Search

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Background Diagnostic delay of hereditary transthyretin amyloidosis (ATTRv, v for variant) prevents timely treatment and, therefore, concurs to the mortality of the disease. The aim of the present study was to explore with nerve ultrasound (US) possible red flags for early diagnosis in ATTRv patients with carpal tunnel syndrome (CTS) and/or polyneuropathy and in pre-symptomatic carriers. Methods Patients and pre-symptomatic carriers with a TTR gene mutation were enrolled from seven Italian centers. Severity of CTS was assessed with neurophysiology and clinical evaluation. Median nerve cross-section area (CSA) was measured with US in ATTRv carriers with CTS (TTR-CTS). One thousand one hundred ninety-six idiopathic CTS were used as controls. Nerve US was also performed in several nerve trunks (median, ulnar, radial, brachial plexi, tibial, peroneal, sciatic, sural) in ATTRv patients with polyneuropathy and in pre-symptomatic carriers. Results Sixty-two subjects (34 men, 28 women, mean age 59.8 years ± 12) with TTR gene mutation were recruited. With regard to CTS, while in idiopathic CTS there was a direct correlation between CTS severity and median nerve CSA (r = 0.55, p r = − 0.473). ATTRv patients with polyneuropathy showed larger CSA than pre-symptomatic carriers in several nerve sites, more pronounced at brachial plexi (p Conclusions The present study identifies nerve morphological US patterns that may help in the early diagnosis (morpho-functional dissociation of median nerve in CTS) and monitoring of pre-symptomatic TTR carriers (larger nerve CSA at proximal nerve sites, especially at brachial plexi).

Purpose Smell alterations are a symptom of COVID-19 and have been associated with olfactory cleft mucosal thickening (OCMT). Although their pathogenesis is unclear, evidences link them to viral neuroinvasive potential. This study aims at estimating the prevalence of OCMT in CT scans of COVID-19 patients and investigating its clinical correlates. Methods In a single-institution retrospective cross-sectional study, we included all patients hospitalized for COVID-19 undergoing head CT scan for any reason. Exclusion criteria were history of recent head trauma or chronic rhinosinusitis; opacification > 2 mm in any sinonasal space other than the olfactory cleft; CT performed during/after invasive ventilation or feeding via nasogastric tube. We recorded the prevalence of OCMT and related it to age, sex, need for invasive ventilation during hospital stay, outcome, length of hospital stay, diffusion of lung SARS-CoV-19 lesions and outcome. Results 63 eligible patients were identified (39 male, 24 female; median age 77.82 ± 17.77 years). OCMT was identified in 16 patients (25.4%; 95% CI 15.3–37.9%). Patients with OCMT had longer hospital stays (median 16 ± 4 vs. 9 ± 14.5 days, p = .009, Mann–Whitney U test) and required invasive ventilation more frequently than patients without mucosal thickening (OR 4.89, 95% CI 0.96–24.89, p = .063, Fisher’s test). No other difference was observed. Conclusion OCMT affects nearly one in four patients hospitalized for COVID-19. It is associated with a worse disease course irrespective of age, sex and diffusion of lung lesions, although with no direct effect on survival.

Adenoidectomia endoscopica: revisione sistematica di risultati e complicanze in 1006 pazienti.L’ipertrofia adenoidea è una condizione estremamente comune nella popolazione pediatrica, correlata a differenti scenari patologici. Laddove la terapia medica non è sufficiente a gestire la patologia, può essere necessario ricorrere all’approccio chirurgico eseguendo un’adenoidectomia. Mentre la tecnica chirurgica tradizionale è una procedura eseguita relativamente “alla cieca”, l’approccio endoscopico permette di eseguire una resezione radicale, con controllo del sanguinamento ed un completo risparmio degli osti tubarici, rendendo l’adenoidectomia video-assistita una scelta più sicura, controllata e funzionale. Nonostante in letteratura venga ampiamente descritta come tecnica, gli studi si sviluppano su piccole casistiche e l’approccio endoscopico non ha mai realmente assunto un posto centrale nella pratica otorinolaringoiatrica. Lo scopo del seguente articolo è di analizzare i risultati dell’adenoidectomia endoscopica eseguita su un’ampia popolazione di pazienti afferenti ad un unico centro. È stata eseguita un’indagine retrospettiva su un database di 1006 bambini sottoposti ad interventi di adenoidectomia endoscopica con o senza tonsillectomia (rispettivamente 513 e 493 pazienti). I dati raccolti si basano su tempo chirurgico, perdite ematiche, tempo di degenza, complicanze a breve e lungo termine, recidive e dolore post-operatorio. L’analisi ha mostrato, in confronto ad ampie casistiche di approcci sia tradizionali che endoscopici, un tempo chirurgico maggiore, ma allo stesso tempo minori perdite ematiche intraoperatoriamente, così come un inferiore tasso di complicanze e recidive. La differenza nei risultati è maggiormente apprezzabile comparando i nostri dati con quelli della tecnica classica piuttosto che con le casistiche su approcci endoscopici. L’adenoidectomia video-assistita dovrebbe dunque essere considerata una tecnica solida che, in mani esperte, riduce le complicanze e le recidive a spese di un maggior impiego di tempo di lavoro.Adenoid hypertrophy (AH) is an extremely common condition in the paediatric population, relating to different pathological scenarios. Failure in responding to medical therapy often leads to adenoidectomy. While traditional adenoidectomy is indeed a relatively “blind” procedure, endoscopic procedures allow more radical resections, bleeding monitoring and complete Eustachian tube sparing, making adenoidectomy a safer, more manageable and functional procedure. Though the literature widely describes endoscopic adenoidectomy, only small case series are available and the procedure itself has never really taken hold in routine otolaryngology practice. The aim of this article is to report data on endoscopic adenoidectomy in a large single centre patient population. We retrospectively evaluated the medical records of 1006 children who underwent endoscopic adenoidectomy with or without tonsillectomy (respectively 493 and 513 patients). Data on surgical time, blood loss, hospital stay, short and long-term complications, recurrences and post-operative pain were collected. Our analysis showed that the endoscopic approach requires a longer surgical time, but it is associated with less intraoperative blood loss, a lower complication rate and less treatment failures compared to large contemporary case series of either traditional or power-assisted approaches. The overall better outcomes are more noticeable when comparing our data with classic technique case series than with power-assisted case series. Endoscopic adenoidectomy should therefore be regarded as a valid technique, which, in expert hands, lowers the rates of complications and recurrences at the expense of a slightly increased surgical time.

AIM: To identify the effect of single nucleotide polymorphism (SNP) interactions on the risk of toxicity following radiotherapy (RT) for prostate cancer (PCa) and propose a new method for polygenic risk score incorporating SNP-SNP interactions (PRSi). MATERIALS AND METHODS: Analysis included the REQUITE PCa cohort that received external beam RT and was followed for 2 years. Late toxicity endpoints were: rectal bleeding, urinary frequency, haematuria, nocturia, decreased urinary stream. Among 43 literature-identified SNPs, the 30% most strongly associated with each toxicity were tested. SNP-SNP combinations (named SNP-allele sets) seen in ≥10% of the cohort were condensed into risk (RS) and protection (PS) scores, respectively indicating increased or decreased toxicity risk. Performance of RS and PS was evaluated by logistic regression. RS and PS were then combined into a single PRSi evaluated by area under the receiver operating characteristic curve (AUC). RESULTS: Among 1,387 analysed patients, toxicity rates were 11.7% (rectal bleeding), 4.0% (urinary frequency), 5.5% (haematuria), 7.8% (nocturia) and 17.1% (decreased urinary stream). RS and PS combined 8 to 15 different SNP-allele sets, depending on the toxicity endpoint. Distributions of PRSi differed significantly in patients with/without toxicity with AUCs ranging from 0.61 to 0.78. PRSi was better than the classical summed PRS, particularly for the urinary frequency, haematuria and decreased urinary stream endpoints. CONCLUSIONS: Our method incorporates SNP-SNP interactions when calculating PRS for radiotherapy toxicity. Our approach is better than classical summation in discriminating patients with toxicity and should enable incorporating genetic information to improve normal tissue complication probability models. ispartof: RADIOTHERAPY AND ONCOLOGY vol:159 pages:241-248 ispartof: location:Ireland status: published

PURPOSE: To analyze the comparative safety and efficacy of two techniques of corneal neurotization (CN) (direct corneal neurotization [DCN] vs indirect corneal neurotization [ICN] for the treatment of neurotrophic keratopathy (NK).DESIGN: Multicenter Interventional Prospective Comparative Case Series.METHODS: Setting: ASST Santi Paolo e Carlo University Hospital, Milan; S.Orsola-Malpighi University Hospital, Bologna; Santa Maria alle Scotte University Hospital, Siena.STUDY POPULATION: Consecutive patients with NK undergoing CN between November 2014 and October 2019; Intervention Procedures: DCN was performed by transferring contralateral supraorbital and supratrochlear nerves; ICN was performed using sural nerve graft.MAIN OUTCOME MEASURES: NK healing; corneal sensitivity; corneal nerve fiber length (CNFL) measured by in vivo confocal microscopy (IVCM); complication rate.RESULTS: 26 eyes of 25 patients were included: 16 were treated with DCN and 10 with ICN. After surgery, NK healed in all patients after a mean period of 3.9 months without differences between DCN and ICN. Mean corneal sensitivity improved significantly 1 year after surgery (from 3.07 to 22.11 mm; p

The Covid-19 pandemic has highlighted the importance of citizens’ behaviors in the containment of the virus. Individuals might change their intention to adhere to public health prescriptions depending on various personal characteristics, including their own emotional status, which has been recognized to be a crucial psychological factor in orienting people’s adherence to public health recommendation during emergency settings. In particular, it is crucial to support citizens’ alliance with authorities and feeling of trust: public engagement is a concept that refers to the general involvement of citizens into public affairs which is generally considered an effective approach to enhance citizens’ understanding of their crucial role in public affairs. However, so far there is no agreement on the metrics and indexes that should be used to measures public engagement during a health crisis. The aim of this paper is to validate a psychometric scale (PHEs-E), which intends to measure the readiness of individuals to adhere to the prescribed behavioral change to contain the emergency. Data were collected throughout the pandemic in Italy: in particular, five independent samples were recruited starting from March 2020 to March 2021. Results showed that the proposed measure has good psychometric characteristics. A general linear model was computed to assess the differences of public engagement across the different data points and among citizens with different sociodemographic characteristics. Correlations with other psychological constructs (i.e. Anxiety, Depression and Self-Efficacy) were also tested, showing that more engaged citizens have a lower level of anxiety and depression, and a higher self-efficacy. This study’s findings indicate that individuals’ characteristics may differentiate citizens’ motivation to engage in public health behavioral recommendation to prevent the COVID-19 contagion. However the scale could be useful to perform a psychological monitoring of psychological readiness to engage in public health strategies to face critical events and settings.

Context: To investigate the association between the single nucleotide polymorphism in the position-889 (C/T) of the promoter region of the IL-1α gene and the susceptibility to tinnitus. Method: This was a case-control study with a sample of 108 independent elderly people over 60 years of age. Information on exposure to occupational noise and tinnitus was obtained by interviews. The genetic polymorphism was analyzed by polymerase chain reaction followed by cleavage with restriction enzyme NcoI. Data were analyzed using the Chi-square test, with the significance level set at 5%. For the statistical analysis all individuals with tinnitus on the right ear were eligible. Results: Among elderly with tinnitus, 42.9% had a history of exposure to occupational noise. There was statistically significant association between IL-1α gene polymorphism and tinnitus in subjects without a history of exposure to occupational noise (P = 0.006 and χ2 = 10.39). The elderly with the T allele were less likely to have tinnitus due to occupational noise exposure when compared to those carrying the C allele. Conclusion: This study suggests an association between the IL-1α gene polymorphism with susceptibility to tinnitus in individuals without a history of exposure to occupational noise. The present study demonstrated that allele T of IL-1α is a protective factor for presence and severity of tinnitus in the elderly and allele C contributes to the pathogenesis of the inflammatory response. The present observation implied the signaling IL-1α is involved in ear aging.

Lingual nerve (LN) injury is one of the most serious consequences of oral surgery. Prompt microsurgical reconstruction of the nerve can alleviate most of those symptoms leading to satisfactory functional recovery.Thirty-five patients with partial to complete LN injury underwent surgery in the period between January 2006 and May 2015. All patients underwent a preoperative clinical and neurological evaluation with the assessment of lingual tactile and pain sensory thresholds and masseteric inhibitory reflex.All patients underwent explorative surgery and direct microneurorrhaphy of distal and proximal stumps in case of complete lesion, while the removal of traumatic neuroma and the following microneurorrhaphy of distal and proximal stumps of the injured nerve was performed in case of incomplete lesion. Nerve grafting has always been avoided because of distal stump mobilization obtained by severing the submandibular branch of the LN.All patients but 1 exhibited good recovery of tongue sensation, never complete, both clinically and electrophysiologically: recovery of the excitability of masseteric inhibitory reflex suppression components SP1 and SP2 was observed, often with increased latencies but consistent with a functional recovery.All patients feeling pain preoperatively experienced complete relief of algic symptoms.The early microsurgical approach is the most suitable choice for the treatment of LN injuries.

Tafamidis is a transthyretin (TTR) stabilizer able to prevent TTR tetramer dissociation. There have been a few encouraging studies on Tafamidis efficacy in early-onset inherited transthyretin amyloidosis (ATTR) due to Val30Met mutation. However, less is known about its efficacy in later disease stages and in non-Val30Met mutations. We performed a multi-center observational study on symptomatic ATTR patients prescribed to receive Tafamidis. We followed up patients according to a standardized protocol including general medical, cardiological and neurological assessments at baseline and every 6 months up to 3 years. Sixty-one (42 males) patients were recruited. Only 28 % of enrolled subjects had the common Val30Met mutation, mean age of onset was remarkably late (59 years) and 18 % was in advanced disease stage at study entry. Tafamidis proved safe and well-tolerated. One-third of patients did not show significant progression along 36 months, independently from mutation type and disease stage. Neurological function worsened particularly in the first 6 months but progression slowed significantly thereafter. Autonomic function remained stable in 33 %, worsened in 56 % and improved in 10 %. Fifteen percent of patients showed cardiac disease progression and 30 % new onset of cardiomyopathy. Overall, Tafamidis was not able to prevent functional progression of the disease in 23 (43 %) subjects, including 16 patients who worsened in their walking ability and 12 patients who reached a higher NYHA score during the follow-up period. A higher mBMI at baseline was associated with better preservation of neurological function. In conclusion, neuropathy and cardiomyopathy progressed in a significant proportion of patients despite treatment. However, worsening of neurological function slowed after the first 6 months and also subjects with more advanced neuropathy, as well as patients with non-Val30Met mutation, benefited from treatment. Body weight preservation is an important favorable prognostic factor.

Synkinetic movements are common among patients with incomplete recovery from facial palsy, with reported rates ranging from 9.1% to almost 100%. The authors propose the separation of the neural stimulus of the orbicularis oculi from that of the zygomatic muscular complex to treat eyelid closure/smiling synkinesis. This technique, associated with an anastomosis between the masseteric nerve and a central branch of the facial nerve, as well as with the use of a cross-facial nerve graft, resolves most of the spasms of the midface musculature, leading to a more relaxed tone when the mimic muscle is at rest and enhancing muscle excursion during voluntary and spontaneous smiling. Between 2011 and 2016, 18 patients affected by segmental paresis of the middle of the face underwent surgical treatment at the Maxillofacial Surgery Department of the San Paolo Hospital (Milan, Italy). Of these patients, 72.22% of cases with hypertone obtained partial to complete relaxation. Synkinesis was completely resolved in 83.33% of cases, and a significant improvement in facial movement was achieved in all patients. Neurorrhaphy of the masseteric nerve and the central branch of the facial nerve appears to produce favorable results. These initial data should be confirmed by further studies.

PURPOSE: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. METHODS: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. RESULTS: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician- (47,025 forms) and patient- (54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade ≥2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). CONCLUSION: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. PATIENT SUMMARY: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short- and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity. ispartof: RADIOTHERAPY AND ONCOLOGY vol:138 pages:59-67 ispartof: location:Ireland status: published

Given the intrinsic complexity of cognitive and affective processes affecting how people reason about taxes and their decisions to be compliant with such social duty, we aimed at exploring those latent processes by combining the analysis of their central and peripheral physiological correlates. We asked participants to make realistic economic decisions concerning tax-payment and manipulated the social vs. individual decisional frame. In addition, we took into account the potential role of tax-compliance trait. Thirty self-employed professionals took part in the study and completed a public good game while their autonomic (skin conductance – SC – and heart rate – HR) and neural brain (electroencephalography – EEG) activities were recorded. The analysis of physiological responses during the feedback phase – where participants could be presented or not with a fiscal audit – highlighted: (i) increased tonic SC levels and theta activity in the social condition than in the individual one; (ii) increased HR values when a fiscal audit did not take place, especially in participants who presented an enforced tax-compliance trait. Present findings support the idea that classic economic theories of tax behaviour developed under the assumption that taxpayers act as rational and individualist agents do not provide a comprehensive account for the decision-making process. They add to available evidence highlighting the contribution of psychological and social-affective variables to individuals’ decision-making processes to pay or evade taxes and to their appraisal of the consequences of such choice, as suggested by the ‘slippery slope’ framework.

Segmental midface paresis with or without synkinesis reflects incomplete recovery from Bell's palsy, operations on the cranial base or parotid, or trauma, in 25%-30% of cases. To correct the deficit, the masseteric nerve was used to deliver a powerful stimulus to the zygomatic muscle complex, with the addition of a cross-face sural nerve graft to ensure more spontaneous smiling. By doing this, the orbicularis oculi muscle continues to have an appropriate stimulus from the facial nerve, and the zygomatic muscle complex is separately innervated, which considerably reduces synkinesis between the two muscle compartments. For those patients with muscular contractures of the midface, the new healthy neural stimulus relaxes muscles at rest. From January 2011 to March 2017, 20 patients presented with segmental facial paresis of the midface and were operated on using this new technique. All patients were evaluated before and after operation using Clinician-Graded Electronic Facial Paralysis Assessment (eFACE), and they showed considerable postoperative improvements in static, dynamic, and synkinetic variables. Our proposed use of the masseteric nerve to treat segmental facial paresis produces favourable results, but our initial data require confirmation by further studies.

Recent facial paralyses, in which fibrillations of the mimetic muscles are still detectable by electromyography (EMG), allow facial reanimation based on giving new neural stimuli to musculature. However, if more time has elapsed, mimetic muscles can undergo irreversible atrophy, and providing a new neural stimulus is simply not effective. In these cases function is provided by transferring free flaps into the face or transposing masticatory muscles to reinstitute major movements, such as eyelid closure and smiling. In a small number of cases, patients affected by paralysis are referred late - more than 18 months after onset. In these cases, reinnervating the musculature carries a high risk of failure because some or all of the mimetic muscles may atrophy irreversibly while axonal ingrowth is taking place. A mixed reanimation technique to address this involves a neurorrhaphy between the masseteric nerve and a facial nerve branch for the orbicularis oculi, to ensure a stronger innervation to that muscle, associated with the transposition of the temporalis muscle to the nasiolabial sulcus. This gives good symmetry in the rest of the midface, while smiling movement is achievable, but not guaranteed. This one-time facial reanimation is particularly indicated for those who refuse major free-flap surgery or when that may be risky, as in previously operated and irradiated fields. More extensive procedures based on utilizing a free flap to recover smiling, while adding a cross-face nerve graft to restore blinking, may be proposed for motivated patients. Between 2010 and 2015, five patients affected by complete unilateral facial palsy underwent this technique in the Maxillofacial Surgery Department, San Paolo Hospital (Milan, Italy). Symmetry of the middle-third of the face at rest and recovery of smiling was quite good. Complete voluntary eyelid closure was obtained in all cases. Combining temporalis flap rotation and a masseteric-to-orbicularis-oculi-facial-nerve branch neurorrhaphy seems to be a valid solution for those medium-term referred patients.

BackgroundIn January 2020, the coronavirus disease 2019 (COVID-19) started to spread in Italy. The Italian government adopted urgent measures to hold its spread. Enforcing compliance to such measures is crucial in order to enhance their effectiveness. Engaging citizens in the COVID-19 preventive process is today urgent in Italy and around the world. However, to the best of our knowledge, no previous studies have investigated the role of health engagement in predicting citizens’ compliance to health emergency containment measures.MethodAn online survey was administered between February 28th and March 4th 2020 on a representative sample of 1000 Italians. The questionnaire included a measure of Health Engagement (PHE-S) and a series of ad hoc items intended to measure both affective and behavioral responses of the citizens to the emergency in terms of perceived susceptibility to and severity of the disease, orientation towards health management, change in habits and in purchases. To investigate the relationship between Health Engagement and these variables, a series of ANOVAs, Logistic regressions and crosstabs have been carried out.ResultsLess engaged people show higher levels of perceived susceptibility to the virus and of severity of the disease; they trust less scientific and healthcare authorities, they feel less self-effective in managing their own health - both in normal conditions and under stress - and are less prone to cooperate with healthcare professionals. Low levels of Health Engagement are also associated with a change in the usual purchase behavior.ConclusionsThe Patient Health Engagement Model (PHE) provides a useful framework for understanding how people will respond to health threats such as pandemics. Therefore, intervention studies should focus on particular groups and on raising their levels of engagement to increase the effectiveness of educational initiatives devoted to promote preventive behaviors.

Human immune system mice are highly valuable for in vivo dissection of human immune responses. Although they were employed for analyzing tuberculosis (TB) disease, there is little data on the spatial organization and cellular composition of human immune cells in TB granuloma pathology in this model. We demonstrate that human immune system mice, generated by transplanted human fetal liver derived hematopoietic stem cells develop a continuum of pulmonary lesions upon Mycobacterium tuberculosis aerosol infection. In particular, caseous necrotic granulomas, which contribute to prolonged TB treatment time, developed, and had cellular phenotypic spatial-organization similar to TB patients. By comparing two recommended drug regimens, we confirmed observations made in clinical settings: Adding Moxifloxacin to a classical chemotherapy regimen had no beneficial effects on bacterial eradication. We consider this model instrumental for deeper understanding of human specific features of TB pathogenesis and of particular value for the pre-clinical drug development pipeline.

Bickerstaff Brainstem Encephalitis (BBE) is a rare autoimmune encephalitis, characterized by acute ophthalmoplegia, ataxia and altered state of consciousness. Together with Guillan-Barre Syndrome (GBS) and Miller-Fisher Syndrome, it forms a spectrum of post-infectious demyelinating diseases. Overlapping forms between BBE and GBS (BBE/GBS) are described in patients with lower limbs weakness and typical signs of BBE, suggesting a combined involvement of Central and Peripheral Nervous System (PNS), but only few reported cases are focused on pediatric population. We reviewed all cases of pediatric BBE in the literature, to determine if any patient showed features suggestive for BBE/GBS. Data analysis focused on the diagnostic tests performed (e.g. anti-GQ1b antibodies), neuroimaging and nerve conduction studies (NCS). Further attention was given to the therapeutic management and to patients' outcome. We additionally present two previously unreported pediatric cases. Our review retrieved 19 cases of BBE/GBS, only 2 of which were originally and correctly diagnosed by the authors. The prevalence was higher in male subjects (ratio 3:1) and median age at diagnosis was 8 years. Anti-GQ1b were positive in 46% of the patients, while NCS were altered in 64%. Only 25% of the patients that underwent brain MRI showed abnormal findings. The incidence of BBE/GBS has been underrated in the past, mostly due to an underestimation of the PNS involvement. We therefore suggest to investigate all patients with a clinical picture suggestive of BBE/GBS through electroencephalogram, NCS, brain and spine MRI in order to promptly achieve the correct diagnosis.

Objective This study aimed at assessing clients’ satisfaction and associated factors among adults. A cross sectional facility based study was conducted on 420 clients of Yekatit 12 Hospital Medical College from 1 June 2016 to 1 July 2016. Data was entered, cleaned, and analyzed using SPSS statistical package. Data was analyzed using a multivariable logistic regression model to find out the most significant predictors for clients satisfaction with outpatient services at Yekatit 12 Hospital Medical College. Results This study showed that the overall clients’ satisfaction level towards out-patient health service at Yekatit 12 Hospital Medical College was 47% at 95% CI (42.5, 51.7%). The most frequently identified problems were: lack of clean toilet in nearby the waiting areas, lack of waiting area particularly at pharmacy, inadequate furniture like chair, lack of adequate drugs and supplies, lack of privacy at the examination room, lack of direction signs, and poor communication between clients and health service providers. In conclusion the overall satisfaction level of the patients is low, so this demands the Hospital to take further action on the identified problems to improve the services delivered to the patients. Electronic supplementary material The online version of this article (10.1186/s13104-018-3603-3) contains supplementary material, which is available to authorized users.

Refractory chronic migraine is a disabling disorder impacting quality of life. BOTOX&reg, (Onabotulinumtoxin A) is approved as a prophylactic treatment of chronic migraine in patients unresponsive to at least three prior preventive treatments. The objective of this study was to determine the prophylactic effect of 145 U XEOMIN&reg, (Incobotulinumtoxin A) injected at 31 specific sites in adult patients with refractory chronic migraine. Sixty-one patients (8 men and 53 women, mean age 50) with migraine were recruited, including 20 patients with isolated chronic migraine, 18 patients with chronic migraine associating tension-type headache, 12 patients with migraine associating medication overuse headache, and 11 patients with episodic disabling migraine. The mean number of injections and duration of treatment per patient was 3.5 (range 2&ndash, 13) and 21 (6&ndash, 68) months, respectively. From baseline to first injection, 44 patients (73%) had &gt, 50% reduction in frequency of migraine episodes, 29 patients (48%) showed &gt, 50% reduction in number of headache days, and 28 patients (46%) had a &gt, 50% reduction in drug intake. Stable response for all three parameters was observed after the last injection. XEOMIN&reg, thus seems to represent an effective and sustained prophylactic treatment of chronic migraine.

Few paediatric cases of clinically isolated syndrome (CIS) have been described in literature, even though it has been increasingly recognized also in this age group. Our study retrospectively enrolled seven Italian patients (four males and three females) who met the International Paediatric Multiple Sclerosis Study Group (IPMSSG) 2012 criteria for clinically isolated syndrome over the period 2010–2014; their clinical, laboratory and imaging findings were compared with current literature and with those seen in five patients (three males and two females) with acute disseminated encephalomyelitis, who were followed in our department over the same years (mean follow-up time 2.84 ± 1.8 years). In our CIS sample, male sex was prevalent, 42.8 % of patients had a multifocal presentation, MRI lesions mostly appeared confluent and with poorly defined margins, and CSF oligoclonal bands (OCBs) were identified in 28.6 %. All acute disseminated encephalomyelitis (ADEM) patients had polyfocal presentation and encephalopathy; large MRI subcortical lesions and polyclonal IgG distribution were identified. During the subsequent follow-up assessments, MRI scan revealed new lesions in three CIS patients, while in ADEM children it appeared normal. Paediatric CIS patients often show peculiar epidemiological, clinical and radiological features, which significantly differ from adult ones. The presence of encephalopathy and of extended MRI lesions leads to a diagnosis of ADEM, instead. In CIS patients the presence of multiple asymptomatic MRI lesions and of OCBs revealed to be the most predictive risk factors for progression to clinically definite multiple sclerosis (CDMS), so a regular long-term follow-up is recommended; in ADEM, no suitable risk factors for a relapse could be identified.

A Spanish group recently reported that four patients with chronic inflammatory demyelinating polyneuropathy carrying IgG4 autoantibodies against contactin 1 showed aggressive symptom onset and poor response to intravenous immunoglobulin. We aimed to describe the clinical and serological features of Japanese chronic inflammatory demyelinating polyneuropathy patients displaying the anti-contactin 1 antibodies. Thirteen of 533 (2.4%) patients with chronic inflammatory demyelinating polyneuropathy had anti-contactin 1 IgG4 whereas neither patients from disease or normal control subjects did (P = 0.02). Three of 13 (23%) patients showed subacute symptom onset, but all of the patients presented with sensory ataxia. Six of 10 (60%) anti-contactin 1 antibody-positive patients had poor response to intravenous immunoglobulin, whereas 8 of 11 (73%) antibody-positive patients had good response to corticosteroids. Anti-contactin 1 IgG4 antibodies are a possible biomarker to guide treatment option.

OBJECTIVE Facial palsy is a well-known functional and esthetic problem that bothers most patients and affects their social relationships. When the time between the onset of paralysis and patient presentation is less than 18 months and the proximal stump of the injured facial nerve is not available, another nerve must be anastomosed to the facial nerve to reactivate its function. The masseteric nerve has recently gained popularity over the classic hypoglossus nerve as a new motor source because of its lower associated morbidity rate and the relative ease with which the patient can activate it. The aim of this work was to evaluate the effectiveness of masseteric–facial nerve neurorrhaphy for early facial reanimation. METHODS Thirty-four consecutive patients (21 females, 13 males) with early unilateral facial paralysis underwent masseteric–facial nerve neurorrhaphy in which an interpositional nerve graft of the great auricular or sural nerve was placed. The time between the onset of paralysis and surgery ranged from 2 to 18 months (mean 13.3 months). Electromyography revealed mimetic muscle fibrillations in all the patients. Before surgery, all patients had House-Brackmann Grade VI facial nerve dysfunction. Twelve months after the onset of postoperative facial nerve reactivation, each patient underwent a clinical examination using the modified House-Brackmann grading scale as a guide. RESULTS Overall, 91.2% of the patients experienced facial nerve function reactivation. Facial recovery began within 2–12 months (mean 6.3 months) with the restoration of facial symmetry at rest. According to the modified House-Brackmann grading scale, 5.9% of the patients had Grade I function, 61.8% Grade II, 20.6% Grade III, 2.9% Grade V, and 8.8% Grade VI. The morbidity rate was low; none of the patients could feel the loss of masseteric nerve function. There were only a few complications, including 1 case of postoperative bleeding (2.9%) and 2 local infections (5.9%), and a few patients complained about partial loss of sensitivity of the earlobe or a small area of the ankle and foot, depending on whether great auricular or sural nerves were harvested. CONCLUSIONS The surgical technique described here seems to be efficient for the early treatment of facial paralysis and results in very little morbidity.

A growing majority of people with cancer is composed of older patients. For many such patients, independence and quality of life are as important as prolongation of survival, emphasizing the need for treatments that are not only effective but also well-tolerated. Given age-related decline in organ function and the prevalence of comorbidities and polypharmacy, optimum management is complex and requires collaboration between oncologists and geriatricians. Advances in surgery now include preoperative assessment and, when indicated, prehabilitation of the patient, as well as the enhanced recovery after surgery approach. Medical treatment is benefiting from the advent of highly effective novel immunomodulatory agents that join the tumor-targeted small molecule tyrosine kinase inhibitors and monoclonal antibodies in modifying the tolerability of therapy. Improved tolerability is evident with radiotherapy (RT). The adoption of stereotactic body RT in community oncology practice is increasing the proportion of elderly patients with comorbidities who can receive curative treatment. A further aspect of precision medicine as it relates to the older cancer patient is the tailoring of intervention to the robustness or frailty and life expectancy of the individual. Quantitative and validated tools for comprehensive geriatric assessment are playing an important role in this process.

Radiomic features derived from the texture analysis of different imaging modalities e show promise in lesion characterisation, response prediction, and prognostication in lung cancer patients. The present study aimed to identify an images-based radiomic signature capable of predicting disease-free survival (DFS) in non-small cell lung cancer (NSCLC) patients undergoing surgery. A cohort of 295 patients was selected. Clinical parameters (age, sex, histological type, tumour grade, and stage) were recorded for all patients. The endpoint of this study was DFS. Both computed tomography (CT) and fluorodeoxyglucose positron emission tomography (PET) images generated from the PET/CT scanner were analysed. Textural features were calculated using the LifeX package. Statistical analysis was performed using the R platform. The datasets were separated into two cohorts by random selection to perform training and validation of the statistical models. Predictors were fed into a multivariate Cox proportional hazard regression model and the receiver operating characteristic (ROC) curve as well as the corresponding area under the curve (AUC) were computed for each model built. The Cox models that included radiomic features for the CT, the PET, and the PET+CT images resulted in an AUC of 0.75 (95%CI: 0.65–0.85), 0.68 (95%CI: 0.57–0.80), and 0.68 (95%CI: 0.58–0.74), respectively. The addition of clinical predictors to the Cox models resulted in an AUC of 0.61 (95%CI: 0.51–0.69), 0.64 (95%CI: 0.53–0.75), and 0.65 (95%CI: 0.50–0.72) for the CT, the PET, and the PET+CT images, respectively. A radiomic signature, for either CT, PET, or PET/CT images, has been identified and validated for the prediction of disease-free survival in patients with non-small cell lung cancer treated by surgery.

The aim of the study was to assess the mid-term effectiveness and safety of an original technique consisting of reconstructing fractures of the medial wall of the orbit with porous polyethylene implants with an exclusive transnasal approach. Twenty-five patients were treated. Each patient underwent a pre-operative ophthalmologic evaluation and a CT scan. The surgery started with an anteroposterior ethmoidectomy of the fractured side; all the fractured bone fragments were removed and all usual landmarks of healthy bony margins were identified. A Medpor sheet was placed endoscopically to reconstruct the fractured wall. Each patient received an immediate postoperative CT scan, and was evaluated at day 1, 7, 30 and 6 months after surgery clinically and with an endoscopic examination. In all patients, preoperative enophthalmos and/or diplopia were corrected. The CT scans showed excellent reconstruction of the fractured bony walls. The immediate postoperative period was characterized by a very high degree of subjective comfort. No perioperative complications were detected. At the 6 months follow up, all meshes appeared covered by epithelialized mucosa at the endoscopic inspection, and clinical results were stable. Scars or lid complications are always prevented. The technique described has become the standard to treat medial wall fractures in our department.

Chronic inflammatory demyelination polyneuropathy is a heterogeneous and treatable immune-mediated disorder that lacks biomarkers to support diagnosis. Recent evidence indicates that paranodal proteins (contactin 1, contactin-associated protein 1, and neurofascin-155) are the targets of autoantibodies in subsets of patients showing distinct clinical presentations. Here, we identified neurofascin-186 and neurofascin-140 as the main targets of autoantibodies in five patients presenting IgG reactivity against the nodes of Ranvier. Four patients displayed predominantly IgG4 antibodies, and one patient presented IgG3 antibodies that activated the complement pathway in vitro. These patients present distinct clinical features compared to those with anti-neurofascin-155 IgG4. Most patients had a severe phenotype associated with conduction block or decreased distal motor amplitude. Four patients had a subacute-onset and sensory ataxia. Two patients presented with nephrotic syndromes and one patient with an IgG4-related retroperitoneal fibrosis. Intravenous immunoglobulin and corticosteroids were effective in three patients, and one patient remitted following rituximab treatment. Clinical remission was associated with autoantibody depletion and with recovery of conduction block and distal motor amplitude suggesting a nodo-paranodopathy. Our data demonstrate that the pathogenic mechanisms responsible for chronic inflammatory demyelination polyneuropathy are broad and may include dysfunctions at the nodes of Ranvier in a subgroup of patients.

Injuries of the inferior alveolar nerve (IAN) related to endodontic treatment are being increasingly reported. However, consensus on the preferred intervention and the timing of and indications for surgical treatment is lacking. Here, we describe our experience with painful IAN injuries arising from endodontic treatment and requiring prompt microsurgical treatment. Seven consecutive patients with painful IAN injuries were referred to the Maxillofacial Surgery Unit of San Paolo Hospital in Milan. All patients had undergone root canals endodontic treatment in the mandibular molar or premolar between 2007 and 2014. The time elapsed between injury and referral for surgical treatment ranged from 10 days to 20 months. Each patient was treated by one of several different microsurgical procedures, described herein. Overall, neurosensory status and IAN-related pain improved in all seven patients. The best results were obtained by IAN replacement with a sural nerve graft. However, complete sensory recovery was not achieved in any of the patients. Although our sample includes only seven patients, early surgical treatment with an interpositional sural nerve graft seems to allow neurosensory recovery. Less satisfactory results are achieved in patients with IAN injuries of > 12 months duration.

The purpose of this project was to explore (a) how nursing students regarded debriefing sessions at the end of a laboratory skills class and (b) the cognitive, affective, and social learning outcomes of debriefing sessions. Survey questionnaires were administered to 378 prelicensure nursing students after their nursing skills laboratory class that included a debriefing session. Most students either agreed or strongly agreed that debriefing facilitated the discussion about their experience and reflection on learning.

Combined central and peripheral demyelination (CCPD) is rare, and current knowledge is based on case reports and small case series. The aim of our study was to describe the clinical features, diagnostic results, treatment and outcomes in a large cohort of patients with CCPD. Thirty-one patients entered this retrospective, observational, two-center study. In 20 patients (65%) CCPD presented, after an infection, as myeloradiculoneuropathy, encephalopathy, cranial neuropathy, length-dependent peripheral neuropathy, or pseudo-Guillain-Barre syndrome. Demyelinating features of peripheral nerve damage fulfilling European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria for CIDP were found in 23 patients (74%), and spatial dissemination of demyelinating lesions on brain MRI fulfilling the 2010 McDonald criteria for multiple sclerosis (MS) in 11 (46%). Two thirds of the patients had a relapsing or progressive disease course, usually related to the appearance of new spinal cord lesions or worsening of the peripheral neuropathy, and showed unsatisfactory responses to high-dose corticosteroids and intravenous immunoglobulins. The clinical presentation of CCPD was severe in 22 patients (71%), who were left significantly disabled. Our data suggest that CCPD has heterogeneous features and shows frequent post-infectious onset, primary peripheral nervous system or central nervous system involvement, a monophasic or chronic disease course, inadequate response to treatments, and a generally poor outcome. We therefore conclude that the current diagnostic criteria for MS and CIDP may not fully encompass the spectrum of possible manifestations of CCPD, whose pathogenesis remains largely unknown.

Purpose: To explore prognostic factors in surgically treated aggressive fibromatosis (extra-abdominal desmoid tumor). Patients and Methods: A total of 203 consecutive patients treated with surgery over a 35-year period at a single referral center were retrospectively reviewed. One hundred twenty-eight were first seen at our institution with primary disease, whereas 75 had a recurrent tumor. All patients underwent macroscopically complete resection. Margins were rated as negative in 146 (97 with primary tumors, 49 with recurrences) and positive in 57 (31 in primary, 26 in recurrences) patients. Median follow-up was 135 months. Results: Patients with primary disease had a better disease-free survival rate than those with recurrence (76% v 59% at 10 years). Presenting with a recurrence was also the strongest predictor of local failure in the multivariate analysis. In patients first treated for primary disease, size and site had prognostic significance, whereas microscopically positive surgical margins did not. In contrast, in patients with recurrence, there was a trend toward better prognosis if margins were negative (although this was not significant at multivariate analysis). Conclusion: Presence of microscopic disease does not necessarily affect long-term disease-free survival in patients with primary presentation of extra-abdominal desmoid tumors. Thus, function-sparing surgery may be a reasonable choice when feasible without leaving macroscopic residual disease. In patients with recurrences, positive margins may more clearly affect prognosis, potentially necessitating adjuvant radiation in selected cases.

Purpose To investigate the influence of the presence of Temporomandibular Disorders (TMD) on postural balance in elderly individuals. Methods The study sample consisted of 150 elderly: 103 women (67.7±5.0 years) and 47 men (69.3±5.5 years). Evaluation of the presence and severity of TMD included an anamnesis questionnaire, an evaluation of the temporomandibular joint (TMJ), and a muscular examination, which allowed the division of the elderly into 2 groups: G1 (experimental, n=95), with TMD; G2 (control, n=55), without TMD. Postural balance was assessed by means of the one-leg stance test (OLST) on a force platform (BIOMEC400), thus permitting the following measurements: center of foot pressure (COP); mean sway velocity (MV) and frequency (MF) of COP in both the anteroposterior (VAP and FAP) and medial/lateral (VML and FML) directions. The statistical analysis of data was performed using independent t-test, Variance Analysis, and Chi Square test (α=5%). Results Presence of TMD was observed in 63.3% of the individuals (Group 2), with different degrees of severity (mild: 42.7%, moderate: 14.7%, severe: 6%). Significantly higher TMD was observed for women (73.8%) compared with men (40.4%) (p=0.0002). No significant difference was found in between the groups for all balance parameters, e.g., presence and severity of TMD, presence of pain to palpation of TMJ and of masticatory and cervical muscles. Conclusion The presence and severity of TMD, in addition to the presence of pain to palpation of TMJ and masticatory and cervical muscles did not alter the variables related to postural balance in this population.

The Patient Health Engagement scale is an instrument based on evidence about the experiences and preferences of patients with chronic diseases regarding their engagement with the treatment they receive.The main goal of this study was to adapt the Patient Health Engagement scale to the Spanish population (S.PHE-s) following the guidelines for cross-cultural adaptations.The sample comprised 413 patients with different chronic diseases.The confirmatory factor analysis showed a one factor model corresponding to the structure proposed by the original authors. The factor structure was invariant by gender. Furthermore, a Rasch Model showed that the S.PHE-s was unidimensional. In addition, every polychoric correlation coefficient was higher than .60. The Ordinal Alpha of the S.PHE-s was .85. Finally, the S.PHE-s was found to be positively related to life satisfaction, positive affect, and treatment adherence and negatively correlated to negative affect, depression, and anxiety.In light of these results, it may be concluded that the S.PHE-s has good psychometric properties and it may be used by the Spanish-speaking scientific community to measure patient engagement.

// Andreas Walther 1,2 , Michel Philipp 3 , Nicla Lozza 1 and Ulrike Ehlert 1,2 1 Clinical Psychology and Psychotherapy, University of Zurich, Zurich, Switzerland 2 University Research Priority Program – Dynamics of Healthy Aging, University of Zurich, Zurich, Switzerland 3 Psychological Methods, Evaluation and Statistics, University of Zurich, Zurich, Switzerland Correspondence to: Ulrike Ehlert, email: // Keywords : aging, sex steroids, decline, biomarker, psychosocial factors, Gerotarget Received : April 20, 2016 Accepted : July 14, 2016 Published : August 31, 2016 Abstract Research on healthy aging in men has increasingly focused on age-related hormonal changes. Testosterone (T) decline is primarily investigated, while age-related changes in other sex steroids (dehydroepiandrosterone [DHEA], estradiol [E 2 ], progesterone [P]) are mostly neglected. An integrated hormone parameter reflecting aging processes in men has yet to be identified. 271 self-reporting healthy men between 40 and 75 provided both psychometric data and saliva samples for hormone analysis. Correlation analysis between age and sex steroids revealed negative associations for the four sex steroids (T, DHEA, E2, and P). Principal component analysis including ten salivary analytes identified a principal component mainly unifying the variance of the four sex steroid hormones. Subsequent principal component analysis including the four sex steroids extracted the principal component of declining steroid hormones (DSH). Moderation analysis of the association between age and DSH revealed significant moderation effects for psychosocial factors such as depression, chronic stress and perceived general health. In conclusion, these results provide further evidence that sex steroids decline in aging men and that the integrated hormone parameter DSH and its rate of change can be used as biomarkers for healthy aging in men. Furthermore, the negative association of age and DSH is moderated by psychosocial factors.

INTRODUCTION: Tinnitus is a subjective sensation of hearing a sound in the absence of an external stimulus, which significantly worsens the quality of life in 15-25% of affected individuals. OBJECTIVE: To assess the effectiveness of acupuncture therapy for tinnitus. METHODS: Randomized clinical trial (REBEC: 2T9T7Q) with 50 participants with tinnitus, divided into two groups: 25 participants in the acupuncture group and 25 participants in the control group. The acupuncture group received acupuncture treatment and the control group received no treatment. After a period of 5 weeks, they were called to perform the final evaluation and the control group received acupuncture treatment for ethical reasons. RESULTS: A statistically significant result was found for the primary outcome, reducing the intensity of tinnitus, with p = 0.0001 and the secondary endpoint, showing improvement in quality of life, with p = 0.0001. CONCLUSION: Chinese scalp acupuncture associated with bilateral electroacupuncture demonstrated, in the short term, a statistically significant improvement by reducing the level of tinnitus intensity, as well as improving the quality of life of individuals with tinnitus. Resumo Introdução: O zumbido é a sensação subjetiva de ouvir um som na ausência de um estímulo externo e piora significativamente a qualidade de vida de 15%-25% das pessoas afetadas. Objetivo: Verificar a efetividade da terapia por acupuntura em indivíduos com zumbido. Método: Ensaio clínico aleatorizado com 50 participantes com zumbido, divididos em dois grupos: 25 participantes no Grupo da Acupuntura (GA) e 25 participantes do Grupo de Controle (GC). O GA recebeu tratamento com a craniopuntura chinês e o GC não recebeu nenhum tratamento. Após o período de 5 semanas, eles foram chamados para realizar a avaliação final e o GC recebeu tratamento de acupuntura por questões éticas de pesquisa. Resultados: Foi encontrado resultado estatisticamente significativo para o desfecho primário, reduzindo a intensidade do zumbido, com p = 0,0001 e o desfecho secundário, apresentando melhora na qualidade de vida, com p = 0,0001. Conclusão: A craniopuntura chinesa associada à eletroacupuntura bilateral nos mostrou no curto prazo, uma melhora estatisticamente significativa, reduzindo o nível de intensidade do zumbido, bem como melhorando a qualidade de vida dos indivíduos com zumbido.

Summary Objective One-stage free-flap facial reanimation may be accomplished by using a gracilis transfer innervated by the masseteric nerve, but this technique does not restore the patient's ability to smile spontaneously. By contrast, the transfer of the latissimus dorsi innervated by the contralateral facial nerve provides the correct nerve stimulus but is limited by variation in the quantity of contraction. The authors propose a new one-stage facial reanimation technique using dual innervation; a gracilis muscle flap is innervated by the masseteric nerve, and supplementary nerve input is provided by a cross-face sural nerve graft anastomosed to the contralateral facial nerve branch. Methods Between October 2009 and March 2010, four patients affected by long-standing unilateral facial paralysis received gracilis muscle transfers innervated by both the masseteric nerve and the contralateral facial nerve. Results All patients recovered voluntary and spontaneous smiling abilities. The recovery time to voluntary flap contraction was 3.8 months, and spontaneous flap contraction was achieved within 7.2 months after surgery. According to Terzis and Noah's five-stage classification of reanimation outcomes, two patients had excellent outcomes and two had good outcomes. Conclusions In this preliminary study, the devised double-innervation technique allows to achieve a good grade of flap contraction as well as emotional smiling ability. A wider number of operated patients are needed to confirm those initial findings.

Guillain-Barré syndrome (GBS) is an acute immune-mediated disorder of the peripheral nervous system and a triggering infectious event is often reported in the weeks before the disease onset. Influenza viruses have been associated with Guillain-Barré syndrome (GBS), both after infection and, in rare cases, after vaccination. However, GBS has rarely reported to be a neurological complication of the recent pandemic influenza A(H1N1) 2009 virus infections. Here we describe the case of a young man, who developed acute severe motor inflammatory demyelinating polyradiculoneuropathy during influenza A(H1N1)2009 infection. Peculiar features are the findings of a mutated haemagglutinin gene (D222E variant), which has never previously been associated with neurological involvement, and the almost simultaneous appearance of respiratory infectious and immune-mediated neurological symptoms. Moreover we review the clinical presentation, laboratory findings and outcome of influenza-related GBS.

Objectives: Botulinum toxin (BTX) injection into the cricopharyngeal (CP) muscle has been proposed for the treatment of neurogenic dysphagia due to CP hyperactivity. The aim was to determine whether an electrophysiological method exploring oropharyngeal swallowing could guide treatment and discriminate responders from non-responders, based on the association of CP dysfunction with other electrophysiological abnormalities of swallowing. Methods: Patients with different neurological disorders were examined: Parkinson disease, progressive supranuclear palsy, multiple system atrophy-Parkinson variant, multiple system atrophy cerebellar variant, stroke, multiple sclerosis and ataxia telangiectasia. All patients presented with clinical dysphagia, and with complete absence of CP muscle inhibition during the hypopharyngeal phase of swallowing. Each patient underwent clinical and electrophysiological investigations before and after treatment with BTX into the CP muscle of one side (15 units of Botox). Clinical and electrophysiological procedures were performed in a blind manner by two different investigators. The following electrophysiological measures were analysed: (1) duration of EMG activity of suprahyoid/submental muscles (SHEMG-D); (2) duration of laryngopharyngeal mechanogram (LPM-D); (3) duration of the inhibition of the CP muscle EMG activity (CPEMG-ID); and (4) interval between onset of EMG activity of suprahyoid/submental muscles and onset of laryngopharyngeal mechanogram (I-SHEMG-LPM). Results: Two months after treatment, 50% of patients showed a significant improvement. Patients with prolonged or reduced SHEMG-D values and prolonged I-SHEMG-LPM values did not respond to BTX. Therefore, values for which BTX had no effect (warning values) were identified. Conclusions: This electrophysiological method can recognise swallowing abnormalities which may affect the outcome of the therapeutic approach to dysphagia with BTX treatment.

Objective Bortezomib is a new chemotherapeutic drug available for the treatment of lymphoid disorders, including multiple myeloma. Although its primary mechanism of action is proteasome inhibition, other mechanisms can contribute to the therapeutic effects, including modulation of inflammatory cytokines and immune response. One of the main toxic effects of bortezomib is peripheral neuropathy, usually occurring in the form of a painful, sensory axonal neuropathy. The mechanisms of peripheral damage, however, are still unclear. We here report a series of patients treated with bortezomib, who developed a peripheral damage possibly related to immuno-mediated, rather than toxic, mechanisms. Methods Five patients who developed a peripheral neuropathy with severe motor involvement under bortezomib treatment underwent CSF, electrophysiological, and spinal cord MRI examinations. Results Peripheral damage was characterized by: demyelinating or mixed axonal-demyelinating neuropathy, with prominent motor involvement; albumin-cytological dissociation; lumbar root enhancement on MRI in 2/5 patients; favourable outcome in 4/5 patients after immune treatments, either steroids (2 patients) or IVIg (2 patients). Conclusions In some instances, the peripheral damage associated with bortezomib may recognize immuno-mediated mechanisms. Significance This form of bortezomib-associated neuropathy needs to be recognized as treatable condition, as it may respond to immune therapies. Unexplained worsening of neurological dysfunction despite bortezomib discontinuation, with prominent motor involvement and CSF signs of inflammation, may be the clues to this complication.

BACKGROUND AND PURPOSE Over and above typical motor alterations, executive and working memory (WM) impairment can also occur in early idiopathic Parkinson's disease (PD). We aimed to investigate the compensatory neural processes involved in WM performance, as well as the networks involved in the long-term memory transfer from short-term stores in PD. METHODS Relative cerebral blood flow (rCBF) was mapped with H2O15-PET in eight treated nondemented PD patients while performing a WM verbal double-task (Brown-Peterson paradigm) using both short (6-second) and long (18-second) delays. RESULTS As compared to nine age-matched healthy subjects, performance of the PD group was only slightly reduced on the short-delay but markedly impaired on the long-delay task. Underlying the relatively preserved short-delay performance, the PD group exhibited overactivation of prefrontal and parietal areas involved in attention-demanding processes, suggestive of efficient compensatory processes. Further supporting this, significant positive correlations were found between short-delay performance and rCBF in the bilateral inferior parietal cortex. In contrast, the lack of overactivation with the long-delay task together with posterior cingulate hypoactivation would support the idea of functional disconnection impairing transfer of information from prefrontal onto (para)limbic areas. These findings suggest novel areas of investigation into early cognitive impairments in PD.

We explored the prognostic meaning of local relapse and surgical margins in adult soft tissue sarcoma of the extremities. Out of a series of 1017 patients with extremity soft tissue sarcoma treated over 20 years, we picked a group of 238 patients operated on at our institution for their first local relapse: 88 after their primary operation performed at the same center and 150 elsewhere. At operation for relapse, margins were microscopically negative in 77% and 75% of patients, respectively. Median follow-up was 107 months. The 10-year mortality rate was 22% in the absence of local relapse, whereas in locally relapsing patients it was 54% and 43%, respectively, for patients first operated on at our institute and for those who were not. The hazard ratio of positive versus negative surgical margins was 1.7 for cause-specific death and 2.1 for distant metastases in patients first operated on at our institute, as opposed to 1.2 and 1.3 for the others. Local relapse was an unfavorable prognostic factor. In the face of a consistent surgical policy for local relapse in a single-institution setting, patients relapsing after the first operation performed at our institution received rescue treatment less frequently than those previously operated on outside a referral center. This is likely due to an inherently higher tumor aggressiveness. In the presence of such a higher aggressiveness, the adequacy of surgical margins at operation for first relapse seemed more critical prognostically. This may have clinical and speculative implications.

Tinnitus is a symptom usually related to cochlear change that may arise from noise exposure and induces expression of proinflammatory cytokines including interleukin-6 (IL6). This study aimed to evaluate the association between the polymorphism of the IL6 gene in the region 174G/C and tinnitus in elderly with history of occupational noise exposure. Settings and Design: This was a cross-sectional study with a sample of 179 independent elderly individuals aged >60 years. Information on exposure to occupational noise was obtained by interviews. Audiological evaluation was performed using pure tone audiometry and genotyped through polymerase chain reaction by restriction fragment length polymorphism (PCR-RFLP). Data were analyzed using the chi-square test and the odds ratio (OR), with the significance level set at 5%. Among the study subjects, 24.6% were homozygous for the G allele, 39.7% were homozygous for the C allele, and 35.8% were heterozygous for IL6 (P > 0.05). Of these, 33.5% reported noise exposure history, with 42.5% having tinnitus. We found significant association between the genotype and allele frequencies of the IL6 −174 gene (rs1800795) and tinnitus among the elderly with history of exposure to occupational noise (P = 0.03). The elderly with the C allele were less likely to have tinnitus associated with history of exposure to occupational noise [OR = 0.167, confidence interval (CI) 95% 0.167-0.749; P = 0.004] when compared to those carrying the G allele. This study suggests that there is an association between polymorphisms in the IL6 gene at region - 174G/C and susceptibility to tinnitus.

Lower cranial and phrenic nerve involvement is exceptional in hereditary neuropathy with liability to pressure palsies (HNPP). Here we report the occurrence of reversible laryngeal and phrenic nerve involvement in a patient with HNPP. The patient recalled several episodes of reversible weakness and numbness of his feet and hands since the age of 30 years. His medical history was uneventful, apart from chronic obstructive pulmonary disease (COPD). At age 44, following severe weight loss, he presented with progressive dysphonia and hoarseness. EMG of cricoarytenoid and thyroarytenoid muscles and laryngeal fibroscopy confirmed vocal cord paralysis. These speech disturbances gradually regressed. Two years later, he reported rapidly worsening dyspnea. Electroneurography showed increased distal latency of the right phrenic nerve and diaphragm ultrasonography documented reduced right hemi-diaphragm excursion. Six months later and after optimization of CODP treatment, his respiratory function had improved and both phrenic nerve conduction and diaphragm excursion were completely restored. We hypothesize that chronic cough and nerve stretching in the context of CODP, together with severe weight loss, may have triggered the nerve paralysis in this patient. Our report highlights the need for optimal management of comorbidities such as CODP as well as careful control of weight in HNPP patients to avoid potentially harmful complications.

After masseteric-facial nerve (V-VII) anastomosis, a new neurological circuit oversees the facial muscles and patients should learn to activate the facial movements using the masseteric function.To monitor the rehabilitative protocol of facial muscles activation through teeth clenching and to assess the clinical evolution after V-VII anastomosis in terms of facial symmetry and functional recovery.Case series.Outpatients clinic.Eleven patients undergone V-VII anastomosis for complete unilateral facial palsy.After surgery, patients underwent a needle electromyography (EMG) and a rehabilitative training with mirror feedback to learn how to reach the symmetry at rest and during facial movements through teeth clenching. The rehabilitative protocol at the first clinical evaluation has been monitored through the Italian version of Sunnybrook Facial Grading System (SFGS) and the Software Facial Assessment by Computer Evaluation (FACE). Functional limitations and quality of life have been evaluated using the Italian version of Facial Disability Index (FDI). The clinical evolution at 18 months was evaluated with EMG, SFGS, biting evaluation and FDI.At the first clinical evaluation after reinnervation, through teeth clenching patients displayed an improvement of symmetry at rest, symmetry of voluntary movement, symmetry of smile and composite score of SFGS. Objective measurement of facial structures with FACE system demonstrated an improvement of symmetry at rest and during smile through teeth clenching. At 18 months patients displayed a good reinnervation with a further improvement of SFGS scores and reduction of functional disability. No biting deficit has been observed.After V-VII anastomosis, at the first rehabilitative visit, patients learn to activate the reinnervated facial muscles through teeth clenching. Eighteen months after the anastomosis, patients display a further improvement of voluntary control on facial symmetry and smile and a reduction of disability.Our study illustrates the rehabilitative protocol after V-VII anastomosis and analyzes the clinical evolution after this intervention in terms of recovery of facial symmetry and reduction of disability. This will be instrumental to standardize the rehabilitative protocol among different centers and to choose the best patient-tailored surgical approach for subjects affected by complete facial palsy.

Absolute and human cytomegalovirus (HCMV)-specific CD4+ and CD8+ T-cell counts were monitored in 38 solid organ (20 heart, 9 lung and 9 kidney) transplant recipients during the first year after transplantation by a novel assay based on T-cell stimulation with HCMV-infected autologous dendritic cells. According to the pattern of T-cell restoration occurring either within the first month after transplantation or later, patients were classified as either early (n = 21) or late responders (n = 17). HCMV-specific CD4+ and CD8+ T-cell counts were consistently lower in late compared to early responders from baseline through 6 months after transplantation. In addition, in late responders, while HCMV infection preceded immune restoration, HCMV-specific CD4+ restoration was significantly delayed with respect to CD8+ T-cell restoration. The number of HCMV-specific CD4+ and CD8+ T-cells detected prior to transplantation significantly correlated with time to T-cell immunity restoration, in that higher HCMV-specific T-cell counts predicted earlier immune restoration. Clinically, the great majority of early responders (18/21, 85.7%) underwent self-resolving HCMV infections (p = 0.004), whereas the great majority of late responders (13/17, 76.5%) were affected by HCMV infections requiring antiviral treatment (p =

We investigated immune reconstitution against human cytomegalovirus (HCMV) in 57 hematopoietic stem cell transplant (HSCT) recipients, aged 1 to 24 years, through a novel method combining T-cell stimulation by HCMV-infected autologous dendritic cells with simultaneous cytometric quantification of HCMV-specific, IFNγ-producing CD4+ and CD8+ T cells. Lymphoproliferative response (LPR) to HCMV antigens was also determined. Patients were stratified into 2 groups according to HCMV serostatus, comprising 39 HCMV-seropositive (R+) and 18 HCMV-seronegative (R–) patients who received a transplant from a sero-positive donor. Recovery of both HCMV-specific CD4+ and CD8+ T-cell immunity occurred in all 39 R+ patients within 6 months and in 6 (33%) of 18 R– patients within 12 months. In R+ patients, the median numbers of HCMV-specific CD8+ and CD4+T cells were significantly higher than those of healthy controls, starting from days +60 and +180, respectively. In R– patients, the median numbers of HCMV-specific T cells were consistently lower than in R+ patients. LPR was delayed compared with reconstitution of IFNγ-producing T cells. Patients with delayed specific immune reconstitution experienced recurrent episodes of HCMV infection. HCMV seropositivity of young HSCT recipients is the major factor responsible for HCMV-specific immune reconstitution, irrespective of donor serostatus, and measurement of HCMV-specific T cells appears useful for correct management of HCMV infection.

BACKGROUND. The authors explored the prognostic factors and clinical outcomes of patients who had malignant peripheral nerve sheath tumors (MPNST) with and without neurofibromatosis type 1 (NF-1). METHODS. Two hundred five patients with localized MPNST who underwent surgery at the Istituto Nazionale per lo Studio e la Cura dei Tumori (Milan, Italy) over 25 years were reviewed. Forty-six patients had concomitant NF-1 syndrome, and 159 patients did not. Local recurrence, distant metastases, and survival rates were studied. RESULTS. One hundred thirty patients presented with primary disease, and 75 patients had locally recurrent tumors. The disease-specific mortality rate was 43% at 10 years, with a continuously disease-free survival rate of no greater than 40%. Presentation with either primary or recurrent disease, tumor size, and tumor site (trunk vs. extremity) were the strongest independent predictors of survival. Margin status and radiation therapy also played a role, mostly related to their effect on local outcome. Pathologic grade influenced distant metastases, but only a trend for survival could be observed. No significant independent differences between patients with and without NF-1 were observed. CONCLUSIONS. To the authors' knowledge, this was among the largest single-institution series to date. The results confirmed that patients with MPNST share similar prognostic factors with patients who have other soft tissue sarcomas and have some of the worst clinical outcomes. The presence of NF-1 syndrome per se did not affect survival, but patients with NF-1 were more likely to have larger tumors. Therefore, such patients should be followed carefully to detect disease as early as possible. Cancer 2006. © 2006 American Cancer Society.

Purpose Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade, cutaneous sarcoma with autocrine overproduction of the platelet-derived growth factor (PDGF) β-chain from gene rearrangement as a key pathogenetic factor, now susceptible of molecular-targeted therapy. The aim of this retrospective analysis was to explore the outcome of patients with primary or recurrent DFSP. Patients and Methods Two hundred eighteen patients surgically treated at the Istituto Nazionale per lo studio e la cura dei Tumori (Milan, Italy) over 20 years were reviewed. Local relapse, distant metastasis, and survival were studied. Results One hundred thirty-six patients (62.4%) presented with a primary DFSP, while 82 patients (37.6%) had a recurrent disease. In the primary group, margins were microscopically positive in 11.8%, while in the recurrent group they were positive in 14.6% (P =.613). In the primary group, patients undergoing re-excision after inadequate previous surgery had residual disease in 62% of cases. Reconstructive surgery was needed in 30%, significantly more frequently in patients with a recurrence or a head and neck tumor. The crude cumulative incidence of local relapses was 4% at 10 years, and 2% at 10 years for distant metastases. No significant difference was found between primary and recurrent patients, as well as between positive and negative margins. Conclusion This being one of the largest mono-institutional series of DFSP, we confirm that long-term outcome is excellent, in terms of both local and distant control, after a wide excision with negative margins. Reconstructive surgery is often needed. Novel medical therapies will be of use in a limited subgroup of patients.

Purpose To explore the prognostic effect of microscopic marginal status after surgery for extremity soft tissue sarcomas. Patients and Methods We analyzed 911 consecutive patients surgically treated throughout a 20-year span at a single referral center. Six hundred forty-two were first seen with a primary tumor, and 269, with a locally recurrent tumor. All patients underwent macroscopically complete resection. Microscopic marginal status was negative (tumor size > 1 mm) in 748 patients and positive (≤ 1 mm) in 163 patients. Median follow-up was 107 months. Results Patients with primary disease had a lower disease-specific mortality in comparison to those first examined for recurrence (25% v 37%, respectively, at 10 years). Size, malignancy grade, depth, histotype, and local recurrence had a statistically significant prognostic effect at multivariable analysis, while microscopically positive surgical margins had not, though a trend in favor of negative margins was observed. However, an extra risk was observed for patients with positive margins after 3 to 5 years (hazard ratio, 1.8 after 5 years v 0.8 before 5 years). In patients treated for a local recurrence, the prognostic impact of positive margins was higher (hazard ratio, 1.6). Conclusion Positive surgical margins had a weak adverse prognostic effect, which was more pronounced for those patients escaping an early relapse. This would seem to justify a policy of surgical adequacy in adult soft tissue sarcomas, though clinical decision making in borderline presentations for conservative surgery might be reasonably flexible and shared with the patient. Once a local relapse has occurred, the impact of local treatments seems more critical.

Hereditary transthyretin (ATTR) amyloidosis is a debilitating highly penetrant autosomal dominant disease leading to motor disability within 5 years and generally fatal within a decade without treatment. In Italy, hereditary ATTR amyloidosis shows broad genetic and phenotypic variability.1 Peripheral nerve damage can be isolated, in the absence of cardiac and autonomic involvement. Such a presentation makes it often difficult to distinguish ATTR amyloidosis-related peripheral neuropathy from other acquired peripheral neuropathies of adulthood. Nowadays, avoiding misdiagnosis of ATTR amyloidosis is of vital importance because diverse treatment options are available, including liver transplantation and anti-amyloidogenic therapies with tafamidis or diflunisal, which all appear to be particularly effective in early disease stages. In this study, we aimed to assess frequency, type and causes of misdiagnosis of ATTR amyloidosis in Italy. We reviewed the medical records of 150 patients with ATTR diagnosed at the Amyloid Research and Treatment Centre between 1999 and 2013. Hundred-four (73%) were male with an average age of onset of 61 years (31–86). Most frequent mutations were Val30Met (p.Val50Met) (39; 26%), Glu89Gln (p.Glu109Gln) (28; 19%), Phe64Leu (p.Phe84Leu) (20; 13%), Ile68Leu (p.Ile88Leu) (14; 9%), Thr49Ala (p.Thr69Ala)(2; 5%). We reviewed electrodiagnostic (EDx) studies of 19 patients misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and we assessed fulfilment of European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) EDx criteria for demyelination. We excluded from the analysis distal motor latency prolongation and distal compound motor action potential (CMAP) duration in the median nerve because of frequent median neuropathy at the wrist from carpal tunnel syndrome and conduction block in the tibial …