Molecular Inversion Probe-Based Sequencing of USH2A Exons and Splice Sites as a Cost-Effective Screening Tool in USH2 and arRP Cases.

A substantial proportion of subjects with autosomal recessive retinitis pigmentosa (arRP) or Usher syndrome type II (USH2) lacks a genetic diagnosis due to incomplete USH2A screening in the early days of genetic testing. These cases lack eligibility for optimal genetic counseling and future therapy. USH2A defects are the most frequent cause of USH2 and are also causative in individuals with arRP. Therefore, USH2A is an important target for genetic screening. The aim of this study was to assess unscreened or incompletely screened and unexplained USH2 and arRP cases for (likely) pathogenic USH2A variants. Molecular inversion probe (MIP)-based sequencing was performed for the USH2A exons and their flanking regions, as well as published deep-intronic variants. This was done to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in 29 unscreened or partially pre-screened USH2 and 11 partially pre-screened arRP subjects. In 29 out of these 40 cases, two (likely) pathogenic variants were successfully identified. Four of the identified SNVs and one CNV were novel. One previously identified synonymous variant was demonstrated to affect pre-mRNA splicing. In conclusion, genetic diagnoses were obtained for a majority of cases, which confirms that MIP-based sequencing is an effective screening tool for USH2A. Seven unexplained cases were selected for future analysis with whole genome sequencing.

Phase I of the Surveillance for Enteric Fever in Asia Project (SEAP): An Overview and Lessons Learned.

Objective: The objective of Phase I of the Surveillance for Enteric Fever in Asia Project (SEAP), a multiphase surveillance study characterizing the burden of disease in South Asia, was to inform data collection for prospective surveillance and to capture clinical aspects of disease. Methods: Through a retrospective record review conducted at hospitals in Bangladesh, India, Nepal, and Pakistan, we examined laboratory and clinical records to assess the culture positivity rate for Salmonella Typhi and Salmonella Paratyphi, age and sex distribution, and antimicrobial susceptability in each country. Results: Of all blood cultures performed in Bangladesh, India, Nepal, and Pakistan, 1.5%, 0.43%, 2%, and 1.49%, respectively, were positive for S. Typhi and 0.24%, 0.1%, 0.5%, and 0.67%, respectively, were positive for S. Paratyphi. A higher proportion of laboratory-confirmed infections in Bangladesh and Pakistan were aged ≤5 years, while India and Nepal had a higher proportion of participants aged 15-25 years. In all countries, the sex of the majority of participants was male. The majority of isolates in all countries were resistant to fluoroquinolones, with a high proportion also resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole. Discussion: Enteric fever remains endemic in South Asia. Data generated by this study can help inform strategies for implementation and evaluation of prevention and control measures.

WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease.

Infantile-onset cerebellar atrophy (CA) is a clinically and genetically heterogeneous trait. Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disease, characterized by microcephaly with brain anomalies including CA in some cases, intellectual disability, and early-infantile-onset nephrotic syndrome. Very recently, WDR73 deficiency was identified as the cause of GMS in five individuals. To evaluate the role of WDR73 mutations as a cause of GMS and other forms of syndromic CA, we performed Sanger or exome sequencing in 51 unrelated patients with CA and variable brain anomalies and in 40 unrelated patients with a diagnosis of GMS. We identified 10 patients from three CA and from two GMS families with WDR73 mutations including the original family described with CA, mental retardation, optic atrophy, and skin abnormalities (CAMOS). There were five novel mutations, of which two were truncating and three were missense mutations affecting highly conserved residues. Individuals carrying homozygous WDR73 mutations mainly presented with a pattern of neurological and neuroimaging findings as well as intellectual disability, while kidney involvement was variable. We document postnatal onset of CA, a retinopathy, basal ganglia degeneration, and short stature as novel features of WDR73-related disease, and define WDR73-related disease as a new entity of infantile neurodegeneration.

Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population.

OBJECTIVE: We aimed to identify novel genetic defects in the LCA5 gene underlying Leber congenital amaurosis (LCA) in the Spanish population and to describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: A cohort of 217 unrelated Spanish families affected by autosomal recessive or isolated retinal dystrophy, that is, 79 families with LCA and 138 families with early-onset retinitis pigmentosa (EORP). A total of 100 healthy, unrelated Spanish individuals were screened as controls. METHODS: High-resolution homozygosity mapping was performed in 44 patients with LCA using genome-wide single nucleotide polymorphism (SNP) microarrays. Direct sequencing of the LCA5 gene was performed in 5 patients who showed homozygous regions at chromosome 6 and in 173 unrelated individuals with LCA or EORP. The ophthalmic history of 8 patients carrying LCA5 mutations was reviewed and additional examinations were performed, including electroretinography (ERG), optical coherence tomography (OCT), and fundus photography. MAIN OUTCOME MEASURES: Single nucleotide polymorphism genotyping, identity-by-descent (IBD) regions, LCA5 mutations, best-corrected visual acuity, visual field assessments, fundus appearance, ERG, and OCT findings. RESULTS: Four novel and 2 previously reported LCA5 mutations have been identified in 6 unrelated families with LCA by homozygosity mapping or Sanger sequencing. Thus, LCA5 mutations have a frequency of 7.6% in the Spanish population. However, no LCA5 mutations were found in 138 patients with EORP. Although most of the identified LCA5 mutations led to a truncated protein, a likely pathogenic missense variant was identified for the first time as a cause of LCA, segregating in 2 families. We also have characterized a novel splicing site mutation at the RNA level, demonstrating that the mutant LCA5 transcript was absent in a patient. All patients carrying LCA5 mutations presented nystagmus, night blindness, and progressive loss of visual acuity and visual field leading to blindness toward the third decade of life. Fundoscopy showed fundus features of pigmentary retinopathy with atrophic macular lesions. CONCLUSIONS: This work reveals a higher frequency of LCA5 mutations in a Spanish LCA cohort than in other populations. This study established gene-specific frequencies and the underlying phenotype of LCA5 mutations in the Spanish population.

Typhoid fever in Fiji: a reversible plague?

The country of Fiji, with a population of approximately 870 000 people, faces a growing burden of several communicable diseases including the bacterial infection typhoid fever. Surveillance data suggest that typhoid has become increasingly common in rural areas of Fiji and is more frequent amongst young adults. Transmission of the organisms that cause typhoid is facilitated by faecal contamination of food or water and may be influenced by local behavioural practices in Fiji. The Fijian Ministry of Health, with support from Australian Aid, hosted a meeting in August 2012 to develop comprehensive control and prevention strategies for typhoid fever in Fiji. International and local specialists were invited to share relevant data and discuss typhoid control options. The resultant recommendations focused on generating a clearer sense of the epidemiology of typhoid in Fiji and exploring the contribution of potential transmission pathways. Additionally, the panel suggested steps such as ensuring that recommended ciprofloxacin doses are appropriate to reduce the potential for relapse and reinfection in clinical cases, encouraging proper hand hygiene of food and drink handlers, working with water and sanitation agencies to review current sanitation practices and considering a vaccination policy targeting epidemiologically relevant populations.

Typhoid Fever surveillance and vaccine use - South-East Asia and Western Pacific regions, 2009-2013.

Typhoid fever is a serious, systemic infection resulting in nearly 22 million cases and 216,500 deaths annually, primarily in Asia. Safe water, adequate sanitation, appropriate personal and food hygiene, and vaccination are the most effective strategies for prevention and control. In 2008, the World Health Organization (WHO) recommended use of available typhoid vaccines to control endemic disease and outbreaks and strengthening of typhoid surveillance to improve disease estimates and identify high-risk populations (e.g., persons without access to potable water and adequate sanitation). This report summarizes the status of typhoid surveillance and vaccination programs in the WHO South-East Asia (SEAR) and Western Pacific regions (WPR) during 2009-2013, after the revised WHO recommendations. Data were obtained from the WHO/United Nations Children's Fund (UNICEF) Joint Reporting Form on Immunization, a supplemental survey of surveillance and immunization program managers, and published literature. During 2009-2013, 23 (48%) of 48 countries and areas of SEAR (11) and WPR (37) collected surveillance or notifiable disease data on typhoid cases, with most surveillance activities established before 2008. Nine (19%) countries reported implementation of typhoid vaccination programs or recommended vaccine use during 2009-2013. Despite the high incidence, typhoid surveillance is weak in these two regions, and vaccination efforts have been limited. Further progress toward typhoid fever prevention and control in SEAR and WPR will require country commitment and international support for enhanced surveillance, targeted use of existing vaccines and availability of newer vaccines integrated within routine immunization programs, and integration of vaccination with safe water, sanitation, and hygiene measures.

Formative research and development of an evidence-based communication strategy: the introduction of Vi typhoid fever vaccine among school-aged children in Karachi, Pakistan.

The authors conducted formative research (a) to identify stakeholders' concerns related to typhoid fever and the need for disease information and (b) to develop a communication strategy to inform stakeholders and address their concerns and motivate for support of a school-based vaccination program in Pakistan. Data were collected during interactive and semi-structured focus group discussions and interviews, followed by a qualitative analysis and multidisciplinary consultative process to identify an effective social mobilization strategy comprised of relevant media channels and messages. The authors conducted 14 focus group discussions with the parents of school-aged children and their teachers, and 13 individual interviews with school, religious, and political leaders. Parents thought that typhoid fever was a dangerous disease, but were unsure of their children's risk. They were interested in vaccination and were comfortable with a school-based vaccination if conducted under the supervision of trained and qualified staff. Teachers and leaders needed information on typhoid fever, the vaccine, procedures, and sponsors of the vaccination program. Meetings were considered the best form of information dissemination, followed by printed materials and mass media. This study shows how qualitative research findings can be translated into an effective social mobilization and communication approach. The findings of the research indicated the importance of increasing awareness of typhoid fever and the benefits of vaccination against the disease. Identification and dissemination of relevant, community-based disease and vaccination information will increase demand and use of vaccination.

Inhibition of Myc-induced cell transformation by brain acid-soluble protein 1 (BASP1).

Cell transformation by the Myc oncoprotein involves transcriptional activation or suppression of specific target genes with intrinsic oncogenic or tumor-suppressive potential, respectively. We have identified the BASP1 (CAP-23, NAP-22) gene as a novel target suppressed by Myc. The acidic 25-kDa BASP1 protein was originally isolated as a cortical cytoskeleton-associated protein from rat and chicken brain, but has also been found in other tissues and subcellular locations. BASP1 mRNA and protein expression is specifically suppressed in fibroblasts transformed by the v-myc oncogene, but not in cells transformed by other oncogenic agents. The BASP1 gene encompasses 2 exons separated by a 58-kbp intron and a Myc-responsive regulatory region at the 5' boundary of untranslated exon 1. Bicistronic expression of BASP1 and v-myc from a retroviral vector blocks v-myc-induced cell transformation. Furthermore, ectopic expression of BASP1 renders fibroblasts resistant to subsequent cell transformation by v-myc, and exogenous delivery of the BASP1 gene into v-myc-transformed cells leads to significant attenuation of the transformed phenotype. The inhibition of v-myc-induced cell transformation by BASP1 also prevents the transcriptional activation or repression of known Myc target genes. Mutational analysis showed that the basic N-terminal domain containing a myristoylation site, a calmodulin binding domain, and a putative nuclear localization signal is essential for the inhibitory function of BASP1. Our results suggest that down-regulation of the BASP1 gene is a necessary event in myc-induced oncogenesis and define the BASP1 protein as a potential tumor suppressor.

Applications of bioconvection for tiny particles due to two concentric cylinders when role of Lorentz force is significant.

The bioconvection flow of tiny fluid conveying the nanoparticles has been investigated between two concentric cylinders. The contribution of Lorenz force is also focused to inspect the bioconvection thermal transport of tiny particles. The tiny particles are assumed to flow between two concentric cylinders of different radii. The first cylinder remains at rest while flow is induced due to second cylinder which rotates with uniform velocity. Furthermore, the movement of tiny particles follows the principle of thermophoresis and Brownian motion as a part of thermal and mass gradient. Similarly, the gyro-tactic microorganisms swim in the nanofluid as a response to the density gradient and constitute bio-convection. The problem is modeled by using the certain laws. The numerical outcomes are computed by using RKF -45 method. The graphical simulations are performed for flow parameters with specific range like 1≤Re≤5, 1≤Ha≤5, 0.5≤Nt≤2.5, 1≤Nb≤3, 0.2≤Sc≤1.8, 0.2≤Pe≤1.0 and 0.2≤Ω≤1.0. It is observed that the flow velocity decreases with the increase in the Hartmann number that signifies the magnetic field. This outcome indicates that the flow velocity can be controlled externally through the magnetic field. Also, the increase in the Schmidt numbers increases the nanoparticle concentration and the motile density.

Ultrasonographic assessment of renal size and its correlation with body mass index in adults without known renal disease.

BACKGROUND: Many conditions affect renal size. To evaluate abnormalities in renal size, knowledge of standardised values for normal renal dimensions is essential as it shows variability in the values of normal renal size depending on body size, age and ethnicity. Ultrasound, being an easily available, noninvasive, safe and less expensive modality, is widely used for evaluation of renal dimensions and repeated follow-ups. The objectives of this study were to determine renal size by ultrasound in adults without any known renal disease, and to determine the relationship of renal size with body mass index. METHODS: Study was conducted in the Department of Diagnostic Radiology, Shifa International Hospital and PIMS Islamabad. Renal size was assessed by ultrasound in 4,035 adult subjects with normal serum creatinine and without any known renal disease, between November 2002 and December 2010. Renal length, width, thickness and volume were obtained and mean renal length and volume were correlated with body mass index and other factors like age, side, gender, weight and height of the subjects. RESULTS: Mean renal length on right side was 101.6 +/- 8.9 mm, renal width 42.7 +/- 7.1 mm, and parenchymal thickness 14.4 +/- 2.9 mm. On left side, mean renal length was 102.7 +/- 9.2 mm, width 47.6 +/- 7.0) mm, and parenchymal thickness 15.1 +/- 3.1 mm. Mean renal volume on right was 99.8 +/- 37.2 cm3 and on left was 124.4 +/- 41.3 cm3. Left renal size was significantly larger than right in both genders. Relationship of mean renal length was significant when correlated with age, side, gender, height and weight, and body mass index. Renal volumes also showed a similar relationship with side, gender, height and weight, and body mass index; but with age such a relationship was seen only for left kidney. CONCLUSION: Pakistani population has mean renal size smaller than reference values available in international literature. Renal length and volume have a direct relationship with body mass index. Mean renal size is related to the side, age, gender, height and weight as well.

Non-typhoidal Salmonella rates in febrile children at sites in five Asian countries.

There is increased recognition of non-typhoidal Salmonella (NTS) as a major cause of severe febrile illness in sub-Saharan Africa. However, little is known about community-based incidence of NTS in Asia. In a multicentre, community-based prospective Salmonella surveillance study, we identified a total of six NTS cases: three in Karachi, Pakistan, one in Kolkata, India, and two in North Jakarta, Indonesia. No NTS cases were identified in Hechi, People's Republic of China, and Hue, Viet Nam. Three cases were in children under 3 years, and one case was in a child aged 10 years and one in a child aged 15 years. Only one case was an adult (29 years). The highest incidence of NTS infection was in Karachi (7.2 culture-proven NTS cases per 100,000 person years in age group of 2-15 years). However, in comparison with sub-Saharan Africa, the NTS burden in Asia appears rather limited.

Modeling and computational analysis of 3D radiative stagnation point flow of Darcy-Forchheimer subject to suction/injection.

BACKGROUND: This manuscript elaborates the three-dimensional radiated Darcy-Forchheimer viscous liquid flow subject to permeable stretched surface. The stretched surface is nonlinear and saturated via Darcy-Forchheimer medium. Energy expression is derived through implementation of first of thermodynamics and discussed subject to convective condition and nonlinear heat flux. Mixed convection is also considered. METHOD: The governing systems of nonlinear equations are tackled numerically by Shooting method. RESULTS: Graphical results are depicted and examined with different values of non-dimensional parameters for velocity and energy equations respectively. Drag force and Nusselt number are computationally computed and analyzed through Tables. CONCLUSIONS: It is concluded from the derived outcomes that both component of velocity decay against higher values of local inertia coefficient and inverse Darcy number variables. For suction case both velocities increases while opposite trend is observed for injection case. Temperature profile has an increasing impact for higher values of Radiation, and Biot number while opposite result is seen for injection. Drag force or skin friction declines via larger injection variable. Nusselt number increases for radiation variable.

Entropy optimized Darcy-Forchheimer nanofluid (Silicon dioxide, Molybdenum disulfide) subject to temperature dependent viscosity.

Background In this research communication, entropy optimized Darcy-Forchheimer flow with magnetohydrodynamic over a stretched surface is considered. Here Molybdenum disulfide (MOS2) and Silicon dioxide (SiO2) are taken as a nanoparticles and Propylene glycol as a continuous phase liquid. Electrically conducting fluid is considered and flow is generated via stretched surface of sheet. The total entropy rate which is depends on four types of irreversibilities i.e., heat transfer, porosity, fluid friction and dissipation) is calculated via second law of thermodynamics. The energy expression is mathematically modeled and discussed subject to heat generation/absorption, dissipation, thermal radiation and Joule heating. Furthermore, temperature dependent viscosity is accounted. Method The nonlinear PDE's (partial differential equations) are first changed to ODE's (ordinary differential equations) through implementation of appropriate similarity variables (transformations). The numerical results of ordinary ones are computed via Built-In-Shooting method. The results for the flow field, temperature, skin friction, Nusselt number and entropy generation are discussed against various sundry flow parameters graphically. Results Salient characteristics of sundry flow parameters on the entropy generation rate, velocity, Bejan number, gradients of velocity, gradient of temperature and temperature are examined and display graphically. The results are computed for both nanoparticles. From obtained results it is observed that temperature field increases versus higher thermal Biot number for both nanoparticles. It is also observed that the thermal field is more in presence of Molybdenum disulfide as compared to Silicon dioxide, because the thermal conductivity of Molybdenum disulfide is higher than Silicon dioxide. Entropy generation and Bejan number show contrast impact versus higher estimations of Brinkman number versus both nanoparticles.

Reports of Coding-Complete Genome Sequences of Five 2019 Novel Coronavirus (SARS-CoV-2) Strains Isolated in Bangladesh.

This study determined five coding-complete genome sequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains isolated from oropharyngeal swab specimens of Bangladeshi patients who were diagnosed with coronavirus disease 2019 (COVID-19) and had no travel history.

Spleen tyrosine kinase expression is correlated with human papillomavirus in head and neck cancer.

OBJECTIVES: Spleen tyrosine kinase (SYK) is a promoter of cell survival in a variety of cell types, including normal and cancerous epithelial cells. We hypothesized that SYK would an important therapeutic target to inhibit for the treatment of HNSCC. MATERIALS AND METHODS: SYK protein abundance in patient tumours was evaluated. SYK protein and mRNA abundance was used to examine patient survival and human papillomavirus (HPV) status. Small-interfering RNAs and gene editing with CRISPR/Cas9 were used to evaluate SYK expression on proliferation in HNSCC cell lines. The potency of SYK inhibitor ER27319 maleate on cellular proliferation was tested using a panel of 28 HNSCC cell lines and in vivo in HNSCC patient-derived xenograft (PDX) models. RESULTS: Moderate to high protein expression of SYK was observed in 24% of patient tumors and high SYK expression was exclusively observed in HPV-positive samples (p < 0.001). SYK inhibition with RNA interference, gene editing or a SYK inhibitor (ER27319) decreased cell proliferation and migration. Treatment of PDXs with ER27319 maleate was observed to reduce tumour burden in vivo in two of three models. CONCLUSIONS: HPV-positive HNSCC harbours high SYK protein levels. We demonstrate that proliferation, migration and overall burden of these tumours can be reduced by genetic or pharmacologic inhibition of SYK. Taken together, these data establish SYK as a therapeutic target for HNSCC.

Nanomaterial based flow of Prandtl-Eyring (non-Newtonian) fluid using Brownian and thermophoretic diffusion with entropy generation.

BACKGROUND: The augmentation of cooling or heating in a mechanical and industrial process may create a saving in energy, decrease process time, protract the working existence of hardware and raise thermal rating. A few procedures are even influenced subjectively by the action of increased heat transport. The advancement of high performance thermal frameworks for heat transport augmentation has turned out to be well known these days. Various works has been conducted to gain an understanding of heat transport execution for their viable application to heat transport enhancement. Consequently the appearance of high heat flow procedures has made huge interest for new innovations to increase the heat transport. Therefore, entropy generation in dissipative nanomaterial flow of Prandtl-Eyring nanofluid subject to heated stretchable surface. The impact of zero shear rate viscosity is discussed through Prandtl-Eyring fluid model. Through implementation of thermodynamics second law's total entropy rate is calculated. Heat and mass transfer features are discussed using Brownian diffusion and thermophoresis. Homogeneous and heterogeneous chemical reactions are also accounted. METHODS: Nonlinear partial differential systems are leads to ordinary systems through adequate similarity transformations. The obtained nonlinear ordinary systems are solved by Newton built in shooting technique. RESULTS: Behaviors of different flow parameters on velocity, temperature, entropy generation rate, Bejan number and concentration are graphically discussed. Skin friction coefficient and heat transfer rate are discussed through tables. Entropy generation rate enhances for larger estimation of material parameter and Brinkman number. Bejan number is equal to one when Brinkman number is equal to zero and then progressively decreases for higher values of Brinkman number. CONCLUSIONS: A significant increment has been observed in the velocity field versus material parameter, while opposite trends is noticed forß.Temperature field enhances against higher values of thermophoresis and Brownian parameters while it decays through larger Prandtl number. Mass concentration upsurges versus higher thermophoresis parameter and declined via larger Brownian parameter and homogeneous and heterogeneous parameters. Furthermore, entropy rate and Bejan number show contrast impact versus material parameter and Brinkman number.

Theoretical and mathematical analysis of entropy generation in fluid flow subject to aluminum and ethylene glycol nanoparticles.

BACKGROUND: Here we have conducted a magnetohydrodynamic (MHD) flow of viscous material with alumina water and ethylene glycol over a stretched surface. The flow is discussed with and without effective Prandtl number. MHD liquid is considered. Electric field is absent. Effect of uniform magnetic field is taken in the vertical direction to the surface. Influence of thermal radiation as well as Joule heating are taken into account for both aluminum oxide-water and aluminum oxide-Ethylene glycol nanofluids. Velocity slip and melting heat effects are considered. METHODS: The nonlinear flow expressions are numerically solved via ND-solve technique (built-in-Shooting). RESULTS: The physical impacts of flow variables like mixed convection parameter, magnetic parameter, Reynold number, Eckert number, melting parameter and heat source/sink parameter are graphically discussed. Moreover, entropy generation (irreversibility) and Bejan number are discussed graphically through various flow variables. Physical quantities like skin friction coefficient and Sherwood and Nusselt numbers are numerically calculated and discussed through Tables. CONCLUSIONS: Impact of magnetic and slip parameters on the velocity field show decreasing behavior for both effective and without effective Prandtl number. Temperature field increases for both effective and without effective Prandtl number for higher values of magnetic and radiative parameters. Entropy number is an increasing function of Reynolds number while Bejan number shows opposite impact against Reynolds number. Moreover, heat transfer rate upsurges versus larger melting and radiative parameter.

Elastic layered rubber-graphene composite fabricated by rubbing-in technology for the multi-functional sensors.

In this work, the elastic layered rubber-graphene composite based multi-functional sensor has been fabricated by rubbing-in technology. The effects of temperature, displacement, pressure and humidity on the impedance of the multi-functional sensor has been investigated in the frequency range of 0-200 kHz. The impedance of the samples decreased under the effect of uniaxial compressive displacement and under the effect of pressure. The temperature coefficient of the samples was found to be -0.836 and -0.862 %/°C with the increase in temperature from 29 °C to 54 °C, respectively, while the impedance of the samples decreased 1.26 ± 0.01 times with the increase in temperature from 29 °C to 54 °C while, respectively. The humidity dependent cross-sensitivity of the samples was investigated in the relative humidity range of (58-93) %RH and no effect of humidity on the performance of the sensor has been observed. The elastic layered rubber-graphene composite potentially can be used as displacement, frequency, temperature and pressure sensors.

Chromatic Full-Field Stimulus Threshold and Pupillography as Functional Markers for Late-Stage, Early-Onset Retinitis Pigmentosa Caused by CRB1 Mutations.

PURPOSE: Mutations in the CRB1 gene cause early-onset retinal degeneration (EORD). Clinical disease progression markers, such as visual fields or electrophysiology, are not reliably measurable in most patients to follow the retinal function in patients with CRB1-mutations. METHODS: Ten patients (five females, five males; age 22-56 years) with EORD caused by CRB1 mutations were examined in a cross-sectional manner using best corrected visual acuity (BCVA), perimetry, full-field and multifocal electroretinography, full-field stimulus threshold (FST), and pupillography to red and blue light. Disease duration was defined as the difference between the age at the first symptoms to the age at examination in years. RESULTS: BCVA was quantifiable in six patients and ranged from light perception to 20/50. The visual field was measurable only in three patients who had the shortest disease duration. Full-field and multifocal electroretinography were not measurable in any patient. FST to blue and red light were measurable in all patients except the one with the longest disease duration; the thresholds ranged from -16.7 to 1.5 dB for red light and from -40.2 to 2.5 dB for blue light (0 dB = 0.01 cd.s/m2) and showed correlations with disease duration (r = 0.87 for blue, r = 0.65 for red, r = 0.8 for blue-red difference). The maximal relative pupil constriction amplitude (MRA) showed low or no correlations with disease duration (r = -0.55 for blue, r = -0.3 for red light); the blue-red difference in the post-illumination pupil responses (PIPR) showed no correlation with disease duration (r = -0.05). Compared to healthy eyes, the MRA to red and blue light was significantly decreased (P < 0.001) and the blue-red PIPR difference was significantly increased (P = 0.003). CONCLUSIONS: FST features a valid clinical marker in late-stage early-onset retinitis pigmentosa caused by CRB1 mutations correlating with disease duration. This indicates the potential as a progression marker of disease. The pupil responses to full-field chromatic stimuli show significant differences from the normal population: the remaining responses, although reduced, indicate a partially preserved inner retinal function despite severe photoreceptor dysfunction. TRANSLATIONAL RELEVANCE: The functional measurements presented in this study present a valid clinical progression marker in late-stage early onset retinitis pigmentosa caused by biallelic CRB1 mutations. Additionally, they can be used as outcome measures for safety and efficacy in clinical therapy trials.

Effects of Residual Stress Distribution on Interfacial Adhesion of Magnetron Sputtered AlN and AlN/Al Nanostructured Coatings on a (100) Silicon Substrate.

The present study investigated the influence of nanoscale residual stress depth gradients on the nano-mechanical behavior and adhesion energy of aluminium nitride (AlN) and Al/AlN sputtered thin films on a (100) silicon substrate. By using a focused ion beam (FIB) incremental ring-core method, the residual stress depth gradient was assessed in the films in comparison with standard curvature residual stress measurements. The adhesion energy was then quantified by using a nanoindentation-based model. Results showed that the addition of an aluminum layer gave rise to additional tensile stress at the coating/substrate interface, which can be explained in terms of the differences of thermal expansion coefficients with the silicon substrate. Therefore, the coatings without the Al layer showed better adhesion because of a more homogeneous compressive residual stress in comparison with the coating having the Al layer, even though both groups of coatings were produced under the same bias voltage. Results are discussed, and some general suggestions are made on the correlation between coating/substrate property combinations and the adhesion energy of multilayer stacks. The results suggested that the Al bond layer and inhomogeneous residual stresses negatively affected the adhesion of AlN to a substrate such as silicon.