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Background Melanopsin retinal ganglion cell (mRGC)-mediated pupillary light reflex (PLR) abnormalities have been documented in several neurodegenerative disorders including Parkinson's disease. Overall, isolated rapid eye movement (REM) sleep behavior disorder (iRBD) represents the strongest prodromal risk factor for impending α-synucleinopathies. Objectives To quantitatively compare PLR and mRGC-mediated contribution to PLR in 16 iRBD patients and 16 healthy controls. Methods iRBD and controls underwent extensive neuro-ophthalmological evaluation and chromatic pupillometry. In iRBD, PLR metrics were correlated with clinical variables and with additional biomarkers including REM atonia index (RAI), DaTscan, and presence of phosphorylated-α-synuclein (p-α-syn) deposition in skin biopsy. Results We documented higher baseline pupil diameter and decreased rod-transient PLR amplitude in iRBD patients compared to controls. PLR rod-contribution correlated with RAI. Moreover, only iRBD patients with evidence of p-α-syn deposition at skin biopsy showed reduced PLR amplitude compared to controls. Conclusion The observed PLR abnormalities in iRBD might be considered as potential biomarkers for the risk stratification of phenoconversion of the disease. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Objective The purpose of this study was to investigate correlations between brain proton magnetic resonance spectroscopy (1H‐MRS) findings with serum biomarkers and heteroplasmy of mitochondrial DNA (mtDNA) mutations. This study enrolled patients carrying mtDNA mutations associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke‐like episodes (MELAS), and MELAS‐Spectrum Syndrome (MSS). Methods Consecutive patients carrying mtDNA mutations associated with MELAS and MSS were recruited and their serum concentrations of lactate, alanine, and heteroplasmic mtDNA mutant load were evaluated. The brain protocol included single‐voxel 1H‐MRS (1.5T) in the medial parieto‐occipital cortex (MPOC), left cerebellar hemisphere, parieto‐occipital white matter (POWM), and lateral ventricles. Relative metabolite concentrations of N‐acetyl‐aspartate (NAA), choline (Cho), and myo‐inositol (mI) were estimated relative to creatine (Cr), using LCModel 6.3. Results Six patients with MELAS (age 28 ± 13 years, 3 [50%] female) and 17 with MSS (age 45 ± 11 years, 7 [41%] female) and 39 sex‐ and age‐matched healthy controls (HC) were enrolled. These patients demonstrated a lower NAA/Cr ratio in MPOC compared to HC (p = 0.006), which inversely correlated with serum lactate (p = 0.021, rho = −0.68) and muscle mtDNA heteroplasmy (p

The study aims to characterize the epilepsy phenotype of maternally inherited Leigh's syndrome (MILS) and neuropathy, ataxia, retinitis pigmentosa (NARP) due to mutations in the mitochondrial ATP6 gene and to correlate electroclinical features with mutant heteroplasmy load (HL). We investigated 17 individuals with different phenotype, from asymptomatic carriers to MILS: 11 carried the m.8993T>G mutation, 5 the m.8993T>C and one the novel, de novo m.8858G>A mutation. Seizures occurred in 37.5% of patients, EEG abnormalities in 73%. We ranked clinical and EEG abnormalities severity and performed quantitative EEG to estimate Abnormality Ratio (AR) and Spectral Relative Power (SRP). Spearman’s rho and Kruskal–Wallis test were used for correlation with heteroplasmy load (HL). HL correlated with disease severity (Rho=0.63, P=0.012) and was significantly higher in patients with seizures or EEG abnormalities (P=0.014). HL correlated with EEG severity score only for the m.8993T>G (Rho=0.73, P=0.040), showing a trend toward a positive correlation with AR and delta SPR, irrespective of the mutation.

Objective Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. Methods We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts. Results Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. Interpretation This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32.

We previously documented that idebenone treatment in OPA1‐Dominant Optic Atrophy (OPA1‐DOA) led to some degrees of visual improvement in seven patients. We here present the results of a cohort study, which investigated the effect of off‐label idebenone administration in a larger OPA1‐DOA group compared with untreated patients. Inclusion criteria were: OPA1‐DOA clinical and molecular diagnosis, baseline visual acuity (VA) greater than/equal to counting fingers and treatment duration greater than 7 months. We found a significant difference between the last visit and baseline VA in favor of stabilization/recovery in idebenone‐treated as compared to untreated patients. This effect was retained after controlling for confounders.

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

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.

The wild boar is one of the most invasive species among large mammals in both its native and introduced ranges. This species represents a main threat for crops and biodiversity and a pest for the pig industry due to the rapid expansion of the African swine fever. Because of its peculiar life history traits, population control programmes and recreational hunting are usually unable to effectively reduce the number of wild boars. Therefore, a reliable approach based on appropriate, cost-effective, monitoring methodologies is urgently required. Effective monitoring should adopt effective sampling strategies, otherwise the detection of population trends can be erroneous and resulting in a mismatch of appropriate management actions. First, we review the status-of-the-art of wildlife monitoring with a special focus on wild boar and feral pigs. Then, we show that nocturnal distance sampling, carried out using thermal cameras, can be an effective monitoring technique for wild boar population assessment regardless of the characteristics of the sampled area. Using data from multiple surveys performed in four study areas in Italy, characterised by contrasting topography, habitats and level of environmental visibility, we found that the estimate of precision is generally good and almost independent of landscape conditions. A simple method to estimate visibility, which may empirically help wildlife managers to design effective nocturnal distance sampling surveys, is proposed. The bias of our population estimates is evaluated using simulations showing that in some areas the estimate is unbiased, while in others there is the tendency towards a negative bias. Based on reported results, we provide guidelines to perform nocturnal distance sampling of wild boar populations.

OBJECTIVE To evaluate the presence of circulating tumour cells (CTCs) at different stages of prostate cancer using the AdnaTest® ProstateCancerDetect kit (Qiagen). Moreover, we aimed to assess the expression of transcripts that are specific for cancer stem cells (AdnaTest StemCell) and epithelial-mesenchymal transition (EMT) in CTCs (AdnaTest EMT), as well as additional genes that are known to promote prostate cancer progression. PATIENTS AND METHODS In this prospective study, we included 81 patients who underwent treatment for prostate cancer between 07/2014 and 02/2015, including: Group A, 18 patients (22.2%) with low-risk clinically localised prostate cancer; Group B, 25 patients (30.9%) with high-risk clinically localised prostate cancer; Group C, 11 patients (13.6%) with metastatic castration-sensitive prostate cancer (mCSPC); and Group D, 27 patients (33.3%) with metastatic castration-resistant prostate cancer (mCRPC). AdnaTest ProstateCancer and AdnaTest StemCell/EMT were performed in all cases. In addition, expression of the androgen receptor (AR), c-met, c-kit and thymidylate synthase (TYMS) in CTCs was assessed using specific polymerase chain reaction assays. RESULTS A positive AdnaTest ProstateCancer was present in three (16.7%), two (8.0%), six (54.5%) and 19 (70.5%) patients in groups A, B, C and D, respectively (P < 0.01, chi-squared test). The AdnaTest EMT and AdnaTest StemCell were positive in zero (0.0%), zero (0.0%), one (9.1%), and two (7.4%); and in five (27.8%), four (16.0%), three (27.3%), and 11 (40.7%) patients in groups A, B, C and D, respectively, with no significant differences noted between groups. CTCs expressing TYMS (44.4% and 50.0% vs 13.9%) or AR (18.2% and 25.9% vs 0.0%) were seen more commonly in patients in groups C and D vs patients with non-metastatic disease (all P < 0.05). Expression of c-kit and c-met were rare events, with only two patients positive for either marker. CONCLUSIONS AdnaTest ProstateCancerDetect exhibits positive results mainly in patients with metastatic disease. Expression of AR and TYMS are frequent events in CTCs of patients with advanced disease, whereas c-met and c-kit gene expression is seen in only a small proportion of patients. The implications of these results for the use of CTC analysis as a decision factor for personalised treatment strategies in advanced prostate cancer remain to be determined.

A systematic review and meta-analysis was carried out to evaluate the efficacy and safety of mirabegron 50 mg and 100 mg in the treatment of storage lower urinary tract symptoms/overactive bladder in comparison with a placebo and tolterodine 4 mg. A total of 491 articles were collected and eight randomized studies were identified as eligible for this meta-analysis. Overall, eight trials were included in the meta-analysis evaluating 10 248 patients. Mirabegron at both doses of 50 mg and 100 mg, and and tolterodine 4 mg were significantly associated with the reduction of incontinence episodes per 24 h, reduction of mean number of micturitions per 24 h, increase of voided volume and reduction of urgency episodes per 24 h, compared to a placebo. Both mirabegron 50 mg and mirabegron 100 mg were associated with a significant reduction of nocturia episodes when compared with a placebo. Conversely, tolterodine 4 mg did not prove to be more effective than a placebo in the reduction of nocturia episodes. Furthermore, mirabegron 50 mg showed a slightly, but significantly, better efficacy than tolterodine 4 mg in the improvement of nocturia episodes. Mirabegron 50 mg and mirabegron 100 mg shared the same risk of overall treatment-emergent adverse events rate with the placebo. Otherwise, tolterodine 4 mg was associated with a significantly greater risk than the placebo. However, mirabegron 100 mg showed a slight trend toward an increased risk of hypertension (odds ratio 1.41; P = 0.08) and cardiac arrhythmia (odds ratio 2.18; P = 0.06). Mirabegron is an effective treatment for patients with storage lower urinary tract symptoms/overactive bladder, providing a reduction of incontinence, urgency and frequency; an improvement of voided volume with a slight, but statistically, significant improvement of nocturia; with a good safety profile. These findings should be considered for the treatment planning of patients with storage lower urinary tract symptoms/overactive bladder.

Author(s): La Morgia, Chiara; Ross-Cisneros, Fred N; Koronyo, Yosef; Hannibal, Jens; Gallassi, Roberto; Cantalupo, Gaetano; Sambati, Luisa; Pan, Billy X; Tozer, Kevin R; Barboni, Piero; Provini, Federica; Avanzini, Pietro; Carbonelli, Michele; Pelosi, Annalisa; Chui, Helena; Liguori, Rocco; Baruzzi, Agostino; Koronyo-Hamaoui, Maya; Sadun, Alfredo A; Carelli, Valerio | Abstract: ObjectiveMelanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction.MethodsWe assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild-moderate AD patients, and in a subgroup of 16 we evaluated rest-activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross-sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid β (Aβ) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age-matched controls.ResultsWe demonstrated an age-related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat-mounted AD retinas, Aβ accumulation was remarkably evident inside and around mRGCs.InterpretationWe show variable degrees of rest-activity circadian dysfunction in AD patients. We also demonstrate age-related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Aβ deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD.

Introduction This patterns of practice study was conducted on behalf of the RANZCR Breast Interest Group in order to document current radiotherapy practices for breast cancer in Australia and New Zealand. The survey identifies variations and highlights potential contentious aspects of radiotherapy management of breast cancer. Methods A fifty-eight question survey was disseminated via the Survey Monkey digital platform to 388 Radiation Oncologists in Australia and New Zealand. Results In total, 156 responses were received and collated. Areas of notable consensus among respondents included hypofractionation (77.3% of respondents would ‘always’ or ‘sometimes’ consider hypofractionation in the management of ductal carcinoma in-situ and 99.3% in early invasive breast cancer); margin status in early breast cancer (73.8% believe a clear inked margin is sufficient and does not require further surgery) and use of bolus in post-mastectomy radiotherapy (PMRT) (91.1% of participants use bolus in PMRT). Areas with a wider degree of variability amongst respondents included regional nodal irradiation and components of radiotherapy planning and delivery (examples include the technique used for delivery of boost and frequency of bolus application for PMRT). Conclusion The results of these patterns of practice survey informs radiation oncologists in Australia and New Zealand of the current clinical practices being implemented by their peers. The survey identifies areas of consensus and contention, the latter of which may lead to a development of research trials and/or educational activities to address these areas of uncertainty.

Background Eradication of invasive alien species supports the recovery of native biodiversity. A new European Union Regulation introduces obligations to eradicate the most harmful invasive species. However, eradications of charismatic mammals may encounter strong opposition. Considering the case study of the eastern grey squirrel (Sciurus carolinensis Gmelin, 1788) in central Italy, we developed a structured decision-making technique based on a Bayesian decision network model and explicitly considering the plurality of environmental values of invasive species management to reduce potential social conflicts. Results The model identified priority areas for management activities. These areas corresponded to the core of the grey squirrel range, but they also included peripheral zones, where rapid eradication is fundamental to prevent the spread of squirrels. However, when the model was expanded to integrate the attitude of citizens towards the project, the intervention strategy slightly changed. In some areas, the citizens' support was limited, and this resulted in a reduced overall utility of intervention. Conclusion The suggested approach extends the scientific basis for management decisions, evaluated in terms of technical efficiency, feasibility and social impact. Here, the Bayesian decision network model analysed the potential technical and social consequences of management actions, and it responded to the need for transparency in the decision-making process, but it can easily be extended to consider further issues that are common in many mammal eradication programmes. Owing to its flexibility and comprehensiveness, it provides an innovative example of how to plan rapid eradication or control activities, as required by the new EU Regulation. © 2016 Society of Chemical Industry.

AIM Breast conserving surgery and adjuvant radiotherapy has equivalent oncological outcomes to mastectomy and is the standard of care for treatment of early-stage invasive breast cancer. Auditing is an essential component of ongoing quality assurance and clinical governance. It also serves to identify patient and tumor factors that have prognostic and therapeutic implications. The aim of this paper is to report on the clinical audit of treatment outcomes for patients undergoing adjuvant radiation treatment for early breast cancer at the Northern Sydney Cancer Care Centre. METHODS A total of 1252 patients with T1/2 breast cancer received adjuvant radiation treatment between January 2003 and December 2010. Medical records, including the departmental database, were reviewed to extract pathological, treatment, patient and clinical details. RESULTS Median follow-up was 54 months (mean 56.4 months). Sixty-six (5.27%) patients died from breast cancer, and 27 (2.16%) patients died from other disease. Twenty-three (1.84%) patients were alive with metastatic disease, 7 (0.56%) patients were alive following ipsilateral breast tumor recurrence and 7 (0.56%) patients were alive with nodal recurrence. 9 (0.72%) patients were alive with contralateral breast cancer. Documented rates of late toxicity were low: 6.8% of patients had grade 1 late toxicity and 1.6% of patients had grade 2-3 late toxicity. CONCLUSION Our ipsilateral breast tumor recurrence rate of 0.56% is well within international standards, as is our toxicity rate. We propose that centralized data collection be implemented on a nation-wide level for breast cancer patients undergoing radiotherapy. Further research is planned to identify potential markers of radio-resistance, and allow tailoring of treatment technique to optimize oncological outcome.

The ecological impact of fine sediments is one of the major causes of ecological degradation affecting lotic systems. Interestingly, many studies have investigated the impact of increased sediment loads on specific compartments of the lotic system, but little or no information is available about the overall impact of sedimentation. Aim of this paper was to analyse the influence of fine sedimentation on allochthonous and autochthonous energy inputs and on the structural and functional characteristics of diatom and macroinvertebrate communities. Data were collected in two Alpine streams in NW Italy, one interested by the presence of an intense mining area and the other pristine, used as a control. The two rivers greatly differed in terms of suspended solids and bed load characteristics. From 10 stations, we analysed main physico-chemical characteristics, fine sediment indicators (using 60 sediment traps), coarse particulate organic matter (CPOM) and photosynthetic pigments amounts, taxonomic and functional characteristics of macroinvertebrate communities. We tested several causal models via path analysis. Functional traits seem to better reflect the integrated impact originating from quarries in the river basin than traditional community metrics like total abundance and specific richness. This outcome was enforced through the co-inertia analysis, which took in consideration also metrics based on diatom communities. Our study yielded quantitative relations between sediment loads induced by quarrying activities and the degree of biological impairment and suggests which metrics are more suitable to assess this specific impact. Copyright © 2015 John Wiley & Sons, Ltd.

Introduction We report on a retrospective dosimetric study, comparing 3D conformal radiotherapy (3DCRT) and hybrid intensity modulated radiotherapy (hIMRT). We evaluated plans based on their planning target volume coverage, dose homogeneity, dose to organs at risk (OARs) and exposure of normal tissue to radiation. The Homogeneity Index (HI) was used to assess the dose homogeneity in the target region, and we describe a new index, the normal tissue index (NTI), to assess the dose in the normal tissue inside the tangent treatment portal. Methods Plans were generated for 25 early-stage breast cancer patients, using a hIMRT technique. These were compared with the 3DCRT plans of the treatment previously received by the patients. Plan quality was evaluated using the HI, NTI and dose to OARs. Results The hIMRT technique was significantly more homogenous than the 3DCRT technique, while maintaining target coverage. The hIMRT technique was also superior at minimising the amount of tissue receiving D105% and above (P