Retinal dystrophies are predominantly caused by mutations affecting the visual phototransduction system and cilia, with few genes identified that function to maintain photoreceptor survival. We ...reasoned that growth factors involved with early embryonic retinal development would represent excellent candidates for such diseases. Here we show that mutations in the transforming growth factor-β (TGF-β) ligand Growth Differentiation Factor 6, which specifies the dorso-ventral retinal axis, contribute to Leber congenital amaurosis. Furthermore, deficiency of gdf6 results in photoreceptor degeneration, so demonstrating a connection between Gdf6 signaling and photoreceptor survival. In addition, in both murine and zebrafish mutant models, we observe retinal apoptosis, a characteristic feature of human retinal dystrophies. Treatment of gdf6-deficient zebrafish embryos with a novel aminopropyl carbazole, P7C3, rescued the retinal apoptosis without evidence of toxicity. These findings implicate for the first time perturbed TGF-β signaling in the genesis of retinal dystrophies, support the study of related morphogenetic genes for comparable roles in retinal disease and may offer additional therapeutic opportunities for genetically heterogeneous disorders presently only treatable with gene therapy.
Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not ...account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10(-72)), CFH (complement factor H) (P =2.3 × 10(-47)), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10(-9)), C3 (complement component 3) (P =2.2 × 10(-3)) and CFI (P =3.6 × 10(-3)) and with more recently reported risk loci at VEGFA (P =1.2 × 10(-3)) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) rs12153855/rs9391734; discovery P =4.3 × 10(-7), replication P =3.0 × 10(-4), combined P =1.3 × 10(-9), odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6 and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10(-8), replication P =3.8 × 10(-5), combined P =2.0 × 10(-11), OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD.
To explore efficacy/safety of natalizumab, a humanized monoclonal anti-α4-integrin antibody, as adjunctive therapy in adults with drug-resistant focal epilepsy.
Participants with ≥6 seizures during ...the 6-week baseline period were randomized 1:1 to receive natalizumab 300 mg IV or placebo every 4 weeks for 24 weeks. Primary efficacy outcome was change from baseline in log-transformed seizure frequency, with a predefined threshold for therapeutic success of 31% relative reduction in seizure frequency over the placebo group. Countable seizure types were focal aware with motor signs, focal impaired awareness, and focal to bilateral tonic-clonic. Secondary efficacy endpoints/safety were also assessed.
Of 32 and 34 participants dosed in the natalizumab 300 mg and placebo groups, 30 (94%) and 31 (91%) completed the placebo-controlled treatment period, respectively (one participant was randomized to receive natalizumab but not dosed due to IV complications). Estimated relative change in seizure frequency of natalizumab over placebo was -14.4% (95% confidence interval CI -46.1%-36.1%;
= 0.51). The proportion of participants with ≥50% reduction from baseline in seizure frequency was 31.3% for natalizumab and 17.6% for placebo (odds ratio 2.09, 95% CI 0.64-6.85;
= 0.22). Adverse events were reported in 24 (75%) and 22 (65%) participants receiving natalizumab vs placebo.
Although the threshold to demonstrate efficacy was not met, there were no unexpected safety findings and further exploration of possible anti-inflammatory therapies for drug-resistant epilepsy is warranted.
The ClinicalTrials.gov registration number is NCT03283371.
This study provides Class I evidence that IV natalizumab every 4 weeks, compared to placebo, did not significantly change seizure frequency in adults with drug-resistant epilepsy. The study lacked the precision to exclude an important effect of natalizumab.
Nuclear transfer stem cells hold considerable promise in the field of regenerative medicine and cell‐based drug discovery. In this study, a total of 29 oocytes were obtained from three young (20–24 ...years old) reproductive egg donors who had been successful in previous cycles. These oocytes, deemed by intended parents to be in excess of their reproductive needs, were donated for research without financial compensation by both the egg donor and intended parents after receiving informed consent. All intended parents successfully achieved ongoing pregnancies with the oocytes retained for reproductive purposes. Mature oocytes, obtained within 2 hours following transvaginal aspiration, were enucleated using one of two methods, extrusion or aspiration, after 45 minutes of incubation in cytochalasin B. Rates of oocyte lysis or degeneration did not differ between the two methods. Somatic cell nuclear transfer (SCNT) embryos were constructed using two established adult male fibroblast lines of normal karyotype. High rates of pronuclear formation (66%), early cleavage (47%), and blastocyst (23%) development were observed following incubation in standard in vitro fertilization culture media. One cloned blastocyst was confirmed by DNA and mitochondrial DNA fingerprinting analyses, and DNA fingerprinting of two other cloned blastocysts indicated that they were also generated by SCNT. Blastocysts were also obtained from a limited number of parthenogenetically activated oocytes. This study demonstrates, for the first time, that SCNT can produce human blastocyst‐stage embryos using nuclei obtained from differentiated adult cells and provides new information on methods that may be needed for a higher level of efficiency for human nuclear transfer.
Disclosure of potential conflicts of interest is found at the end of this article.
Immunotherapies such as immune checkpoint inhibitors (ICI) are effective in multiple tumor entities but induce a plethora of side effects. Comprehensive real-world analyses are essential to identify ...new signals, characterize diagnostic features, enable risk assessment, determine pathomechanisms, assess effectiveness of side effect management and compare tumor outcomes.
The international online `Side-Effect Registry Immuno-Oncology´ (SERIO; www.serio-registry.org) collects rare, complex, and severe immunotherapy-induced side effects across all tumor entities with a strong focus on ICI-induced immune-related adverse events (irAE). The relational database management system (RDMS) contains structured data on patient and tumor characteristics, type of immunotherapy, treatment of side effects, and outcome of tumor and irAE. Data are captured within 25 organ modules including new modules for immune effector cell-associated neurotoxicity syndrome (ICANS) for CAR-T-cell therapies and cytokine release syndrome (CRS) for bispecific antibodies. Information on biological samples is gathered.
A total of 1398 irAE cases have been documented by 58 centers from 13 countries in patients with 17 tumor types. IrAEs were induced by nine different immunotherapies including tebentafusp and CAR-T cell therapies, and resulted, among others, in neurological (7.6%), pulmonary (4.0%), and cardiac toxicities (2.9%). 50.0% of all irAEs were graded severe or life-threatening and 23.0% of patients received second-line therapy for steroid-refractory or steroid-dependent irAE. SERIO has contributed to 44 original publications on topics ranging from irMyocarditis to irEncephalitis to long-term persistent sequelae of immunotherapy.
A reliable evidence base is crucial for decision-making in rare, complex or therapy-refractory irAE. SERIO can help optimize side effect management and thereby reduce morbidity and mortality induced by immunotherapy.
•Growing number of challenging immune-related adverse events (irAE)•Real-world international database - Side Effect Registry Immuno-Oncology (SERIO)•1330 rare, complex, and therapy-refractory irAE cases from 58 centers worldwide•44 original publications ranging from irMyocarditis to life-threatening irAEs•To optimize irAE management and reduce immunotherapy-induced morbidity and mortality
Abstract Objective There is evidence that perceptions of treatment may be more predictive than illness perceptions, e.g. medication adherence is often better predicted by beliefs about medication ...than by beliefs about illness. The present study aims to assess the generality of this finding, by comparing the extent to which self-care behaviours of patients with type 2 diabetes are predicted by patients' beliefs about those behaviours, compared with their illness perceptions. Methods This study is a one year prospective cohort analysis of 453 patients recruited to a randomised trial of blood glucose self-monitoring. Behaviour was assessed by the Medication Adherence Report Scale (MARS) and Diabetes Self-Care Activities (DSCA) scales; illness perceptions by IPQ-R; study-specific scales of beliefs about diet and physical activity were constructed by factor analysing items based on beliefs elicited in an earlier interview study involving patients with type 2 diabetes. Results Past behaviour, trial group allocation, and clinical and demographic factors predicted between 16% and 35% variance in medication adherence, exercise, and diet scales. Illness perceptions added between 0.9% and 4.5% additional variance; beliefs about behaviour added a further 1.1% to 6.4% additional variance. Beliefs regarding, respectively, the importance of exercise in controlling diabetes, the need to east less, and enjoyment from eating sweet or fatty food, added unique variance. Conclusion Beliefs about behaviour are at least as important as beliefs about illness in predicting several health-related behaviours. This suggests the possibility that behaviour change interventions with patient groups would be more effective by targeting beliefs about behaviour, rather than beliefs about illness.
Abstract
In situ observations of cloud properties made by airborne probes play a critical role in ice cloud research through their role in process studies, parameterization development, and ...evaluation of simulations and remote sensing retrievals. To determine how cloud properties vary with environmental conditions, in situ data collected during different field projects processed by different groups must be used. However, because of the diverse algorithms and codes that are used to process measurements, it can be challenging to compare the results. Therefore it is vital to understand both the limitations of specific probes and uncertainties introduced by processing algorithms. Since there is currently no universally accepted framework regarding how in situ measurements should be processed, there is a need for a general reference that describes the most commonly applied algorithms along with their strengths and weaknesses. Methods used to process data from bulk water probes, single-particle light-scattering spectrometers and cloud-imaging probes are reviewed herein, with emphasis on measurements of the ice phase. Particular attention is paid to how uncertainties, caveats, and assumptions in processing algorithms affect derived products since there is currently no consensus on the optimal way of analyzing data. Recommendations for improving the analysis and interpretation of in situ data include the following: establishment of a common reference library of individual processing algorithms, better documentation of assumptions used in these algorithms, development and maintenance of sustainable community software for processing in situ observations, and more studies that compare different algorithms with the same benchmark datasets.
Decades of research have revealed relationships between the abundance of coral reef taxa and local conditions, especially at small scales. However, a rigorous test of covariation requires a robust ...dataset collected across wide environmental or experimental gradients. Here, we surveyed spatial variability in the densities of major coral reef functional groups at 122 sites along a 70 km expanse of the leeward, forereef habitat of Curaçao in the southern Caribbean. These data were used to test the degree to which spatial variability in community composition could be predicted based on assumed functional relationships and site-specific anthropogenic, physical, and ecological conditions. In general, models revealed less power to describe the spatial variability of fish biomass than cover of reef builders (R
2
of best-fit models: 0.25 fish and 0.64 reef builders). The variability in total benthic cover of reef builders was best described by physical (wave exposure and reef relief) and ecological (turf algal height and coral recruit density) predictors. No metric of anthropogenic pressure was related to spatial variation in reef builder cover. In contrast, total fish biomass showed a consistent (albeit weak) association with anthropogenic predictors (fishing and diving pressure). As is typical of most environmental gradients, the spatial patterns of both fish biomass density and reef builder cover were spatially autocorrelated. Residuals from the best-fit model for fish biomass retained a signature of spatial autocorrelation while the best-fit model for reef builder cover removed spatial autocorrelation, thus reinforcing our finding that environmental predictors were better able to describe the spatial variability of reef builders than that of fish biomass. As we seek to understand spatial variability of coral reef communities at the scale of most management units (i.e., at kilometer- to island-scales), distinct and scale-dependent perspectives will be needed when considering different functional groups.
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