by the hospital directors. Data were collected through a structured interview with one of the professionals in charge of the medication system and non-participant and direct observation during one week. The results indicated the points requiring improvement, such as the use of abbreviations, lack of standardization in medication administration times, lack of updated and complete information about the patient, the pharmacy's not working 24 hours a day in hospitals and others. 66 phases were shown in Hospital A, 58 in B, 70 in C, and 80 in D concerning the medication system. Simplifying the processes by reducing the number of phases is the key to reducing medication errors. Esa investigación identificó y analizó el sistema de medicación en 04 hospitales universitarios en las ciudades de Recife, Ribeirão Preto, Goiânia y São Paulo, Brasil. Los datos fueron recopilados en dos etapas. En la primera etapa se realizó una entrevista estructurada con uno de los profesionales responsables por el sistema de medicación. En la segunda, se hizo observación no participativa y directa durante una semana. Los resultados indicaron los puntos que necesitan ser perfeccionados, tales como uso de abreviaciones, la falta de un padrón de horarios, falta de información actualizada y completa del paciente, farmacia que no funciona las 24 horas en un hospital, y otros. Se observó en el Hospital A 66 etapas, en el B 58 etapas, en el C 70 etapas y en el D 80 etapas respecto al sistema de medicación. Simplificar el proceso, diminuyendo el número de etapas, es la clave para reducir los márgenes de errores en la medicación.

Background Giant cell arteritis (GCA) is the most common systemic vasculitis in adults aged 50 years or above. Annual incidence rates vary widely from 6.9–76.6 per 10 5 of adults in this age group, depending on the region. 1 Objectives To determine the incidence rate of GCA in our population. Methods We prospectively collected incident cases of GCA from January 1st 2011 to December 31st 2012 at our department of rheumatology which is a part of an integrated secondary/tertiary university teaching hospital that is the only referral center serving a region representing approximately a quarter of the national adult population. Additionally, newly diagnosed cases of GCA between January 1st 2009 and December 31st 2010 were retrospectively identified by searching the electronic patient records for ICD-10 codes M31.5 and M31.6 at our department. The retrospective approach and search strategy was also applied on electronic medical records at the departments of infectious diseases and ophthalmology between January 1st 2009 and December 31st 2012. To further reduce possibility of underreporting, the attached medical faculty9s Institute of Pathology provided a list of all temporal artery biopsies examined during the observation period which were then cross-referenced with the hospital9s electronic medical records. Annual incidence rate for GCA was then calculated. Results During the four year observation period we identified 97 new cases of GCA (68% female; mean (SD) age 75.6 (8.1) years) from a well-defined adult white Caucasian population of 232,041 inhabitants aged 50 or above. The temporal artery biopsy was consistent with GCA, negative or not performed in 75.3%, 18.6, and 6.2% of cases, respectively. Thus, the annual incidence of GCA in our population is 10.5 (95% CI 8.5–12.7), and 4.7 (95% CI 3.8–5.7) per 10 5 adults aged 50, and 20 years or above, respectively. Conclusions The annual incidence rate of 10.5 per 10 5 adults aged 50 or above makes GCA the most common systemic vasculitis in this age group of our population. Although the GCA almost exclusively affects adults over 50 years of age, the incidence rate of 4.7 per 10 5 adults aged 20 and above, also makes it the most common systemic vasculitis in the adult population overall, with IgA vasculitis coming a close second with 3.7 per 10 5 adults aged 20 years or above. References Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ et al. Epidemiology of Giant Cell Arteritis and Polymyalgia Rheumatica. Arthritis Rheum 2009;61:1454-61. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1968