Search

Abstract 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.

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

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 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.

Objective: The management of chronic prostatitis/chronic pelvic pain syndrome type III (CP/CPPS) has been always considered complex due to several biopsychological factors underlying the disease. In this clinical study, we aimed to evaluate the efficacy of the treatment with Palmitoylethanolamide, Epilobium and Calendula extract in patients with CP/CPPS III. Materials and methods: From June 2023 to July 2023, we enrolled 45 consecutive patients affected by CP/CPPS type III in three different institution. We included patients aged between 18 and 75 years with symptoms of pelvic pain for 3 months or more before the study, a total National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score ≥ 12 point and diagnosed with NIH category III, according to 4-glass test Meares-Stamey test. Patients were then allocated to receive rectal suppositories of PEA, Epilobium and Calendula, 1 suppository/ die for 1 month. All patients have been tested with standard urinalysis in order to assess urinary leukocytes (U-WBC). The primary endpoint of the study was the reduction of NIHCPSI. The secondary outcomes were the change of peak flow, post-void residual (PVR), IIEF-5, VAS score, PSA and decrease of U-WBC. Results: A total of 45 patients concluded the study protocol. At baseline, the median age of all the patients included in the cohort was 49 years, the median PSA was 2.81 ng/mL, the median NIH-CPSI was 18.55, the median IIEF-5 was 18.27, the median U-WBC was 485.3/mmc, the median VAS score was 6.49, the median PVR was 26.5 mL and the median peak flow was 16.3 mL/s. After 1 month of therapy we observed a statistically significant improvement of NIH-CPSI, U-WBC, PSA, IIEF-5, peak flow, PVR and VAS. Conclusions: In this observational study, we showed the clinical efficacy of the treatment with PEA, Epilobium and Calendula, 1 suppository/die for 1 month, in patients with CP/CPPS III. The benefits of this treatment could be related to the reduction of inflammatory cells in the urine that could imply a reduction of inflammatory cytokines. These results should be confirmed in further studies with greater sample size.

Abstract 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.

BackgroundMajor depressive disorder (MDD) exhibits gender disparities, and emerging evidence suggests the involvement of the gut microbiome, necessitating exploration of sex-specific differences.MethodsA 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.ResultsFive 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.ConclusionsThe findings underscore the importance of recognizing gender-specific 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 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.

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.

Purpose: Ferredoxin reductase (FDXR) is a flavoprotein that functions in both iron sulfur cluster biogenesis and steroid biosynthesis pathways in the mitochondria. Not surprisingly, loss of FDXR function causes severe mitochondrial diseases in humans. Although several FDXR-related mitochondriopathy (FRM) cohorts have been reported in the literature, further characterization of the natural history of FRM is warranted. Methods: To better understand the spectrum of FRM, a natural history study of FRM was performed. New cases were added to previously reported FRM cases for analysis (n = 62 cases). Results: Optic atrophy, movement disorder, and developmental delay were frequent findings. Mortality is high, with 18% of patients, often infants, passing from complications. Notably, 25% of cases were homozygous or compound heterozygous for the previously reported p.Arg386Trp “hotspot” variant. Of the obtained ancestry, all but 1 individual heterozygous for the p.Arg386Trp variant was Hispanic, with many reporting Mexican heritage. Utilizing recent large-scale genome sequencing surveys, the carrier frequency of the p.Arg386Trp variant was estimated as 1 of 185 in the Mexican population. Conclusion: Given the high mortality of FRM and carrier frequency of the common variant, consideration of a new approach for population carrier screening and development of therapeutics for affected individuals is needed.

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 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.gov NCT02881203 . Registered on 26 August 2016.

Abstract 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 Background Myoclonus, Epilepsy and Ragged-Red-Fibers (MERRF) is a mitochondrial encephalomyopathy due to heteroplasmic mutations in mitochondrial DNA (mtDNA) most frequently affecting the tRNA Lys gene at position m.8344A > G. Defective tRNALys severely impairs mitochondrial protein synthesis and respiratory chain when a high percentage of mutant heteroplasmy crosses the threshold for full-blown clinical phenotype. Therapy is currently limited to symptomatic management of myoclonic epilepsy, and supportive measures to counteract muscle weakness with co-factors/supplements. Methods We tested two therapeutic strategies to rescue mitochondrial function in cybrids and fibroblasts carrying different loads of the m.8344A > G mutation. The first strategy was aimed at inducing mitochondrial biogenesis directly, over-expressing the master regulator PGC-1α, or indirectly, through the treatment with nicotinic acid, a NAD+ precursor. The second was aimed at stimulating the removal of damaged mitochondria through prolonged rapamycin treatment. Results The first approach slightly increased mitochondrial protein expression and respiration in the wild type and intermediate-mutation load cells, but was ineffective in high-mutation load cell lines. This suggests that induction of mitochondrial biogenesis may not be sufficient to rescue mitochondrial dysfunction in MERRF cells with high-mutation load. The second approach, when administered chronically (4 weeks), induced a slight increase of mitochondrial respiration in fibroblasts with high-mutation load, and a significant improvement in fibroblasts with intermediate-mutation load, rescuing completely the bioenergetics defect. This effect was mediated by increased mitochondrial biogenesis, possibly related to the rapamycin-induced inhibition of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and the consequent activation of the Transcription Factor EB (TFEB). Conclusions Overall, our results point to rapamycin-based therapy as a promising therapeutic option for MERRF.

The intertidal zone is a harsh environment for marine life as conditions are often both extreme and variable. A wide range of sessile organisms are partially or fully emersed (exposed above the water line) during low tide. In the tropics, when corals are emersed, high light and temperature can be detrimental to their survival. To date, there is no commercially-available logger that can detect periods of emersion, information that is useful for marine research and for coastal resource management. Here, we present a low-cost Arduino-based multi-parameter logger called ‘EmerSense’ which can detect instances of emersion while simultaneously recording light and temperature profiles. We describe the different steps involved in fabricating EmerSense, including hardware construction and software design, and discuss the results of our field testing at an intertidal coral reef in Singapore.

Abstract 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 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

Abstract 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

Optic neuritis (ON) often occurs at the presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). The recommended treatment of high-dose corticosteroids for ON is based on a North American study population, which did not address treatment timing or antibody serostatus. The Acute Optic Neuritis Network (ACON) presents a global, prospective, observational study protocol primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON. Patients presenting within 30 days of the inaugural ON will be enrolled. For the primary analysis, patients will subsequently be assigned into the MS-ON group, the aquapotin-4-IgG positive ON (AQP4-IgG+ON) group or the MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from the onset of visual loss to high-dose corticosteroids (days-to-Rx). The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. In addition, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON, and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include low-contrast best-corrected visual acuity (LC-BCVA), optical coherence tomography (OCT), magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4-IgG and MOG-IgG levels, neurofilament, and glial fibrillary protein), and patient reported outcome measures (headache, visual function in daily routine, depression, and quality of life questionnaires) at presentation at 6-month and 12-month follow-up visits. Data will be collected from 28 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, and Australia. Planned recruitment consists of 100 MS-ON, 50 AQP4-IgG+ON, and 50 MOG-IgG+ON. This prospective, multimodal data collection will assess the potential value of early high-dose corticosteroid treatment, investigate the interrelations between functional impairments and structural changes, and evaluate the diagnostic yield of laboratory biomarkers. This analysis has the ability to substantially improve treatment strategies and the accuracy of diagnostic stratification in acute demyelinating ON.Trial registrationClinicalTrials.gov, identifier: NCT05605951.

Auditory Neuropathy (AN) is characterized by disruption of temporal coding of acoustic signals in auditory nerve fibers resulting in alterations of auditory perceptions. Mutations in several genes have been associated to the most forms of AN. Underlying mechanisms include both pre-synaptic and post-synaptic damage involving inner hair cell (IHC) depolarization, neurotransmitter release, spike initiation in auditory nerve terminals, loss of auditory fibers and impaired conduction. In contrast, outer hair cell (OHC) activities (otoacoustic emissions [OAEs] and cochlear microphonic [CM]) are normal. Disordered synchrony of auditory nerve activity has been suggested as the basis of both the alterations of auditory brainstem responses (ABRs) and reduction of speech perception. We will review how electrocochleography (ECochG) recordings provide detailed information to help objectively define the sites of auditory neural dysfunction and their effect on receptor summating potential (SP) and neural compound action potential (CAP), the latter reflecting disorders of ribbon synapses and auditory nerve fibers.

Objective REFLECT is the first randomised, double-masked, placebo-controlled multicentre phase 3 clinical trial that evaluated the efficacy and safety of bilateral intravitreal (IVT) injection of lenadogene nolparvovec in subjects with Leber hereditary optic neuropathy carrying the m.11778G>A mutation.Methods and analysis A total of 98 subjects were enrolled with vision loss of ≤12 months. The subjects were randomised to one of two treatment arms with all subjects receiving an intravitreal (IVT) injection of lenadogene nolparvovec in their first affected eye and the second-affected eye randomised to receive IVT of either lenadogene nolparvovec or placebo.Results The majority of subjects were male with a mean duration of vision loss of 8.3 months. All but one subject experienced bilateral loss of vision at the time of injection. The mean best-corrected visual acuity of first-affected eyes was worse compared with second/not-yet-affected eyes. Analysis of retinal anatomical parameters showed increased thinning in the first-affected eyes when compared with the second/not-yet-affected eyes with both treatment arms showing significant changes compared with unaffected individuals.Conclusion The REFLECT trial is the third and the largest phase 3 clinical study evaluating lenadogene nolparvovec in m.11778G>A Leber hereditary optic neuropathy (LHON) subjects. The observed demographics in REFLECT are consistent with previous reports in LHON subjects in the acute and dynamic phases of LHON disease. Combined with the visual function and anatomical parameters obtained in the previous RESCUE and REVERSE trials, REFLECT has provided a uniformly collected data set that should help direct future LHON clinical trials.

Abstract 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

Abstract 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.

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 Introduction To create and clinically validate knowledge‐based planning (KBP) models for gynaecologic (GYN) and rectal cancer patients. Assessment of ecologic generalisability and predictive validity of conventional planning versus single calculation KBP was reviewed against practical metrics of planning time (PT) and radiation oncologist plan preference. Method Study cohorts were 34 and 42 consecutively treated GYN and rectal cancer patients dosimetrically archived within the centre’s research databank. For model training, structures and dose distributions from 22 and 32 GYN and rectal volumetric‐modulated arc therapy (VMAT) plans were used in RapidPlan™. Prescription doses ranged from 45 to 60Gy in 25 fractions using a simultaneous integrated boost to 2–4 targets and up to 9 organ‐at‐risk volumes. For model validation, 12 GYN and 10 rectal were independent of the archive and a single pass KBP VMAT plan was created. Each plan was evaluated against the archived treated plan under blinded conditions for radiation oncologist preference using standard dosimetric quality parameters. Results All 22 plans generated in the KBP validation cohort met pre‐set GYN and rectal cancer dosimetric quality metrics. Fifty per cent of GYN plans and eighty per cent of rectal plans were judged superior to the manually optimised plans. KBP reduced PT considerably for both tumour sites. Conclusion Single pass KBP for GYN and rectal cancer patients produced clinically acceptable treatment plans which were non‐inferior to conventionally optimised plans in 14 of 22 cases. Efficiencies captured by KBP will have predictable impacts on institutional workflows and resource allocation to facilitate adaptive planning.

Abstract 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.

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.

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.

The accomplishment of a Favourable Conservation Status (FCS) for habitats and species is the Habitats Directive's primary goal (HD, 92/43/EEC). As tools for assessing the measurable parameters of conservation status, the European Commission identified Favourable Reference Values (FRVs), and it described the methodology to set them. However, examples of its application are rare.We propose a mixed reference-/model-based approach to set the Favourable Reference Population (FRP) and Range (FRR) for a threatened butterfly, Parnassius apollo, in the Italian Alps. The approach involves the use of a habitat suitability map obtained via Maxent as a basis for a clumping procedure to identify discrete patches of suitable habitat (clumps), corresponding to potentially viable local (meta)populations. The number and distribution of clumps occupied by the species along geographical gradients are compared to the distribution of all available clumps to define the FRVs.According to our analyses, 41 clumps are occupied by P. apollo in the Italian Alps. Since their distribution reflects clump availability along all geographical gradients, this value can be used to express the FRP, and to subsequently define the FRR as the envelope including the 41 clumps.Our approach considers several conditions reflecting the species persistence and provides insights for conservation and monitoring. Our objective, transparent method of setting FRVs can be applied to assess FCSs for other threatened species occurring in discrete units, with disjunct populations or local metapopulations.

Increasing evidence suggests that the gut microbiome is associated with both cancer chemotherapy (CTX) outcomes and adverse events (AEs). This review examines the relationship between the gut microbiome and CTX as well as the impact of CTX on the gut microbiome. A literature search was conducted in electronic databases Medline, PubMed and ScienceDirect, with searches for “cancer” and “chemotherapy” and “microbiome/microbiota”. The relevant literature was selected for use in this article. Seventeen studies were selected on participants with colorectal cancer (CRC; n=5), Acute Myeloid Leukemia (AML; n=3), Non-Hodgkin’s lymphoma (n=2), breast cancer (BCa; n=1), lung cancer (n=1), ovarian cancer (n=1), liver cancer (n=1), and various other types of cancers (n=3). Seven studies assessed the relationship between the gut microbiome and CTX with faecal samples collected prior to (n=3) and following CTX (n=4) showing that the gut microbiome is associated with both CTX efficacy and toxicity. Ten other prospective studies assessed the impact of CTX during treatment and found that CTX modulates the gut microbiome of people with cancer and that dysbiosis induced by the CTX is related to AEs. CTX adversely impacts the gut microbiome, inducing dysbiosis and is associated with CTX outcomes and AEs. Current evidence provides insights into the gut microbiome for clinicians, cancer survivors and the general public. More research is required to better understand and modify the impact of CTX on the gut microbiome.

Abstract Introduction Charles Bonnet syndrome is characterized by simple or complex visual hallucinations (VH) due to damage along the visual pathways. We report a functional MRI study of brain correlates of VH in the context of a severe optic atrophy in a patient with Leber’s Hereditary Optic Neuropathy (LHON). Case report A 62-year-old man was diagnosed with LHON (11778/ND4 mtDNA mutation) after subacute visual loss in left eye (right eye was amblyopic). One month later, he experienced VH of a few seconds consisting in “moving red and blue miniature cartoons”. One year later VH content changed in colored mosaic (10–15 s duration), usually stress-related, and blue and white flashes (2–5 s), triggered by unexpected auditory stimuli. Audiometry revealed mild sensorineural hearing loss. Three block design functional MRI paradigms were administrated: 1) random “clap”, 2) “checkerboard” and 3) non-random “beep”. After random “claps” simple flashes were evoked with bilateral activation of primary and secondary visual cortex, cuneus, precuneus and insula. Neither hallucinations nor cortex activation were registered after “checkerboard” stimulation, due to the severe visual impairment. Primary and secondary auditory cortices were “beep”-activated, without eliciting VH by non-random “beep”. Conclusions The peculiarity of our case is that VH were triggered by random auditory stimuli, possibly due to a cross-modal plasticity between visual and auditory networks, likely influenced by the sensorineural deafness. Functional alterations of both networks in resting conditions have been demonstrated in LHON patients, even without an auditory deficit. Finally, the absence of VH triggered by expected stimuli is consistent with the “expectation suppression theory”, based on increased neural activations after unexpected but not by predicted events.

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.

One of the main challenges in river management is the setting of nutrient thresholds that support good ecological status, which is the main objective to achieve for the European member states. This is a complex process, which needs an accurate analysis of the data collected so far for the ecological classification of rivers belonging to different typologies. We analysed the data of the multiannual monitoring concerning diatoms and nutrients in the upper Po River (NW Italy) with the aim of exploring the response of diatom community in terms of species composition, ecological guilds and indices. We considered data of 390 samples, of which 2/3 belonging to the “Central macrotype” (i.e. lowland stretches) and 1/3 to “Alpine siliceous”. We performed a Principal Coordinate Analysis to detect community patterns with respect to water chemical classification and macrotypes highlighting species and ecological guilds characteristic of samples along a water quality gradient. We then performed a partial RDA to focus on the role of environmental and spatial factors in shaping the diatom community in each of the two macrotypes. Finally, we investigated the concordance between the Italian normative indices ICMi (for diatoms) and LIMECO (a chemical index of water quality). We found significant differences in the diatom communities of the two macrotypes and in their response to water quality and to spatial factors. Communities resulted as much more uniform in sites with a low water quality, with characteristic species such as Navicula gregaria, Nitzschia palea and Sellaphora nigri. On the other hands, moderately disturbed sites (in terms of trophic level) were characterised by the highest guild diversity. The RDA confirmed the importance of spatial factors in shaping the diatom assemblages, especially in Alpine streams where the physical barriers may condition species dispersion. The comparison between the two normative indices highlights that the correspondence in the classification is achieved in the 57% (Alpine macrotype) and 43% (Central macrotype) of samples. According to our findings, we suggest the revision of the ICMi, both class boundaries and reference value. In addition, we recommend to lower LIMECO threshold for total phosphorus: indeed, several studies have shown significant changes in the diatom community composition starting from very low values (below the current LIMECO threshold, i.e. 50 µgL-1). Moreover, the extension of our study to the whole Po River basin will complete our knowledge of species not yet included in the diatom indices and of the community response to nutrient levels also in other macrotypes.

Leber's hereditary optic neuropathy (LHON) is due to missense point mutations affecting mitochondrial DNA (mtDNA); 90% of cases harbor the m.3460G>A, m.11778G>A, and m.14484T>C primary mutations. Here, we report and discuss five families with patients affected by symptomatic LHON, in which we found five novel mtDNA variants. Remarkably, these mtDNA variants are located in complex I genes, though without strong deleterious effect on respiration in cellular models: this finding is likely linked to the tissue specificity of LHON. This study observes that in the case of a strong clinical suspicion of LHON, it is recommended to analyze the whole mtDNA sequence, since new rare mtDNA pathogenic variants causing LHON are increasingly identified.

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies.Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control.Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss.Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences.Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4.Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of −0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (−0.32 LogMAR, p < 0.0001).Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies.Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.

Purpose: Our purpose was to report outcomes of a novel palliative radiation therapy protocol that omits computed tomography simulation and prospectively collects electronic patient-reported outcomes (ePROs). Methods and Materials: Patients receiving extracranial, nonstereotactic, linear accelerator-based palliative radiation therapy who met inclusion criteria (no mask-based immobilization and a diagnostic computed tomography within 4 weeks) were eligible. Global pain was scored with the 11-point numerical pain rating scale (NPRS). Patients were coded as having osseous or soft tissue metastases and no/mild versus severe baseline pain (NPRS ≥ 5). Pain response at 4 weeks was measured according to the international consensus (no analgesia adjustment). Transition to ePRO questionnaires was completed in 3 phases. Initially, pain assessments were collected on paper for 11 months, then pilot ePROs for 1 month and then, after adjustments, revised ePROs from 1 year onwards. ePRO feasibility criteria were established with reference to the paper-based process and published evidence. Results: Between May 2018 and November 2019, 542 consecutive patients were screened, of whom 163 were eligible (30%), and 160 patients were successfully treated. The proportion of patients eligible for the study improved from approximately 20% to 50% by study end. Routine care pain monitoring via ePROs was feasible. One hundred twenty-seven patients had a baseline NPRS recording. Ninety-five patients had osseous (61% severe pain) and 32 had soft tissue (25% severe pain) metastases. Eighty-four patients (66%) were assessable for pain response at 4 weeks. In the 41 patients with severe osseous pain, overall and complete pain response was 78% and 22%, respectively. Conclusions: By study completion, 50% of patients receiving palliative extracranial radiation therapy avoided simulation, streamlining the treatment process and maximizing patient convenience. Pain response for patients with severe pain from osseous lesions was equivalent to published evidence.

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.

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.

Background Several studies have identified fatigue as one of the major symptoms experienced during and after cancer treatment. However, there are limited options to manage cancer related fatigue (CRF) with pharmacological interventions. Several acupuncture studies suggested that acupuncture has a positive impact on CRF. This review aims to assess the evidence of acupuncture for the treatment of CRF. Method Electronic database searches were conducted on 4 English databases (Medline, PubMed, Embase, and ScienceDirect). Search keywords were; “acupuncture” and “cancer,” or “cancer related fatigue.” Studies published as full text randomized controlled trials (RCTs) in English were included. Estimates of change in fatigue cores were pooled using a random effects meta-analysis where randomized comparisons were available for true acupuncture versus sham acupuncture and true acupuncture versus usual care. The quality of original papers were assessed using the Cochrane Collaboration’s tool for assessing risk of bias (ROB). Results Nine RCTs were selected for review with a total of 809 participants and a range of 13 to 302 participants within the studies. Six RCTs reported significant improvement of CRF for the acupuncture intervention compared to the control groups. Pooled estimates suggest Brief Fatigue Inventory scores are 0.93 points lower 95% CI (−1.65, −0.20) in true acupuncture versus sham acupuncture and 2.12 points lower 95% C (−3.21, −1.04) in true acupuncture versus usual care. Six studies had low risk of bias (ROB) and 3 studies had a moderate ROB predominantly in blinding of participants, blinding of assessors and incomplete data outcomes. Among the 9 RCTs, 2 studies have reported the occurrence of minor adverse effects (spot bleeding and bruising) related to acupuncture treatment. No serious adverse reactions related to acupuncture were reported. Conclusion The current literature review suggests that acupuncture has therapeutic potential in management of CRF for cancer survivors. Promotion of acupuncture in cancer care to manage CRF may improve the quality of life of cancer survivors.

Intrinsically photosensitive melanopsin retinal ganglion cells (mRGCs) are crucial for non-image forming functions of the eye, including the photoentrainment of circadian rhythms and the regulation of the pupillary light reflex (PLR). Chromatic pupillometry, using light stimuli at different wavelengths, makes possible the isolation of the contribution of rods, cones, and mRGCs to the PLR. In particular, post-illumination pupil response (PIPR) is the most reliable pupil metric of mRGC function. We have previously described, in post-mortem investigations of AD retinas, a loss of mRGCs, and in the remaining mRGCs, we demonstrated extensive morphological abnormalities. We noted dendrite varicosities, patchy distribution of melanopsin, and reduced dendrite arborization. In this study, we evaluated, with chromatic pupillometry, the PLR in a cohort of mild-moderate AD patients compared to controls. AD and controls also underwent an extensive ophthalmological evaluation. In our AD cohort, PIPR did not significantly differ from controls, even though we observed a higher variability in the AD group and 5/26 showed PIPR values outside the 2 SD from the control mean values. Moreover, we found a significant difference between AD and controls in terms of rod-mediated transient PLR amplitude. These results suggest that in the early stage of AD there are PLR abnormalities that may reflect a pathology affecting mRGC dendrites before involving the mRGC cell body. Further studies, including AD cases with more severe and longer disease duration, are needed to further explore this hypothesis.

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.

Purpose To evaluate the impact of preoperative patient characteristics and flow rate on failure, early postoperative complications, and voiding in patients who underwent transvaginal tension-free vaginal tape-obturator (TVT-O) treatment for uncomplicated stress urinary incontinence (SUI). Methods We retrospectively reviewed patients who underwent TVT-O for SUI at 3 Italian centres. The exclusion criteria were predominant voiding and storage symptoms suggestive of detrusor overactivity, the presence of grade >1 urogenital prolapse, previous pelvic radiotherapy or other clinical contraindications for surgical procedures, neurogenic bladder dysfunction, and collagen diseases. Multivariate logistic regression models were constructed to identify predictors of early voiding dysfunction after TVT-O. Results A total of 219 patients underwent TVT-O between January 2010 and December 2015. All patients received follow-up at 3, 6, and 12 months, and underwent a stress test, uroflowmetry, and bladder ultrasound to evaluate the postvoid residual volume. They also responded to the Urogenital Distress Inventory (UDI-6) questionnaire. The rates of persistent incontinence after TVT-O, postoperative complications, and satisfaction were 16.4% (36 of 219), 24.2% (53 of 219), and 86.3% (189 of 219), respectively. Nineteen patients (9.5%) experienced early voiding dysfunction. Based on an analysis of baseline characteristics, we determined that a cutoff value of 9.0 on the UDI-6 predicted postoperative SUI with 62% specificity, 72% sensitivity, and 66% accuracy. In the multivariate logistic regression analysis, a preoperative UDI-6≥9.0 was an independent predictor of postoperative SUI. The predictors of complications were menopause (P = 0.04) and the preoperative UDI-6 score (P = 0.01). Conclusions Menopause and UDI-6 scores could be prognostic factors for persistent SUI after TVT-O. Well-designed prospective studies with a suitable number of patients are needed to corroborate our findings.

Objective: The risk factors for benign prostatic enlargement (BPE) are not well understood and particularly few data are available from Italian population. Materials and methods: This was an observational cross sectional study aimed to examine the association between several risk factors and BPE. During the “#Controllati2017” initiative, men aged 18 years or more were invited to attend participating urologic centers for a free of charge visit for counseling about urologic or andrologic conditions. Each participating man underwent a physical examination including digital rectal examination (DRE). Further he was asked about his medical history, urologic symptoms, sexual activity and related problems. Diagnosis of BPE was made by the urologist after DRE. Results: Out of the 1902 [mean age 54 years (SD 12, range 18-92)] considered men, a total of 603 subjects (31.7%) had diagnosis of BPE. The diagnosis of BPE increased from 9.3% in men aged < = 50 years, to 34.1% in those aged 51-60 years and to 58.7% among men aged > 60 years. A history of hypertension, diabetes, heart diseases, hypercholesterolemia and hypertriglyceridemia were all significantly associated with an increased risk of BPE in the total series and, although not always in a statistically significant way, in strata of age. Physical activity (PA) was significantly associated with a decreased risk of BPE. We have further analyzed the risk of BPE in men with one or more of the identified risk factors (i.e. hypertension, diabetes, heart disease, hypercholesterolemia, hypertriglyceridemia and low PA): the risk of BPE increased with number of risk factors reported by the subjects. The estimated risk were higher among younger men. Conclusion: In our study a history of hypertension, diabetes, heart disease, hypercholesterolemia and hypertriglyceridemia increased the risk and physical activity lowered the risk of BPE. This risk profile was observed also in men aged < 50 years.

Objective: The management of chronic prostatitis/ chronic pelvic pain syndrome type III (CP/CPPS) has been always considered complex due to several biopsychological factors underling the disease. In this clinical study, we aimed to evaluate the efficacy of the treatment with Curcumin and Calendula extract in patients with CP/CPPS III. Material and methods: From June 2015 to January 2016 we enrolled 60 consecutive patients affected by CP/CPPS III in our institution. Patients between 20 and 50 year of age with symptoms of pelvic pain for 3 months or more before study, a total National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score ≥ 15 point and diagnosed with NIH category III. Patients were then allocated to receive placebo (Group A) or treatment (Group B). Treatment consisted of rectal suppositories of Curcumin extract 350 mg (95%) and Calendula extract 80 mg (1 suppository/die for 1 month). Patients of Group B received 1 suppository/die for 1 month of placebo. The primary endpoint of the study was the reduction of NIH-CPSI. The secondary outcomes were the change of peak flow, IIEF-5, VAS score and of premature ejaculation diagnostic tool (PEDT). Results: A total of 48 patients concluded the study protocol. The median age of the all cohort was 32.0 years, the median NIH-CPSI was 20.5, the median IIEF-5 was 18.5, the median PEDT was 11.0, the median VAS score was 7.5 and the median peak flow was 14.0. After 3 months of therapy in group A we observed a significant improvement of NIH-CPSI (-5.5; p < 0.01), IIEF-5 (+ 3.5; p < 0.01), PEDT (-6.5; p < 0.01), peak flow (+2.8; p < 0.01) and VAS (-6.5; p < 0.01) with significant differences over placebo group (all p-value significant). Conclusions: In this phase II clinical trial we showed the clinical efficacy of the treatment with Curcumin and Calendula in patients with CP/CPPS III. The benefits of this treatment could be related to the reduction of inflammatory cytokines and of inflammatory cells. These results should be confirmed in further studies with greater sample size.