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Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are 'omics' technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic loci C3, CFB, CFI, CFH, and ARMS2/HTRA1 are currently ongoing, and a phase III clinical trial for C3 inhibition recently showed a modest reduction of lesion growth in geographic atrophy. The EYERISK consortium recently developed a genetic test for AMD that allows genotyping of common and rare variants in AMD-associated genes. Polygenic risk scores (PRS) were applied to quantify AMD genetic risk, and may aid in predicting AMD progression. In conclusion, genomic studies represent a turning point in our exploration of AMD. The results of those studies now serve as a driving force for several clinical trials. Expanding to omics and systems genomics will further decipher function and causality from the associations that have been reported, and will enable the development of therapies that will lessen the burden of AMD.

The definition, characterization and implementation of Positive Energy Districts is crucial in the path towards urban decarbonization and energy transition. However, several issues still must be addressed: the need for a clear and comprehensive definition, and the settlement of a consistent design approach for Positive Energy Districts. As emerged throughout the workshop held during the fourth edition of Smart and Sustainable Planning for Cities and Regions Conference (SSPCR 2022) in Bolzano (Italy), further critical points are also linked to the planning, modeling and assessment steps, besides sustainability aspects and stakeholders’ involvement. The “World Café” methodology adopted during the workshop allowed for simple—but also effective and flexible—group discussions focused on the detection of key PED characteristics, such as morphologic, socio-economic, demographic, technological, quality-of-life and feasibility factors. Four main work groups were defined in order to allow them to share, compare and discuss around five main PED-related topics: energy efficiency, energy flexibility, e-mobility, soft mobility, and low-carbon generation. Indeed, to properly deal with PED challenges and crucial aspects, it is necessary to combine and balance these technologies with enabler factors like financing instruments, social innovation and involvement, innovative governance and far-sighted policies. This paper proposes, in a structured form, the main outcomes of the co-creation approach developed during the workshop. The importance of implementing a holistic approach was highlighted: it requires a systematic and consistent integration of economic, environmental and social aspects directly connected to an interdisciplinary cross-sectorial collaboration between researchers, policymakers, industries, municipalities, and citizens. Furthermore, it was reaffirmed that, to make informed and reasoned decisions throughout an effective PED design and planning process, social, ecological, and cultural factors (besides merely technical aspects) play a crucial role. Thanks to the valuable insights and recommendations gathered from the workshop participants, a conscious awareness of key issues in PED design and implementation emerged, and the fundamental role of stakeholders in the PED development path was confirmed.

For disorders with X-linked inheritance, variants may be transmitted through multiple generations of carrier females before an affected male is ascertained. Pathogenic RS1 variants exclusively cause X-linked retinoschisis (XLRS). While RS1 is constrained to variation, recurrent variants are frequently observed in unrelated probands. Here, we investigate recurrent pathogenic variants to determine the relative burden of mutational hotspot and founder allele events to this phenomenon. A cohort RS1 variant analysis and standardized classification, including variant enrichment in the XLRS cohort and in RS1 functional domains, were performed on 332 unrelated XLRS probands. A total of 108 unique RS1 variants were identified. A subset of 19 recurrently observed RS1 variants were evaluated in 190 probands by a haplotype analysis, using microsatellite and single nucleotide polymorphisms. Fourteen variants had at least two probands with common variant-specific haplotypes over ~1.95 centimorgans (cM) flanking RS1. Overall, 99/190 of reportedly unrelated probands had 25 distinct shared haplotypes. Examination of this XLRS cohort for common RS1 haplotypes indicates that the founder effect plays a significant role in this disorder, including variants in mutational hotspots. This improves the accuracy of clinical variant classification and may be generalizable to other X-linked disorders.

Background: Late dumping syndrome (LDS) refers to reactive hyperinsulinemic hypoglycemia episodes that occur one to 3 h following a high-carbohydrate meal in persons who have had gastric surgery. Dietary adjustments (such as regular composite meals containing lipids, protein, and carbohydrates with a low glycemic index) are effective in treating the majority of LDS patients; however, pharmaceutical interventions are required in some cases. Case presentation: We describe the case of a 60-year-old woman with type 2 diabetes (T2DM) who developed late dumping syndrome symptoms following a gastric cancer gastrectomy. Both the 75-g oral glucose tolerance test (OGTT) and the mixed-meal tolerance test (MMTT) revealed reactive hyperinsulinemic hypoglycemia. We began therapy with canagliflozin, a sodium glucose-cotransporter (SGLT) inhibitor 300 mg before lunch after realizing that dietary changes were insufficient in reducing the occurrence of symptomatic hypoglycemic episodes. We repeated the OGTT after treatment, and the results showed still the presence of symptomatic hypoglycemia without significant differences in peak insulin values compared to the OGTT performed before treatment. Instead, the MMT showed a small, flattened insulin response without any hypoglycemic episodes. Furthermore, improvements were observed in glucose trends/targets as demonstrated by time in (TIR), above (TAR) and below (TBR) range and glucose variability (e.g. coefficient of variation) based on data collected from Flash Glucose Monitoring (FGM) before and during canagliflozin therapy. Conclusion: The rapid transit of inadequately digested chyme from the stomach into the small intestine is one of the most important pathophysiological processes in LDS. Canagliflozin, unlike other molecules in the same family, inhibits intestine SGLT-1. By delaying glucose absorption at that level, it may reduce postprandial glucose and insulin rises. Our case report, however, demonstrates that the effect of canagliflozin on glucose homeostasis is determined by appropriate dietary habits, which seem to be critical for successfully reducing symptoms related to reactive hyperinsulinemic hypoglycemia following a gastric bypass surgery.

Test anxiety affects a sizable proportion of college students, especially in competitive STEM fields. Prior research has proposed interventions aimed at changing students’ implicit beliefs about intelligence (intelligence mindset) to help reduce students’ test anxiety, but results have been mixed and the mechanisms underlying this relationship are unclear. We propose that students’ beliefs about effort regulation may partially mediate the relationship between intelligence mindsets and test anxiety. We tested our model as an exploratory post-hoc analysis in a small sample of introductory physics students reporting psychological threat in a laboratory study. Effort regulation was measured as self-reported judgements of persistence in the face of difficulty and test anxiety was measured on a problem by problem basis during a laboratory physics assessment. Students’ intelligence mindset at pretest was a significant predictor of test anxiety at posttest, and this relationship was mediated by self-reported effort regulation. We discuss potential implications of these findings for mindset-based interventions aimed at reducing test anxiety.

PurposeTo review past and current National Eye Institute (NEI)-supported age-related macular degeneration (AMD) activities and initiatives and preview upcoming coordinated efforts for studying AMD.MethodsWe conducted and summarized a portfolio analysis and literature review of NEI intramural and extramural AMD activities.ResultsThe NEI supports a broad range of AMD research, both by individual independent investigators as well as through networks and consortia. The International AMD Genomics Consortium, Age-Related Eye Disease Study, Age-Related Eye Disease Study 2 (AREDS2), and Comparison of AMD Treatments Trial legacy work probed the complex genetics, clinical presentation, and standards of patient care, respectively. The NEI AMD Pathobiology Working Group identified gaps and opportunities for future research efforts. The AMD Ryan Initiative Study and clinical trials testing the efficacies of minocycline to modulate retinal microglia activity and induced pluripotent stem cells-derived retinal pigmented epithelium (RPE) patch implants to rescue photoreceptor cell death are among the future directions for NEI-supported AMD research. Finally, NEI commissioned the creation of AREDS2 participant-derived induced pluripotent stem cell (iPSC) lines linked to their associated genomic and phenotypic datasets. These datasets will also be linked to the data obtained using their associated iPSC-derived cells (RPE, retina, choroid) and made publicly available.ConclusionsInvestments by NEI for AMD research will continue to provide invaluable resources to investigators committed to addressing this complex blinding disease and other retinal degenerative diseases.Translational relevanceNEI now stands poised to expand the resources available to clinical investigators to uncover disease mechanisms and move experimental therapies into clinical trials.

Climate change and its effects are becoming clear on a global scale either from the perspective of global warming and the increase in the rate of occurrence of weather events of extreme magnitude. This has impacts also for sure on the standard building performance analysis approach, since the buildings designed today are supposed to withstand for the following decades climate impacts that may be different than those they were designed for.The paper proposes a simple, easy to use and freely available building simulation utility which performs morphing of existing weather data files and, by connecting to the Energy Plus simulation routine, allows to perform future climate building simulation analyses. Users are required to select one of the ASHRAE buildings models or provide one of their own choosing and to input the original weather data file. The tool will generate a future weather data file with the preferred assumptions (e.g. RCP scenarios, time frame) and elaborate results in terms of heating and cooling required for air conditioning.The paper proposes also an implementation of the tool to a case study aimed at showing the potential of the application proposed. A typical office building model from the ASHRAE library was simulated in two different locations under different climate change assumptions up to the year 2090. The analysis of the results in the two locations of Palermo (Italy) and Copenhagen (Denmark) highlight relevant increases in the current century of up to +20% of cooling requirements and similar reductions for heating in both case studies, if compared to current levels.The research targets a specific limit in the investigation of climate resilience of buildings and follows the principles described by SDSN in the definition of SDGs and the interest at the EU level towards climate neutral and innovative cities.In this context, the paper may contribute to the limited availability of easy to use and free tools available for practitioners to investigate the design of climate resilience buildings.

BackgroundHashimoto’s thyroiditis (HT) is the most common autoimmune disease. HT may be associated with nonthyroidal autoimmune diseases, including celiac disease (CD) or other gluten-related conditions (GRC). In the last years, interest about gluten-free diet (GFD) has increased for its supposed extraintestinal anti-inflammatory effect; thus, many patients with HT initiate GFD on their own.ObjectivesThe aim of this meta-analysis is to examine all available data in literature about the effect of a GFD on TgAb, TPOAb, TSH, FT4, and FT3 levels in patients with HT and no symptoms or histology of CD.MethodsThe study was conducted according to MOOSE (Meta-analysis Of Observational Studies in Epidemiology). The search was performed on databases PubMed and Scopus. The last search was performed on 7 February 2023. Quality assessment was performed. Meta-analyses were performed using the random-effect model. Hedges’ g was used to measure the effect size (ES). Statistical analyses were performed using StataSE 17.ResultsThe online search retrieved 409 articles, and 4 studies with a total of 87 patients were finally included for quantitative analysis. The risk of bias was generally low. The mean period of GFD was almost 6 months. The meta-analyses showed reduction in antibody levels with ES: −0.39 for TgAb (95% CI: −0.81 to +0.02; p = 0.06; I² = 46.98%) and −0.40 for TPOAb (95% CI: −0.82 to +0.03; p = 0.07; I² = 47.58%). TSH showed a reduction with ES: −0.35 (95% CI: −0.64 to −0.05; p = 0.02; I² = 0%) and FT4 showed an increase with ES: +0.35% (95% CI: 0.06 to 0.64; p = 0.02; I² = 0%). FT3 did not display variations (ES: 0.05; 95% CI: −0.38 to +0.48; p = 0.82; I² = 51%). The heterogeneity of TgAb, TPOAb, and FT3 data was solved performing sub-analyses between patients with or without GRC (TgAb p = 0.02; TPOAb p = 0.02; FT3 p = 0.04) and only for FT3, performing a sub-analysis between patients taking and not taking LT4 (p = 0.03).ConclusionThis is the first meta-analysis investigating the effect of GFD on HT. Our results seem to indicate a positive effect of the gluten deprivation on thyroid function and its inflammation, particularly in patients with HT and GRC. However, current lines of evidence are not yet sufficient to recommend this dietary approach to all patients with a diagnosis of HT.

Metabolic syndrome (MS), a cluster of cardiometabolic disorders, and sexual dysfunction are two conditions that impact a large proportion of the general population. Although they can occur independently, they are frequently linked and significantly affect people's quality of life. In recent years, research has increasingly focused on the importance of diet, particularly the Mediterranean diet (MD), in modulating sexual function due to its anti-inflammatory, antioxidant, and vasodilatory properties. In this narrative review, we examined the relationship between MS and sexual function in both men and women, with a special emphasis on the MD's therapeutic efficacy in improving sexual dysfunction. In men, MD has been shown to ameliorate erectile dysfunction, as well as several sperm parameters, perhaps leading to improved fertility. On the other hand, adherence to MD has been demonstrated to partially recover several sexual dysfunctions in women, such as those related to their menstrual cycle, menopause, endometriosis, and polycystic ovary syndrome. These favorable effects of MD have been demonstrated in both sexes also among people affected by MS. However, more targeted studies are needed to validate these data for different dietary approaches as well. [ABSTRACT FROM AUTHOR]

The definition, characterization and implementation of Positive Energy Districts is crucial in the path towards urban decarbonization and energy transition. However, several issues still must be addressed: the need for a clear and comprehensive definition, and the settlement of a consistent design approach for Positive Energy Districts. As emerged throughout the workshop held during the fourth edition of Smart and Sustainable Planning for Cities and Regions Conference (SSPCR 2022) in Bolzano (Italy), further critical points are also linked to the planning, modeling and assessment steps, besides sustainability aspects and stakeholders' involvement. The "World Café" methodology adopted during the workshop allowed for simple—but also effective and flexible—group discussions focused on the detection of key PED characteristics, such as morphologic, socio-economic, demographic, technological, quality-of-life and feasibility factors. Four main work groups were defined in order to allow them to share, compare and discuss around five main PED-related topics: energy efficiency, energy flexibility, e-mobility, soft mobility, and low-carbon generation. Indeed, to properly deal with PED challenges and crucial aspects, it is necessary to combine and balance these technologies with enabler factors like financing instruments, social innovation and involvement, innovative governance and far-sighted policies. This paper proposes, in a structured form, the main outcomes of the co-creation approach developed during the workshop. The importance of implementing a holistic approach was highlighted: it requires a systematic and consistent integration of economic, environmental and social aspects directly connected to an interdisciplinary cross-sectorial collaboration between researchers, policymakers, industries, municipalities, and citizens. Furthermore, it was reaffirmed that, to make informed and reasoned decisions throughout an effective PED design and planning process, social, ecological, and cultural factors (besides merely technical aspects) play a crucial role. Thanks to the valuable insights and recommendations gathered from the workshop participants, a conscious awareness of key issues in PED design and implementation emerged, and the fundamental role of stakeholders in the PED development path was confirmed. [ABSTRACT FROM AUTHOR]

Over 1,500 variants in the ABCA4 locus cause phenotypes ranging from severe, early-onset retinal degeneration to very late-onset maculopathies. The resulting ABCA4/Stargardt disease is the most prevalent Mendelian eye disorder, although its underlying clinical heterogeneity, including penetrance of many alleles, are not well-understood. We hypothesized that a share of this complexity is explained by trans-modifiers, i.e., variants in unlinked loci, which are currently unknown. We sought to identify these by performing exome sequencing in a large cohort for a rare disease of 622 cases and compared variation in seven genes known to clinically phenocopy ABCA4 disease to cohorts of ethnically matched controls. We identified a significant enrichment of variants in 2 out of the 7 genes. Moderately rare, likely functional, variants, at the minor allele frequency (MAF) 25, were enriched in ROM1, where 1.3% of 622 patients harbored a ROM1 variant compared to 0.3% of 10,865 controls (p = 2.41E04; OR 3.81 95% CI [1.77; 8.22]). More importantly, analysis of common variants (MAF>0.1) identified a frequent haplotype in PRPH2, tagged by the p.Asp338 variant with MAF = 0.21 in the matched general population that was significantly increased in the patient cohort, MAF 0.25, p = 0.0014. Significant differences were also observed between ABCA4 disease subgroups. In the late-onset subgroup, defined by the hypomorphic p.Asn1868Ile variant and including c.4253+43G>A, the allele frequency for the PRPH2 p.Asp338 variant was 0.15 vs 0.27 in the remaining cohort, p = 0.00057. Known functional data allowed suggesting a mechanism by which the PRPH2 haplotype influences the ABCA4 disease penetrance. These associations were replicated in an independent cohort of 408 patients. The association was highly statistically significant in the combined cohorts of 1,030 cases, p = 4.00E-05 for all patients and p = 0.00014 for the hypomorph subgroup, suggesting a substantial trans-modifying role in ABCA4 disease for both rare and common variants in two unlinked loci.

PurposeCiliary neurotrophic factor (CNTF) protects rod photoreceptors from retinal degenerative disease in multiple nonhuman models. Thus far, CNTF has failed to demonstrate rod protection in trials for human retinitis pigmentosa. Recently, CNTF was found to improve cone photoreceptor function in a canine CNGB3 achromatopsia model. This study explores whether this finding translates to humans with CNGB3 achromatopsia.MethodsA five-subject, open-label Phase I/II study was initiated by implanting intraocular microcapsules releasing CNTF (nominally 20 ng/d) into one eye each of CNGB3 achromat participants. Fellow eyes served as untreated controls. Subjects were followed for 1 year.ResultsPupil constriction in treated eyes gave evidence of intraocular CNTF release. Additionally, scotopic ERG responses were reduced, and dark-adapted psychophysical absolute thresholds were increased, attributable to diminished rod or rod pathway activity. Optical coherence tomography revealed that the cone-rich fovea underwent structural changes as the foveal hyporeflective zone (HRZ) became diminished in CNTF-treated eyes. No objectively measurable enhancement of cone function was found by assessments of visual acuity, mesopic increment sensitivity threshold, or the photopic ERG. Careful measurements of color hue discrimination showed no change. Nonetheless, subjects reported beneficial changes of visual function in the treated eyes, including reduced light sensitivity and aversion to bright light, which may trace to decreased effective ambient light from the pupillary constriction; further they noted slowed adaptation to darkness, consistent with CNTF action on rod photoreceptors.ConclusionsCiliary neurotrophic factor did not measurably enhance cone function, which reveals a species difference between human and canine CNGB3 cones in response to CNTF. (ClinicalTrials.gov number, NCT01648452.).

PurposeTo analyze the genetic test results of probands referred to eyeGENE with a diagnosis of hereditary maculopathy.MethodsPatients with Best macular dystrophy (BMD), Doyne honeycomb retinal dystrophy (DHRD), Sorsby fundus dystrophy (SFD), or late-onset retinal degeneration (LORD) were screened for mutations in BEST1, EFEMP1, TIMP3, and CTRP5, respectively. Patients with pattern dystrophy (PD) were screened for mutations in PRPH2, BEST1, ELOVL4, CTRP5, and ABCA4; patients with cone-rod dystrophy (CRD) were screened for mutations in CRX, ABCA4, PRPH2, ELOVL4, and the c.2513G>A p.Arg838His variant in GUCY2D. Mutation analysis was performed by dideoxy sequencing. Impact of novel variants was evaluated using the computational tool PolyPhen.ResultsAmong the 213 unrelated patients, 38 had BMD, 26 DHRD, 74 PD, 8 SFD, 6 LORD, and 54 CRD; six had both PD and BMD, and one had no specific clinical diagnosis. BEST1 variants were identified in 25 BMD patients, five with novel variants of unknown significance (VUS). Among the five patients with VUS, one was diagnosed with both BMD and PD. A novel EFEMP1 variant was identified in one DHRD patient. TIMP3 novel variants were found in two SFD patients, PRPH2 variants in 14 PD patients, ABCA4 variants in four PD patients, and p.Arg838His GUCY2D mutation in six patients diagnosed with dominant CRD; one patient additionally had a CRX VUS. ABCA4 mutations were identified in 15 patients with recessive CRD.ConclusionsOf the 213 samples, 55 patients (26%) had known causative mutations, and 13 (6%) patients had a VUS that was possibly pathogenic. Overall, selective screening for mutations in BEST1, PRPH2, and ABCA4 would likely yield the highest success rate in identifying the genetic basis for macular dystrophy phenotypes. Because of the overlap in phenotypes between BMD and PD, it would be beneficial to screen genes associated with both diseases.