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PURPOSE: To describe the clinical phenotype of a cohort of patients with Wolfram syndrome (WS), focusing on the pattern of optic atrophy correlated with brain magnetic resonance imaging (MRI) measurements, as compared with patients with OPA1-related dominant optic atrophy (DOA).center dot DESIGN: Retrospective, comparative cohort study.center dot METHODS: We reviewed 25 patients with WS and 33 age-matched patients affected by OPA1-related DOA. Ophthalmologic, neurologic, endocrinologic, and MRI data from patients with WS were retrospectively retrieved. Ophthalmologic data were compared with data from patients with OPA1-related DOA and further analyzed for age dependency dividing patients in age quartiles. In a subgroup of patients with WS, we correlated the structural damage assessed by optical coherence tomography (OCT) with brain MRI morphologic measurements. Visual acuity (VA), visual field mean defect (MD), retinal nerve fiber layer (RNFL), and ganglion cell layer (GCL) thickness were assessed by OCT and MRI morphologic measurements of anterior and posterior visual pathways.center dot RESULTS: Optic atrophy was present in 100% of patients with WS. VA, MD, and RNFL thickness loss were worse in patients with WS with a faster decline since early age as compared with patients with DOA, who displayed a more stable visual function over the years. Conversely, GCL sectors were overall thinner in patients with DOA since early age compared to patients with WS, in which GCL thickness started to decline later in life. The neuroradiologic subanalysis on 11 patients with WS exhibited bilateral thinning of the anterior optic pathway, especially the prechiasmatic optic nerves and optic tracts. Optic tract thinning was significantly correlated with GCL thickness but not with RNFL parameters.center dot CONCLUSIONS: Our results showed a generally more severe and diffuse degeneration of both anterior and posterior visual pathways in patients with WS, with fast deterioration of visual function and structural OCT parameters since early age. The pattern observed with OCT suggests that retinal ganglion cell axonal degeneration (ie, RNFL) precedes cellular body atrophy (ie, GCL) by about a decade. This differs substantially from DOA, in which a more stable visual function is evident with predominant early loss of GCL, indirectly supporting the lack of a primary mitochondrial dysfunction in patients with WS. (Am J Ophthalmol 2022;241: 206-216. (c) 2022 Elsevier Inc. All rights reserved.)

Narcolepsy type 1 (NT1) is due to selective loss of hypocretin (hcrt)-producing-neurons. Hcrt is a neuropeptide regulating the sleep/wake cycle, as well as feeding behavior. A subset of NT1 patients become overweight/obese, with a dysmetabolic phenotype. We hypothesized that mitochondrial DNA (mtDNA) sequence variation might contribute to the metabolic features in NT1 and we undertook an exploratory survey of mtDNA haplogroups in a cohort of well-characterized patients. We studied 246 NT1 Italian patients, fully defined for their metabolic features, including obesity, hypertension, low HDL, hypertriglyceridemia and hyperglycemia. For haplogroup assignment, the mtDNA control region was sequenced in combination with an assessment of diagnostic markers in the coding region. NT1 patients displayed the same mtDNA haplogroups (H, HV, J, K, T, U) frequency as those reported in the general Italian population. The majority of NT1 patients (64%) were overweight: amongst these, 35% were obese, 48% had low HDL cholesterol levels, and 31% had hypertriglyceridemia. We identified an association between haplogroups J, K and hypertriglyceridemia (P = 0.03, 61.5% and 61.5%, respectively vs. 31.3% of the whole sample) and after correction for age and sex, we observed a reduction of these associations (OR = 3.65, 95%CI = 0.76-17.5, p = 0.106 and 1.73, 0.52-5.69, p = 0.368, respectively). The low HDL level showed a trend for association with haplogroup J (P = 0.09, 83.3% vs. 47.4% of the whole sample) and after correction we observed an OR = 6.73, 95%CI = 0.65-69.9, p = 0.110. Our study provides the first indication that mtDNA haplogroups J and K can modulate metabolic features of NT1 patients, linking mtDNA variation to the dysmetabolic phenotype in NT1.

The aim of this multicenter study was to investigate the prognostic role of neutrophil-to-lymphocyte ratio (NLR) and to validate the NLR cutoff of 3 in a large multi-institutional cohort of patients with primary T1 HG/G3 non-muscle-invasive bladder cancer (NMIBC)., M.D.V. is supported by the Scholarship Foundation of the Republic of Austria - OeAD and by the EUSP Scholarship - European Association of Urology.

Aromatase inhibitor-induced arthralgia (AIA) contributes to poor adherence of aromatase inhibitor therapies in patients with breast cancer. A systematic review using network meta-analysis (NMA) was conducted to examine the clinical effectiveness of multiple therapies and rank probabilities for the management of AIA. Randomized controlled trials (RCTs) assessing treatments for AIA in postmenopausal women with stage 0-III hormone receptor-positive breast cancer were searched from inception to October 2021. The main NMA involved 1516 participants from 17 RCTs. Acupuncture was the highest ranked intervention to improve pain intensity followed by sham acupuncture, multicomponent herbal medicine, exercise, duloxetine, vitamin D, omega-3 fatty acids, physical therapy, testosterone, and inactive controls. Single natural products were inferior to controls. The current review provides new insights into the management of AIA in breast cancer survivors for increased survival and can be utilized to make evidence-based decisions regarding treatment.

INTRODUCTION AND OBJECTIVES: To analyze postoperative complications and to assess for significant predictive factors during partial nephrectomy (PN) using a large multicenter dataset. METHODS: Patients who underwent PN for clinical T1 renal tumors at 19 urological Italian centers (Registry of Conservative Renal Surgery [RECORd] project) were evaluated between 2009 and 2012. Anthropometric data, comorbidities and perioperative outcomes were analyzed. Complications were divided as intra- and postoperative, medical and surgical, as appropriate. The severity of postoperative complications was graded according to the modified Clavien classification system. Patients who experienced intraoperative complications were excluded from the analyses for the potential confounding effect in the evaluation of predicting factors for postoperative complications. RESULTS: Overall, 979 patients were analyzed: open, laparoscopic and robot-assisted (available since 2011) surgical approaches were used in 522 (56.4%), 286 (30.9%) and 117 (12.6%) cases, respectively. Surgical postoperative complications were reported in 121 (13.1%) cases (32 (3.5%) were Clavien 3), medical were reported in 52 (5.6%) cases (3 (0.3%) were Clavien 3). No Clavien 4 complications were reported. At multivariable analysis, ECOG score ≥1 (OR 1.98; p = 0.002), lower preoperative hemoglobin (OR 0.71; p < 0.0001) and open surgical approach (2.91; p = 0.02) were significant predictive factors of overall surgical postoperative complications, ECOG score ≥1 (OR 1.93; p = 0.04) and surgical approach (p = 0.05) were significant predictive factors of Clavien 3 either surgical or medical postoperative complications. CONCLUSIONS: Comorbidities and surgical approach should be considered in preoperative evaluation of patients undergoing PN, as they resulted to play a significant role in the occurrence of postoperative complications.

Melanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive photoreceptors contributing both to image and non-image-forming (NIF) functions of the eye. They convey light signal to the brain to modulate circadian entrainment, sleep, alertness, cognition, brightness perception and coarse vision. Given that rods and cones also contribute to all these impacts of light, isolating mRGC visual and NIF roles in humans is challenging so that mRGC functions remains to be fully characterized. Here, we evaluated light-driven visual and cognitive brain responses in Leber’s Hereditary Optic Neuropathy (LHON), an inherited optic neuropathy that is characterized by a selective relative sparing of the melanopsin-expressing retinal ganglion cells (mRGCs). Twelve patients and twelve matched healthy controls (HC) were enrolled in a functional brain magnetic resonance imaging (fMRI) protocol including visual and visual-cognitive paradigms under blue (480 nm) and red (620 nm) light exposures. Primary visual cortex activation was detected in LHON patients; in particular higher occipital activation was found in response to sustained blue vs. red stimulation in LHON vs. HC. Similarly, brain responses to the executive task were larger under blue vs. red light in LHON over lateral prefrontal cortex. These findings are in line with the relative mRGC sparing demonstrated in LHON and support the mRGC contribution to both non-visual and visual brain functions, with potential implication for visual rehabilitation in hereditary optic neuropathy patients.

Incomplete penetrance characterizes the two most frequent inherited optic neuropathies, Leber's Hereditary Optic Neuropathy (LHON) and dominant optic atrophy (DOA), due to genetic errors in the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA), respectively. For LHON, compelling evidence has accumulated on the complex interplay of mtDNA haplogroups and environmental interacting factors, whereas the nDNA remains essentially non informative. However, a compensatory mechanism of activated mitochondrial biogenesis and increased mtDNA copy number, possibly driven by a permissive nDNA background, is documented in LHON; when successful it maintains unaffected the mutation carriers, but in some individuals it might be hampered by tobacco smoking or other environmental factors, resulting in disease onset. In females, mitochondrial biogenesis is promoted and maintained within the compensatory range by estrogens, partially explaining the gender bias in LHON. Concerning DOA, none of the above mechanisms has been fully explored, thus mtDNA haplogroups, environmental factors such as tobacco and alcohol, and further nDNA variants may all participate as protective factors or, on the contrary, favor disease expression and severity. Next generation sequencing, complemented by transcriptomics and proteomics, may provide some answers in the next future, even if the multifactorial model that seems to apply to incomplete penetrance in mitochondrial optic neuropathies remains problematic, and careful stratification of patients will play a key role for data interpretation. The deep understanding of which factors impinge on incomplete penetrance may shed light on the pathogenic mechanisms leading to optic nerve atrophy, on their possible compensation and, thus, on development of therapeutic strategies.

Multiparametric magnetic resonance imaging (mpMRI) is gaining acceptance to guide targeted biopsy (TB) in prostate cancer (PC) diagnosis. We aimed to compare the detection rate of software-assisted fusion TB (SA-TB) versus cognitive fusion TB (COG-TB) for PC and to evaluate potential clinical features in detecting PC and clinically significant PC (csPC) at TB.This was a retrospective cohort study of patients with rising and/or persistently elevated prostate-specific antigen (PSA) undergoing mpMRI followed by either transperineal SA-TB or transrectal COG-TB. The analysis showed a matched-paired analysis between SA-TB versus COG-TB without differences in clinical or radiological characteristics. Differences among detection of PC/csPC among groups were analyzed. A multivariable logistic regression model predicting PC at TB was fitted. The model was evaluated using the receiver operating characteristic-derived area under the curve, goodness of fit test, and decision-curve analyses.One hundred ninety-one and 87 patients underwent SA-TB or COG-TB, respectively. The multivariate logistic analysis showed that SA-TB was associated with overall PC (odds ratio [OR], 5.70; P .01) and PC at TB (OR, 3.00; P .01) but not with overall csPC (P = .40) and csPC at TB (P = .40). A nomogram predicting PC at TB was constructed using the Prostate Imaging Reporting and Data System version 2.0, age, PSA density and biopsy technique, showing improved clinical risk prediction against a threshold probability of 10% with a c-index of 0.83.In patients with suspected PC, software-assisted biopsy detects most cancers and outperforms the cognitive approach in targeting magnetic resonance imaging-visible lesions. Furthermore, we introduced a prebiopsy nomogram for the probability of PC in TB.

The aim of this study is to test the association between dietary flavonoids intake and prostate cancer (PCa) in a sample of southern Italian individuals.A population-based case-control study on the association between PCa and dietary factors was conducted from January 2015 to December 2016, in a single institution.Patients with elevated PSA (Prostate Specific Antigen) and/or suspicion of PCa underwent transperineal prostate biopsy (≥12 cores). A total of 118 histopathological-verified PCa cases were collected and matched with controls, which were selected from a sample of 2044 individuals randomly recruited among the same reference population. Finally, a total of 222 controls were selected.Prevalence of PCa.Consumption of certain groups of flavonoids significantly differed between controls and cases, in particular: flavonols (63.36 vs 37.14 mg/d, P 0.001), flavanols (107.61 vs. 74.24 mg/d, P = .016), flavanones (40.92 vs. 81.32 mg/d, P 0.001), catechins (63.36 vs. 36.18 mg/d, P = .006). In the multivariate model, flavanols and flavones were associated with reduced risk of PCa, despite not in the highest quartile of intake. Higher flavonol and catechin intake was consistently associated with reduced risk of PCa (Odds Ratio (OR) = 0.19, 95% CI: 0.06-0.56 and OR = 0.12, 95% CI: 0.04-0.36). In contrast, the highest intake of flavanones was positively associated with PCa.Flavonols and catechins have proved to be the most promising molecules for a potential protective role against PCa. Nevertheless, further research on flavanones is needed to better establish whether they are associated with PCa.

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.

Hybridization and introgression frequently occur in animal communities, both in nature or caused by human actions. In the genus Lepus (Mammals, Lagomorphs) genetic mixing has been widely documented and it probably affected the population dynamics of species, particularly during climatic oscillations. We thus propose and investigate a mathematical model, with the aim to describe and predict the outcome of interspecific interactions in a three-population system including European ( Lepus europaeus ), mountain ( Lepus timidus ) and hybrid hares. Our results show that the three-population system can survive at a stable level, but equilibria involving only parental species could also be feasible. This implies that, depending on initial conditions, the mountain hare could suffer from the competition with European and hybrid hares and its population could disappear in the near future. Under climate change scenarios, the conditions for coexistence will become even more restrictive, mountain hare populations could be depressed and finally collapse. Thus, at present the hybridization phenomenon does not necessarily represent a threat to the conservation of the unique genomes of the parental species, but climate change and human intervention, namely the introduction of European hares in the range of the Alpine mountain species, could result in an increase in the contact zones between populations, finally promoting hybridization and biotic homogenization.

This present study is devoted to investigate the vibration transmissibility of the elbow along the forearm direction as a function of hand grip force. The vibration was from 6 to 500 Hz, which was generated on a single-axis electric shaker. It was transmitted to the elbow from an instrumented handle fixed on the shaker through the hand-arm system. 34 healthy adults participated in the measurement experiment. Each of them applied a constant grip force while maintaining the forearm in horizontal direction with a 90° elbow angle. The grip force was controlled in terms of the percent maximum voluntary contraction and three levels (20%, 30% and 40%) most frequently observed at workplaces were used in the experiment. A laser vibrometer was used to measure the vibration on the bony surface of the elbow along the forearm direction. The measured vibration transmissibility spectrum was expressed in an equal frequency band with a resolution of less than 1 Hz. This study found that increasing the grip force did not significantly change the first resonant peak at 8 Hz but it increased the second resonant frequency and the vibration transmissibility at higher frequencies. Relevance to industry The effect of the grip force on the elbow vibration transmissibility can be used to enhance the understanding of the vibration-induced disorders. The force-specific transmissibility can also be used as a frequency-weighting factor to quantify the exposure. They may help improve the method for the risk assessment of vibration-induced elbow injuries and disorders.

Background Many potential chemopreventive agents have been used in PCa prevention, including selenium (Se) and lycopene (Ly). However, their role has been matter of debate over the years, due to potential of promotion of PCa. Purpose In this study we aimed at evaluating the incidence risk of prostate cancer (PCa) in a cohort of patients treated with Se and Ly. Methods The Procomb trial design has been previously published (ISRCTN78639965). From April 2012 to April 2014 209 patients were followed and underwent prostate biopsy when PSA ≥4 ng/ml and/or suspicion of PCa. The all cohort was composed by patients treated with Se and Ly (Group A = 134 patients) and control (Group B = 75 patients). Results During the follow-up time of 2 years, a total of 24 patients (11.5%) underwent prostate biopsy, of which 9 (4.3%) where diagnosed with PCa and 15 (7.2%) where diagnosed with benign prostatic hyperplasia. We did not observe statistical differences in terms of mean changes of PSA between the two groups (p-value for trend = 0.33). The relative risk (RR) for PCa was 1.07 and 0.89 in group A and B, respectively (p = 0.95). At the multivariate Cox regression analysis supplementation with Se and Ly was not associated with greater risk of PCa (hazard ratio: 1.38; p = 0.67). Conclusion In this analysis we did not show evidences supporting a detrimental role of Selenium and Lycopene supplementation in increasing PCa after 2 years of therapy, nor supporting a protective role.