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Introduction: The aim was to determine which immobilisation device improved inter‐fraction reproducibly of pelvic tilt and required the least pre‐treatment setup and planning interventions. Methods: Sixteen patients were retrospectively reviewed, eight immobilised using the BodyFIX system (BodyFIX®, Elekta, Stockholm, Sweden) and eight using the Butterfly Board (BB) (Bionix Radiation Therapy, Toledo, OH, USA). The daily pre‐treatment images were reviewed to assess setup variations between each patient and groups for pelvic tilt, pubic symphysis, sacral promontory and the fifth lumbar spine (L5). Results: Compared with the planning CT, pelvic tilt for most patients was within ±2° using the BodyFIX and ± 4° for the BB. The Butterfly Board had a slightly higher variance both for patient‐to‐patient (standard deviation of the systematic error) and day‐to‐day error (standard deviation of the random error). Variance in position between individual patients and the two stabilisation devices were minimal in the anterior–posterior (AP) and superior–inferior (SI) direction for the pubic symphysis, sacral promontory and L5 spine. Re‐imaged fractions due to pelvic tilt reduced by about half when BodyFIX was used (39.1% BB, 19.4% BodyFIX). One patient treated with the BB required a re‐scan for pelvic tilt. Three patients required a re‐scan for body contour variations (two using BodyFIX and one with the BB). Conclusions: BodyFIX resulted in a more accurate inter‐fraction setup and efficient treatment and is used as the standard stabilisation for gynaecological patients at our centre. It reduced the pelvic tilt variance and reduced the need for re‐imaging pre‐treatment by half. [ABSTRACT FROM AUTHOR]

Leber's Hereditary Optic Neuropathy (LHON) is a maternally inherited optic nerve disease primarily caused by mutations in mitochondrial DNA (mtDNA). The peak of onset is typically between 15 and 30 years, but variability exists. Misdiagnosis, often as inflammatory optic neuritis, delays treatment, compounded by challenges in timely genetic diagnosis. Given the availability of a specific treatment for LHON, its early diagnosis is imperative to ensure therapeutic appropriateness. This work gives an updated guidance about LHON differential diagnosis to clinicians dealing also with multiple sclerosi and neuromyelitis optica spectrtum disorders-related optic neuritis. LHON diagnosis relies on clinical signs and paraclinical evaluations. Differential diagnosis in the acute phase primarily involves distinguishing inflammatory optic neuropathies, considering clinical clues such as ocular pain, fundus appearance and visual recovery. Imaging analysis obtained with Optical Coherence Tomography (OCT) assists clinicians in early recognition of LHON and help avoiding misdiagnosis. Genetic testing for the three most common LHON mutations is recommended initially, followed by comprehensive mtDNA sequencing if suspicion persists despite negative results. We present and discuss crucial strategies for accurate diagnosis and management of LHON cases. [ABSTRACT FROM AUTHOR]

Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by visual loss, and rarely associated with extraocular manifestations including multiple sclerosis‐like lesions. The association of LHON and neuromyelitis optica spectrum disorders has rarely been reported. Here is reported a case of glial fibrillary acidic protein astrocytopathy presenting with area postrema syndrome in a patient with previously diagnosed recessive LHON due to mutations in the nuclear gene DNAJC30. This case emphasizes the necessity of extensive investigations for other treatable conditions in patients with LHON and otherwise unexplained extraocular involvement and the possibility that also visual symptoms can respond to immune therapy. [ABSTRACT FROM AUTHOR]

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Purpose: Augmented adiposity may negatively impact sexual sphere through its metabolic effects and its detrimental impact on reproductive hormones. Moreover, a dysregulated metabolic pathway may promote apoptosis among spermatogenic cells. Based on these premises, a relation between weights loss and ameliorate semen parameters seems beneficial. To investigate if physical activity may affect semen parameters and fertility rate, a systematic literature search on major dataset has been performed. Materials and Methods: The search terms included: “Assisted reproduction therapies,” “fertility,” “semen parameters,” “sperm parameters,” and “physical activity.” This analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines and it was registered on PROSPERO (CRD42023384471). A total of 47 studies have been identified; 1 reference has been eliminated after duplication check. After preliminary screening 32 papers have been excluded. Considering the exclusion criteria, 15 full-text articles were evaluated for eligibility. After a full-text review, six studies published during a span of eight years (2014–2022) have been included in the meta-analysis. Semen parameters, pregnancy and birth rates were investigated. The revised Cochrane risk of bias tool (Rob2) has been used to check the risk of bias. Results: The number of patients enrolled in studies ranges from 17 to 521; in the end, a total of 1,637 patients have been enrolled in the study. Fertility parameters investigated were semen quality parameters and pregnancy rates and live births. A statistically significant relationship between physical exercise and sperm concentration (p=0.02), total sperm motility (p<0.01), total sperm count (p<0.01), normal morphology (p<0.01) has been established. Moreover, the study registered a statistically significant association within physical activity and total pregnancy rate (p<0.01) and live birth rate (p<0.01). Conclusions: We demonstrated that physical activity is significantly associated with amelioration of semen parameters and may be crucial in improving or even reverting male infertility. [ABSTRACT FROM AUTHOR]

Background: Respiratory problems are frequent in newborns, and are mainly studied with chest X-rays, whereas CT scans are usually needed for the evaluation of rare malformations and diseases. Lung ultrasound (LUS] has been proposed as an alternative method of diagnosing a variety of respiratory conditions. In recent years, there has been a rapid increase in LUS studies, thanks to the ability of LUS to rapidly exclude complications and significantly reduce radiation exposure in this fragile population. We aimed to summarize the current knowledge about LUS. Methods: A literature search was conducted on the Medline and Cochrane databases using appropriate terms. The inclusion criteria were: English language and human species. Exclusion criteria were: non-English language, animal species, case reports, case series, non-systematic reviews, and editorials. Results: The search returned 360 results. No Cochrane reviews were found. Titles and abstracts were screened, and 37 were finally considered. Studies concerning the use of lung ultrasound for the following conditions were presented: neonatal respiratory distress syndrome, transient tachypnea of the newborn, pneumothorax, pulmonary hemorrhage, pneumonia, bronchopulmonary dysplasia, and prediction of extubation success. Conclusions: We discussed the utility of LUS for the diagnosis and treatment of neonatal diseases according to the most recent literature. [ABSTRACT FROM AUTHOR]

Leigh syndrome spectrum (LSS) is a primary mitochondrial disorder defined neuropathologically by a subacute necrotizing encephalomyelopathy and characterized by bilateral basal ganglia and/or brainstem lesions. LSS is associated with variants in several mitochondrial DNA genes and more than 100 nuclear genes, most often related to mitochondrial complex I (CI) dysfunction. Rarely, LSS has been reported in association with primary Leber hereditary optic neuropathy (LHON) variants of the mitochondrial DNA, coding for CI subunits (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4 and m.14484T>C in MT-ND6). The underlying mechanism by which these variants manifest as LSS, a severe neurodegenerative disease, as opposed to the LHON phenotype of isolated optic neuropathy, remains an open question. Here, we analyse the exome sequencing of six probands with LSS carrying primary LHON variants, and report digenic co-occurrence of the m.11778G > A variant with damaging heterozygous variants in nuclear disease genes encoding CI subunits as a plausible explanation. Our findings suggest a digenic mechanism of disease for m.11778G>A-associated LSS, consistent with recent reports of digenic disease in individuals manifesting with LSS due to biallelic variants in the recessive LHON-associated disease gene DNAJC30 in combination with heterozygous variants in CI subunits. [ABSTRACT FROM AUTHOR]

Background: This work aimed to study the Village Test (VT) in a group of patients with Alzheimer's disease (AD) and compare the results with those of a group of patients with mild cognitive impairment (MCI) and controls. Methods: A total of 50 patients with AD, 28 patients with MCI, and 38 controls were evaluated. All participants underwent the VT and an extensive neuropsychological evaluation. Results: The mean ages of the participants were 74.4 years for those with AD, 74 for those with MCI, and 70.2 for the controls. The AD group built smaller and essential villages with a scarce use of pieces, a poor use of dynamic pieces, and scarce use of human figures. All constructions were often concentrated in the center of the table. Conclusions: The villages built by the AD group represent a cognitive and affective coarctation and indicate a sense of existential disorientation and isolation. The VT is a useful aid for getting in touch with the inner emotional and existential states of patients with AD, and it could represent a complementary screening tool for orienting cognitive impairment diagnoses. [ABSTRACT FROM AUTHOR]

Estimating demographic parameters for wide‐ranging and elusive species living at low density is challenging, especially at the scale of an entire country. To produce wolf distribution and abundance estimates for the whole south‐central portion of the Italian wolf population, we developed an integrated spatial model, based on the data collected during a 7‐month sampling campaign in 2020–2021. Data collection comprised an extensive survey of wolf presence signs, and an intensive survey in 13 sampling areas, aimed at collecting non‐invasive genetic samples (NGS). The model comprised (i) a single‐season, multiple data‐source, multi‐event occupancy model and (ii) a spatially explicit capture‐recapture model. The information about species' absence was used to inform local density estimates. We also performed a simulation‐based assessment, to estimate the best conditions for optimizing sub‐sampling and population modelling in the future. The integrated spatial model estimated that 74.2% of the study area in south‐central Italy (95% CIs = 70.5% to 77.9%) was occupied by wolves, for a total extent of the wolf distribution of 108,534 km2 (95% CIs = 103,200 to 114,000). The estimate of total population size for the Apennine wolf population was of 2557 individuals (SD = 171.5; 95% CIs = 2127 to 2844). Simulations suggested that the integrated spatial model was associated with an average tendency to slightly underestimate population size. Also, the main contribution of the integrated approach was to increase precision in the abundance estimates, whereas it did not affect accuracy significantly. In the future, the area subject to NGS should be increased to at least 30%, while at least a similar proportion should be sampled for presence‐absence data, to further improve the accuracy of population size estimates and avoid the risk of underestimation. This approach could be applied to other wide‐ranging species and in other geographical areas, but specific a priori evaluations of model requirements and expected performance should be made. [ABSTRACT FROM AUTHOR]

Chromosomal structural rearrangements consist of anomalies in genomic architecture that may or may not be associated with genetic material gain and loss. Evaluating the precise breakpoint is crucial from a diagnostic point of view, highlighting possible gene disruption and addressing to appropriate genotype–phenotype association. Structural rearrangements can either occur randomly within the genome or present with a recurrence, mainly due to peculiar genomic features of the surrounding regions. We report about three non-related individuals, harboring chromosomal structural rearrangements interrupting SETBP1, leading to gene haploinsufficiency. Two out of them resulted negative to Chromosomal Microarray Analysis (CMA), being the rearrangement balanced at a microarray resolution. The third one, presenting with a complex three-chromosome rearrangement, had been previously diagnosed with SETBP1 haploinsufficiency due to a partial gene deletion at one of the chromosomal breakpoints. We thoroughly characterized the rearrangements by means of Optical Genome Mapping (OGM) and Whole Genome Sequencing (WGS), providing details about the involved sequences and the underlying mechanisms. We propose structural variants as a recurrent event in SETBP1 haploinsufficiency, which may be overlooked by laboratory routine genomic analyses (CMA and Whole Exome Sequencing) or only partially determined when associated with genomic losses at breakpoints. We finally introduce a possible role of SETBP1 in a Noonan-like phenotype. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) exhibits gender disparities, and emerging evidence suggests the involvement of the gut microbiome, necessitating exploration of sex-specific differences. Methods: A review was conducted, encompassing a thorough examination of relevant studies available in Medline via Ovid, Embase via OvidSP, CINAHL, and PsycINFO databases from their inception to June 2023. The search strategy employed specific keywords and Medical Subject Headings (MeSH) terms tailored to major depressive disorder in women, encompassing unipolar depression, depressive symptoms, and dysbiosis. Results: Five studies were included. Among the four studies, alterations in alpha (n=1) and beta diversity (n=3) in the gut microbiome of individuals with MDD were revealed compared to controls. Gender-specific differences were observed in four studies, demonstrating the abundance of specific bacterial taxa and highlighting potential sex-specific implications in MDD pathophysiology. Correlation analyses (n=4) indicated associations between certain bacterial taxa and the severity of depressive symptoms, with varying patterns between males and females. Studies (n=3) also highlighted promising findings regarding the potential utility of microbial markers in diagnosing MDD, emphasizing the crucial role of sex stratification in understanding the disease pathophysiology Conclusions: The findings underscore the importance of recognizing genderspecific differences in the composition of the gut microbiome and its relationship with MDD. Further comprehensive robust studies are required to unravel the intricate mechanisms underlying these disparities. [ABSTRACT FROM AUTHOR]

The evaluation of pupillary light reflex (PLR) by chromatic pupillometry may provide a unique insight into specific photoreceptor functions. Chromatic pupillometry refers to evaluating PLR to different wavelengths and intensities of light in order to differentiate outer/inner retinal photoreceptor contributions to the PLR. Different protocols have been tested and are now established to assess in-vivo PLR contribution mediated by melanopsin retinal ganglion cells (mRGCs). These intrinsically photosensitive photoreceptors modulate the non-image-forming functions of the eye, which are mainly the circadian photoentrainment and PLR, via projections to the hypothalamic suprachiasmatic and olivary pretectal nucleus, respectively. In this context, chromatic pupillometry has been used as an alternative and non-invasive tool to evaluate the mRGC system in several clinical settings, including hereditary optic neuropathies, glaucoma, and neurodegenerative disorders such as Parkinson's disease (PD), idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD), and Alzheimer's disease (AD). The purpose of this article is to review the key steps of chromatic pupillometry protocols for studying in-vivo mRGC-system functionality and provide the main findings of this technique in the research setting on neurodegeneration. mRGC-dependent pupillary responses are short-wavelength sensitive, have a higher threshold of activation, and are much slower and sustained compared with rod- and cone-mediated responses, driving the tonic component of the PLR during exposure to high-irradiance and continuous light stimulus. Thus, mRGCs contribute mainly to the tonic component of the post-illumination pupil response (PIPR) to bright blue light flash that persists after light stimulation is switched off. Given the role of mRGCs in circadian photoentrainment, the use of chromatic pupillometry to perform a functional evaluation of mRGcs may be proposed as an early biomarker of mRGC-dysfunction in neurodegenerative disorders characterized by circadian and/or sleep dysfunction such as AD, PD, and its prodromal phase iRBD. The evaluation by chromatic pupillometry of mRGC-system functionality may lay the groundwork for a new, easily accessible biomarker that can be exploited also as the starting point for future longitudinal cohort studies aimed at stratifying the risk of conversion in these disorders. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a prevalent malignancy affecting men worldwide, and plant-based diets have been widely advocated for their health benefits. The aim of this study was to test the association between general, healthy, and unhealthy pro-vegetarian plant-based diets and PCa severity on 118 consecutive patients undergoing prostatectomy in a university hospital in Italy. Food frequency questionnaires were used to calculate scores for dietary patterns. Multivariate logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to test the associations. A general plant-based diet was not associated with cancer severity, while patients reporting a higher adherence to a healthy plant-based diet were less likely to have a more severe PCa (for medium/high vs. low-risk PCa, OR = 0.27, 95% CI: 0.08, 0.88; for high vs. medium/low-risk PCa, OR = 0.09, 95% CI: 0.02, 0.39). Patients resulting in higher adherence to an unhealthy plant-based diet were more likely to be diagnosed with more severe PCa (OR = 6.15, 95% CI: 1.70, 22.24). In conclusion, plant-based dietary patterns may have a different impact on PCa severity depending on the quality of the foods included. [ABSTRACT FROM AUTHOR]

Background Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disorder characterised by complex I defect leading to sudden degeneration of retinal ganglion cells. Although typically associated with pathogenic variants in mitochondrial DNA, LHON was recently described in patients carrying biallelic variants in nuclear genes DNAJC30, NDUFS2 and MCAT. MCAT is part of mitochondrial fatty acid synthesis (mtFAS), as also MECR, the mitochondrial trans-2-enoyl-CoA reductase. MECR mutations lead to a recessive childhood-onset syndromic disorder with dystonia, optic atrophy and basal ganglia abnormalities. Methods We studied through whole exome sequencing two sisters affected by sudden and painless visual loss at young age, with partial recovery and persistent central scotoma. We modelled the candidate variant in yeast and studied mitochondrial dysfunction in yeast and fibroblasts. We tested protein lipoylation and cell response to oxidative stress in yeast. Results Both sisters carried a homozygous pathogenic variant in MECR (p.Arg258Trp). In yeast, the MECRR258W mutant showed an impaired oxidative growth, 30% reduction in oxygen consumption rate and 80% decrease in protein levels, pointing to structure destabilisation. Fibroblasts confirmed the reduced amount of MECR protein, but failed to reproduce the OXPHOS defect. Respiratory complexes assembly was normal. Finally, the yeast mutant lacked lipoylation of key metabolic enzymes and was more sensitive to H2O2 treatment. Lipoic Acid supplementation partially rescued the growth defect. Conclusion We report the first family with homozygous MECR variant causing an LHON-like optic neuropathy, which pairs the recent MCAT findings, reinforcing the impairment of mtFAS as novel pathogenic mechanism in LHON. [ABSTRACT FROM AUTHOR]

In the European Alps, where the mountain hare Lepus timidus partly overlaps with the European hare (L. europaeus), climate change, hybridization and gene introgression are thought to interact, with synergic adverse effects on the mountain hare. However, to depict future scenarios for conserving the mountain hare is not feasible without knowledge of the magnitude and geographical pattern of hare distribution. As a first attempt to fill this gap and assess the impacts of climate change, we investigated the distributional pattern of hare species in a valley in the Western Italian Alps using non-invasive genetic techniques based on mtDNA, and resampling the same locations after 12 years (2009–2021). The mountain hare was more common as altitude increases, in pioneer vegetation and rocky areas. However, we also detected the European hare at high altitudes, in atypical landscapes for this lowland species, and the overlap area between hares was quite broad. The proportion of European hare samples increased in time, and the co-occurrence pattern changed, with an increase of the European hare at intermediate-high altitudes. Our data allowed us to assess directly, and for the first time, the impact of climate change on hare species in the Italian Alps. The mountain hare-only areas seem restricted to a very narrow, high-altitude strip. The considerable spatial overlap suggests that the European-mountain hare system could evolve towards a complete admixture situation. Conservation measures should aim to mitigate climate change effects and appropriately manage European hare populations. [ABSTRACT FROM AUTHOR]

Background: The level of food processing has gained interest as a potential determinant of human health. The aim of this study was to assess the relationship between the level of food processing and prostate cancer severity. Methods: A sample of 120 consecutive patients were examined for the following: their dietary habits, assessed through validated food frequency questionnaires; their dietary intake of food groups, categorized according to the NOVA classification; and their severity of prostate cancer, categorized into risk groups according to European Association of Urology (EAU) guidelines. Uni- and multivariate logistic regression analyses were performed to test the association between the variables of interest. Results: Individuals reporting a higher consumption of unprocessed/minimally processed foods were less likely to have greater prostate cancer severity than those who consumed less of them in the energy-adjusted model (odds ratio (OR) = 0.38, 95% confidence interval (CI): 1.17–0.84, p = 0.017 and OR = 0.33, 95% CI: 0.12–0.91, p = 0.032 for medium/high vs. low grade and high vs. medium/low grade prostate cancers, respectively); however, after adjusting for potential confounding factors, the association was not significant anymore. A borderline association was also found between a higher consumption of ultra-processed foods and greater prostate cancer severity in the energy-adjusted model (OR = 2.11, 95% CI: 0.998–4.44; p = 0.051), but again the association was not significant anymore after adjusting for the other covariates. Conclusions: The level of food processing seems not to be independently associated with prostate cancer severity, while potentially related to other factors that need further investigation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Prostate cancer (PCa) is a significant health concern, and its incidence and prevalence are influenced by various lifestyle factors, including diet. In recent years, the Mediterranean diet has gained popularity due to its potential health benefits and associations with reduced risk for various diseases. However, the impact of the Mediterranean diet on PCa remains a topic of debate. OBJECTIVE: The aim of this study was to test the association between adherence to the Mediterranean diet and PCa severity. METHODS: Background, clinical and dietary information (from food frequency questionnaires) were collected from 118 consecutive patients attending a university hospital in Southern Italy. Multivariate logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to test the associations. RESULTS: Patients reporting higher adherence to the Mediterranean diet were less likely to have more at risk PCa both when comparing intermediate/high vs. low risk and high vs. intermediate /low risk PCa (OR = 0.12, 95% CI: 0.02, 0.85 and OR = 0.05, 95% CI: 0.01, 0.31, respectively). CONCLUSIONS: In conclusion, higher adherence to the Mediterranean diet may be associated with a clinically less severe clinical PCa. [ABSTRACT FROM AUTHOR]

We read with great interest the recent publication by Rocatcher and colleagues[1] entitled 'The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands', reporting on the experience of a national diagnostic centre for hereditary optic neuropathies (HON) in France. This flexible approach enlarges the number of genes screened, compared with the fixed number of 87 genes included in the custom targeted gene panel reported by Rocatcher I et al i .[1] Therefore, we found pathogenic variants in 30 genes, of which 18 were in single families (8.4%), whereas in the French cohort, only 21 genes were found to carry pathogenic variants, with seven singleton cases (1.5%). This is currently the standard algorithm followed by I in silico i panel analysis, prioritizing variants in known HON genes, to eventually discover new disease genes. Thus, the top 10 genes are consolidated by the contribution of the Italian cohort, with I OPA1 i , I WFS1 i and I ACO2 i accounting for 76% of diagnosed HON, due to a nuclear gene defect. [Extracted from the article]

Purpose: In this study, we aimed to identify prognostic factors of cancer mortality in patients who received radical cystectomy and to identify genomic alterations in a sub-cohort of patients with locally advanced (pT3-4) and/or positive lymph nodes bladder cancer (BC). Methods: We collected 101 BC samples from 2010 to 2018 who previously received radical cystectomy. Immunohistochemical slides were evaluated for PPAR, cAMP, IMP3, Ki67, CDK4, POU5F1, Cyclin E and MDM2, p65, CD3, CD4, CD8, CD20, CD68, CD163, FOXP3, PD-1 and PD-L1 expression. We calculated a prognostic score (PS) based on the positivity to PD-1, PD-L1 and of cAMP (final score ranging from 0 to 3). DNA of each sample have been used for sequencing by NGS in a sub-cohort of 6 patients with locally advanced (pT3-4) and/or positive lymph nodes BC. Results: PD-1 + (HR [hazard ratio] 2.59; p = 0.04), PD-L1+ (HR = 6.46; p < 0.01) and cAMP+ (HR 3.04; p = 0.02) were independent predictors of cancer-specific mortality (CSM). Increase of PS (score = 0 as reference) was associated with CSM, 0.81 (p = 0.80), 4.72 (p = 0.01) and 10.51 (p < 0.0) for PS 1, 2 and 3, respectively. ERBB2 was the gene most frequently mutated. Conclusion: BC exhibited heterogenous protein expression and variable genomic features. Identification of expression of PD-1, PD-L1 and cAMP could help in predicting oncological outcomes. [ABSTRACT FROM AUTHOR]

Objective: In Alzheimer's disease (AD), the presence of circadian dysfunction is well‐known and may occur early in the disease course. The melanopsin retinal ganglion cell (mRGC) system may play a relevant role in contributing to circadian dysfunction. In this study, we aimed at evaluating, through a multimodal approach, the mRGC system in AD at an early stage of disease. Methods: We included 29 mild–moderate AD (70.9 ± 11 years) and 26 (70.5 ± 8 years) control subjects. We performed an extensive neurophtalmological evaluation including optical coherence tomography with ganglion cell layer segmentation, actigraphic evaluation of the rest‐activity rhythm, chromatic pupillometry analyzed with a new data‐fitting approach, and brain functional MRI combined with light stimuli assessing the mRGC system. Results: We demonstrated a significant thinning of the infero‐temporal sector of the ganglion cell layer in AD compared to controls. Moreover, we documented by actigraphy the presence of a circadian‐impaired AD subgroup. Overall, circadian measurements worsened by age. Chromatic pupillometry evaluation highlighted the presence of a pupil‐light response reduction in the rod condition pointing to mRGC dendropathy. Finally, brain fMRI showed a reduced occipital cortex activation with blue light particularly for the sustained responses. Interpretation: Overall, the results of this multimodal innovative approach clearly document a dysfunctional mRGC system at early stages of disease as a relevant contributing factor for circadian impairment in AD providing also support to the use of light therapy in AD. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 is an autosomal-dominant condition caused by NF1 gene inactivation. Clinical diagnosis is corroborated by genetic tests on gDNA and cDNA, which are inconclusive in approximately 3–5% of cases. Genomic DNA approaches may overlook splicing-affecting intronic variants and structural rearrangements, especially in regions enriched in repetitive sequences. On the other hand, while cDNA-based methods provide direct information about the effect of a variant on gene transcription, they are hampered by non-sense-mediated mRNA decay and skewed or monoallelic expression. Moreover, analyses on gene transcripts in some patients do not allow tracing back to the causative event, which is crucial for addressing genetic counselling, prenatal monitoring, and developing targeted therapies. We report on a familial NF1, caused by an insertion of a partial LINE-1 element inside intron 15, leading to exon 15 skipping. Only a few cases of LINE-1 insertion have been reported so far, hampering gDNA studies because of their size. Often, they result in exon skipping, and their recognition of cDNA may be difficult. A combined approach, based on Optical Genome Mapping, WGS, and cDNA studies, enabled us to detect the LINE-1 insertion and test its effects. Our results improve knowledge of the NF1 mutational spectrum and highlight the importance of custom-built approaches in undiagnosed patients. [ABSTRACT FROM AUTHOR]

Background: Deep inspiration breath hold (DIBH) reduces radiotherapy cardiac dose for left-sided breast cancer patients. The primary aim of the BRAVEHeart (Breast Radiotherapy Audio Visual Enhancement for sparing the Heart) trial is to assess the accuracy and usability of a novel device, Breathe Well, for DIBH guidance for left-sided breast cancer patients. Breathe Well will be compared to an adapted widely available monitoring system, the Real-time Position Management system (RPM). Methods: BRAVEHeart is a single institution prospective randomised trial of two DIBH devices. BRAVEHeart will assess the DIBH accuracy for Breathe Well and RPM during left-sided breast cancer radiotherapy. After informed consent has been obtained, 40 patients will be randomised into two equal groups, the experimental arm (Breathe Well) and the control arm (RPM with in-house modification of an added patient screen). The primary hypothesis of BRAVEHeart is that the accuracy of Breathe Well in maintaining the position of the chest during DIBH is superior to the RPM system. Accuracy will be measured by comparing chest wall motion extracted from images acquired of the treatment field during breast radiotherapy for patients treated using the Breathe Well system and those using the RPM system. Discussion: The Breathe Well device uses a depth camera to monitor the chest surface while the RPM system monitors a block on the patient's abdomen. The hypothesis of this trial is that the chest surface is a better surrogate for the internal chest wall motion used as a measure of treatment accuracy. The Breathe Well device aims to deliver an easy-to-use implementation of surface monitoring. The findings from the study will help inform the technology choice for other centres performing DIBH. Trial registration: ClinicalTrials.govNCT02881203. Registered on 26 August 2016. [ABSTRACT FROM AUTHOR]

Introduction: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. Methods: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. Results: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was − 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P < 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P < 0.01) and at last observation (76.1% versus 44.4%; P < 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was − 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P < 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection. Conclusion: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection. Trial Registration Numbers: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY). [ABSTRACT FROM AUTHOR]

Cryptocurrencies are increasingly popular. Even people who are not experts have started to invest in these assets, and nowadays, cryptocurrency exchanges process transactions for over 100 billion US dollars per month. Despite this, many cryptocurrencies have low liquidity and are highly prone to market manipulation. This paper performs an in-depth analysis of two market manipulations organized by communities over the Internet: The pump and dump and the crowd pump. The pump and dump scheme is a fraud as old as the stock market. Now, it has new vitality in the loosely regulated market of cryptocurrencies. Groups of highly coordinated people systematically arrange this scam, usually on Telegram and Discord. We monitored these groups for more than 3 years, detecting around 900 individual events. We report on three case studies related to pump and dump groups. We leverage our unique dataset of the verified pump and dumps to build a machine learning model able to detect a pump and dump in 25 seconds from the moment it starts, achieving the results of 94.5% of F1-score. Then, we move on to the crowd pump, a new phenomenon that hit the news in the first months of 2021, when a Reddit community inflated the price of the GameStop stocks (GME) by over 1,900% on Wall Street, the world’s largest stock exchange. Later, other Reddit communities replicated the operation on the cryptocurrency markets. The targets were DogeCoin (DOGE) and Ripple (XRP). We reconstruct how these operations developed and discuss differences and analogies with the standard pump and dump. We believe this study helps understand a widespread phenomenon affecting cryptocurrency markets. The detection algorithms we develop effectively detect these events in real-time and helps investors stay out of the market when these frauds are in action. [ABSTRACT FROM AUTHOR]

Simple Summary: Maculinea butterflies are endangered social parasites of Myrmica ants. In late summer, caterpillars abandon their foodplants and wait for a Myrmica worker to retrieve and carry them into the nest. Here the caterpillars spend 11 months consuming the ant brood or being fed by workers; then they pupate early in summer, and in one month the adults emerge. Our study aimed to assess the spatial relationship between nests parasitized by Maculinea teleius and those unparasitized and the factors influencing the parasite presence inside host nests. We searched for Ma. teleius caterpillars in ant nests in autumn, during the initial larval development, and in the following late spring. Unsurprisingly, we found a substantial decrease in the proportion of parasitized nests from autumn to late spring. The biggest Myrmica nests adopted a higher number of parasites, but mid-size nests provided the best trade-off between competition and resource availability, leading to high parasite survival observed in spring. The spatial distribution of parasitized nests in autumn was uniform, while the colonies in which Ma. teleius survived until pupation were grouped. Overall, our results suggest that host colonies' features and spatial relationships should be considered when trying to preserve these rare butterflies. The parasitic relationship between Maculinea butterflies and Myrmica ants has been extensively studied but little information is available on the spatial occurrence of Maculinea larvae. We searched for the presence of Maculinea teleius in 211 ant nests at two sites in two crucial phases of its life cycle, i.e., in autumn, during the initial larval development, and in the following late spring, before pupation. We assessed variations in the proportion of infested nests and factors correlated with spatial distributions of parasites in Myrmica colonies. The parasitism rate in autumn was very high (∼50% of infestation rate) but decreased in the following spring. The most important factor explaining parasite occurrence in both seasons was the nest size. Further factors, such as the presence of other parasites, the Myrmica species or the site, concurred to explain the differential survival of Ma. teleius until the final development. Irrespective of the host nest distribution, the parasite distribution changed from even in autumn to clumped in late spring. Our work showed that the survival of Ma. teleius is correlated with colony features but also with the nest spatial distribution, which therefore should be taken into consideration in conservation strategies aiming at preserving these endangered species. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate Cancer (PCa) is still ranked as the first cancer in the male population and evidence has suggested an alteration of glycemic and lipidic metabolism that are related to its progression and prognosis. We demonstrated that the expression of ATP-lyase, CPT-1a, SCD, SREBP, ACC-1, and FAS were associated with AR. Finally, SCD+ expression in PCa patients with total cholesterol ≥ 200 mg/dL was independently associated with ISUP ≥ 4, and CPT-1a+ was associated with biochemical recurrence. Our results support the evidence that the manipulation of lipidic metabolism could serve in the future to contrast PCa progression. Prostate Cancer (PCa) is still ranked as the first cancer in the male population and evidences have suggested an alteration of glycemic and lipidic metabolism that are related to its progression and prognosis. The aim of the study is to investigate associations between enzymes' expression, especially involved in the lipidic pathway, and PCa aggressiveness. We retrospectively analyzed data from 390 patients with PCa or benign prostatic hyperplasia (BPH) at the Department of Urology, University of Catania. Immunohistochemical slides were evaluated for the expression of proteins related to glucose and lipidic metabolism. A total of 286 were affected by PCa while 104 by BPH. We demonstrated that ATP-lyase (odds ratio [OR]: 1.71; p < 0.01), fatty acid synthase (OR: 4.82; p < 0.01), carnitine palmitoyl transferase-1a (OR: 2.27; p < 0.05) were associated with androgen receptor (AR) expression. We found that steaoryl Co-A desaturase expression in PCa patients with total cholesterol ≥ 200 mg/dL was independently associated with ISUP ≥4 (OR: 4.22; p = 0.049). We found that CPT-1a+ was associated with biochemical recurrence (hazard ratio: 1.94; p = 0.03]). Our results support the evidence that the manipulation of lipidic metabolism could serve in the future to contrast PCa progression. [ABSTRACT FROM AUTHOR]

Dear Sirs, Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder causing selective loss of motor neurons in brain motor cortex and spinal cord in which muscle denervation and atrophy are associated with pyramidal involvement, typically spreading to contiguous muscular regions and leading eventually to a fatal paralysis. Here, we report two ALS cases carrying the m.11778A > G/ I MT-ND4 i (R340H) mitochondrial DNA (mtDNA) mutation pathogenic for Leber's hereditary optic neuropathy (LHON), a maternally inherited disease due to mtDNA mutations affecting complex I function and usually leading to isolated optic atrophy [[2]]. Pathogenic mtDNA mutations have been found in ALS phenocopies with a primary mitochondrial disorder [[12]] and, more recently, mutations in nuclear genes, such as I CHCHD10 i , have been associated with ALS and mitochondrial myopathy with accumulation of mtDNA multiple deletions [[13]]. [Extracted from the article]

A compact broadband Edge-Line Coupler (ELC) based on Parity Time-reversal Duality (PTD) symmetry has been conceived, designed, constructed and measured. The coupler connects four PTD bifilar edge lines (BELs), recently introduced by the authors. The PTD-BELs are constituted by a parallel plate waveguide whose walls are formed by a junction between Perfect Electric Conductor (PEC) and Perfect Magnetic Conductor (PMC) boundary conditions. Reversing the axis orthogonal to the plates interchanges the position of PEC and PMC. Such a waveguide supports unimodal transverse electromagnetic (TEM) propagation, extremely confined along the top and bottom junction edges; its propagation is protected against backscattering from any discontinuity that preserves the PTD symmetry. The ELC presented here is constituted by a 4-port junction in which each port is intrinsically matched due to the PTD symmetry, strongly coupled with a second port, strongly decoupled with a third port, and weakly coupled with a fourth port. The ELC is designed by using a mushroom metasurface for the PMC portion of the device; the connection is based on a switch circuit which imposes open and short conditions on the two opposite sides of the structure. Switching simultaneously the open and short circuits reroutes the signal in a different port, while maintaining the same level of coupling with the other ports. A static prototype has been built and its measurements have confirmed the matching performance and the good directionality of the coupler in a broadband frequency range between 24 and 30 GHz. [ABSTRACT FROM AUTHOR]

This article presents the results of an international research project carried out in Italy and Canada, conducted by architects, landscape architects, sociologists and medical doctors. The study originated in the conviction that health and well-being are crucial objectives integrated within the notion of a sustainable city. For this reason, the configuration of urban space plays a decisive role in defining lifestyles and can contribute to improving the welfare of citizens. Many of today’s diseases are caused by a sedentary lifestyle; it is essential, therefore, to centre prevention on the promotion of physical well-being encouraging an active lifestyle, which can be achieved by changing the urban structure. With the aim of bringing about sustainable and healthy lifestyles, streets are in vogue. Streets are meeting and experimental places, theatres of everyday life and settings for cultural events. They provide crucial urban space for people and, in the context of urban studies, offer intellectual research nourishment to reflect on this fundamental element of the structure of the city. The research project presented here is aimed at encouraging active lifestyles, walkability and the use of public transport by facilitating accessibility to four sites in Rome and Montreal, and by exploring the potential leveraging of existing infrastructures and services. The research-based design proposals start with the idea of redeveloping the system of public spaces, beginning with the increase of bicycle and pedestrian routes in relation to schools, commerce, sports facilities and archaeological heritage. The goal is to build feasible, safe, recognisable and attractive routes and well-equipped public spaces in order to discourage the use of private vehicles, especially for short trips. The projects presented here are based on a systemic vision and make use of existing, but often abandoned or undervalued, spaces and resources. [ABSTRACT FROM AUTHOR]

This article presents the design and experimental characterization of microwave structures based on parity time-reversal duality symmetric bifilar edge waveguides (PTD-BEWs) realized through a parallel plate waveguide (PPW) loaded by a metasurface. The analyzed structures include transmission lines with bends and multiple line arrangements. Due to their unique symmetry properties, these structures are robust against backscattering, thus resembling the behavior of topological WGs, despite the fact they are reciprocal. This makes it possible to guide the electromagnetic (EM) waves along the edge with low insertion losses and unique matching properties. Measurements, performed in the frequency range between 24 and 32 GHz, have confirmed the feasibility of the theoretical concept. [ABSTRACT FROM AUTHOR]

Simple Summary: Invasive alien species are non-native species introduced deliberately or unintentionally beyond their past or present natural distribution, and their introduction and spread threatens local biological diversity. The Eastern grey squirrel is native to North America and was introduced to the British Islands, Italy, and South Africa. Around the year 2000, a new population of grey squirrels was recorded in Perugia, central Italy, where the species populated an area of approximately 50 km2, both in woodland and urban areas. The Eastern grey squirrel represents a huge threat to the conservation of the native Eurasian red squirrel when the two species coexist. Moreover, given their confident behaviour with humans, the non-native squirrels can negatively impact public health. The U-SAVEREDS Project was set up for Eurasian red squirrel conservation in Umbria through the eradication of the alien species and it also provided information on the health status of the Eastern grey squirrel to identify any infectious agents. The recovery of zoonotic pathogens allowed to assess the Eastern grey squirrel's impact on human and domestic and wild animals' health, provide helpful feedback for the management and eradication procedures, and raise public awareness through environmental education. The introduction of the Eastern grey squirrel (Sciurus carolinensis) in Europe is one of the best-known cases of invasive alien species (IAS) colonisation, that poses a severe risk to the conservation of biodiversity. In 2003, it was released in a private wildlife park near the city of Perugia (Italy), where it is replacing the native Eurasian red squirrel (Sciurus vulgaris). The LIFE13 BIO/IT/000204 Project (U-SAVEREDS) was set up for the Sciurus vulgaris conservation in Umbria through an eradication campaign of grey squirrels. One hundred and fifty-four animals were analysed for bacteriological, mycological, virological, and serological investigations (C4 action). Sanitary screening showed that Sciurus carolinensis is a dermatophyte carrier, and therefore, it could cause public health issues for humans, considering its confident behaviour. Moreover, it has been marginally responsible for the spreading of Candida albicans, Coxiella burnetii, and Borrelia lusitaniae. Health status evaluation conducted on the Sciurus carolinensis population indicated that it is necessary to raise awareness of its impacts on biodiversity and human health. Moreover, the health status and behaviours of the IAS must be considered when control or eradication campaigns are planned. [ABSTRACT FROM AUTHOR]

Background: Parkinsonian features have been described in patients harboring variants in nuclear genes encoding for proteins involved in mitochondrial DNA maintenance, such as TWNK.Objectives: The aim was to screen for TWNK variants in an Italian cohort of Parkinson's disease (PD) patients and to assess the occurrence of parkinsonism in patients presenting with TWNK-related autosomal dominant progressive external ophthalmoplegia (TWNK-adPEO).Methods: Genomic DNA of 263 consecutively collected PD patients who underwent diagnostic genetic testing was analyzed with a targeted custom gene panel including TWNK, as well as genes causative of monogenic PD. Genetic and clinical data of 18 TWNK-adPEO patients with parkinsonism were retrospectively analyzed.Results: Six of 263 PD patients (2%), presenting either with isolated PD (n = 4) or in combination with bilateral ptosis (n = 2), carried TWNK likely pathogenic variants. Among 18 TWNK-adPEO patients, 5 (28%) had parkinsonism.Conclusions: We show candidate TWNK variants occurring in PD without PEO. This finding will require further confirmatory studies. © 2022 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of the present study is to investigate genetic changes associated with lymph node metastasis in a cohort of hormone-naïve prostate cancer patients. We found mostly concordance between both primary PCa samples and matched lymph node metastasis in terms of genomic alteration. Indeed, the analysis of hotspot regions in genes such as ERBB4, AKT1, FGFR2 and MLH1 underline that specific alterations in the primary tumor are extremely important for cancer prognosis prediction. Background: Prostate cancer (PCa) is a disease with a wide range of clinical manifestations. Up to the present date, the genetic understanding of patients with favorable or unfavorable prognosis is gaining interest for giving the appropriate tailored treatment. We aimed to investigate genetic changes associated with lymph node metastasis in a cohort of hormone-naïve Pca patients. Methods: We retrospectively analyzed data from 470 patients who underwent surgery for PCa between 2010 and 2020 at the Department of Urology, University of Catania. Inclusion criteria were patients with lymph node metastasis and patients with PCa with extra capsular extension (pT3) and negative lymph node metastasis. The final cohort consisted of 17 different patients (11 PCa with lymph node metastasis and 6 PCa without lymph node metastasis). Through the cBioPortal online tool, we analyzed gene alterations and their correlations with clinical factors. Results: A total of 688 intronic, synonym and nonsynonym mutations were sequenced. The gene with the most sequenced mutations was ERBB4 (83 mutations, 12% of 688 total), while the ones with the lower percentage of mutations were AKT1, FGFR2 and MLH1 (1 mutation alone, 0.14%). Conclusion: In the present study we found mostly concordance concerning the ERBB4 mutation between both primary PCa samples and matched lymph node metastasis, underlining that the identification of alterations in the primary tumor is extremely important for cancer prognosis prediction. [ABSTRACT FROM AUTHOR]

Isolated complex I deficiency represents the most common mitochondrial respiratory chain defect involved in mitochondrial disorders. Among these, the mitochondrial DNA (mtDNA) m.13513G>A pathogenic variant in the NADH dehydrogenase 5 subunit gene (MT-ND5) has been associated with heterogenous manifestations, including phenotypic overlaps of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, Leigh syndrome, and Leber's hereditary optic neuropathy (LHON). Interestingly, this specific mutation has been recently described in patients with adult-onset nephropathy. We, here, report the unique combination of LHON, nephropathy, sensorineural deafness, and subcortical and cerebellar atrophy in association with the m.13513G>A variant. [ABSTRACT FROM AUTHOR]

Simple Summary: The introduction of alien species outside their native range represents one of the main threats to biodiversity conservation and it is mainly driven by human activities. In this work, we used the introduction of an alien lagomorph (Sylvilagus floridanus) outside its natural range as a case study to describe and evaluate the long-term effects on the native lagomorph community. In particular, S. floridanus was host to different exotic parasites, which adapted to new biotic and abiotic conditions and, as a consequence, invaded and largely altered the parasite community of native Lagomorpha species. This work represents the first exploratory study on the ecological macro-community formed by native and alien host species and their parasitofauna. Further efforts are needed to fully understand the strategies and factors conditioning the evolution of these specific parasite communities, and more in general the factors influencing the effect and evolution of alien pathogens in a new geographic area. The Convention on Biological Diversity classifies "Invasive Alien Species" as those whose introduction and spread represents a threat for biodiversity. Introduction of alien pathogens, including parasites, is one of the main consequences of the introduction of invasive alien species. The objective of this work was to assess the parasite community composition in native lagomorphs (Lepus europaeus and Lepus timidus varronis) in sympatric and non-sympatric conditions with an alien lagomorph (Sylvilagus floridanus), and to evaluate the phenotypic traits of exotic parasites in such conditions. We firstly describe the characteristics of the parasite community in the different host species (richness, prevalence, abundance and intensity), and, secondly, the phenotypic traits of the observed parasite species in each host. Nine helminths were reported on: eight nematodes (Obeliscoides cuniculi, Trichostrongylus calcaratus, Trichostrongylus retortaeformis, Trichostrongylus affinis, Trichuris leporis, Trichostrongylus colubriformis, Passalurus ambiguus, and Nematodirus sp.) and one unidentified cestode. In addition, exotic parasites showed significantly different phenotypic plasticity after spillover from S. floridanus to L. europaeus, whereas endemic parasite species were not isolated in the alien S. floridanus. Our results highlight that the community of autochthonous and allochthonous Lagomorpha in northwestern Italy represents an extremely interesting system for modelling ecological and evolutionary interactions between parasites and their hosts. [ABSTRACT FROM AUTHOR]

New strategies are needed to fight the emergence of multidrug-resistant bacteria caused by an overuse of antibiotics in medical and veterinary fields. Due to the importance of biofilms in clinical infections, antibiofilm peptides have a great potential to treat infections. In recent years, an increased interest has emerged in antimicrobial peptides (AMPs). One of the richest sources of AMPs is represented by amphibian skin. In the present work, we investigated the effects of two peptides derived from the frog skin AMP esculentin-1, namely, Esc(1-21) and Esc(1-18), on the growth, biofilm formation, and gene expression of the non-pathogenic Escherichia coli strain K12 and of enterohemorrhagic E. coli O157:H7. Both peptides showed minimal bactericidal concentrations ranging from 4 to 8 µM for Esc(1-21) and from 32 to 64 µM for Esc(1-18). They also, at sub-MIC doses, reduced the formation of biofilm, as supported by both microbiological assays and scanning electron microscopy, while they displayed no marked activity against the planktonic form of the bacteria. Transcriptional analysis in E. coli O157:H7 showed that both AMPs induced the expression of several genes involved in the regulation of formation and dispersal of biofilm, as well as in the stress response. In conclusion, we demonstrated that these AMPs affect E. coli O157:H7 growth and biofilm formation, thus suggesting a great potential to be developed as novel therapeutics against infections caused by bacterial biofilms. [ABSTRACT FROM AUTHOR]

The recent description of biallelic DNAJC30 variants in Leber hereditary optic neuropathy (LHON) and Leigh syndrome challenged the longstanding assumption for LHON to be exclusively maternally inherited and broadened the genetic spectrum of Leigh syndrome, the most frequent paediatric mitochondrial disease. Herein, we characterize 28 so far unreported individuals from 26 families carrying a homozygous DNAJC30 p.Tyr51Cys founder variant, 24 manifesting with LHON, two manifesting with Leigh syndrome, and two remaining asymptomatic. This collection of unreported variant carriers confirms sex-dependent incomplete penetrance of the homozygous variant given a significant male predominance of disease and the report of asymptomatic homozygous variant carriers. The autosomal recessive LHON patients demonstrate an earlier age of disease onset and a higher rate of idebenone-treated and spontaneous recovery of vision in comparison to reported figures for maternally inherited disease. Moreover, the report of two additional patients with childhood- or adult-onset Leigh syndrome further evidences the association of DNAJC30 with Leigh syndrome, previously only reported in a single childhood-onset case. [ABSTRACT FROM AUTHOR]

Background: SFRS1 is a member of the splicing factor protein family. Through a specific sequence of alteration, SRSF1 can move from the cytoplasm to the nucleus where it can work autonomously as a splicing activator, or as a silencer when interacting with other regulators. Alternative splicing (AS) is a fundamental biological process that ensures protein diversity. In fact, different proteins, produced by alternative splicing, can gain different and even antagonistic biological functions. Methods: Our review is based on English articles published in the MEDLINE/PubMed medical library between 2000 and 2021. We retrieved articles that were specifically related to SRSF1 and cancers, and we excluded other reviews and meta-analyses. We included in vitro studies, animal studies and clinical studies, evaluated using the Medical Education Research Study Quality Instrument (MERSQI) and the Newcastle–Ottawa Scale-Education (NOSE). Result: SRSF1 is related to various genes and plays a role in cell cycle, ubiquitin-mediated proteolysis, nucleotide excision repair, p53 pathway, apoptosis, DNA replication and RNA degradation. In most cases, SRSF1 carries out its cancer-related function via abnormal alternative splicing (AS). However, according to the most recent literature, SRSF1 may also be involved in mRNA translation and cancer chemoresistance or radio-sensitivity. Conclusion: Our results showed that SRSF1 plays a key clinical role in tumorigenesis and tumor progression in several types of cancer (such as Prostate, Lung, Breast, Colon, Glioblastoma), through various mechanisms of action and different cellular pathways. This review could be a starting point for several studies regarding the biology of and therapies for cancer. [ABSTRACT FROM AUTHOR]

Introduction: Aimed to develop a simple and robust volumetric modulated arc radiotherapy (VMAT) solution for comprehensive lymph node (CLN) breast cancer without increase in low‐dose wash. Methods: Forty CLN‐breast patient data sets were utilised to develop a knowledge‐based planning (KBP) VMAT model, which limits low‐dose wash using iterative learning and base‐tangential methods as benchmark. Another twenty data sets were employed to validate the model comparing KBP‐generated ipsilateral VMAT (ipsi‐VMAT) plans against the benchmarked hybrid (h)‐VMAT (departmental standard) and bowtie‐VMAT (published best practice) methods. Planning target volume (PTV), conformity/homogeneity index (CI/HI), organ‐at‐risk (OAR), remaining‐volume‐at‐risk (RVR) and blinded radiation oncologist (RO) plan preference were evaluated. Results: Ipsi‐ and bowtie‐VMAT plans were dosimetrically equivalent, achieving greater nodal target coverage (P < 0.05) compared to h‐VMAT with minor reduction in breast coverage. CI was enhanced for a small reduction in breast HI with improved dose sparing to ipsilateral‐lung and humeral head (P < 0.05) at immaterial expense to spinal cord. Significantly, low‐dose wash to OARs and RVR were comparable between all plan types demonstrating a simple VMAT class solution robust to patient‐specific anatomic variation can be applied to CLN breast without need for complex beam modification (hybrid plans, avoidance sectors or other). This result was supported by blinded RO review. Conclusions: A simple and robust ipsilateral VMAT class solution for CLN breast generated using iterative KBP modelling can achieve clinically acceptable target coverage and OAR sparing without unwanted increase in low‐dose wash associated with increased second malignancy risk. [ABSTRACT FROM AUTHOR]

Introduction: Until late 2018, standard of practice at the Northern Sydney Cancer Centre (NSCC) for breast and nodal treatment was a conformal mono‐isocentric technique. A planning study comparing an existing mono‐isocentric three‐dimensional conformal radiotherapy (3D‐CRT) planning technique to a hybrid intensity‐modulated radiotherapy (hIMRT) approach for the whole breast and supraclavicular fossa (SCF) region was undertaken with the aim to improve plan quality by improving dose conformity/homogeneity across target volumes and reducing hotspots outside the target. Methods: A cohort of 17 patients was retrospectively planned using the proposed hIMRT technique, keeping the same planning constraints as the original treated breast and SCF 3D‐CRT plan and normalising the 3D‐CRT plans to achieve minimum breast/SCF target coverage to compare organs at risk (OARs). Normal tissue index (NTI) and homogeneity index (HI) were compared for plan quality as well as for evaluating OARs. Results: The hIMRT technique showed statistically significant improvements in NTI and HI, as well as improvement in maximum brachial plexus and thyroid doses. There was a negligible increase in maximum oesophagus dose which could be improved if used in optimisation. Other OAR doses in the irradiated region were comparable to the 3D‐CRT plans, however maximum doses were reduced overall. Conclusion: The hIMRT planning technique maintained clinically acceptable doses to OARs and reduced normal tissue dose while maintaining equivalent dose coverage to breast and SCF planning target volumes with improved conformity and homogeneity. The reduction in maximum doses promotes a favourable toxicity profile, with potential benefit of improved long‐term cosmesis. [ABSTRACT FROM AUTHOR]

Introduction: Both prevalence and clinical features of the various movement disorders in adults with primary mitochondrial diseases are unknown. Methods: Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", we reviewed the clinical, genetic, neuroimaging and neurophysiological data of adult patients with primary mitochondrial diseases (n = 764) where ataxia, myoclonus or other movement disorders were part of the clinical phenotype. Results: Ataxia, myoclonus and movement disorders were present in 105/764 adults (13.7%), with the onset coinciding or preceding the diagnosis of the mitochondrial disease in 49/105 (46.7%). Ataxia and parkinsonism were the most represented, with an overall prevalence at last follow-up of 59.1% and 30.5%, respectively. Hyperkinetic movement disorders were reported in 15.3% at last follow-up, being the less common reported movement disorders. The pathogenic m.8344A > G and POLG variants were always associated with a movement disorder, while LHON variants and mtDNA single deletions were more commonly found in the subjects who did not present a movement disorder. The most common neuroimaging features were cortical and/or cerebellar atrophy, white matter hyperintensities, basal ganglia abnormalities and nigro-striatal degeneration. Almost 70% of patients with parkinsonism responded to dopaminergic therapy, mainly levodopa, and 50% with myoclonus were successfully treated with levetiracetam. Conclusion: Movement disorders, mainly ataxia and parkinsonism, are important findings in adult primary mitochondrial diseases. This study underlies the importance of looking for a mitochondrial etiology in the diagnostic flowchart of a movement disorder and may help direct genetic screening in daily practice. [ABSTRACT FROM AUTHOR]

To evaluate differences in macular and optic disc circulation in patients affected by Wolfram Syndrome (WS) employing optical coherence tomography-angiography (OCTA) imaging. In this retrospective study, 18 eyes from 10 WS patients, 16 eyes of 8 patients affected by type I diabetes and 17 eyes from 17 healthy controls were enrolled. All patients were imaged through OCT and OCTA and vascular parameters, as perfusion density (PD) and vessel length density (VLD) were measured. OCTA showed reduced PD in WS patients at the macular superficial capillary plexus (SCP, 27.8 ± 5.3%), deep vascular complex (DVC, 33.2 ± 1.9%) and optic nerve head (ONH, 21.2 ± 9.1%) compared to both diabetic patients (SCP 33.9 ± 1.9%, P < 0.0001; DVC 33.2 ± 0.7%, P = 1.0; ONH 33.9 ± 1.3, P < 0.0001) and healthy controls (SCP 31.6 ± 2.5, P = 0.002; DVC 34.0 ± 0.7%, P = 0.089; ONH 34.6 ± 0.8%, P < 0.0001). Similarly, VLD was lower in WS patients at the SCP (10.9 ± 2.7%) and ONH levels (7.5 ± 4.1%) compared to diabetic patients (SCP 13.8 ± 1.2%, P = 0.001; DVC 13.8 ± 0.2%, P < 0.0001; ONH 13.0 ± 0.7%, P = < 0.0001), but higher in DVC (15.7 ± 1.2%, P < 0.0001). Furthermore, VLD was lower in WS patients in all the vascular parameters compared to controls (SCP 13.8 ± 1.5%, P < 0.0001; DVC 17.3 ± 0.6%, P < 0.0001; ONH 15.7 ± 0.5%, P < 0.0001). A significant microvasculature impairment in the macular SCP and ONH microvasculature was demonstrated in eyes affected by WS. Microvascular impairment may be considered a fundamental component of the neurodegenerative changes in WS. [ABSTRACT FROM AUTHOR]